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Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial.

Peter Horby1, M Mafham1, Louise Linsell1, Jennifer L Bell1, Natalie Staplin1, Jonathan Emberson1, Martin Wiselka2, Andrew Ustianowski3, E Elmahi4, B Prudon5, A Whitehouse6, Timothy Felton7, John Williams8, J Faccenda, Jonathan Underwood9, J K Baillie10, Lucy C Chappell11, Saul N. Faust12, Thomas Jaki13, Katie Jeffery1, Wei Shen Lim14, Alan A Montgomery15, Kathy Rowan, Joel Tarning1, James A Watson1, Nicholas J. White1, Edmund Juszczak1, Richard Haynes1, Martin J Landray1 •
University of Oxford1, University of Leicester2, North Manchester General Hospital3, Northampton General Hospital4, North Tees and Hartlepool NHS Foundation Trust5, University Hospitals Birmingham NHS Foundation Trust6, University of Manchester7, James Cook University Hospital8, Cardiff and Vale University Health Board9, University of Edinburgh10, King's College London11, University Hospital Southampton NHS Foundation Trust12, University of Cambridge13, Nottingham University Hospitals NHS Trust14, University of Nottingham15
15 Jul 2020-medRxiv (Cold Spring Harbor Laboratory Press)-
TL;DR: In patients hospitalized with COVID-19, hydroxychloroquine was not associated with reductions in 28-day mortality but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death.
Abstract: Background Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (COVID-19) on the basis of in vitro activity, uncontrolled data, and small randomized studies. Methods The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of hydroxychloroquine vs. usual care alone. The primary outcome was 28-day mortality. Results 1561 patients randomly allocated to receive hydroxychloroquine were compared with 3155 patients concurrently allocated to usual care. Overall, 418 (26.8%) patients allocated hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days (rate ratio 1.09; 95% confidence interval [CI] 0.96 to 1.23; P=0.18). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to hydroxychloroquine were less likely to be discharged from hospital alive within 28 days (60.3% vs. 62.8%; rate ratio 0.92; 95% CI 0.85-0.99) and those not on invasive mechanical ventilation at baseline were more likely to reach the composite endpoint of invasive mechanical ventilation or death (29.8% vs. 26.5%; risk ratio 1.12; 95% CI 1.01-1.25). There was no excess of new major cardiac arrhythmia. Conclusions In patients hospitalized with COVID-19, hydroxychloroquine was not associated with reductions in 28-day mortality but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death. Funding Medical Research Council and NIHR (Grant ref: MC_PC_19056). Trial registrations The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).

Summary (4 min read)

Jump to: [INTRODUCTION] – [Trial design and participants] – [Randomization] – [Procedures] – [Outcome measures] – [Statistical Analysis] – [Sample size and decision to stop enrolment] – [Patients] – [Secondary outcomes] – [Subsidiary outcomes] – [DISCUSSION] – [Table and figures Table 1: Baseline characteristics by randomized allocation] and [Table 2: Effect of allocation to hydroxychloroquine on main study outcomes]

INTRODUCTION

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID- 19), emerged in China in late 2019 from a zoonotic source.
  • A substantial proportion of infected individuals develop a respiratory illness requiring hospital care, 2 which can progress to critical illness with hypoxemic respiratory failure requiring prolonged ventilatory support. [3] [4] [5] [6].
  • The exact mechanism of antiviral action is uncertain but these drugs increase the pH of endosomes that the virus uses for cell entry and also interfere with the glycosylation of the cellular receptor of SARS-CoV, angiotensin-converting enzyme 2 (ACE2), and associated gangliosides.
  • Following oral administration they are rapidly absorbed, even in severely ill patients.
  • A few small controlled trials of hydroxychloroquine and chloroquine for the treatment of COVID-19 infection have been inconclusive. [25] [26] [27] [28].

Trial design and participants

  • Hospitalized patients were eligible for the study if they had clinically suspected or laboratory confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial.
  • Initially, recruitment was limited to patients aged at least 18 years but from 9 May 2020, the age limit was removed.
  • Patients with known prolonged electrocardiograph QTc interval were ineligible for the hydroxychloroquine arm.
  • Written informed consent was obtained from all patients or from a legal representative if they were too unwell or unable to provide consent.

Randomization

  • Baseline data collected using a web-based case report form included demographics, level of respiratory support, major comorbidities, the suitability of the study treatment for a particular patient, and treatment availability at the study site.
  • Eligible and consenting patients were assigned in a ratio of 2:1 to either usual standard of care or usual standard of care plus hydroxychloroquine or one of the other available treatment arms using web-based simple randomization with allocation concealment.
  • Patients allocated to hydroxychloroquine sulfate (200mg tablet containing 155mg base equivalent) received a loading dose of 4 tablets (800 mg) at zero and 6 hours, followed by 2 tablets (400 mg) starting at 12 hours after the initial dose and then every 12 hours for the next 9 days or until discharge (whichever occurred earlier) .
  • 15 Allocated treatment was prescribed by the attending clinician.
  • Participants and local study staff were not blinded to the allocated treatment.

Procedures

  • A single online follow-up form was to be completed when participants were discharged, had died or at 28 days after randomization (whichever occurred earlier).
  • Information was recorded on adherence to allocated study treatment, receipt of other study treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including cause of death).
  • From 12 May 2020, extra information was recorded on the occurrence of new major cardiac arrhythmia.
  • In addition, routine health care and registry data were obtained including information on vital status (with date and cause of death); discharge from hospital; respiratory and renal support therapy.

Outcome measures

  • Outcomes were assessed at 28 days after randomization, with further analyses specified at 6 months.
  • Secondary outcomes were time to discharge from hospital and, among patients not on invasive mechanical ventilation at randomization, invasive mechanical ventilation (including extra-corporal membrane oxygenation) or death.
  • Subsidiary clinical outcomes included cause-specific mortality, use of hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subset), and receipt and duration of ventilation.

Statistical Analysis

  • For the primary outcome of 28-day mortality, the log-rank 'observed minus expected' statistic and its variance were used to both test the null hypothesis of equal survival curves and to calculate the one-step estimate of the average mortality rate ratio, comparing all patients allocated hydroxychloroquine with all patients allocated usual care.
  • The same methods were used to analyze time to hospital discharge, with patients who died in hospital right-censored on day 29.
  • Estimates of absolute risk differences between patients allocated hydroxychloroquine and patients allocated usual care were also calculated.
  • One further prespecified subgroup analysis will be conducted once data collection is completed.
  • All p-values are 2-sided and are shown without adjustment for multiple testing.

Sample size and decision to stop enrolment

  • As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the COVID-19 pandemic.
  • In such a circumstance, the Committee would inform the Trial Steering Committee who would make the results available to the public and amend the trial arms accordingly.
  • On 4 June, in response to a request from the MHRA, the independent Data Monitoring Committee conducted a review of the data and recommended the chief investigators review the unblinded data on the hydroxychloroquine arm of the trial.
  • The Chief Investigators and Trial Steering Committee concluded that the data showed no beneficial effect of hydroxychloroquine in patients hospitalized with COVID-19.

Patients

  • Of the 11,197 patients randomized while the hydroxychloroquine arm was open (25 March to 5 June 2020), 7513 (67%) were eligible to be randomized to hydroxychloroquine (that is hydroxychloroquine was available in the hospital at the time and the attending clinician was of the opinion that the patient had no known indication for or contraindication to hydroxychloroquine) .
  • No children were enrolled in the hydroxychloroquine comparison.
  • A history of diabetes was present in 27% of patients, heart disease in 26%, and chronic lung disease in 22%, with 57% having at least one major comorbidity recorded.
  • 90% of patients had laboratory confirmed SARS-CoV-2 infection, with the result currently awaited for 1%. 13 (0.4%) of the usual care arm received hydroxychloroquine.

Secondary outcomes

  • Allocation to hydroxychloroquine was associated with a longer time until discharge alive from hospital than usual care (median 16 days vs. 13 days) and a lower probability of discharge alive within 28 days (rate ratio 0.92, 95% CI 0.85 to 0.99) (Table 2 ).
  • Among those not on invasive mechanical ventilation at baseline, the number of patients progressing to the pre-specified composite secondary outcome of invasive mechanical ventilation or death was higher among those allocated to hydroxychloroquine (risk ratio 1.12, 95% CI 1.01 to 1.25).

Subsidiary outcomes

  • Information on the occurrence of new major cardiac arrhythmia was collected for 698 (44.7%) patients in the hydroxychloroquine arm and 1357 (43.0%) in the usual care arm since these fields were added to the follow-up form on 12 May 2020.
  • Analyses of cause-specific mortality, receipt of renal dialysis or hemofiltration, and duration of ventilation will be presented once all relevant information (including certified cause of death) is available.
  • There was one report of a serious adverse reaction believed related to hydroxychloroquine; a case of torsades de pointes from which the patient recovered without the need for intervention.

DISCUSSION

  • These results indicate that hydroxychloroquine is not an effective treatment for patients hospitalized with COVID-19.
  • Around 15% of all patients hospitalized with COVID-19 in the UK over the study period were enrolled in the trial and the fatality rate in the usual care arm is consistent with the hospitalized case fatality rate in the UK and elsewhere.
  • The exception is a Brazilian study which was stopped early because of cardiotoxicity.
  • 15 We did not observe excess mortality in the first 2 days of treatment with hydroxychloroquine, the time when early effects of dose-dependent toxicity might be expected.the authors.the authors.
  • The findings indicate that hydroxychloroquine is not an effective treatment for hospitalized patients with COVID-19 but do not address its use as prophylaxis or in patients with less severe SARS-CoV-2 infection managed in the community.

Table and figures Table 1: Baseline characteristics by randomized allocation

  • Results are count (%), mean ± standard deviation, or median (inter-quartile range).*.
  • No children (aged <18 years) were enrolled.
  • † † SARS-Cov-2 test results are captured on the follow-up form, so are currently unknown for some.
  • The 'oxygen only' group includes non-invasive ventilation.
  • Severe liver disease defined as requiring ongoing specialist care.

Table 2: Effect of allocation to hydroxychloroquine on main study outcomes

  • RR=rate ratio for the outcomes of 28-day mortality and hospital discharge, and risk ratio for the outcome of receipt of invasive mechanical ventilation or death.
  • For the prespecified composite secondary endpoint of receipt of invasive mechanical ventilation or death the absolute risk difference was 3.3 percentage points (95% CI 0.3 to 6.3).
  • Squares (with areas of the squares proportional to the amount of statistical information) and the lines through them correspond to the 95% confidence intervals.
  • The 'oxygen only' group includes patients receiving non-invasive ventilation.
  • One further pre-specified subgroup analysis will be conducted once data collection is completed.

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Figures (4)

Content maybe subject to copyright    Report

Hydroxychloroquine for COVID-19 – Preliminary Report
1
1
2
Effect of Hydroxychloroquine in Hospitalized Patients 3
with COVID-19: Preliminary results from a 4
multi-centre, randomized, controlled trial. 5
Running title: Hydroxychloroquine for COVID-19 – Preliminary Report 6
7
RECOVERY Collaborative Group* 8
9
10
*The writing committee and trial steering committee are listed at the end of this manuscript and 11
a complete list of collaborators in the Randomised Evaluation of COVID-19 Therapy 12
(RECOVERY) trial is provided in the Supplementary Appendix. 13
14
Correspondence to: Dr Peter W Horby and Dr Martin J Landray, RECOVERY Central 15
Coordinating Office, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 16
7LF, United Kingdom. 17
Email: recoverytrial@ndph.ox.ac.uk
18
19
Word count: 20
Abstract – 235 words 21
Main text – 2997 22
References – 39 23
Tables & Figures – 2 + 3 24
25
26
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted July 15, 2020. ; https://doi.org/10.1101/2020.07.15.20151852doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
Hydroxychloroquine for COVID-19 – Preliminary Report
2
ABSTRACT 27
Background: Hydroxychloroquine and chloroquine have been proposed as treatments for 28
coronavirus disease 2019 (COVID-19) on the basis of in vitro activity, uncontrolled data, and 29
small randomized studies. 30
Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a 31
randomized, controlled, open-label, platform trial comparing a range of possible treatments with 32
usual care in patients hospitalized with COVID-19. We report the preliminary results for the 33
comparison of hydroxychloroquine vs. usual care alone. The primary outcome was 28-day 34
mortality. 35
Results: 1561 patients randomly allocated to receive hydroxychloroquine were compared with 36
3155 patients concurrently allocated to usual care. Overall, 418 (26.8%) patients allocated 37
hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days (rate 38
ratio 1.09; 95% confidence interval [CI] 0.96 to 1.23; P=0.18). Consistent results were seen in 39
all pre-specified subgroups of patients. Patients allocated to hydroxychloroquine were less likely 40
to be discharged from hospital alive within 28 days (60.3% vs. 62.8%; rate ratio 0.92; 95% CI 41
0.85-0.99) and those not on invasive mechanical ventilation at baseline were more likely to 42
reach the composite endpoint of invasive mechanical ventilation or death (29.8% vs. 26.5%; risk 43
ratio 1.12; 95% CI 1.01-1.25). There was no excess of new major cardiac arrhythmia. 44
Conclusions: In patients hospitalized with COVID-19, hydroxychloroquine was not associated 45
with reductions in 28-day mortality but was associated with an increased length of hospital stay 46
and increased risk of progressing to invasive mechanical ventilation or death. 47
Funding: Medical Research Council and NIHR (Grant ref: MC_PC_19056). 48
Trial registrations: The trial is registered with ISRCTN (50189673) and clinicaltrials.gov 49
(NCT04381936). 50
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted July 15, 2020. ; https://doi.org/10.1101/2020.07.15.20151852doi: medRxiv preprint
Hydroxychloroquine for COVID-19 – Preliminary Report
3
Keywords: COVID-19, hydroxychloroquine, clinical trial. 51
52
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted July 15, 2020. ; https://doi.org/10.1101/2020.07.15.20151852doi: medRxiv preprint
Hydroxychloroquine for COVID-19 – Preliminary Report
4
INTRODUCTION 53
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus 54
disease 2019 (COVID-19), emerged in China in late 2019 from a zoonotic source.
1
The majority 55
of COVID-19 infections are either asymptomatic or result in only mild disease. However, a 56
substantial proportion of infected individuals develop a respiratory illness requiring hospital 57
care,
2
which can progress to critical illness with hypoxemic respiratory failure requiring 58
prolonged ventilatory support.
3-6
Amongst COVID-19 patients admitted to UK hospitals, the case 59
fatality rate is around 26%, and is over 37% in patients requiring invasive mechanical 60
ventilation.
7
61
Hydroxychloroquine and chloroquine, 4-aminoquinoline drugs developed over 70 years ago and 62
used to treat malaria and rheumatological conditions, have been proposed as treatments for 63
COVID-19. Chloroquine has in vitro activity against a variety of viruses, including SARS-CoV-2 64
and the related SARS-CoV-1.
8-13
The exact mechanism of antiviral action is uncertain but these 65
drugs increase the pH of endosomes that the virus uses for cell entry and also interfere with the 66
glycosylation of the cellular receptor of SARS-CoV, angiotensin-converting enzyme 2 (ACE2), 67
and associated gangliosides.
10,14
The 4-aminoquinoline concentrations required to inhibit SARS-68
CoV-2 replication in vitro are relatively high by comparison with the free plasma concentrations 69
observed in the prevention and treatment of malaria.
15
These drugs are generally well tolerated, 70
inexpensive and widely available. Following oral administration they are rapidly absorbed, even 71
in severely ill patients. If active, therapeutic hydroxychloroquine concentrations could be 72
expected in the human lung shortly after an initial loading dose. 73
Small pre-clinical studies have reported that hydroxychloroquine prophylaxis or treatment had 74
no beneficial effect of clinical disease or viral replication.
16
Clinical benefit and antiviral effect 75
from the administration of these drugs alone or in combination with azithromycin to patients with 76
COVID-19 infections has been reported in some observational studies
17-21
but not in others.
22-24
77
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted July 15, 2020. ; https://doi.org/10.1101/2020.07.15.20151852doi: medRxiv preprint
Hydroxychloroquine for COVID-19 – Preliminary Report
5
A few small controlled trials of hydroxychloroquine and chloroquine for the treatment of COVID-78
19 infection have been inconclusive.
25-28
Here we report preliminary results of the effects of a 79
randomized controlled trial of hydroxychloroquine in patients hospitalized with COVID-19. 80
81
METHODS 82
Trial design and participants 83
The RECOVERY trial is an investigator-initiated, individually randomized, controlled, open-label, 84
platform trial to evaluate the effects of potential treatments in patients hospitalized with COVID-85
19. The trial is conducted at 176 hospitals in the United Kingdom (see Supplementary 86
Appendix), supported by the National Institute for Health Research Clinical Research Network. 87
The trial is coordinated by the Nuffield Department of Population Health at University of Oxford, 88
the trial sponsor. Although the hydroxychloroquine, dexamethasone, and lopinavir-ritonavir arms 89
have now been stopped, the trial continues to study the effects of azithromycin, tocilizumab, and 90
convalescent plasma (and other treatments may be studied in the future). 91
Hospitalized patients were eligible for the study if they had clinically suspected or laboratory 92
confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the 93
attending clinician, put the patient at significant risk if they were to participate in the trial. Initially, 94
recruitment was limited to patients aged at least 18 years but from 9 May 2020, the age limit 95
was removed. Patients with known prolonged electrocardiograph QTc interval were ineligible for 96
the hydroxychloroquine arm. Co-administration with medications that prolong the QT interval 97
was not an absolute contraindication but attending clinicians were advised to check the QT 98
interval by performing an electrocardiogram. 99
Written informed consent was obtained from all patients or from a legal representative if they 100
were too unwell or unable to provide consent. The trial was conducted in accordance with the 101
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted July 15, 2020. ; https://doi.org/10.1101/2020.07.15.20151852doi: medRxiv preprint
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Drug treatments for covid-19: living systematic review and network meta-analysis.

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Reed A C Siemieniuk1, Jessica J Bartoszko1, Long Ge2, Dena Zeraatkar1, Ariel Izcovich, Elena Kum1, Hector Pardo-Hernandez3, Anila Qasim1, Juan Pablo Diaz Martinez1, Bram Rochwerg1, Francois Lamontagne, Mi Ah Han4, Qin Liu5, Arnav Agarwal6, Arnav Agarwal1, Thomas Agoritsas1, Derek K. Chu1, Rachel Couban1, Ellen Cusano1, Andrea Darzi1, Tahira Devji1, Bo Fang5, Carmen Fang, Signe Flottorp7, Signe Flottorp8, Farid Foroutan9, Farid Foroutan1, Maryam Ghadimi1, Diane Heels-Ansdell1, Kimia Honarmand10, Liangying Hou2, Xiaorong Hou5, Quazi Ibrahim1, Assem M. Khamis11, Bonnie Lam1, Mark Loeb1, Maura Marcucci1, Shelley McLeod6, Sharhzad Motaghi1, Srinivas Murthy12, Reem A. Mustafa13, Reem A. Mustafa1, John Neary1, Gabriel Rada14, Irbaz Bin Riaz15, Behnam Sadeghirad1, Nigar Sekercioglu1, Lulu Sheng5, Ashwini Sreekanta1, Charlotte Switzer1, Britta Tendal16, Lehana Thabane1, George Tomlinson17, Tari Turner16, Per Olav Vandvik, Robin W.M. Vernooij18, Andrés Viteri-García, Ying Wang1, Liang Yao1, Zhikang Ye1, Gordon H Guyatt1, Romina Brignardello-Petersen1 •
McMaster University1, Lanzhou University2, Cochrane Collaboration3, Chosun University4, Chongqing Medical University5, University of Toronto6, University of Oslo7, Norwegian Institute of Public Health8, Toronto General Hospital9, University of Western Ontario10, Hull York Medical School11, University of British Columbia12, University of Kansas13, Pontifical Catholic University of Chile14, Mayo Clinic15, Monash University16, University Health Network17, Utrecht University18
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A Novel Coronavirus from Patients with Pneumonia in China, 2019.

[...]

Na Zhu1, Dingyu Zhang, Wenling Wang1, Xingwang Li2, Bo Yang1, Jingdong Song1, Xiang Zhao1, Baoying Huang1, Weifeng Shi, Roujian Lu1, Peihua Niu1, Faxian Zhan1, Xuejun Ma1, Dayan Wang1, Wenbo Xu1, Wenbo Xu3, Guizhen Wu1, George F. Gao, Wenjie Tan1 •
Chinese Center for Disease Control and Prevention1, Capital Medical University2, Anhui University of Science and Technology3
24 Jan 2020-The New England Journal of Medicine
TL;DR: Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily, which is the seventh member of the family of coronaviruses that infect humans.
Abstract: In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).

21,455 citations

Journal Article•DOI•
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.

[...]

Fei Zhou1, Ting Yu, Ronghui Du, Guohui Fan2, Ying Liu, Zhibo Liu1, Jie Xiang3, Yeming Wang4, Bin Song, Xiaoying Gu1, Xiaoying Gu2, Lulu Guan, Yuan Wei, Li Hui1, Xudong Wu, Jiuyang Xu5, Shengjin Tu, Yi Zhang1, Hua Chen, Bin Cao •
Peking Union Medical College1, China-Japan Friendship Hospital2, Wuhan Jinyintan Hospital3, Capital Medical University4, Tsinghua University5
28 Mar 2020-The Lancet
TL;DR: Wang et al. as discussed by the authors used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death, including older age, high SOFA score and d-dimer greater than 1 μg/mL.

20,189 citations

Journal Article•DOI•
A pneumonia outbreak associated with a new coronavirus of probable bat origin

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Peng Zhou1, Xing-Lou Yang1, Xian Guang Wang2, Ben Hu1, Lei Zhang1, Wei Zhang1, Hao Rui Si1, Yan Zhu1, Bei Li1, Chao Lin Huang2, Hui-Dong Chen2, Jing Chen1, Yun Luo1, Hua Guo1, Ren Di Jiang1, Meiqin Liu1, Ying Chen1, Xu Rui Shen1, Xi Wang1, Xiao Shuang Zheng1, Kai Zhao1, Quanjiao Chen1, Fei Deng1, Lin Lin Liu3, Bing Yan1, Fa Xian Zhan3, Yan-Yi Wang1, Gengfu Xiao1, Zhengli Shi1 •
Chinese Academy of Sciences1, Wuhan Jinyintan Hospital2, Centers for Disease Control and Prevention3
03 Feb 2020-Nature
TL;DR: Identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China, and it is shown that this virus belongs to the species of SARSr-CoV, indicates that the virus is related to a bat coronav virus.
Abstract: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV. Characterization of full-length genome sequences from patients infected with a new coronavirus (2019-nCoV) shows that the sequences are nearly identical and indicates that the virus is related to a bat coronavirus.

16,857 citations

Journal Article•DOI•
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

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Nanshan Chen1, Min Zhou2, Xuan Dong1, Jie-Ming Qu2, Fengyun Gong1, Yang Han1, Yang Qiu3, Jingli Wang1, Ying Liu1, Yuan Wei1, Jia'an Xia1, Ting Yu1, Xinxin Zhang2, Li Zhang1 •
Wuhan Jinyintan Hospital1, Shanghai Jiao Tong University2, Chinese Academy of Sciences3
30 Jan 2020-The Lancet
TL;DR: Characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia, and further investigation is needed to explore the applicability of the Mu LBSTA scores in predicting the risk of mortality in 2019-nCoV infection.

16,282 citations

Journal Article•DOI•
Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.

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Roujian Lu1, Xiang Zhao1, Juan Li2, Peihua Niu1, Bo Yang3, Honglong Wu, Wenling Wang1, Hao Song4, Baoying Huang1, Na Zhu1, Yuhai Bi4, Xuejun Ma1, Faxian Zhan3, Liang Wang4, Tao Hu2, Hong Zhou2, Zhenhong Hu, Weimin Zhou1, Li Zhao1, Jing Chen5, Yao Meng1, Ji Wang1, Yang Lin, Jianying Yuan, Zhihao Xie, Jinmin Ma, William J. Liu1, Dayan Wang1, Wenbo Xu1, Edward C. Holmes6, George F. Gao4, George F. Gao1, Guizhen Wu1, Weijun Chen, Weifeng Shi2, Wenjie Tan1, Wenjie Tan4 •
Chinese Center for Disease Control and Prevention1, Peking Union Medical College2, Centers for Disease Control and Prevention3, Chinese Academy of Sciences4, Wenzhou Medical College5, University of Sydney6
22 Feb 2020-The Lancet
TL;DR: The phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans.

9,474 citations

Related Papers (5)
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20 Mar 2020-International Journal of Antimicrobial Agents
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In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

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28 Jul 2020-Clinical Infectious Diseases
Xueting Yao, Fei Ye, Miao Zhang, Cheng Cui, Baoying Huang, Peihua Niu, Xu Liu, Li Zhao, Erdan Dong, Chunli Song, Siyan Zhan, Roujian Lu, Haiyan Li, Wenjie Tan, Dongyang Liu 
A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

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18 Mar 2020-The New England Journal of Medicine
Bin Cao, Yeming Wang, Danning Wen, Wen Liu, Jingli Wang, Guohui Fan, Lianguo Ruan, Bin Song, Yanping Cai, Ming Wei, Xingwang Li, Jia'an Xia, Nanshan Chen, Jie Xiang, Ting Yu, Tao Bai, Xuelei Xie, Li Zhang, Caihong Li, Ye Yuan, Hua Chen, Huadong Li, Hanping Huang, Shengjing Tu, Fengyun Gong, Ying Liu, Yuan Wei, Chongya Dong, Fei Zhou, Xiaoying Gu, Jiuyang Xu, Zhibo Liu, Yi Zhang, Li Hui, Lianhan Shang, Ke Wang, Kunxia Li, Xia Zhou, Xuan Dong, Zhaohui Qu, Sixia Lu, Xujuan Hu, Shunan Ruan, Shanshan Luo, Jing Wu, Lu Peng, Fang Cheng, Lihong Pan, Jun Zou, Chunmin Jia, Juan Wang, Xia Liu, Shuzhen Wang, Xudong Wu, Qin Ge, Jing He, Haiyan Zhan, Fang Qiu, Li Guo, Chaolin Huang, Thomas Jaki, Frederick G. Hayden, Peter Horby, Dingyu Zhang, Chen Wang