Insight into 2019 novel coronavirus —

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Mingxuan Xie
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Insight into 2019 novel coronavirus — an updated intrim review and

lessons from SARS-CoV and MERS-CoV

Mingxuan Xie, Qiong Chen

PII: S1201-9712(20)30204-6
DOI: https://doi.org/10.1016/j.ijid.2020.03.071
Reference: IJID 4077

To appear in: International Journal of Infectious Diseases

Received Date: 8 March 2020

Revised Date: 23 March 2020
Accepted Date: 24 March 2020

Please cite this article as: { doi: https://doi.org/

This is a PDF file of an article that has undergone enhancements after acceptance, such as
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© 2019 Published by Elsevier.

Insight into 2019 novel coronavirus — an updated intrim review and lessons
from SARS-CoV and MERS-CoV

Mingxuan Xiea,b, Qiong Chen a,b*

a
Department of Geriatrics / Department of Respiratory Medicine, Xiangya Hospital,
Central South University, Changsha 410008, China;
b
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central
South University, Changsha 410008, China.
*Correspondence: Qiong Chen: Email: qiongch@163.com; Tel.: +86 73189753056;
Address: 87 Xiangya Rd, Xiangya Hospital, Changsha, Hunan Province, China.

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Highlights
The COVID-19 had a high R0, a long incubation period, and a short serial interval.
 The COVID-19 had a general low CFR, but much higher in patients with comorbidities.

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 The spike protein binding to ACE2 may explain the high R0 of COVID-19.

 Autopsy showed more exudative lesions, and less fibrosis and consolidation.

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Remdesivir, chloroquine, tocilizumab, and convalescent plasma may be effective.
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Abstract:
Background: The rapid spread of the coronavirus disease 2019 (COVID-19), caused by
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a zoonotic beta-coronavirus entitled 2019 novel coronavirus (2019-nCoV), has become

a global threat. Awareness of the biological features of 2019-nCoV should be updated
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in time and needs to be comprehensively summarized to help optimize control

measures and make therapeutic decisions.
Methods: Based on recently published literatures, official documents and selected
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up-to-date preprint studies, we reviewed the virology and origin, epidemiology, clinical
manifestations, pathology and treatment of 2019-nCoV infection, in comparison with
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severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east

respiratory syndrome coronavirus (MERS-CoV) infection.
Results: The genome of 2019-nCoV partially resembled SARS-CoV and MERS-CoV,
and indicating a bat origin. The COVID-19 generally had a high reproductive number,
a long incubation period, a short serial interval and a low case fatality rate (much higher
in patients with comorbidities) than SARS and MERS. Clinical presentation and
pathology of COVID-19 greatly resembled SARS and MERS, with less upper

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respiratory and gastrointestinal symptoms, and more exudative lesions in
post-mortems. Potential treatments included remdesivir, chloroquine, tocilizumab,
convalescent plasma and vaccine immunization (when possible).
Conclusion: The initial experience from the current pandemic and lessons from the
previous two pandemics can help improve future preparedness plans and combat
disease progression.

Keywords: 2019-nCoV; COVID-19; SARS-CoV-2; SARS-CoV; MERS-CoV.

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Introduction
In late December 2019, a pneumonia outbreak of unknown etiology took place in
Wuhan, Hubei province, China, and spread quickly nationwide. Chinese Center for
Disease Control and Prevention (CCDC) identified a novel beta-coronavirus called
2019-nCoV, now officially known as severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) (Gorbalenya et al., 2020), that responsible for the pandemic. This was
the third zoonotic coronavirus breakout in the first two decades of 21st century that
allowing human-to-human transmission and raising global health concerns. Chinese
government had taken immediate, transparent and extraordinary measures, and reached
initial achievements to control the outbreak. As of 11 March 2020, the pandemic

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caused accumulated 80955 confirmed cases and 3162 deaths in China, 37364
confirmed cases and 1130 deaths in 113 other countries worldwide. World Health

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Organization (WHO) deeply concerned the unprecedented swift global spread and
severity of the outbreak, and by ignorance and inaction of some countries. Therefore,
WHO announced the COVID-19 can be characterized as a pandemic(WHO, 2020a).
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Biological features of 2019-nCoV and experiences combating COVID-19 should
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be updated in time and needs to be comprehensively summarized to help optimize
control measures and make therapeutic decisions. What’s more, the 2019-nCoV
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demonstrated partial resemblance with SARS-CoV and MERS-CoV, in phylogenetic

analysis, clinical manifestations and pathological findings. Scientific advances from
the SARS and MERS outbreaks can provide valuable insight into rapid understanding
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and control measures of the current pandemic. We searched literatures and guidelines
in Pubmed, Web of Science, Embase, CNKI, Wanfang, VIP, preprint bioRxiv and
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medRxiv databases from the earliest available date to 11 March, 2020. Initial search
terms were "2019-nCoV" OR “2019 novel coronavirus" OR "SARS-CoV-2" OR
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"COVID-19" OR "corona virus disease 2019" OR "NCP" OR "Novel coronavirus

pneumonia". Further search words were above keywords, "SARS" OR "SARS-CoV"
OR "severe acute respiratory syndrome", "MERS" OR "MERS-CoV" OR "middle
east respiratory syndrome", in combinations of with "spike protein" OR "genome" OR
"reproductive number" OR "incubation period" OR "serial interval" OR "fatality rate"
OR "clinical characteristics" OR "pathology" OR "autopsy" OR "treatment".

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Moreover, official documents and news released by National Health Commission of
P.R. China, CCDC, CDC(USA) and WHO were accessed for up-to-date information
on COVID-19. Only the articles in English or Chinese were considered.
In this review, we highlight the pandemic potential and pathological indications
of emerging coronavirus, comprehensively and systematically summarize the
up-to-date knowledge of the biological characteristics of 2019-nCoV, including
virology and origin, epidemiology, clinical manifestations, pathology and treatment. Because of

its natural structures and biological features to bind receptors on host cells, the spike
protein of 2019-nCoV may played an essential role in disease spreading. We

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summarized all of the four available pathology studies of COVID-19 biopsy and
autopsy, and compared the results with previous two deadly coronavirus diseases.

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New therapeutic measures are emerging one after another. Potential effective
treatments were remdesivir, chloroquine, tocilizumab, convalescent plasma and
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vaccine immunization (when possible). Evidence-based medicine should always be
advocated to guide our clinical decision.
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Virology and origin
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Coronavirus belongs to the subfamily Orthocoronavirinae in the family of

Coronaviridae in the order Nidovirales, which mainly caused infections in respiratory
and gastrointestinal tract. The 2019-nCoV is a novel enveloped beta-coronavirus which
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has a single stranded positive sense RNA genome(Zhu et al., 2020). Concerning the
origin of the virus, several phylogenetic analysis suggested the bat to be the most
probable animal reservoir. Based on genome sequencing, 2019-nCoV is about 89%
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identical to bat SARS-like-CoVZXC21, 82% identical to human SARS-CoV and about

50% to MERS-CoV(Chan et al., 2020; Lu et al., 2020). As both SARS-CoV and
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MERS-CoV were transmitted from bats to palm civets or dromedary camels, and
finally to humans, there should be another animal representing as an intermediate host
between bat and human. Pangolins were suggested as the possible intermediate hosts,
because their genome had approximately 85.5%-92.4% similarity to 2019-nCoV,
representing two sub-lineages of 2019-nCoV in the phylogenetic tree, one of which
(GD/P1L and GDP2S) was extremely closely related to 2019-nCoV(Lam et al., 2020).
Other research suggested 2019-nCoV was the recombinant virus of bat coronavirus and
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snake coronavirus, by comparison in conjunction with relative synonymous codon
usage bias among different animal species(Ji et al., 2020). The truth is yet to be
discovered.
The spike surface glycoprotein of coronavirus plays an essential role in binding to
receptors on host cells and determines host tropism. Spike protein(S-protein) of
2019-nCoV is reported to bind with angiotensin-converting enzyme 2 (ACE2), the
same receptor of SARS-CoV to invade host cells; whereas MERS-CoV uses dipeptidyl
peptidase 4 (DPP4) as the primary receptor(Wu et al., 2020). The amino acid sequence
of S-protein in 2019-nCoV is 76.47% identical to that of SARS-CoV, with the same
structural confirmation and electrostatic properties in the interaction interface. The

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residues at positions 442, 472, 479, 487, and 491 in S-protein are reported to be at
receptor complex interface with ACE2. However, four of the five critical residues in the

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2019-nCoV S-protein are not preserved except for Tyr491. The binding free energy for
2019-nCoV S-protein to bind with human ACE2, increases by 28 kcal mol–1 compared
to SARS-CoV S-protein (-50.6kcal mol–1 vs. -78.6kcal mol–1), due to the loss of
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hydrogen bond interactions by replacing Arg426 with Asn426(Xu et al., 2020a).
Furin-like cleavage site was supposed to be cleaved by proprotein convertase furin at
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special viral envelope glycoproteins, thereby enhancing viral fusion with host cell
membranes. Coutard and colleagues (2020) reported a furin-like cleavage site in the
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S-protein of 2019-nCoV, which is absent in other lineage b beta-coronaviruses.

Another research team also discovered an “RRAR” furin recognition site by an
insertion in the S1/S2 protease cleavage site in 2019-nCoV, instead of a single arginine
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in SARS-CoV. After quantifying the kinetics mediating the interaction via surface
plasmon resonance, ACE2 is calculated to bind to 2019-nCoV ectodomain with ~15
nM affinity, which is approximately 10- to 20-fold higher affinity than ACE2 binding
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to SARS-CoV(Wrapp et al., 2020). In all, the binding affinity between 2019-nCoV

S-protein and ACE2 is comparable or even stronger than SARS-CoV S-protein and
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ACE2. This may explain the rapid development and strong ability of human-to-human
transmission in COVID-19.

Epidemiology
The pandemic escalated exponentially at the beginning of 2020, which might only
be the tip of the iceberg due to delayed case reporting and deficiency in testing kits(Li et
al., 2020). The onset of first cluster cases were reported an exposure history to the
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Huanan seafood(wild animal) wholesale market in Wuhan. However,
phyloepidemiologic analyses suggested that Huanan market was not the origin of
2019-nCoV. The virus was imported from elsewhere and boosted in the crowded
market(Yu et al., 2020). The proportion of infected cases without an exposure history
and in health care workers gradually increased. All of the evidence indicated the
human-to-human transmission ability of 2019-nCoV, which may already be spread
silently between people in Wuhan before the cluster of cases from Huanan market was
discovered in late December. Person-to-person transmission may occur mainly through
droplet or contact transmission. According to Guan’s latest pilot study, 2019-nCoV was
detected positive in the gastrointestinal tract specimens (stool and rectal swabs) as well

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as in saliva and urine, and even in esophageal erosion and bleeding site of severe peptic
ulcer patients(Guan et al., 2020). Four important epidemiological parameters of

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2019-nCoV were reviewed in comparison with those of SARS-CoV and
MERS-CoV(shown in Table 1).
Reproductive number is an indication of the transmissibility of a virus,
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representing the average number of new infections generated by an infectious person in
a totally naïve population. For R0˃1, the number of infected is likely to increase; for R0
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˂1, transmission is likely to decline and die out. The reproductive number updated
along with the development of the outbreak and interventions. R0 was estimated to be
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around 3 for SARS(Bauch et al., 2005) and ˂1 for MERS(Bauch and Oraby, 2013). The
preliminary R0 of 2019-nCoV was reported as 2.24-3.58(Liu et al., 2020). Several
research groups reported estimated R0 of the outbreak depending on distinct estimation
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methods and the validity of underlying assumptions. Liu et al. (2020) reviewed all of
the 12 references of an estimated R0 ranged from 1.4 to 6.49, with a mean of 3.28 and a
median of 2.79. In clinical studies, a 425-case study by 22 January 2020, reported an R0
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of approximately 2.2(95%CI, 1.4-3.9)(Li et al., 2020), while another 4021-case study

by 26 January 2020, estimated 3.77(95%CI, 3.51-4.05) (Yang et al., 2020). The
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discrepancy may be due to sample number and different stages of the pandemic.
Incubation period is defined as the interval from initial exposure to an infectious
agent to onset of any symptoms or signs it causes. A long incubation period may lead to
a high rate of asymptomatic and subclinical infection. The first prediction of mean
incubation period was 5.2 days (95%CI, 4.1-7.0 days), with the 95th percentile of the
distribution at 12.5 days, based on 2019-nCoV exposure histories of the first 425 cases
in Wuhan(Li et al., 2020). A 4021-case study reported 4.75 days (interquartile range:
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3.0-7.2 days) (Yang et al., 2020). Another 88-exported-case study calculated the mean
incubation period to be 6.4 days (95%CI, 5.6–7.7 days), using known travel histories to
and from Wuhan and symptom onset dates(Backer et al., 2020). All these literatures lay
the foundation to set 14 days as the medical observation period if any exposure
occurred. A latest study collected 1099 cases from 552 hospitals in 31 provinces in
China and declared a median incubation period of 3.0 days, ranging from 0 to
surprisingly 24.0 days. An adjustments in screening and control policies may be
needed. The 2019-nCoV generally has a longer incubation time than SARS-CoV (4.0
days, 95% CI 3.6-4.4 days) (Lessler et al., 2009) and MERS-CoV (range 4.5-5.2 days)
(Park et al., 2018).

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Serial interval is the interval from illness onset in a primary case to illness onset in
the secondary case. The mean serial interval was estimated at 7.5 days(95% CI,

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5.3-19days) using contact tracing data from early Wuhan cases in 2019-nCoV
pandemic, which was shorter than the 8.4-day mean serial interval reported for SARS
(Lipsitch et al., 2003) and 12.6-day for MERS(Cowling et al., 2015). Another
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estimation of the mean serial interval from 26 infector-infectee pairs was surprisingly
2.6 days, which was shorter than the median incubation period, suggesting a substantial
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proportion of secondary transmission before illness onset(Nishiura et al., 2020).
The CFR in early studies of COVID-19 involving relatively small samples of
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confirmed cases in Wuhan, varied from 4.3% to 14.6%(Chen et al., 2020a; Huang et al.,
2020; Wang et al., 2020a), but that may not be able to reflect the truth. The CFR in
Wuhan was undoubtedly higher than CFR outside of Wuhan. The reported CFR ranged
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1.4%-3.06% in large nationwide case studies(Guan et al., 2020; Yang et al., 2020).
Prognosis factors such as male, elderly patients aged≥ 60 years, underlying disease,
severe pneumonia at baseline and a delay from onset to diagnosis >5 days substantially
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elevated the CFRs(Yang et al., 2020). CFRs in patients with cardiovascular disease,
diabetes, hypertension and respiratory disorders were as high as 10.5%, 7.3%, 6.0%
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and 6.3%, respectively. According to WHO announcement, SARS accounted for 8096
cases and 774 death, with a CFR of 9.6%(WHO, 2004). MERS-CoV infection were
responsible for 2229 cases and 791 death, with a crude CFR of 35.5%(WHO, 2018). A
study of 44672 cases conducted by CCDC reported a CFR of 2.3% nationwide, with a
CFR of 2.9% in Hubei province compared to 0.4% in other parts of China(Wu and
McGoogan, 2020). Despite a gradually stable CFR around 3, the prognosis and
outcome of COVID-19 was also extraordinarily destructive and causing more death
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because of its enormous infected population. We can see a family close relative
clustering phenomenon of severe and death cases. Genome sequencing and linkage
analysis of ACE2 gene polymorphism may help determine individual susceptibility to
2019-nCoV and provide early-warning detection mode of severe COVID-19 in clinical
practice.

Clinical manifestations
Clinical presentation of COVID-19 greatly resembled viral pneumonia such as
SARS and MERS. Most cases are mild cases(81%), whose symptoms were usually
self-limiting and recovery in two weeks(Wu and McGoogan, 2020). Severe patients

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progressed rapidly with acute respiratory distress syndrome (ARDS) and septic shock,
eventually ended in multiple organ failure.

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General information of four inpatient case studies with relatively comprehensive
data were summarized in supplementary table 1. The 2019-nCoV was more likely to
infect elderly men with comorbidities. Males were more susceptible to 2019-nCoV
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infection, same as SARS-CoV and MERS-CoV studies(Badawi and Ryoo, 2016), due
to X chromosome and sex hormones’ role on innate and adaptive immunity(Jaillon et
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al., 2019). Chronic underlying diseases (mainly hypertension, cardio-cerebrovascular
diseases and diabetes) may increase the risk of 2019-nCoV infection(Guan et al., 2020),
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which is similar to MERS-CoV infection(Badawi and Ryoo, 2016). Smoking may be a

negative prognostic indicator for COVID-19(Chen et al., 2020a; Guan et al., 2020).

Clinical information of the above four selected inpatient case studies were
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summarized in supplementary table 2. Onset of symptoms were usually mild and

nonspecific, presenting by fever, dry cough and shortness of breath. Very few
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COVID-19 patients had prominent upper respiratory tract and gastrointestinal

symptoms (eg, diarrhea) (Guan et al., 2020; Huang et al., 2020), compared to 20–25%
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of patients with MERS-CoV or SARS-CoV infection developed diarrhea(Assiri et al.,

2013). However, only 43.8% of COVID-19 patients had an initial presentation of
fever, and developed to 87.9% following hospitalization(Guan et al., 2020), compared
to as high as 99% and 98% frequent in SARS-CoV and MERS-CoV infection(Badawi
and Ryoo, 2016). Those patients without fever or even asymptomatic may be left
un-quarantined as silent infection source, if the surveillance methods focused heavily
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on fever detection. Moreover, the onset of symptoms may help physicians identifying
patients with poor prognosis. Patients admitted to the ICU were more likely to report
pharyngeal pain, dyspnea, dizziness, abdominal pain and anorexia(Wang et al.,
2020a).
In terms of laboratory findings, a substantial decrease in the total number of
lymphocytes could be used as an index in the diagnosis of 2019-nCoV infection,
indicating a consumption of immune cells and an impairment to cellular immune
function(Chen et al., 2020a). Non-survivors developed more severe lymphopenia over
time(Wang et al., 2020a). Initial proinflammatory plasma cytokine concentrations were
higher in COVID-19 patients than in healthy adults. ICU patients had even higher

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plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα compared to
non-ICU patients(Huang et al., 2020). There were numerous differences in laboratory

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findings between patients admitted to the ICU and those not, including higher white
blood cell and neutrophil counts, higher levels of D-dimer, creatine kinase, and creatine
in ICU patients(Wang et al., 2020a). -p
Typical chest CT manifestation of COVID-19 pneumonia were initially small
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subpleural ground glass opacities that grew larger with crazy-paving pattern and
consolidation. After two weeks of growth, the lesions were gradually absorbed leaving
extensive opacities and subpleural parenchymal bands in recovery patients. However,
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Guan et al. ( 2020) demonstrated that patients with normal radiologic findings on initial
presentation consisted of 23.9% and 5.2% of severe and non-severe cases respectively,
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which add the complexity to disease control.

Pathology
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Autopsy or biopsy studies would always be the key to understand the biological
features of 2019-nCoV. Histological examinations of two patients underwent lung
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lobectomies for adenocarcinoma, revealed edema, proteinaceous exudate, focal

hyperplasia of pneumocytes with only patchy inflammatory cellular infiltration without
prominent hyaline membranes. Since both patients didn’t develop symptoms of
COVID-19 pneumonia at the time of surgery, these changes likely represent an early
phase of the lung pathology of COVID-19 pneumonia. Qian and his colleagues (2020)
first reported the pathological characteristics of a patient who died from COVID-19.
General observation from raw eyes showed less fibrosis and consolidation, instead
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more exudative lesions in COVID-19 than SARS. Microscopic examination showed
bilateral diffuse alveolar damage with cellular fibromyxoid exudates, indicating
ARDS. Interstitial mononuclear inflammatory infiltrates were dominated by
lymphocytes. Multinucleated syncytial cells with atypical enlarged pneumocytes
showed viral cytopathic-like changes, without obvious intranuclear or intracytoplasmic
viral inclusions. Results from flow cytometric analysis demonstrated that the counts of
peripheral CD4+ and CD8+ T cells were substantially reduced, while their status were
hyper-activated. It indicated the severe immune injury in later stage of COVID-19, but
not by virus direct destruction(Xu et al., 2020b). Based on the public database and
single-cell RNA-Seq technique, pathological studies revealed that male donors had a

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higher ACE2-expressing cell ratio than their female counterparts. The only Asian male
specimen has five more times as much as ACE2 expressing on the white and African

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American donors. This might explain why the 2019-nCov and previous SARS-CoV
pandemic were concentrated in the Asian population and a heightened susceptibility of
male patients, although more evidence was needed to draw such conclusion(Yu et al.,
2020).
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Pathological manifestations of SARS and MERS infected patients may shed lights
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to control current 2019-nCoV pandemic. Histology examination demonstrated a
considerably higher viral load of SARS-CoV RNA in lung and small bowels than other
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organs of the body, suggesting an reason for manifestation of pneumonia and diarrhea
in SARS patients. Living 2019-nCoV was also detected positive in stool specimens and
rectal swabs of infected patients, indicating possible transmission route of oral-faecal
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transmission. Proper handling with the infected corpse and disposal of human excreta
of infected patients were of great importance(Nicholls et al., 2003). Thrombi were seen
in all six autopsies of SARS-CoV infected patients, with even huge thrombus formation
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in part of pulmonary vessels. Coagulation function disorders were reported in most of

the severe COVID-19 patients, by elevated levels of D-Dimer and prolonged
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prothrombin time, some of whom ended in disseminated intravascular

coagulation(Chen et al., 2020a; Huang et al., 2020; Wang et al., 2020a). This may
explain some sudden death of clinical recovery patients and serve as an indication for
disease severity. In an autopsy study, the only one patient without usage of
corticosteroids demonstrated increased CD3+ lymphocyte than five other specimen
treated by corticosteroids(Pei et al., 2005). It suggested an inhibition of immune system

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and a careful usage of corticosteroids in COVID-19 treatment. Much is to be
discovered in more 2019-nCoV autopsies.

Treatment
There are currently no vaccine or specific effective antiviral therapies for
COVID-19 in general. Thus there is an urgent need for global surveillance of
COVID-19 patients. New therapeutic drugs are emerging one after another. However,
double-blinded randomized controlled trials with larger sample size are needed to
determine the safety and efficacy of these new drugs and guide clinical decision.
Medical interventions can be divided into four major categories: general treatment,

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coronavirus specific treatments, antiviral treatments and others.
General treatments included nutritional interventions, immuno-enhancers and

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Chinese medicine. Interferon, intravenous gamma-globulin and thymosin were
believed to boost our immune system to fight with SARS-CoV and MERS-CoV as well
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as 2019-nCoV. Chloroquine, an old Chinese medicine for treatment of malaria and
autoimmune disease, had demonstrated remarkable inhibition in the spread of
SARS-CoV by interfering with ACE2 in Vero E6 cell lines(Vincent et al., 2005). Wang
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et al. (2020b) demonstrated that chloroquine functioned at both entry and post-entry
stages of the 2019-nCoV infection in Vero E6 cells, as well as an immune-modulating
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activity that enhanced antiviral effect in vivo. Recent multicenter clinical trails
conducted in China have also reported obvious efficacy and acceptable safety in
COVID-19 patients by reducing exacerbation of pneumonia, improving radiological
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findings, promoting a virus negative conversion, and shortening the disease course(Gao
et al., 2020).
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Due to the indispensable role of the S-protein in coronavirus, therapies and vaccine
exploration targeting S-protein-ACE2 interaction may be very promising. Previous
therapies targeting SARS-CoV and MERS-CoV may accelerate the development of
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treatment of COVID-19 because of their structure resemblance and genome

similarities. The human monoclonal antibody could efficiently neutralize SARS-CoV
and inhibit syncytia formation between S-protein and ACE2 expressing cells(Sui et al.,
2004). Appropriate modification of the monoclonal antibody may be effective for
treatment of COVID-19. What’s more, potential therapies targeting the
renin-angiotensin system, to increase ACE2 expression and inhibit ACE may be

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developed to treat COVID-19 in the future. Hoffmann et al. (2020) reported a cellular
protease TMPRSS2 for 2019-nCoV priming upon entrance into cells and viral spread in
the infected host cells. The serine protease inhibitor camostat mesylate against
TMPRSS2, can efficiently blocked 2019-nCoV-S-protein-driven cell entry, which
could be a promising treatment for 2019-nCoV infection.
There are no effective antiviral treatment for coronavirus infection, even the strong
candidates as lopinavir/ritonavir and abidol exhibited no remarkable effect on clinical
improvement, day 28 mortality or virus clearance(Chen et al., 2020). Expectation and
attention were shifted to “remdesivir” which may be the most potential wide-spectrum
drug for antiviral treatment of 2019-nCoV. Remdesivir is an adenosine analogue,

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which incorporates into novel viral RNA chains and results in pre-mature termination.
It is currently under clinical development for the treatment of Ebola virus

ro
infection(Mulangu et al., 2019). Wang et al. (2020b) revealed that remdesivir were
highly effective and safe in the control of 2019-nCoV infection in Vero E6 cells and
Huh-7 cells. A successful appliance of remdesivir on the first 2019-nCoV infected case
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in the United States when the his clinical status was getting worsen, were recently
released(Holshue et al., 2020). Animal experiments also showed superiority of
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remdesivir over lopinavir/ritonavir combined with interferon-β, by reducing
MERS-CoV titers of infected mice and improving the lung tissue damage(Sheahan et
lP

al., 2020). The effectiveness and safety of remdesivir can be expected by the clinical
trial lead by Dr Bin Cao.
The 2019-nCoV infection is associated with a cytokine storm triggered by
na

over-activated immune system(Huang et al., 2020; Xu et al., 2020b), similar to SARS

and MERS. The aberrant and excessive immune responses lead to a long-term lung
function and structure damage in patients survived from ICU. Ongoing trials of IL-6
ur

antagonist tocilizumab, which shown effective against cytokine release syndrome

resulting from CAR-T cell infusion against B cell acute lymphoblastic leukemia, may
Jo

be expanded to restore T cell counts and treat severe 2019-nCoV infection(Le et al.,
2018). The available observational studies and meta-analysis of corticosteroid
treatment suggested impaired antibody response, increased mortality and secondary
infection rates in influenza, increased viraemia and impaired virus clearance of
SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in
survivors(Zumla et al., 2020). Therefore, corticosteroid should not be recommended
for treatment of 2019-nCoV, or use on severe patient with special caution. A review
12
on convalescent plasma for treatment of SARS-CoV and severe influenza infection,
suggested a reduction in hospital stay and mortality rate, especially when
administered early after symptom onset (Mair-Jenkins et al., 2015). However, another
study demonstrated no significant improvement of convalescent plasma transfusion
on survival of Ebola virus infected patients. Possible reasons may be the unknown
levels of neutralizing antibodies in convalescent plasma and transfusion timing(van
Griensven et al., 2016). In terms of vaccine, if any cross-reactive epitopes were
identified between 2019-nCoV and SARS-CoV, previous vaccine for SARS-CoV
might be re-utilized to facilitate 2019-nCoV vaccine development. We recommend an
influenza and Streptococcus pneumoniae vaccination for prophylaxis, especially in

of
elderly adults(Chen et al., 2020b). Both pandemic viruses result in similar respiratory
symptoms and hard to distinguish. The 2019-nCoV pandemic initiated in flu season

ro
which easy to develop a combination infection of 2019-nCoV and influenza or
Streptococcus infection. Vaccination against influenza and Streptococcus pneumonia
in vulnerable elderly people with comorbidities are highly cost-effective, which is
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demonstrated to associate with reductions in the risk of hospitalization and death from
all causes during influenza seasons(Nichol et al., 2003).
re
Conclusion
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In conclusion, it still remains a challenging task to fight the 2019-nCoV of

unknown origin and mysterious biological features, and to control an outbreak of
COVID-19 with such a high R0, a long incubation period and a short serial interval, by
na

limited treatment and prevention measures. Lessons learned from the MERS and SARS
outbreaks can provide valuable insight into how to handle the current pandemic. The
successful public health outbreak response tactics of Chinese government, such as hand
ur

hygiene, wearing masks, isolation, quarantine, social distancing, and community

containment, can be copied by other countries according to their national situation. As
Jo

the pandemic is still ongoing and expanding, experiences and research literatures from
China and other countries will increase. The 2019-nCoV should be monitored of any
possible gene variation of antigenic drift or antigenic conversion, to avoid another
round of outbreak. Another lessons from this pandemic will be awe for nature and love
for life.

13
Author Contributions: Author Mingxuan Xie is responsible for conceptualization,
literature reviewing, manuscript drafting and submitting. Author Qiong Chen is
responsible for supervision, literature reviewing, manuscript drafting and revising. All
authors have read and agreed to the published version of the manuscript.

Funding Source: This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.

Ethical Approval: The ethical approval or individual consent was not applicable.

Conflicts of Interest: All authors declare no conflict of interest. All authors don’t have

of
any financial and personal relationships with other people or organizations that could

ro
influence our work.

Acknowledgments: Thanks for Dr Jin Fan for advice and guidance in pathology part.
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Jo

14
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 Table 1. Epidemiology characteristics of COVID-19, SARS and MERS
COVID-19 SARS MERS
Original location Wuhan, China Guangdong, China Jeddah, Saudi Arabia
Total cases (global) 85403+ 8096 2229
Total death (global) 1753+ 774 791
Healthcare worker cases(%) 3.8 21 18.6
Reproductive number 3.28 3.0 <1.0
Incubation period (days) 4.75-6.4 4.0 4.5-5.2
Serial interval (days) 2.6-7.5 8.4 12.6
Case-fatality rate (%) 3.0 9.6 35.5

of
CFR with comorbidities (%) 73.3 46.0 60.0

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19
 Supplementary Table 1. General information of 2019-nCoV inpatients
Studies Huang et al. Chen et al. Wang et al. Guan et al.
Collecting time(year of 2020) January 22 January1-22 January 1-28 January 29
Number of cases 41 99 138 1099
Location Wuhan Wuhan Wuhan Mainland China
Mean Age (yrs) 49 55.5 56 47
Sex ratio (male: female) 73%:27% 68%:32% 54.3%:45.7% 58.1%:41.9%
Exposure history (%) 66 49 8.7 71.8
Underlying diseases (%) 32 50 NA 23.2
Diabetes (%) 20 13 10.1 7.4
Hypertension(%) 15 NA 31.2 14.9

of
Cardio-cerebrovascular 15 40 19.6 3.9
disease(%)

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Malignancy(%) NA 1 7.2 0.9
Prognosis
Remain hospitalization(%)
Discharged(%)
17
68
58
31
-p 61.6
34.1
93.6
5.8
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Died(%) 15 11 4.3 1.36
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20
 Supplementary Table 2. Clinical information of 2019-nCoV inpatients
Studies Huang et al. Chen et al. Wang et al. Guan et al.

Symptoms
Fever (%) 98 83 98.6 87.9
Cough (%) 76 82 59.4 67.7
Myalgia (%) 44 11 34.8 14.8
Fatigue (%) NA 69.6 38.1
Shortness of breath (%) 55 31 31.2 31-55
Headache(%) 8 8 6.5 13.6
Diarrhea (%) 3 2 10.1 3.7
Examinations
Lymphopenia (%) 63 35 70.3 82.1

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Leukopenia (%) 25 9 NA 33.7
Prolonged prothrombin time (%) NA 5 58 NA
Aspartate aminotransferase elevation (%) 37 35 NA 22.2

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Lactate dehydrogenase elevation (%) 73 76 39.9 41
Pneumonia in CT (%) 100 100 100 76.4
Progression ( time from onset of symptoms)
Hospital admission(days)
Dyspnea (days)
7
8
-p NA
NA
7
5
NA
NA
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ARDS(days) 9 NA 8 NA
Mechanical ventilation (days) 10.5 NA NA NA
Admission to ICU(%) 15 23 26.1 5
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Complications
ARDS(%) 29 17 61.1 3.4
Acute cardiac injury(%) 12 NA 7.2 NA
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Secondary infection(%) 10 NA NA NA
Acute kidney injury (%) 7 3 3.6 0.5
Shock(%) 7 4 30.6 1
Treatments
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Antiviral therapy(%) 93 76 89.9 35.8

Antibiotic treatment(%) 100 71 Most 57.5
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Systematic corticosteroids(%) 22 19 44.9 18.6

Immunoglobin(%) NA 27 NA 13
CRRT(%) 7 9 1.5 0.8
Non-invasive ventilation or 24 13 14 5.1
high-flow nasal cannula(%)
Invasive ventilation (%) 5 4 12 2.2
ECMO(%) 5 3 2.9 0.5
(ECMO=extracorporeal membrane oxygenation. CRRT=continuous renal replacement therapy.)

21
Another random document with
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having his own way about—about anything! Whether we like it or
not, he’ll go and do what—what he said he would do just now.”
Madrasia looked down at the table, and began to study the pattern of
the cloth.
“Well?” she said.
“I don’t think it’s at all well,” said I. “Supposing—just supposing, you
know—supposing we fell in with his wishes and—and got married.
I’m just supposing, of course!”
“Well?” she said, again.
“Don’t you see what a dreadful thing that would be?” I said.
She gave me a quick flash of her eye—there, and gone in a second.
“Why?” she demanded.
“People would say I married you for your money,” I declared boldly.
“That would be awful for both of us!”
She remained silent a moment, tracing the pattern of the cloth with
the tip of her finger. Then she spoke—emphatically.
“Rot!” she said.
“No!” said I, with equal emphasis. “Because they would! I know ’em!
And it’s beastly hard on me; it upsets my plans. Parslewe’s upset all
my plans. If I’d only known——”
“Only known what?” she asked.
“Only known that he was going to spring this on us!” I answered,
bitterly. “If I’d only known that, I’d—I’d have——”
“You’d have what?” she asked, as I paused and hesitated.
“Well—I’d have proposed to you this morning when we were in the
hotel garden, or in that carriage, or in the wood, when Parslewe was
ahead,” I answered. “Or yesterday, or the day before, or the day
before that—any time since I first met you. But now—wouldn’t it look
as if I were proposing to the Palkeney estate?”
She suddenly looked up, gave me a queer glance, and rising from
her chair walked over to one of the embrasured windows. I followed
her—and after a moment’s silence, slipped my arm round her waist.
“What on earth’s to be done?” I asked her. “Tell me!”
I got her to look round at last.
“You’re an awful old ass!” she said in a whisper. “I saw the way out at
once. He didn’t say he’d give all this to me! He said he’d give it to—
us!”
“Is it going to be—us, then?” I demanded eagerly.
“Seems very like it, I think, doesn’t it?” she answered, demurely.
So—but not for a little while—we went to tell Parslewe.
THE END
 TRANSCRIBER’S NOTES:
Obvious typographical errors have been corrected.
Inconsistencies in hyphenation have been
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