IMG 1:

CoV infections, like lopinavir/ritonavir, and interferon-1B revealed in vitro anti-MERS-CoV

action. The in vivo experiment carried out in the nonhuman primate model of common
marmosets treated with lopinavir/ritonavir and interferon beta showed superior protective
results in treated animals than in the untreated ones (190). A combination of
these drugs is being evaluated to treat MERS in humans (MIRACLE trial) (191). These two
protease inhibitors (lopinavir and ritonavir), in combination
with ribavirin, gave encouraging clinical outcomes in SARS patients, suggesting their
therapeutic values (165). However, in the current scenario, due to the

IMG 2:
infections clinically or through routine lab tests. Therefore travel history becomes important.
However, as the epidemic spreads, the travel history will become irrelevant.
Treatment |21, 23]

IMG 3:
nsps and Accessory Proteins
Besides the important structural proteins, the SARS-CoV-2 genome contains 15 nsps, nspl to
nsp10 and nspl2 to nsp16, and 8 accessory proteins (3a, 3b, po, 7a, 7b, 8b, 9b, and ORF14)
(16). All these proteins play a specific role in viral replication
(27). Unlike the accessory proteins of SARS-CoV, SARS-CoV-2 does not contain 8a protein
and has a longer 8b and shorter 3b protein (16). The nsp7, nsp13, envelope, matrix, and po
and 8b accessory proteins have not been detected with any amino acid substitutions compared
to the sequences of other

IMG 4:

[median 17 d]. In the case series of children discussed earlier, all children recovered with
basic treatment and did not need intensive care [17).
There is anecdotal experience with use of remdeswir, a broad spectrum anti

IMG 5:
understanding of the lung inflammation associated with this infection (24).
SARS is a viral respiratory disease caused by a formerly unrecognized animal CoV that
originated from the wet markets in southern China after adapting to the human host, thereby
enabling transmission between humans 90). The SARS outbreak reported in 2002 to 2003
had 8,098 confirmed cases with 774 total deaths (9.6%) (93).
The outbreak severely affected the Asia Pacific region, especially mainland China (94). Even
though the case fatality rate (CFR) of SARS-CoV-2

IMG 6:
WEXX, has conducted large-scale testing
testing for
COVID-19 in specimens collected from dogs and cats. However, none of the tests turned out
to be positive (334).
In a study conducted to investigate the potential of different animal species to act as the
intermediate host of SARS-CoV-2, it was found that both ferrets and cats can be infected via
experimental inoculation of the virus. In addition, infected cats efficiently transmitted the
disease to naive cats (329). SARS-CoV-2 infection and subsequent transmission in ferrets
were found to recapitulate the clinical aspects of COVID-19 in humans. The infected ferrets
also

IMG 7:
insertion in RmYN02 does not functionally represent a polybasic cleavage site, it provides
support for the notion that this characteristic, initially considered unique to SARS-CoV-2, has
been acquired naturally?. A structural study suggested that the furin-cleavage site can reduce
the stability of SARS-CoV-2 S protein and facilitate the conformational adaption that is
required for the binding of the RBD to its receptor. Whether the higher transmissibility of
SARS-CoV-2 compared with SARS-CoV is a gain of function associated with acquisition of
the furin-like cleavage site is yet to be demonstrated?6.
An additional distinction is the accessory gene orf8 of SARS-CoV-2, which encodes a novel
protein showing only 40% amino acid identity to ORF8 of SARS-CoV.
Unlike in SARS-CoV, this new ORF8 protein does
1111

IMG 8:
observed through both in vivo and in vitro experiments. There is an enhanced nasal secretion
observed along with local oedema because of the damage of the host cell, which further
stimulates the synthesis of inflammatory mediators. In addition, these reactions can induce
sneezing, difficulty breathing by causing airway inhibition and elevate mucosal temperature.
These viruses, when released, chiefly affect the lower respiratory tract, with the signs and
symptoms existing clinically. Also, the virus further affects

IMG 9
comorbidities), it may progress to pneumonia, acute respiratory distress syndrome (ARDS)
and multi organ dysfunction. Many people are asymptomatic. The case fatality rate is
estimated to range from 2 to 3%.
Diagnosis is by demonstration of the

IMG10
encircled with
an envelope containing viral
nucleocapsid. The nucleocapsids in CoVs are arranged in helical symmetry, which reflects an
atypical attribute in positive-sense RNA viruses (30).
IMG 11
The electron micrographs of SARS-CoV-2 revealed a diverging spherical outline with some
degree of pleomorphism, virion diameters varying from 60 to 140 nm, and distinct spikes of 9
to 12 mm, giving the virus the appearance of a solar corona (3). The CoV genome is arranged
linearly as 5'-leader-UTR-replicase-structural genes (S-E-M-N)-3' UTR-poly(A) (32).
Accessory genes, such as 3a/b, 4a/b, and the hemagglutinin-esterase gene (HE), are also

IMG 12
alarming rate all over the world. The outbreak of the virus has confronted the world's
economic, medical and public health infrastructure. Elderly and immunocompromised
patients also are susceptible to the virus's mortal impacts.
Currently, there is no documented cure for the virus and no vaccine has been created,
although some treatment protocols have been promising.
Therefore, the virus can be controlled with the appropriate prevention strategies. Also,
attempts have to be made to formulate

IMG13
in the twenty-first century. At the end of 2019, a novel coronavirus designated as SARS-
CoV-2 emerged in the city of Wuhan, China, and caused an outbreak of unusual viral
pneumonia. Being highly transmissible, this novel coronavirus disease, also known as
coronavirus disease 2019 (COVID-19), has spread fast all over the world??
It has overwhelmingly surpassed SARS and MERS in terms of both the number of infected
people and the spatial range of epidemic areas. The ongoing outbreak of COVID-19 has
posed an extraordinary threat to global public health*. In this Review, we summarize the
current understanding of the nature of SARS-CoV-2 and COVID-19. On the basis of recently
published findings, this comprehensive Review covers the basic biology
of SARS-CoV.) including the genetic characteristics

IMG14
Based on molecular characterization, SARS-CoV-2 is considered a new Betacoronavirus
belonging to the subgenus Sarbecovirus (3). A few other critical zoonotic viruses (MERS-
related CoV and SARS-related CoV) belong to the same genus.
However, SARS-CoV-2 was identified as a distinct virus based on the percent identity with
other Betacoronavirus; conserved open reading frame la/b (ORFla/b) is below 90% identity
(3). An overall 80% nucleotide identity was observed between SARS-CoV-2 and the original
SARS-CoV, along with 89% identity with ZC45 and ZXC21 SARS-related CoVs of bats (2,
31, 36). In addition, 82%
IMG 15
Recently, another
FDA-approved drug,
ivermectin, was reported to inhibit the in vitro replication of SARS-CoV-2. The findings
from this study indicate that a single treatment of this drug was able to induce an ~5,000-fold
reduction in the viral RNA at 48 h in cell culture. (308). One of the main disadvantages that
limit the clinical utility of ivermectin is its potential to cause cytotoxicity.
However, altering the vehicles used in the formulations, the pharmacokinetic properties can
be modified, thereby having significant control over the systemic concentration of ivermectin
(338). Based on the pharmacokinetic simulation, it was also found

IMG 15
11 CLINICAL MANAGEMENT AND TREATMENT
In severe COVID-19 cases, treatment should be given to support vital organ functions.
People who think they may have been exposed to COVID-19 should contact their healthcare
provider immediately. Healthcare personnel should care for patients in an Airborne Infection
Isolation Room (AllR). Precautions must be taken by the healthcare professional, such as
contact precautions and airborne precautions

IMG 16
exponentially in other countries including South Korea, Italy and Iran.
Of those infected, 20% are in critical condition, 25% have recovered, and 3310 (3013 in
China and 297 in other
countries) have died [2]. India, which

IMG17
(181). CEPI has also funded Moderna to develop a vaccine for COVID-19 in partnership with
the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious
Diseases (NIAID), part of the National Institutes of Health (NIH) (182).
By employing mRNA vaccine platform technology, a vaccine candidate expressing SARS-
CoV-2 spike protein is likely to go through clinical testing in the coming months (180). On
16 March 2020, Jennifer Haller became the first person outside China to receive an
experimental vaccine, developed by Moderna, against this pandemic virus. Moderna, along
with China's CanSino Biologics, became the

IMG 18
significance of frequent and good hand hygiene and sanitation practices needs to be given due
emphasis
IMG 19
(249-252). Future explorative research needs to be conducted with regard to the fecal-oral
transmission of SARS-CoV-2, along with focusing
On
environmental investigations to find out if this virus could stay viable in situations and
atmospheres facilitating such potent routes of transmission. The correlation of fecal
concentrations of viral RNA with disease severity needs to be determined, along with
assessing the gastrointestinal symptoms and the possibility of fecal SARS-CoV-2 RNA
detection during the COVID-19 incubation period or

IMG 20

All of these therapeutic approaches have revealed both in vitro and in vivo anti-CoV
potential.
Although in vitro research carried out with these therapeutics showed efficacy, most need
appropriate support from randomized animal or human trials.
Therefore, they might be of limited applicability and require trials against SARS-CoV-2 to
gain practical usefulness. The binding of SARS-CoV-2 with ACE2 leads to the exacerbation
of pneumonia as a consequence of the imbalance in the renin-angiotensin system (RAS). The
virus-induced pulmonary inflammatory responses may be reduced by the administration of
ACE inhibitors (ACED and

IMG 21
Epidemiology and Pathogenesis
[10, 11]
All ages are susceptible. Infection is transmitted through large droplets generated during
coughing and sneezing by symptomatic patients but

IMG 22
Initially, the epicenter of the SARS-CoV-2 pandemic was China, which reported a significant
number of deaths associated with COVID-19, with 84,458 laboratory-confirmed cases and
4,644 deaths as of 13 May 2020 (Fig. 4). As of 13 May 2020, SARS-CoV-2 confirmed cases
have been reported in more than 210 countries apart from China (Fig. 3 and 4) (WHO
Situation Report 114) (25, 64).
COVID-19 has been reported on all continents except Antarctica. For many weeks, Italy was
the focus of concerns regarding the large number of cases, with 221,216 cases and 30,911
deaths, but now, the United States is the country with the largest
IMG 23
prongs, face mask, high flow nasal cannula (HFNC) or non-invasive
ventilation is indicated. Mechanical ventilation and even extra corporeal membrane oxygen
support may be needed. Renal replacement therapy may be needed in some. Antibiotics and
antifungals are required if co-

IMG 24
The interferon response is one of the major innate immunity defences against virus invasion.
Interferons induce the expression of diverse interferon-stimulated genes, which can interfere
with every step of virus replication. Previous studies identified type I interferons as a
promising therapeutic candidate for SARS'49.
In vitro data showed SARS-CoV-2 is even more sensitive to type I interferons than SARS-
CoV, suggesting the potential effectiveness of type I interferons in the early treatment of
COVID-19 (REF.159. In China, vapor inhalation of interferon-a is included in the COVID-19
treatment guideline!51. Clinical trials are ongoing across the world to evaluate the efficacy of
different therapies involving interferons, either alone or in combination

IMG 25
Currently, our knowledge on the animal origin of SARS-CoV-2 remains incomplete to a large
part. The reservoir hosts of the virus have not been clearly proven.
It is unknown whether SARS-CoV-2 was transmitted to humans through an intermediate host
and which animals may act as its intermediate host. Detection of RaTG13, RmYN02 and
pangolin coronaviruses implies that diverse coronaviruses similar to SARS-CoV-2 are
circulating in wildlife. In addition, as previous studies showed recombination as the potential
origin of some sarbecoviruses such as SARS-CoV, it cannot be excluded that viral RNA
recombination among different related coronaviruses was involved in the evolution of SARS-
CoV-2. Extensive surveillance of SARS-CoV-2-

IMG 26
require in-depth knowledge regarding the virus, which currently is a novel agent;
consequently, further studies are required.
Comparing the genome of SARS-CoV-2 with that of the closely related SARS/SARS-like
CoV revealed that the sequence coding for the spike protein, with a total length of 1,273
amino acids, showed 27 amino acid substitutions. Six of these substitutions are in the region
of the receptor-binding domain (RBD), and another six substitutions are in the underpinning
subdomain (SD) (16). Phylogenetic analyses have revealed that SARS-CoV-2 is closely
related (88% similarity) to two SARS-like CoVs
IMG 27
The exploration of fully human antibodies (human single-chain antibodies; HuscFvs) or
humanized nanobodies (single-domain antibodies; sdAb, VH/VHH) could aid in blocking
virus replication, as these agents can traverse the virus-infected cell membranes (transbodies)
and can interfere with the biological characteristics of the replicating virus proteins. Such
examples include transbodies to the influenza virus, hepatitis C virus, Ebola virus, and
dengue virus (206). Producing similar transbodies against intracellular proteins of
coronaviruses, such as papain-like proteases (PLpro), cysteine-like protease (3CLpro), or
other nsps, which

IMG 28
13 CONVALESCENT PLASMA
THERAPY
Guo Yanhong, an official with the National Health Commission (NHC), stated that
convalescent plasma therapy is a significant method for treating severe COVID-19 patients.
Among the COVID-19 patients currently receiving convalescent plasma therapy in the virus-
hit Wuhan, one has been discharged from hospital, as reported by Chinese science authorities
on Monday, 17th February 2020 in

IMG 29
differs from that in SARS-CoV in the five residues critical for ACE2 binding, namely
Y455L, L486F, N493Q, D494S and T501N (FIG. 3b,c). Owing to these residue changes,
interaction of SARS-CoV-2 with its receptor stabilizes the two virus-binding hotspots on the
surface of hACE2 (REF.59 (FIG. 3d). Moreover, a four-residue motif in the RBM of SARS-
CoV-2 (amino acids 482-485:
G-V-E-G) results in a more compact conformation of its hACE2-binding ridge than in SARS-
CoV and enables better contact with the N-terminal helix of hACE2
(REF."). Biochemical data confirmed that the structural features of the SARS-CoV-2 RBD
has strengthened its hACE2 binding affinity compared with that of SARS-Co V50,52,53

IMG 30
polymorphism at nucleotide position 28,144, which results in amino acid substitution of Ser
for Lys at residue 84 of the ORF8 protein. Those variants with this mutation make up a single
subclade labelled as clade $'33,34 Currently, however, the available sequence data are not
sufficient to interpret the early global transmission history of the virus, and travel patterns,
IMG 31
founder effects and public health measures also strongly influence the spread of particular
lineages, irrespective of potential biological differences between different virus variants.
Animal host and spillover
Bats are important natural hosts of alphacoronavi-ruses and betacoronaviruses. The closest
relative

IMG 32
mice, and hDPP4-Tg mice (transgenic for expressing hDPP4) for MERS-CoV infection
(221). The CRISPR-Cas9 gene-editing tool has been used for inserting genomic alterations in
mice, making them susceptible to MERS-CoV infection (222). Efforts are under way to
recognize suitable animal models for SARS-CoV2/COVID-19, identify the receptor affinity
of this virus, study pathology in experimental animal models, and explore virus-specific
immune responses and protection studies, which together would increase the pace of efforts
being made for developing potent vaccines and drugs to counter this emerging virus. Cell
lines, such as monkey epithelial

IMG 33
in vitro and in vivo 55-158. Compared with convalescent plasma, which has limited
availability and cannot be amplified, monoclonal antibodies can be developed in larger
quantities to meet clinical requirements. Hence, they provide the possibility for the treatment
and prevention of COVID-19. The neutralizing epitopes of these monoclonal antibodies also
offer important information for vaccine design. However, the high cost and limited capacity
of manufacturing, as well as the problem of bioavailability, may restrict the wide application
of monoclonal antibody therapy.
Vaccines
Vaccination is the most effective method for a long-term

IMG 34
relaxation drugs to prevent ventilator-related lung injury
associated
with human-machine
incoordination (122). The result obtained from a clinical study of four patients infected with
COVID-19 claimed that combination therapy using lopinavir/ritonavir, arbidol, and Shufeng
Jiedu capsules (traditional Chinese medicine) was found to be effective in managing COVID-
19 pneumonia
(193). It is difficult to evaluate the therapeutic potential of a drug or a combination of drugs
for managing a disease based on such a limited sample size. Before choosing the ideal
therapeutic agent for the management of COVID-19, randomized clinical
IMG 35
respiratory syncytial virus, rhinovirus, human metapneumovirus and SARS coronavirus. It is
advisable to distinguish COVID-19 from other pneumonias such as mycoplasma pneumonia,
chlamydia pneumonia and bacterial pneumonia. 33 Several published pieces of literature
based on the novel coronavirus reported in China declared that stool and blood samples can
also collected from the suspected persons in order to detect the virus. However, respiratory
samples show better viability in identifying the virus, in comparison with the

IMG 36
other countries that have not reported the disease until now. The possibility of an imported
case of COVID-19 leading to sustained human-to-human transmission was estimated to be
0.41. This can be reduced to a value of 0.012 by decreasing the mean time from the onset of
symptoms to hospitalization and can only be made possible by using intense disease
surveillance systems (235). The silent importations of infected individuals (before the
manifestation of clinical signs) also contributed significantly to the spread of disease across
the major cities of the world. Even though the travel ban was implemented in Wuhan (89),
infected persons

IMG37
primary anti-genic epitopes mainly those recognised by neutralising antibodies. The spike S-
protein being in a spike form is subjected to a structural rearrangement process so that fusing
the outer membrane of the virus with the host-cell membrane becomes easier. 19, 20 Recent
SARS-CoV work has also shown that the membrane exopeptidase ACE enzyme
(angiotensin-converting enzyme) functions as a COVID-19 receptor to enter the human
cell.21

IMG 38
in Yunnan. This novel bat virus, denoted 'RmYN02, is 93.3% identical to SARS-CoV-2
across the genome.
In the long lab gene, it exhibits 97.2% identity to SARS-CoV-2, which is even higher than for
RaTG13 (REF.?*). In addition to RaTG13 and RmYN02, phylogenetic analysis shows that
bat coronaviruses ZC45 and ZXC21 previously detected in Rhinolophus pusillus bats from
eastern China also fall into the SARS-CoV-2 lineage of the subgenus Sarbecovirus? (FIG. 2).
The discovery of diverse bat coronaviruses closely related to SARS-CoV-2 suggests that bats
are possible reservoirs of SARS-CoV-2 (REF."). Nevertheless, on the basis of current
findings, the divergence between SARS-CoV-2 and related bat coronaviruses likely
represents more than
20 vears of sequence evolution. suagesting that these hat
IMG 39
into the host cell. Heptad repeat 1 (HR1) and heptad repeat 2 (HR2) can interact and form a
six-helix bundle that brings the viral and cellular membranes in close proximity, facilitating
its fusion. The sequence alignment study conducted between COVID-19 and SARS-CoV
identified that the S2 subunits are highly conserved in these CoVs. The HRi and HR2
domains showed 92.6% and 100% overall identity, respectively (210). From these findings,
we can confirm the significance of COVID-19 HR1 and HR2 and their vital role in host cell
entry. Hence, fusion inhibitors target the HRI domain of S protein, thereby preventing viral
fusion

IMG 39
minimum signs and symptoms (82). Another study, conducted in South Korea, related to
SARS-CoV-2 viral load, opined that SARS-CoV-2 kinetics were significantly different from
those of earlier reported CoV infections, including SARS-CoV (253). SARS-CoV-2
transmission can occur early in the viral infection phase; thus, diagnosing cases and isolation
attempts for this virus warrant different strategies than those needed to counter SARS-CoV.
Studies are required to establish any correlation between SARS-CoV-2 viral load and
cultivable virus. Recognizing patients with fewer or no symptoms, along with having modest
detectable viral RNA in the

IMG 40
Practice Points from an Indian Perspective
At the time of writing this article, the risk of coronavirus in India is
extremely low. But that may change in the next few weeks. Hence the

IMG 41
A suspected case of COVID-19 infection is said to be confirmed if the respiratory tract
aspirate or blood samples test positive for SARS-CoV-2 nucleic acid using RT-PCR or by the
identification of SARS-CoV-2 genetic sequence in respiratory tract aspirate or blood samples
(80). The patient will be confirmed as cured when two subsequent oral swab results are
negative (153). Recently, the live virus was detected in the self-collected saliva of patients
IMG 42
infected with COVID-19. These findings were confirmative of using saliva as a noninvasive
specimen for the diagnosis of COVID-19 infection in suspected

IMG 43
The results of the studies related to SARS-CoV-2 viral loads reflect active replication of this
virus in the upper respiratory tract and prolonged viral shedding after symptoms disappear,
including via stool. Thus, the current case definition needs to be updated along with a
reassessment of the strategies to be adopted for restraining the SARS-CoV-2 outbreak spread
(248). In some cases, the viral load studies of SARS-CoV-2 have also been useful to
recommend precautionary measures when handling specific samples, e.g., feces. In a recent
survey from 17 confirmed cases of SARS-CoV-2 infection with available data (representing
days 0 to 13 after onset),

IMG 44
Inhibition of virus replication. Replication inhibitors include remdesivir (GS-5734), favilavir
(T-705), riba-virin, lopinavir and ritonavir. Except for lopinavir and ritonavir, which inhibit
3CLpro, the other three all target RdRp 128,135 (FIG. 5). Remdesivir has shown activity
against SARS-CoV-2 in vitro and in vivo 28,136. A clinical study revealed a lower need for
oxygen support in patients with COVID-19 (REF 137). Preliminary results of the Adaptive
COVID-19 Treatment Trial (ACTT) clinical trial by the National Institute of Allergy and
Infectious Diseases (NIAID) reported that remdesivir can shorten the recovery time in
hospitalized adults with COVID-19 by a couple days compared with placebo, but the differ-
ence in mortality was not statistically significantl38
The

IMG 45
warrant full exploitation of real-time disease mapping by employing geographical
information systems (GIS), such as the GIS software Kosmo 3.1, web-based real-time tools
and dashboards, apps, and advances in information technology (356-359).
Researchers have also developed a few prediction tools/models, such as the prediction model
risk of bias assessment tool (PROBAST) and critical appraisal and data extraction for
systematic reviews of prediction modeling studies (CHARMS), which could aid in assessing
the possibility of getting infection and estimating the prognosis in patients; however, such
models may suffer from bias issues
IMG 46
The high transmissibility of SAks-CoV-2 may be attributed to the unique virological features
of SARS-CoV-2. Transmission of SARS-CoV occurred mainly after illness onset and peaked
following disease severity'5.
. However, the SARS-CoV-2 viral load
in upper respiratory tract samples was already highest during the first week of symptoms, and
thus the risk of pharyngeal virus shedding was very high at the beginning of infection,9. It
was postulated that undocumented infections might account for 79% of documented cases
owing to the high transmissibility of the virus during mild disease or the asymptomatic
period®®. A patient with COVID-19 spreads viruses in liquid droplets during speech.
However, smaller and
muich more numernnic nartidec Inoum ac gerneol narti

IMG 47
covib-191s an Intectious aisease caused Dy SARS-CoV-2, which is also termed the novel
coronavirus and is diligently associated with the SARS virus. The Ministry of Science and
Technology from the People's Republic of China declared three potential antiviral medicines
suitable for treating COVID-19. Those three medicines are, namely, Favilavir, chloroquine
phosphate and remdesivir. A clinical trial was conducted to test the efficacy of those three
drugs, and the results proved that out of the three medicines above only Favilavir is effective

IMG 48
as an entry receptor while exhibiting an RBD similar to that of SARS-CoV (17, 87, 254,
255). Several countries have provided recommendations to their people traveling to China
(88, 89). Compared to the previous coronavirus outbreaks caused by SARS-CoV and MERS-
CoV, the efficiency of SARS-CoV-2 human-to-human transmission was thought to be less.
This assumption was based on the finding that health workers were affected less than they
were in previous outbreaks of fatal coronaviruses (2).
Superspreading events are considered the main culprit for the extensive transmission of
SARS and
MERS (90, 91). Almost half of the MERS-CoV

IMG 49
have published protective measures to mitigate the spread of COVID-19. This involves
frequent hand washing with handwash containing 60% of alcohol and soap for at least 20
seconds.
Another important measure is avoiding close contact with sick people and keeping a social
distance of 1 metre always to everyone who is coughing and sneezing. Not touching the nose,
IMG 50
eyes and mouth was also suggested. While coughing or sneezing, covering the mouth and
nose with a cloth/tissue or the bent elbow is advised. Staying at home is recommended for

IMG 51
addition to all of the above findings, sequencing and phylogenetics are critical in the correct
identification and confirmation of the causative viral agent and useful to establish
relationships with previous isolates and sequences, as well as to know, especially during an
epidemic, the nucleotide and amino acid mutations and the molecular divergence. The rapid
development and implementation of diagnostic tests against emerging novel diseases like
COVID-19 pose significant challenges due to the lack of resources and logistical limitations
associated with an outbreak (155).
SARS-CoV-2 infection can also be confirmed by

IMG 52
that are present in the submucosa of the respiratory tract and nasal cavity are considered the
primary barrier against this virus (92). Advanced in-depth analysis of the genome has
identified 380 amino acid substitutions between the amino acid sequences of SARS-CoV-2
and the SARS/SARS-like coronaviruses. These differences in the amino acid sequences
might have contributed to the difference in the pathogenic divergence of SARS-CoV-2 (16).
Further research is required to evaluate the possible differences in tropism, pathogenesis, and
transmission of this novel agent associated with this change in the amino acid sequence. With
the current

IMG 53
identified angiotensin receptor 2
(ACE2) as the receptor through which the virus enters the respiratory mucosa
[11].
The basic case reproduction rate (BCR) is estimated to range from 2 to 6.47 in

IMG 54
dogs have low susceptibility, while the chickens, ducks, and pigs are not at all susceptible to
SARS-
CoV-2 (329).
Similarly, the National Veterinary Services Laboratories of the USDA have reported COVID-
19 in tigers and lions that exhibited respiratory signs like dry cough and wheezing. The zoo
animals are suspected to have been infected by an asymptomatic zookeeper (335). The total
number of COVID-19-positive cases in human beings is increasing at a high rate, thereby
creating ideal conditions for viral spillover to other species, such as pigs. The evidence
obtained from SARS-CoV suggests that pigs can get

IMG 55
in the epidemic strain (104). Transmission can also occur directly from the reservoir host to
humans without RBD adaptations. The bat coronavirus that is currently in circulation
maintains specific "poised" spike proteins that facilitate human infection without the
requirement of any mutations or adaptations
(105). Altogether, different species of bats carry a massive number of coronaviruses around
the world
(106).
The high plasticity in receptor usage, along with the feasibility of adaptive mutation and
recombination, may result in frequent interspecies

IMG 56
to the direct transmission mainly occurring via droplets of sneezing and coughing, other
routes, such as fecal excretion and environmental and fomite contamination, are contributing
to SARS-CoV-2 transmission and spread (249-252). Fecal excretion has also been
documented for SARS-CoV and MERS-CoV, along with the potential to stay viable in
situations aiding fecal-oral transmission. Thus, SARS-CoV-2 has every possibility to be
transmitted through this mode. Fecal-oral transmission of SARS-CoV-2, particularly in
regions having low standards of hygiene and poor sanitation, may have grave consequences
with regard to the high spread of this

IMG 57
to the direct transmission mainly occurring via droplets of sneezing and coughing, other
routes, such as fecal excretion and environmental and fomite contamination, are contributing
to SARS-CoV-2 transmission and spread (249-252). Fecal excretion has also been
documented for SARS-CoV and MERS-CoV, along with the potential to stay viable in
situations aiding fecal-oral transmission. Thus, SARS-CoV-2 has every possibility to be
transmitted through this mode. Fecal-oral transmission of SARS-CoV-2, particularly in
regions having low standards of hygiene and poor sanitation, may have grave consequences
with regard to the high spread of this
IMG 58

Consequently, a SARS-CoV transgenic mouse model has been developed by inserting the
hACE2 gene into the mouse genome (219). The inability of MERS-CoV to replicate in the
respiratory tracts of animals (mice, hamsters, and ferrets) is another limiting factor. However,
with genetic engineering, a
288-330+/+ MERS-CoV genetically modified mouse model was developed and now is in use
for the assessment of novel drugs and vaccines against MERS-CoV (220). In the past, small
animals (mice or hamsters) have been targeted for being closer to a humanized structure, such
as mouse DPP4 altered with human DPP4 (hDPP4), hDPP4-transduced

IMG 59
by the University of Oxford. In a randomized controlled phase I/II trial, it induced
neutralizing antibodies against SARS-CoV-2 in all 1,077 participants after a second vaccine
dose, while its safety profile was acceptable as well 63. The NIAID and Moderna co-
manufactured mRNA-1273, a lipid nanoparticle-formulated mRNA vaccine candidate that
encodes the stabilized prefusion SARS-CoV-2 S protein. Its immunogenicity has been
confirmed by a phase I trial in which robust neutralizing antibody responses were induced in
a dose-dependent manner and increased after a second dose 64. Regarding inactivated
vaccines, a successful phase I/II trial involving 320 participants has been reported in China.
The whole-virus COVID-19 vaccine had a low rate of adverse

IMG 60
vitro antiviral potential of FAD-approved drugs, viz., ribavirin, penciclovir, nitazoxanide,
nafamostat, and
chloroquine, tested in comparison to remdesivir and favipiravir (broad-spectrum antiviral
drugs) revealed remdesivir and chloroquine to be highly effective against SARS-CoV-2
infection in vitro (194).
Ribavirin, pencilovir, and favipiravir might not possess noteworthy in vivo antiviral actions
for SARS-CoV-2, since higher concentrations of these nucleoside analogs are needed in vitro
to lessen the viral infection. Both remdesivir and chloroquine are being used in humans to
treat other diseases, and such safer drugs can be explored for assessing their

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while discharging any COVID-19-infected patient based on negative oral swab test results
due to the possibility of fecal-oral transmission. Even though the viral loads in stool samples
were found to be less than those of respiratory samples, strict precautionary measures have to
be followed while handling stool samples of COVID-19 suspected or infected patients (151).
Children infected with SARS-CoV-2 experience only a mild form of illness and recover
immediately after treatment. It was recently found that stool samples of SARS-CoV-2-
IMG 62
infected children that gave negative throat swab results were positive within ten days of
negative

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trimeric S1 locates itself on top of the trimeric S2 stalk (45). Recently, structural analyses of
the s proteins of COVID-19 have revealed 27 amino acid substitutions within a 1,273-amino-
acid stretch (16).
Six substitutions are located in the RBD (amino acids 357 to 528), while four substitutions
are in the RBM at the CTD of the S1 domain (16). Of note, no amino acid change is seen in
the RBM, which binds directly to the angiotensin-converting enzyme-2 (ACE2) receptor in
SARS-CoV (16, 46). At present, the main emphasis is knowing how many differences would
be required to change the host tropism.
Sequence comparison revealed 17 nonsynonymous

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evaluated for travel history and placed under contact and droplet isolation. Regular
decontamination of surfaces
should be done. They should be tested for etiology using multiplex
PCR panels if logistics permit and if no pathogen is identified, refer
the samnles for testino for CARS-

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outbreak investigation and it also helps us to derive a retrospective assessment of the disease
by estimating the attack rate. 32
According to the recent literature, paired serum samples can also help clinicians to diagnose
COVID-19 in case of false negative results in NAAT essays.37 The literature also declared
that the commercial and non-commercial serological tests are under consideration in order to
support the practising clinicians by assisting them in diagnosis. Similarly, there are studies
published on COVID-19 which are comprised of

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induced inflammatory cascades are characterized by the release of proinflammatory
interleukin-1 (IL-1) family members, such as IL-1 and IL-33. Hence, there exists a possibility
that the inflammation associated with coronavirus can be inhibited by utilizing anti-
IMG 67
inflammatory cytokines that belong to the IL-1 family (92). It has also been suggested that
the actin protein is the host factor that is involved in cell entry and pathogenesis of SARS-
CoV-2. Hence, those drugs that modulate the biological activity of this protein, like
ibuprofen, might have some therapeutic application in managing the disease
(174). The plasma angiotensin 2 level was found to

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Personal protective equipment (PPE), like face masks, will help to prevent the spread of
respiratory infections like COVID-19. Face masks not only protect from infectious aerosols
but also prevent the transmission of disease to other susceptible individuals while traveling
through public transport systems (313). Another critical practice that can reduce the
transmission of respiratory diseases is the maintenance of hand hygiene. However, the
efficacy of this practice in reducing the transmission of respiratory viruses like SARS-CoV-2
is much dependent upon the size of droplets produced. Hand hygiene will reduce disease
transmission only if the

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and other SARSr-CoVs (FIG. 2). Using sequences of five conserved replicative domains in
pp lab (3C-like protease (3CLpro), nidovirus RNA-dependent RNA polymerase (RdRp)-
associated nucleotidyltransferase (NiRAN), RdRp, zinc-binding domain (ZBD) and HEL1),
the Coronaviridae Study Group of the International Committee on Taxonomy of Viruses
estimated the pairwise patristic distances between SARS-CoV-2 and known coronaviruses,
and assigned SARS-CoV-2 to the existing species SARSr-CoV". Although phylogenetically
related, SARS-CoV-2 is distinct from all other coronaviruses from bats and pangolins in this
species.
The SARS-CoV-2 S protein has a full size of 1,273 amino acids, longer than that of SARS-
CoV

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Interestingly, disease in patients outside Hubei province has been reported to be milder than
those from Wuhan [17). Similarly, the severity and case fatality rate in patients outside China
has been reported to be milder
[6]. This may either be due to selection
IMG 71
(using suitable animal models) should be conducte to evaluate the risk of future epidemics.
Presently licensed antiviral drugs or vaccines against SARS CoV, MERS-CoV, and SARS-
CoV-2 are lacking However, advances in designing antiviral drugs an vaccines against
several other emerging diseases wil help develop suitable therapeutic agents agains COVID-
19 in a short time. Until then, we must rel exclusively on various control and preventio
measures to prevent this new disease from becomin a pandemic.

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proteins without the presence of S protein would not confer any noticeable protection, with
the absence of detectable serum SARS-CoV-neutralizing antibodies
(170). Antigenic determinant sites present over S and N structural proteins of SARS-CoV-2
can be explored as suitable vaccine candidates (294). In the Asian population, S, E, M, and N
proteins of SARS-CoV-2 are being targeted for developing subunit vaccines against COVID-
19 (295).
The identification of the immunodominant region among the subunits and domains of S
protein is critical for developing an effective vaccine against the coronavirus. The C-terminal
domain of the S1

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assays offer high accuracy in the diagnosis of SARS-CoV-2, but the current rate of spread
limits its use due to the lack of diagnostic assay kits. This will further result in the extensive
transmission of COVID-19, since only a portion of suspected cases can be diagnosed. In such
situations, conventional serological assays,
like
enzyme-linked
immunosorbent assay (ELISA), that are specific to
COVID-19 IgM and IgG antibodies can be used as a high-throughput alternative (149). At
present, there is no diagnostic kit available for detecting the SARS-CoV-2 antibody (150).
The specific antibody profiles
of

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it had spread massively to all 34 provinces of China. The number of confirmed cases
suddenly increased, with thousands of new cases diagnosed daily during late January'. On 30
January, the WHO declared the novel coronavirus outbreak a public health emergency of
IMG 75
international concern. On 11 February, the International Committee on Taxonomy of Viruses
named the novel coronavirus 'SARS-CoV-2', and the WHO named the disease 'COVID-19'
(REF.'7).
The outbreak of COVID-19 in China reached an epidemic peak in February. According to the
National Health Commission of China, the total number of cases continued to rise sharply in
early February at an average rate of more than 3.000 newlv confirmed cases

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with SARS and MERS (117).
SARS-CoV-2 invades the lung parenchyma, resulting in severe interstitial inflammation of
the lungs. This is evident on computed tomography (CT) images as ground-glass opacity in
the lungs. This lesion initially involves a single lobe but later expands to multiple lung lobes
(118). The histological assessment of lung biopsy samples obtained from COVID-19-infected
patients revealed diffuse alveolar damage, cellular fibromyxoid exudates, hyaline membrane
formation, and desquamation of pneumocytes, indicative of acute respiratory distress
sundrome (119). It was also

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thermore, SARS-CoV-2 is genetically dis n SARS-CoV (79% similarity) and MERS-arly
50%) (17). COVID-19 is associated ictions of the lungs in all cases and gene racteristic chest
computer tomography find h as the presence of multiple lesions in lung appear as dense,
ground-glass opaque struc occasionally coexist with consolidation sha

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might be lower. Further genetic analysis is required between SARS-CoV-2 and different
strains of SARS-CoV and SARS-like (SL) CoVs to evaluate the possibility of repurposed
vaccines against COVID-19. This strategy will be helpful in the scenario of an outbreak,
since much time can be saved, because preliminary evaluation, including in vitro studies,
already would be completed for such vaccine candidates.
Multiepitope subunit vaccines can be considered a promising preventive strategy against the
ongoing
COVID-19 pandemic. In silico and advanced immuninformatic tools can be used to develop
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suffering from novel SARS-CoV-2, with more than 4,170,424 cases and 287,399 deaths
across the globe.
There is an urgent need for a rational international campaign against the unhealthy food
practices of China to encourage the sellers to increase hygienic food practices or close the
crude live-dead animal wet markets. There is a need to modify food policies at national and
international levels to avoid further life threats and economic consequences from any
emerging or reemerging pandemic due to close animal-human interaction (285).
Even though individuals of all ages and sexes are

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6.1 Laboratory testing for coronavirus disease 2019 (COVID-
19) in suspected human cases
The assessment of the patients with COVID-19 should be based on the clinical features and
also epidemiological factors. The screening protocols must be prepared and followed per the
native context. 31 Collecting and testing of specimen samples from the suspected individual
is considered to be one of the main principles for controlling and managing the

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Middle East respiratory syndrome (MERS) began to emerge in 2002 and 2012, respectively.
Recently, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2), causing coronavirus disease 2019 (COVID-19), emerged in late 2019, and it has posed a
global health threat, causing an ongoing pandemic in many countries and territories (1).
Health workers worldwide are currently making efforts to control further disease outbreaks
caused by the novel CoV (originally named 2019-nCoV), which was first identified in Wuhan
City, Hubei Province, China, on 12 December 2019. On 11

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anti-SARS-CoV-2 activity is far higher than the maximum plasma concentration achieved by
administering the approved dose (340). However, ivermectin, being a host-directed agent,
exhibits antiviral activity by targeting a critical cellular process of the mammalian cell.
Therefore, the administration of ivermectin, even at lower doses, will reduce the viral load at
a minor level. This slight decrease will provide a great advantage to the immune system for
mounting a large-scale antiviral response against SARS-CoV-2 (341). Further, a combination
of ivermectin and hydroxychloroquine might have a synergistic effect, since ivermectin
IMG 83
explored targeting molecular dynamic simulations, evaluating their interaction with
corresponding major histocompatibility complex class I molecules. They potentially induce
immune responses (176). The recombinant vaccine can be designed by using rabies virus
(RV) as a viral vector. RV can be made to express MERS-CoV S1 protein on its surface so
that an immune response is induced against MERS-CoV.
The RV vector-based vaccines against MERS-CoV can induce faster antibody response as
well as higher degrees of cellular immunity than the Gram-positive enhancer matrix (GEM)
particle vector-based vaccine. However, the latter can induce a very high

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strong immune response which may cause cytokine storm syndrome,61
. Thus, immunomodulatory agents
that inhibit the excessive inflammatory response may be a potential adjunctive therapy for
COVID-19.
Dexamethasone is a corticosteroid often used in a wide range of conditions to relieve
inflammation through its anti-inflammatory and immunosuppressant effects.
Recently, the RECOVERY trial found dexamethasone reduced mortality by about one third
in hospitalized patients with COVID-19 who received invasive mechanical ventilation and by
one fifth in patients receiving oxygen. By contrast, no benefit was found in patients without
respiratory support 46
Tocilizumab and sarilumab, two types of interleukin-6
T6 recentor cnerific antibodies nrevinudly used tol

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There is a steady increase in the reports of
COVID-19 in companion and wild animals around the world. Further studies are required to
evaluate the potential of animals (especially companion animals) to serve as an efficient
reservoir host that can further alter the dynamics of human-to-human transmission (330). To
date, two pet dogs (Hong Kong) and four pet cats (one each from Belgium and Hong Kong,
two from the United States) have tested positive for SARS-CoV-2 (335). The World
Organization for Animal Health (OIE) has confirmed the diagnosis of COVID-19 in both
dogs and cats due to human-to-animal transmission (331). The

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that remdesivir has to be further evaluated for its efficacy in the treatment of COVID-19
infection in humans. The broad-spectrum activity exhibited by remdesivir will help control
the spread of disease in the event of a new coronavirus outbreak.
IMG 87
Chloroquine is an antimalarial drug known to possess antiviral activity due to its ability to
block virus-cell fusion by raising the endosomal pH necessary for fusion. It also interferes
with virus-receptor binding by interfering with the terminal glycosylation of SARS-CoV
cellular receptors, such as ACE2 (196). In a recent multicenter clinical trial that was
conducted in China, chloroquine phosphate

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category A agents (cholera, plague).
Patients should be placed in separate rooms or cohorted together. Negative pressure rooms
are not generally needed. The rooms and surfaces and equipment should undergo regular
decontamination preferably with sodium hypochlorite. Healthcare

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Swine acute diarrhea syndrome coronavirus (SADS-CoV) was first identified in suckling
piglets having severe enteritis and belongs to the genus Alphacoronavirus (106). The
outbreak was associated with considerable scale mortality of piglets (24,693 deaths) across
four farms in China
(134). The virus isolated from the piglets was almost identical to and had 95% genomic
similarity with horseshoe bat (Rhinolophus species) coronavirus
HKU2, suggesting a bat origin of the pig virus (106, 134, 135). It is also imperative to note
that the SADS-CoV outbreak started in Guangdong province, near the location of the SARS
pandemic origin

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viruses in nasal washes, saliva, urine and faeces for up to 8 days after infection, and a few
naive ferrets with only indirect contact were positive for viral RNA, suggesting airborne
transmission. In addition, transmission of the virus through the ocular surface and prolonged
presence of SARS-CoV-2 viral RNA in faecal samples were also documented 1°1,102
. Coronaviruses can persist
on inanimate surfaces for days, which could also be the case for SARS-CoV-2 and could pose
a prolonged risk of infection 03. These findings explain the rapid geographic spread of
COVID-19, and public health interventions to reduce transmission will provide benefit to
mitigate the epidemic, as has proved successful in China and several other countries, such as
South Korea® ,104,105
IMG 91

pneumonia might not be evident in X-ray chest radiography. In such situations, a chest CT
examination can be performed, as it is considered highly specific for COVID-19 pneumonia
(118).
Those patients having COVID-19 pneumonia will exhibit the typical ground-glass opacity in
their chest
CT images (154). The patients infected with
COVID-19 had elevated plasma angiotensin 2 levels.
The level of angiotensin 2 was found to be linearly associated with viral load and lung injury,
indicating its potential as a diagnostic biomarker (121). The chest CT imaging abnormalities
associated with COVID-19 pneumonia have also been observed even

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betacoronaviruses based on the s protein, virus sequences from different subgenera grouped
into separate clusters. SARS-CoV-2 sequences from Wuhan and other countries exhibited a
close relationship and appeared in a single cluster (Fig. 1).
The CoVs from the subgenus Sarbecovirus appeared jointly in SplitsTree and divided into
three subclusters, namely, SARS-CoV-2, bat-SARS-like-CoV (bat-SL-CoV), and SARS-CoV
(Fig. 1). In the case of other subgenera, like Merbecovirus, all of the sequences grouped in a
single cluster, whereas in Embecovirus, different species, comprised of canine respiratory
CoVs, bovine CoVs, equine CoVs, and
haค Nal atenin 0n2)

IMG 93
extendea to other crues or Mubel
province. Cases of COVID-19 in countries outside China were reported
in those with no history of travel to China suggesting that local human-to-human
transmission was occurring in
these countries [9]. Airports in different countries including India put

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returning from China/ evacuated from China are being evaluated for clinical symptoms,
isolated and tested for COVID-19 for 2 wks even if
asymptomatic. However, now with rapid world wide spread of the virus these travel
restrictions have extended
to other countries. Whether these
IMG 95
Respiratory droplets are the major carrier for coronavirus transmission. Such droplets can
either stay in the nose or mouth or enter the lungs via the inhaled air. Currently, it is known
that COVID-19's transmission from one person to another also occurs through touching either
an infected surface or even an object. With the current scant awareness of the transmission
systems however, airborne safety measures with a high-risk procedure have been proposed in
many countries. Transmission levels, or the rates from one person to another, reported

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death (92). Most of the identified coronaviruses cause the common cold in humans. However,
this changed when SARS-CoV was identified, paving the way for severe forms of the disease
in humans (22).
Our previous experience with the outbreaks of other coronaviruses, like SARS and MERS,
suggests that the mode of transmission in COVID-19 as mainly human-to-human
transmission via direct contact, droplets, and fomites (25). Recent studies have demonstrated
that the virus could remain viable for hours in aerosols and up to days on surfaces; thus,
aerosol and fomite contamination could play potent roles in the transmission of SARS-CoV-2
(257).

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Chinese city of Wuhan, now termed COVID-19, and its rapid transmission, threatens people
around the world. Because of its pandemic nature, the National Institutes of Health (NIH) and
pharmaceutical companies are involved in the development of COVID-19 vaccines. Xu
Nanping, China's vice-minister of science and technology, announced that the first vaccine is
expected to be ready for clinical trials in China at the end of April 2020.54 There is no
approved vaccine and treatment for COVID-19 infections.

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Coronavirus genomes and subgenomes encode six ORFs (31). The majority of the 5' end is
occupied by ORFla/b, which produces 16 nsps. The two polyproteins, ppla and pplab, are
initially produced from ORFla/b by a -1 frameshift between ORFla and ORFIb (32). The
virus-encoded proteases cleave polyproteins into individual nsps (main protease [Mpro],
chymotrypsin-like protease [3CLpro], and
papain-like proteases [PLPs]) (42). SARS-CoV-2 also encodes these nsps, and their functions
have been elucidated recently (31). Remarkably, a difference between SARS-CoV-2 and
other CoVs is the identification of a novel short putative protein
IMG 99
The pathogenesis of SARS-CoV-2 infection in humans manifests itself as mild symptoms to
severe respiratory failure. On binding to epithelial cells in the respiratory tract, SARS-CoV-2
starts replicating and migrating down to the airways and enters alveolar epithelial cells in the
lungs. The rapid replication of SARS-CoV-2 in the lungs may trigger a strong immune
response. Cytokine storm syndrome causes acute respiratory distress syndrome and
respiratory failure, which is considered the main cause of death in patients with COVID-19
(REFS60,61). Patients of older age (>60 years) and with serious pre-existing diseases have a
greater risk of developing acute respiratory distress syndrome and death 2-64 (FIG. 4).
Multiple organ failure has also been
renorted in some COVIN-19 cases

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to manage critically ill adults suggest the use of systemic corticosteroids in mechanically
ventilated adults with ARDS (303). The generalized use of corticosteroids is not indicated in
COVID-19, since there are some concerns associated with the use of corticosteroids in viral
pneumonia. Stem cell therapy using mesenchymal stem cells (MSCs) is another hopeful
strategy that can be used in clinical cases of
COVID-19 owing
to
its
potential
immunomodulatory capacity. It may have a beneficial role in attenuating the cytokine storm
that is observed in severe cases of SARS-CoV-2 infection, thereby reducing mortality.
Among the
1: Chaont

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covers two thirds of the genome, and encodes a large polyprotein (pp lab),which is
proteolytically cleaved into 16 non-structural proteins that are involved in transcription and
virus replication. Most of these SARS-CoV-2 non-structural proteins have greater than 85%
amino acid sequence identity with SARS-CoV».
The phylogenetic analysis for the whole genome shows that SARS-CoV-2 is clustered with
SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) found in bats, placing it in the
subgenus Sarbecovirus of the genus Betacoronavirus. Within this clade, SARS-CoV-2 is
grouped in a distinct lineage together with four horseshoe bat coronavirus isolates (RaTG13,
Rm YN02, ZC45 and ZXC21) as well as novel coronaviruses recently iden-
fified in nanoolins which aroun narallel to SARS_CoV
IMG 102
Coronavirus is the most prominent example of a virus that has crossed the species barrier
twice from wild animals to humans during SARS and MERS outbreaks (79, 102). The
possibility of crossing the species barrier for the third time has also been suspected in the case
of SARS-CoV-2 (COVID-19).
Bats are recognized as a possible natural reservoir host of both SARS-CoV and MERS-CoV
infection.
In contrast, the possible intermediary host is the palm civet for SARS-CoV and the
dromedary camel for MERS-CoV infection (102). Bats are considered the ancestral hosts for
both SARS and MERS (103).
Bats are also considered the reservoir host of human

IMG 103
human) transmission occurred (71). Although SARS-CoV-2 is alleged to have originated
from an animal host (zoonotic origin) with further human-to-human transmission (Fig. 6), the
likelihood of foodborne transmission should be ruled out with further investigations, since it
is a latent possibility
(1). Additionally, other potential and expected routes would be associated with transmission,
as in other respiratory viruses, by direct contact, such as shaking contaminated hands, or by
direct contact with contaminated surfaces (Fig. 6). Still, whether blood transfusion and organ
transplantation (276), as well as transplacental and perinatal routes, are possible

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confirmed cases, and this population does not seem to be at higher risk for the disease than
adults. There is no difference in the COVID-19 symptoms between adults and children.
However, the available evidence indicated that children diagnosed with COVID-19 have
milder symptoms than the adults, with a low mortality rate.
48, 49 On the contrary, older people who are above the age of 65 years are at higher risk for a
severe course of disease. In the United Stated, approximately 31-59% of those with
confirmed COVID-19 between the ages of 65 and 84 years

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in asymptomatic patients. These abnormalities progress from the initial focal unilateral to
diffuse bilateral ground-glass opacities and will further progress to or coexist with lung
consolidation changes within 1 to 3 weeks (159). The role played by radiologists in the
current scenario is very important. Radiologists can help in the early diagnosis of lung
abnormalities associated with COVID-19 pneumonia. They can also help in the evaluation of
disease severity, identifying its progression to acute respiratory distress syndrome and the
presence of secondary bacterial infections
(160). Even though chest CT is considered an
IMG 106
and ennances the tanscripton emciency or the virus (55, 56). It contains three highly
conserved and distinct domains, namely, an NTD, an RNA-binding domain or a linker region
(LKR), and a CTD (57).
The NTD binds with the 3' end of the viral genome, perhaps via electrostatic interactions, and
is highly diverged both in length and sequence (58). The charged LKR is serine and arginine
rich and is also known as the SR (serine and arginine) domain (59).
The LKR is capable of direct interaction with in vitro
RNA interaction and is responsible for cell signaling (60, 61). It also modulates the antiviral
response of the host by working as an antagonist for interferon
Me and PA interference
(ho Comnared to thot

IMG 107
(Delphinapterus leucas)
(138).
In recent decades,
several novel coronaviruses were identified from different animal species. Bats can harbor
these viruses without manifesting any clinical disease but are persistently infected (30). They
are the only mammals with the capacity for self-powered flight, which enables them to
migrate long distances, unlike land mammals. Bats are distributed worldwide and also
account for about a fifth of all mammalian species (6). This makes them the ideal reservoir
host for many viral agents and also the source of novel coronaviruses that have yet to be
identified. It has become a necessity to study the diversity of

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vaccine that can produce cross-reactive antibodies.
However, the success of such a vaccine relies greatly on its ability to provide protection not
only against present versions of the virus but also the ones that are likely to emerge in the
future. This can be achieved by identifying antibodies that can recognize relatively conserved
epitopes that are maintained as such even after the occurrence of considerable variations
(362). Even though several vaccine clinical trials are being conducted around the world,
pregnant women have been completely excluded from these studies. Pregnant women are
highly vulnerable to emerging diseases such as COVID-19
IMG 109
appeared asymptomatic. Another serological study detected SARS-CoV-2 neutralizing
antibodies in cat serum samples collected in Wuhan after the COVID-19 outbreak, providing
evidence for SARS-CoV-2 infection in cat populations in Wuhan, although the potential of
SARS-CoV-2 transmission from cats to humans is currently uncertain*6
Receptor use and pathogenesis
SARS-CoV-2 uses the same receptor as SARS-CoV, angiotensin-converting enzyme 2
(ACE2) ,47. Besides human ACE2 (hACE2), SARS-CoV-2 also recognizes ACE2 from pig,
ferret, rhesus monkey, civet, cat, pan-golin, rabbit and dog 1,43,48,49.
. The broad receptor usage

IMG110

article gives a bira's eye view about this new virus. Since knowledge about this virus is
rapidly evolving, readers are urged to update themselves regularly.
History
Coronaviruses are enveloped positive

IMG 111

studies are required for evaluating the therapeutic potential of these newly identified
compounds in the management of COVID-19 infection.
Passive Immunization/Antibody Therapy/MAb
Monoclonal antibodies (MAbs) may be helpful in the intervention of disease in CoV-exposed
individuals. Patients recovering from SARS showed robust neutralizing antibodies against
this CoV infection (164). A set of MAbs aimed at the MERS-CoV S protein-specific
domains, comprising six specific epitope groups interacting with receptor-binding, membrane
fusion, and sialic acid-binding

IMG 112
appropriate epitopes and functions of the S protein.
The cross-neutralization ability of SARS-CoV RBD-specific neutralizing MAbs considerably
relies on the resemblance between their RBDs; therefore, SARS-CoV RBD-specific
antibodies could cross-neutralized SL CoVs, i.e., bat-SL-CoV strain WIVI (RBD with eight
IMG 113
amino acid differences from SARS-CoV) but not bat-SL-CoV strain SHC014 (24 amino acid
differences) (200).
Appropriate RBD-specific MAbs can be recognized by a relative analysis of RBD of SARS-
CoV-2 to that of SARS-CoV, and cross-neutralizing SARS-CoV RBD-specific MAbs could
be explored

IMG 114
RBD, indicating
its potential as a therapeutic agent
in the management of COVID-19. It can be used alone or in combination with other effective
neutralizing antibodies for the treatment and prevention of COVID-19 (202). Furthermore,
SARS-CoV-specific neutralizing antibodies, like m396 and CR3014, failed to bind the S
protein of SARS-CoV-2, indicating that a particular level of similarity is mandatory between
the RBDs of SARS-CoV and SARS-CoV-2 for the cross-reactivity to occur.
Further
assessment is necessary before
confirming the effectiveness of such combination therapy. In addition, to prevent further
community

IMG 115
tial pneumonia than young monkeys'6, which is similar to what is seen in patients with
COVID-19. In human ACE2-transgenic mice infected with SARS-CoV-2, typical interstitial
pneumonia was present, and viral antigens were observed mainly in the bronchial epithelial
cells, macrophages and alveolar epithelia. Some human ACE2-transgenic mice even died
after infection?0,71 In wide-type mice, a SARS-CoV-2 mouse-adapted strain with the N501Y
alteration in the RBD of the S protein was generated at passage 6. Interstitial pneumonia and
inflammatory responses were found in both young and aged mice after infection with the
mouse-adapted strain". Golden hamsters also showed typical symptoms after being infected
with SARS-CoV-2 (REF77. In other

IMG 116
Origin and Spread of COVID-19
[1, 2, 6]
In December 2019, adults in Wuhan, capital city of Hubei province and a major
transportation hub of China started presenting to local hospitals
IMG 117
Early transmission of SARs-CoV-< in Wuhan in December 2019 was initially linked to the
Huanan Seafood Wholesale Market, and it was suggested as the source of the
outbreak®,22,60
. However, community
transmission might have happened before that. Later, ongoing human-to-human transmission
propagated the outbreak®. It is generally accepted that SARS-CoV-2 is more transmissible
than SARS-CoV and MERS-CoV; however, determination of an accurate reproduction
number (RO) for COVID-19 is not possible yet, as many asymptomatic infections cannot be
accurately accounted for at this stage®. An estimated RO of 2.5 (ranging from 1.8 to 3.6) has
been proposed for SARS-CoV-2 recently, compared with 2.0-3.0 for SARS-CoV%. Notably,
most

IMG 118
caused by vertical transmission in the SARS and
MERS epidemics.43
The CDC asserts that infants born to mothers with confirmed COVID-19 are considered
persons under investigation (PUI) and should be temporarily separated from the mother and
isolated. 46
7.1 Breastfeeding and infant care
The data available to date is limited and cannot confirm whether or not COVID-19 can be

IMG 119
Inhibition of virus entry. SARS-CoV-2 uses ACE2 as the receptor and human proteases as
entry activators; subsequently it fuses the viral membrane with the cell membrane and
achieves invasion. Thus, drugs that interfere with entry may be a potential treatment for
COVID-19.
Umifenovir (Arbidol) is a drug approved in Russia and China for the treatment of influenza
and other respiratory viral infections. It can target the interaction between the S protein and
ACE2 and inhibit membrane fusion (FIG. 5). In vitro experiments showed that it has activity
against SARS-CoV-2, and current clinical data revealed it may be more effective than
lopinavir and ritonavir in treating COVID-19 (REFS 22,123). However, other clinical
studies showed umifenovir might not improve the proo-

IMG 120
pandemic flu where patients were asked to resume work/school once afebrile for 24 h or by
day 7 of illness.
IMG 121
Negative molecular tests were not a prerequisite for discharge.
At the community level, people should be asked to avoid crowded areas and
nostnone non-essential travel to niaces

IMG 122
Coronavirus S protein is a large, multifunctional class I viral transmembrane protein. The size
of this abundant S protein varies from 1,160 amino acids (IBV, infectious bronchitis virus, in
poultry) to 1,400 amino acids (FCoV, feline coronavirus) (43). It lies in a trimer on the virion
surface, giving the virion a corona or crown-like appearance. Functionally it is required for
the entry of the infectious virion particles into the cell through interaction with various host
cellular receptors (44).
Furthermore, it acts as a critical factor for tissue tropism and the determination of host range
(45).
Notably, S protein is one of the vital

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We also predict the possibility of an tbreak, as predicted by Fan et al. (6). Indeed sent
outbreak caused by SARS-CoV-2 (CO' ) was expected. Similar to previous outbreaks rent
outbreak also will be contained sho wever, the real issue is how we are plannir inter the next
zoonotic CoV epidemic that is l occur within the next 5 to 10 years or even so g. 7).

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consolidation. It is also abnormal in asymptomatic patients/ patients with no clinical evidence
of lower
respiratory tract involvement. In fact, abnormal CT scans have been used to
diagnose COVID-19 in suspect cases with negative molecular diagnosis; many of these
patients had positive

IMG 125
aminotransferase, bilirubin, and, especially, D-dimer
(244). Middle-aged and elderly patients with primary chronic diseases, especially high blood
pressure and diabetes, were found to be more susceptible to respiratory failure and, therefore,
had poorer prognoses. Providing respiratory support at early stages improved the disease
prognosis and facilitated recovery (18). The ARDS in COVID-19 is due to the occurrence of
IMG 126
cytokine storms that results in exaggerated immune response, immune regulatory network
imbalance, and, finally, multiple-organ failure (122). In addition to the exaggerated
inflammatory response seen in patients with

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however, efficacy and safety issues of these drugs require additional clinical trials (187, 281).
A controlled trial of ritonavir-boosted lopinavir and interferon alpha 2b treatment was
performed on
COVID-19
hospitalized
patients
(ChiCTR2000029308) (188). In addition, the use of hydroxychloroquine and tocilizumab for
their potential role in modulating inflammatory responses in the lungs and antiviral effect has
been proposed and discussed in many research articles. Still, no fool-proof clinical trials have
been published (194, 196, 197, 261-272). Recently, a clinical trial conducted on adult patients
suffering from severe

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o All clinicians should keep themselves updated about recent developments including
global spread of the disease.
o Non-essential international travel should be avoided at this time.
o People should stop spreading

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another study, the average reproductive number of COVID-19 was found to be 3.28, which is
significantly higher than the initial WHO estimate of 1.4 to 2.5 (77). It is too early to obtain
the exact Ro value, since there is a possibility of bias due to insufficient data. The higher Ro
value is indicative of the more significant potential of SARS-CoV-2 transmission in a
susceptible population. This is not the first time where the culinary practices of China have
IMG 130
been blamed for the origin of novel coronavirus infection in humans. Previously, the animals
present in the live-animal market were identified to be the intermediate hosts of the SARS
outbreak in China

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populatons. Ine in vuro and in vivo studies carnea out on the isolated virus confirmed that
there is a potential risk for the reemergence of SARS-CoV
infection from the viruses
that are currently
circulating in the bat population (105).
CLINICAL PATHOLOGY OF SARS-CoV-2
(COVID-19)
The disease caused by SARS-CoV-2 is also named severe specific contagious pneumonia
(SSCP), Wuhan pneumonia, and, recently, COVID-19 (110). Compared to SARS-CoV,
SARS-CoV-2 has less severe pathogenesis but has superior

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CONCLUDING REMARKS
Several years after the global SARS epidemic, the current SARS-CoV-2/COVID-19
pandemic has served as a reminder of how novel pathogens can rapidly emerge and spread
through the human population and eventually cause severe public health crises. Further
research should be conducted to establish animal models for SARS-CoV-2 to investigate
replication, transmission dynamics, and pathogenesis in humans. This may help develop and
evaluate potential therapeutic strategies against zoonotic CoV epidemics. Present trends
suggest the occurrence of future outbreaks of CoVs due to

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The M protein is the most abundant viral protein present in the virion particle, giving a
definite shape to the viral envelope (48). It binds to the nucleocapsid and acts as a central
organizer of coronavirus assembly (49). Coronavirus M proteins are highly diverse in amino
acid contents but maintain overall structural similarity within different genera (50). The M
protein has three transmembrane domains, flanked by a short amino terminus outside the
virion and a long carboxy terminus inside the virion (50). Overall, the viral scaffold is
maintained by M-M interaction. Of note, the M protein of SARS-CoV-2 does not have an
amino acid
IMG 134
range of hosts, producing symptoms and diseases ranging from the common cold to severe
and ultimately fatal illnesses, such as SARS, MERS, and, presently, COVID-19. SARS-CoV-
2 is considered one of the seven members of the CoV family that infect humans (3), and it
belongs to the same lineage of CoVs that causes SARS; however, this novel virus is
genetically distinct. Until 2020, six CoVs were known to infect humans, including human
CoV 229E (HCoV-229E), HCoV-NL63, HCoV-OC43, HCoV-
HKUI, SARS-CoV, and MERS-CoV. Although SARS-CoV and MERS-CoV have resulted in
outbreaks with high mortality, others remain

IMG 135
involved in the COVID-19 outbreak is of great importance, because the strain on their mental
wellbeing will affect their attention, concentration, and decision-making capacity. Hence, for
control of the COVID-19 outbreak, rapid steps should be taken to protect the mental health of
medical workers (229).
Since the living mammals sold in the wet market are suspected to be the intermediate host of
SARS-Cov-2, there is a need for strengthening the regulatory mechanism for wild animal
trade (13).
The total number of COVID-19 confirmed cases is on a continuous rise and the cure rate is
relatively low making disease control very difficult to achieve.

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In contrast to their response to the 2002 SARS outbreak, China has shown immense political
openness in reporting the COVID-19 outbreak promptly. They have also performed rapid
sequencing of COVID-19 at multiple levels and shared the findings globally within days of
identifying the novel virus (225). The move made by China opened a new chapter in global
health security and diplomacy. Even though complete lockdown was declared following the
COVID-19 outbreak in Wuhan, the large-scale movement of people has resulted in a
radiating spread of infections in the surrounding provinces as well as to several other
IMG 137
the occurrence ot COVi-1y
infection
on
several cruise ships gave us a preliminary idea regarding the transmission pattern of the
disease.
Cruise ships act as a closed environment and provide an ideal setting for the occurrence of
respiratory disease outbreaks. Such a situation poses a significant threat to travelers, since
people from different countries are on board, which favors the introduction of the pathogen
(320). Although nearly 30 cruise ships from different countries have been found harboring
COVID-19 infection, the major cruise ships that were involved in the COVID-19 outbreaks
are the Diamond Princess, Grand
Duinnear

IMG 138
world is on the rise. The success of preventive measures put forward by every country is
mainly dependent upon their ability to anticipate the approaching waves of patients. This will
help to properly prepare the health care workers and increase the intensive care unit (ICU)
capacity (321).
Instead of entirely relying on lockdown protocols, countries should focus mainly on
alternative intervention strategies, such as large-scale testing, contract tracing, and localized
quarantine of suspected cases for limiting the spread of this pandemic virus. Such
intervention strategies will be useful either at the beginning of the pandemic or

IMG 139
(238). A smartphone-integrated home-based point-of-care testing (POCT) tool, a paper-based
POCT combined with LAMP, is a useful point-of-care diagnostic (353). An Abbott ID Now
COVID-19 molecular POCT-based test, using isothermal nucleic acid amplification
technology, has been designed as a point-of-care test for very rapid detection of SARS-CoV-
2 in just 5 min (344). A CRISPR-based SHERLOCK (specific high-sensitivity enzymatic
reporter unlocking) diagnostic for rapid detection of SARS-CoV-2 without the requirement of
specialized instrumentation has been reported to be very useful in the clinical diagnosis of
COVID-19 (360). A
IMG 140
respiratory infection (SARI) and respiratory distress, shock or hypoxaemia. Patients with
SARI can be given conservative fluid therapy only when there is no evidence of shock.
Empiric antimicrobial therapy must be started to manage SARI. For patients with sepsis,
antimicrobials must be administered within 1 hour of initial assessments. The WHO and CDC
recommend that glucocorticoids not be used in patients with COVID-19 pneumonia except
where there are other indications (exacerbation of chronic obstructive pulmonary disease).59

IMG 141
membrane organelles. Human coronaviruses are thought to invade cells, primarily through
different receptors. For 229E and OC43, amino peptidase-N (AP-N) and a sialic acid
containing receptor, respectively, were known to function in this role. After the virus enters
the host cell and uncoating process occurs, the genome is transcribed, and then, translated. A
characteristic feature of replication is that all mRNAs form an enclosed group of typical 3'
ends; only the special portions of the 5' ends are translated. In total, about 7 mRNAs are

IMG 142
Prevention |21, 30]
Since at this time there are no
approved treatments for this infection, prevention is crucial. Several properties of this virus
make prevention difficult namely, non-

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From experience with
several outbreaks
associated with known emerging viruses, higher pathogenicity of a virus is often associated
with lower transmissibility. Compared to emerging viruses like Ebola virus, avian H7N9,
SARS-CoV, and MERS-CoV, SARS-CoV-2 has relatively lower pathogenicity and moderate
transmissibility (15).
The risk of death among individuals infected with
IMG 144
COVID-19 was calculated using the infection fatality risk (IFR). The IFR was found to be in
the range of 0.3% to 0.6%, which is comparable to that of a previous Asian influenza
pandemic (1957 to 1958) (73, 277).

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Some therapeutic options for treating COVID-19 showed efficacy in in vitro studies;
however, to date, these treatments have not undergone any randomized animal or human
clinical trials, which limit their practical applicability in the current pandemic (7, 9,
19-21).
The present comprehensive review describes the various features of SARS-CoV-2/COVID-
19 causing the current disease outbreaks and advances in diagnosis and developing vaccines
and therapeutics.
It also provides a brief comparison with the earlier
SARS and MERS CoVs, the veterinary perspective

IMG 146
results of the clinical trial showed that the patients who were given chloroquine had a
significant reduction in their body temperature.
The clinical trial also showed better recovery among the patients who were given chloroquine
and hydroxy chloroquine. 63-65
Hydroxychloroquine treatment is significantly associated with viral load reduction as well as
disappearance in COVID-19 patients. Further, the outcome is reinforced by azithromycin.
The role of lopinavir and ritonavir in the treatment of COVID-19 is uncertain. A potential
benefit

IMG 147
snakes, and various other wild animals (20, 30, 79, 93, 124, 125, 287). Coronavirus infection
is linked to different kinds of clinical manifestations, varying from enteritis in cows and pigs,
upper respiratory disease in chickens, and fatal respiratory infections in humans (30).
Among the CoV genera, Alphacoronavirus and
Betacoronavirus infect mammals,
while
IMG 148
Gammacoronavirus and Deltacoronavirus mainly infect birds, fishes, and, sometimes,
mammals (27, 29, 106). Several novel coronaviruses that come under the genus
Deltacoronavirus have been discovered in the past from birds. like Wigeon

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the SARS- CoV. Environmental samples from the Huanan sea food market also
tested positive, signifying that the virus originated from there [7). The number of cases
started increasing
exponentially, some of which did not have exposure to the live animal market, suggestive of
the fact that

IMG 150
investigation due to the possibility of fecal-oral transmission. SARS-CoV-2 present in
environmental compartments such as soil and water will finally end up in the wastewater and
sewage sludge of treatment plants (328). Therefore, we have to reevaluate the current
wastewater and sewage sludge treatment procedures and introduce advanced techniques that
are specific and effective against SARS-CoV-2.
Since there is active shedding of SARS-CoV-2 in the stool, the prevalence of infections in a
large population can be studied using wastewater-based epidemiology. Recently, reverse
transcription-quantitative PCR (RT-qPCR) was used to enumerate

IMG 151
had >95% homology with the bat coronavirus and > 70% similarity with the SARS- CoV.
Environmental samples from the Huanan sea food market also
tested positive, signifying that the virus originated from there [7]. The number of cases
started increasing
exponentially, some of which did not
IMG 152
(96.7%), and S genes (90.4%). The RBD of S protein in CoV isolated from pangolin was
almost identical (one amino acid difference) to that of SARS-CoV-2.
A
comparison of the genomes suggests recombination between pangolin-CoV-like viruses with
the bat-CoV-RaTG13-like virus. All this suggests the potential of pangolins to act as the
intermediate host of SARS-CoV-2 (145).
Human-wildlife interactions,
which
are
increasing in the context of climate change (142), are further considered high risk and
responsible for the emergence of SARS-CoV. COVID-19 is also suspected of having a
similar mode of origin. Hence.

IMG 153
evaluate the suscepubmy or ammat species lo MERS-CoV infection, llamas and pigs were
found to be susceptible, indicating the possibility of MERS-CoV circulation in animal species
other than dromedary camels (109).
Following the outbreak of SARS in China, SARS-CoV-like viruses were isolated from
Himalayan palm civets (Paguma larvata) and raccoon dogs (Nyctereutes procyonoides) found
in a live-animal market in Guangdong, China. The animal isolates obtained from the live-
animal market retained a 29-nucleotide sequence that was not present in most of the human
isolates (78). These
findinos were crifical in identifuing the noccibility of

IMG 154
severe disease. The platelet count is usually normal or mildly low. The CRP and ESR are
generally elevated but procalcitonin levels are usually normal. A high procalcitonin level may
indicate a bacterial co-infection. The
ALT/AST, prothrombin time, creatinine, D-dimer, CPK and LDH may be elevated
and high leves are associated with

IMG 155
PCR, are considered an effective method for confirming the diagnosis in clinical cases of
COVID-19 (148). Several companies across the world are currently focusing on developing
and marketing SARS-CoV-2-specific nucleic acid detection kits.
IMG 156
Multiple laboratories are also developing their own in-house RT-PCR. One of them is the
SARS-CoV-2 nucleic acid detection kit produced by Shuoshi Biotechnology (double
fluorescence PCR method)
(150). Up to 30 March 2020, the U.S. Food and Drug Administration (FDA) had granted 22
in vitro diagnostics Emergency Use Authorizations (EUAs), including for the RT-PCR
diagnostic panel for the

IMG 157
mask and practice cough hygiene.
Caregivers should be asked to wear a surgical mask when in the same room as patient and use
hand hygiene every
15-20 min.
The greatest risk in COVID-19 is transmission to healthcare workers. In

IMG 158
countries.
Large-scale screening programs might
help us to control the spread of this virus. However, this is both challenging as well as time-
consuming due to the present extent of infection (226). The current scenario demands
effective implementation of vigorous prevention and control strategies owing to the prospect
of COVID-19 for nosocomial infections (68). Follow-ups of infected patients by telephone on
day 7 and day 14 are advised to avoid any further unintentional spread or nosocomial
transmission (312). The availability of public data sets provided by independent analytical
teams will act as robust evidence that would guide us in

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BoCoV inflicts neonatal calf diarrhea in adult cattle, leading to bloody diarrhea (winter
dysentery) and respiratory disease complex (shipping fever) in cattle of all age groups (126).
BoCoV-like viruses have been noted in humans, suggesting its zoonotic potential as well
(127). Feline enteric and feline infectious peritonitis (FIP) viruses are the two major feline
CoVs (128), where feline CoVs can affect the gastrointestinal tract, abdominal cavity
(peritonitis), respiratory tract, and central nervous system (128).
IMG 160
Canines are also affected by CoVs that fall under different genera, namely, canine enteric
coronavirus in Alphacoronavirus and canine respiratory

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fatigue. Individuals with asymptomatic and atypical clinical manifestations were also
identified recently, further adding to the complexity of disease transmission dynamics.
Atypical clinical manifestations may only express symptoms such as fatigue instead of
respiratory signs such as fever, cough, and sputum. In such cases, the clinician must be
vigilant for the possible occurrence of asymptomatic and atypical clinical manifestations to
avoid the possibility of missed diagnoses.
The present outbreak caused by SARS-CoV-2 was, indeed, expected. Similar to previous
outbreaks, the current pandemic also will be contained shortly.

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or even die, whereas most young people and children have only mild diseases (non-
pneumonia or mild pneumonia) or are asymptomatic,81,82
. Notably, the risk
of disease was not higher for pregnant women. However, evidence of transplacental
transmission of SARS-CoV-2 from an infected mother to a neonate was reported, although it
was an isolated cases,81. On infection, the most common symptoms are fever, fatigue and dry
cough 3,60,80,81. Less common symptoms include sputum production, headache,
haemoptysis, diarrhoea, anorexia, sore throat, chest pain, chills and nausea and vomiting in
studies of patients in Chinal 3,60,80,81
. Self-reported olfac-
tory and taste disorders were also reported by patients in Italys
. Most people showed signs of diseases after an

IMG 163
and deaths. The COVID-19 outbreak has also been associated with severe economic impacts
globally due to the sudden interruption of global trade and supply chains that forced
multinational companies to make decisions that led to significant economic losses (66). The
recent increase in the number of confirmed critically ill patients with COVID-19 has already
surpassed the intensive care supplies, limiting intensive care services to only a small portion
of critically ill patients (67). This might also have contributed to the increased case fatality
rate observed in the COVID-19 outbreak.
IMG 164
susceptible individuals. Hence, hand hygiene is equally as important as the use of appropriate
PPE, like face masks, to break the transmission cycle of the virus; both hand hygiene and face
masks help to lessen the risk of COVID-19 transmission (315).
Medical staff are in the group of individuals most at risk of getting COVID-19 infection. This
is because they are exposed directly to infected patients. Hence, proper training must be given
to all hospital staff on methods of prevention and protection so that they become competent
enough to protect themselves and others from this deadly disease (316). As a preventive
measure, health care

IMG 165
14551, F456V and G4/05, are located near the binding interface in the RBD, but their effects
on binding to the host receptor are unknown. The alteration D614G in the S1 subunit was
found far more frequently than other S variant sites, and it is the marker of a major subclade
of SARS-CoV-2 (clade G). Since March 2020, SARS-CoV-2 variants with G614 in the S
protein have replaced the original D614 variants and become the dominant form circulating
globally. Compared with the D614 variant, higher viral loads were found in patients infected
with the G614 variant, but clinical data suggested no significant link between the D614G
alteration and disease severity? Pseudotyped viruses carrying the S protein with G614
generated higher infectious titres than viruses carrying the S protein with D614, suggesting
the altera-
tion mor haro incroncod the infortirrit of CA DO ol a

IMG 166
exponentially in other countries including South Korea, Italy and Iran.
Of those infected, 20% are in critical condition, 25% have recovered, and 3310 (3013 in
China and 297 in other
countries) have died [2]. India, which
IMG 167
wrought
havoc in
China and
caused
pandemic
situation in the worldwide population, leading to disease outbreaks that have not been
controlled to date, although extensive efforts are being put in place to counter this virus (25).
This virus has been proposed to be designated/named severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses
(ICTV), which determined the virus belongs to the Severe acute respiratory syndrome-related
coronavirus category and found this virus is related to SARS-CoVs (26). SARS-CoV-2 is a
member of the order Nidovirales, family Coronaviridae,

IMG 168
symptomatic patients (82). Although initially it was thought that viral load would be
associated with poor outcomes,
some case reports have shown
asymptomatic individuals with high viral loads
(247). Recently, the viral load in nasal and throat swabs of 17 symptomatic patients was
determined, and higher viral loads were recorded soon after the onset of symptoms,
particularly in the nose compared to the throat. The pattern of viral nucleic acid shedding of
SARS-CoV-2-infected patients was similar to that of influenza patients but seemed to be
different from that of SARS-CoV patients. The viral load detected in asymptomatic patients
resembled

IMG 169
Even though a high similarity has been reported between the genome sequence of the new
coronavirus (SARS-CoV-2) and SARS-like CoVs, the comparative analysis recognized a
furin-like cleavage site in the SARS-CoV-2 S protein that is missing from other SARS-like
CoVs (99). The furin-like cleavage site is expected to play a role in the life cycle of the virus
and disease pathogenicity and might even act as a therapeutic target for furin inhibitors. The
highly contagious nature of SARS-CoV-2 compared to that of its predecessors might be the
result of a stabilizing mutation that occurred in the endosome-associated-protein-like domain
of
IMG 170
including 1L2, 1L7, 1L10, GCSE, 1P10, MCP1, MIP1A, and TNFa [15]. The median time
from onset of symptoms to dyspnea was 5 d, hospitalization 7 d and acute respiratory distress
syndrome (ARDS) 8 d. The need for intensive care admission was in 25-
30% of affected patients in published

IMG 171
high commercial value, since they are used in traditional Chinese medicine (TCM).
Therefore, the handling of bats for trading purposes poses a considerable risk of transmitting
zoonotic CoV epidemics (139).
Due to the possible role played by farm and wild animals in SARS-CoV-2 infection, the
WHO, in their novel coronavirus (COVID-19) situation report, recommended the avoidance
of unprotected contact with both farm and wild animals (25). The live-animal markets, like
the one in Guangdong, China, provides a setting for animal coronaviruses to amplify and to
be transmitted to new hosts, like

IMG 172
A Nasopharyngeal and oropharyngeal swab should be collected using Dacron or polyester
flocked swabs. It should be transported to the laboratory at a temperature of 4°C and stored in
the laboratory between 4 and -70°C on the basis of the number of days and, in order to
increase the viral load, both nasopharyngeal and oropharyngeal swabs should be placed in the
same tube. Bronchoalveolar lavage and nasopharyngeal aspirate should be collected in a
sterile container and transported similarly to the laboratory by maintain a temperature of

IMG 173
infection include virus binding molecules, molecules or inhibitors targeting particular
enzymes implicated in replication and transcription process of the virus, helicase inhibitors,
vital viral proteases and proteins, protease inhibitors of host cells, endocytosis inhibitors,
IMG 174
short interfering RNA (siRNA), neutralizing antibodies, MAbs against the host receptor,
MAbs interfering with the S1 RBD, antiviral peptide aimed at S2, and natural
drugs/medicines (7, 166, 186). The S protein acts as the critical target for developing CoV
antivirals, like inhibitors of S protein and S cleavage, neutralizing antibodies, RBD-ACE2
blockers, siRNAs, blockers

IMG 175
other emerging viral diseases. Several therapeutic and preventive strategies, including
vaccines, immunotherapeutics, and antiviral drugs, have been exploited against the previous
CoV outbreaks (SARS-CoV and MERS-CoV) (8, 104, 164-167).
These valuable options have already been evaluated for their potency, efficacy, and safety,
along with several other types of current research that will fuel our search for ideal
therapeutic agents against COVID-19 (7, 9, 19, 21, 36). The primary cause of the
unavailability of approved and commercial vaccines, drugs, and therapeutics to counter the
earlier SARS-CoV and MERS-CoV seems to owe to

IMG 176
We assessed the nucleotide percent similarity using the MegAlign software program, where
the similarity between the novel SARS-CoV-2 isolates was in the range of 99.4% to 100%.
Among the other Serbecovirus CoV sequences, the novel SARS-CoV-2 sequences revealed
the highest similarity to bat-SL-CoV, with nucleotide percent identity ranges between 88.12
and 89.65%. Meanwhile, earlier reported SARS-CoVs showed 70.6 to 74.9% similarity to
SARS-CoV-2 at the nucleotide level.
Further, the nucleotide percent similarity was 55.4%, 45.5% to 47.9%, 46.2% to 46.6%, and
45.0% to
46 3% to
the other
four
suhaenera
namely
IMG 177
administration of the recombinant adenovirus-based vaccine in BALB/c mice was found to
induce long-lasting neutralizing immunity against MERS spike pseudotyped virus,
characterized by the induction of systemic IgG, secretory IgA, and lung-resident memory T-
cell responses (177). Immunoinformatics methods have been employed for the genome-wide
screening of potential vaccine targets among the different immunogens of MERS-CoV (178).
The N protein and the potential B-cell epitopes of MERS-CoV E protein have been suggested
as immunoprotective targets inducing both T-cell and

IMG 178
onsible for MERS-CoV and SARS-CoV (3) ly emerged SARS-CoV-2 is a group navirus (2).
The genome sequences of S. /-2 obtained from patients share 79.5% sequ larity to the
sequence of SARS-CoV (63).
As of 13 May 2020, a total of 4,17 firmed cases of COVID-19 (with 287,399 dc e been
reported in more than 210 aff ntries worldwide (WHO Situation Report

IMG 179
It is also evident that remdesivir was effective in treating the patients who were infected with
Ebola virus. Per this evidence, China has already started testing the efficacy of remdesivir in
treating the patients with COVID-19, especially in Wuhan, where the outbreak occurred.
Chloroquine, which is an existing drug which is currently used in treating malaria cases, was
given to more than 100 patients who were affected with novel coronavirus to test its
efficacy.62

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been controlled by adopting appropriate and strict prevention and control measures, and
patients for clinical trials will not be available. The newly developed drugs cannot be
marketed due to the lack of end users.
Vaccines
The S protein plays a significant role in the induction of protective immunity against SARS-
CoV by mediating T-cell responses and neutralizing antibody production (168). In the past
few decades, we have seen several attempts to develop a vaccine
IMG 181
The N protein of coronavirus is multipurpose.
Among several functions, it plays a role in complex formation with the viral genome,
facilitates M protein interaction needed during virion assembly, and enhances the
transcription efficiency of the virus (55, 56). It contains three highly conserved and distinct
domains, namely, an NTD, an RNA-binding domain or a linker region (LKR), and a CTD
(57).
The NTD binds with the 3' end of the viral genome, perhaps via electrostatic interactions, and
is highly diverged both in length and sequence (58). The charged LKR is serine and arginine
rich and is also known as the SR (serine and arginine) domain (59).

IMG 182
been used based on the experience with SARS and MERS. In a historical control study in
patients with SARS, patients treated with lopinavir-ritonavir with ribavirin had better
outcomes as compared to those given ribavirin alone (15].

IMG 183
The symptoms of COVID-19 remain very similar to those of the other respiratory epidemics
in the past, which include SARS and MERS, but here the range of symptoms includes mild
rhinitis to septic shock. Some intestinal disturbances were reported with the other epidemics,
but COVID-19 was devoid of such symptoms. When examined, unilateral or bilateral
involvement compatible with viral pneumonia is observed in the patients, and bilateral
multiple lobular and sub-segmental consolidation areas were observed in patients

IMG 184
alum inactivated vaccine, adenovirus type 5 vector vaccine, LNP-encapsulated mRNA
vaccine, DNA plasmid vaccine, and S protein, S-trimer, and Ii-Key peptide as a subunit
protein vaccine, among others
IMG 185
(298). The process of vaccine development usually takes approximately ten years, in the case
of inactivated or live attenuated vaccines, since it involves the generation of long-term
efficacy data.
However, this was brought down to 5 years during the Ebola emergency for viral vector
vaccines. In the urgency associated with the COVID-19 outbreaks, we expect a vaccine by
the end of this year (343).
The development of an effective vaccine against

IMG 186
belonging to the positive-strand RNA viruses category that has the largest known genomes of
RNA. The structures of the coronavirus are more spherical in shape, but their structure has
the potential to modify their morphology in response to environmental conditions, being
pleomorphic. The capsular membrane which represents the outer envelope usually has
glycoprotein projection and covers the nucleus, comprising a matrix protein containing a
positive-strand RNA. Since the structure possesses 5'-capped and 3'-polyadenylated

IMG 187
The comprehensive sequence analysis of the SARS-CoV-2 RNA genome identified that the
CoV from Wuhan is a recombinant virus of the bat coronavirus and another coronavirus of
unknown origin. The recombination was found to have happened within the viral spike
glycoprotein, which recognizes the cell surface receptor. Further analysis of the genome
based on codon usage identified the snake as the most probable animal reservoir of SARS-
CoV-2 (143). Contrary to these findings, another genome analysis proposed that the genome
of SARS-CoV-2 is 96% identical to bat coronavirus, reflecting its origin from bats (63). The
involvement

IMG 188
glass opacities and sub segmental consolidation. It is also abnormal in asymptomatic patients/
patients with no clinical evidence of lower
respiratory tract involvement. In fact, abnormal CT scans have been used to
IMG 189
of persistent local transmission or contact with patients with similar travel history or those
with confirmed
COVID-19 infection. However cases may be asymptomatic or even without fever. A
confirmed case is a suspect case with a positive molecular test.

IMG 190
19-infected mothers to their neonates in China based upon the rise in IgM and IgG antibody
levels and cytokine values in the blood obtained from newborn infants immediately postbirth;
however, RT-PCR failed to confirm the presence of SARS-CoV-2 genetic material in the
infants (283). Recent studies show that at least in some cases, preterm delivery and its
consequences are associated with the virus.
Nonetheless, some cases have raised doubts for the likelihood of vertical transmission (240-
243).
COVID-19 infection was associated with pneumonia, and some developed acute respiratory
distress syndrome (ARDS). The blood biochemistry

IMG 191
and chest discomfort, and in severe cases dyspnea anc bilateral lung infiltration. Among the
first 27 documented hospitalized patients, most cases were epidemi-ologically linked to
Huanan Seafood Wholesale Market a wet market located in downtown Wuhan, which sell:
not only seafood but also live animals, including poultry and wildlife". According to a
retrospective study, the onset of the first known case dates back to 8 December 2019 (REF.').
On 31 December, Wuhan Municipal Health Commission notified the public of a pneumonia
out break of unidentified cause and informed the World Health Organization (WHO)° (FIC.
1).
By metagenomic RNA sequencing and virus isola
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Initially, the epicenter of the SARS-CoV-2 pandemic was China, which reported a significant
number of deaths associated with COVID-19, with 84,458 laboratory-confirmed cases and
4,644 deaths as of 13 May 2020 (Fig. 4). As of 13 May 2020, SARS-CoV-2 confirmed cases
have been reported in more than 210 countries apart from China (Fig. 3 and 4) (WHO
Situation Report 114) (25, 64).
COVID-19 has been reported on all continents except Antarctica. For many weeks, Italy was
the focus of concerns regarding the large number of cases, with 221,216 cases and 30,911
deaths, but now, the United States is the country with the largest

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was linked to a family member and 26 children had history of travel/residence to Hubei
province in China. All the patients were either asymptomatic (9%) or had mild disease. No
severe or critical cases were seen. The most common symptoms were fever (50%) and cough

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speculation was based on previous available scientific reports on coronaviruses during
pregnancy (SARS-CoV and MERS-CoV) as well as the limited number of COVID-19 cases.
41-43
Analysing the clinical features and outcomes of 10 newborns (including two sets of twins) in
China, whose mothers are confirmed cases of COVID-19, revealed that perinatal infection
with
2019-nCoV may lead to adverse outcomes for the neonates, for example, premature labour,
respiratory distress, thrombocytopenia with abnormal liver function and even death.44 It is

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corticosterolas must be avolded unless specified for chronic obstructive pulmonary disease
exacerbation or septic shock, as it is likely to prolong viral replication as detected in MERS-
CoV patients. 58
12 EARLY SUPPORTIVE
THERAPY AND MONITORING
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Management of patients with suspected or documented COVID-19 consists of ensuring
appropriate infection control and supportive
care WHO and the CDC nosted clinical guidance

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originated in bats and was transmitted to humans through yet unknown intermediary animals
in Wuhan, Hubei province, China in December 2019.
There have been around 96,000
reported cases of coronavirus disease 2019 (COVID-2019) and 3300 reported deaths to date
(05/03/2020). The disease
ie tranemittod hrr inhalation or contant

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spectively 40. However, this study did not in ontrol arm, and most of the trials of favilavir sed
on a small sample size. For more reliable a ent of the effectiveness of favilavir for tre VID-
19, large-scale randomized controlled ould be conducted.
Lopinavir and ritonavir were reported to vitro inhibitory activity against SARS-Col ERS-
CoV 41,142. Alone, the combination of lop

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Cases continued to increase
exponentially and modelling studies reported an epidemic doubling time of 1.8 d [10]. In fact
on the 12th of February, China changed its definition of confirmed cases to include patients
with negative/ pending molecular tests

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residues for receptor bindingt° (FIG. 3b). In comparison with the Guangdong strains,
pangolin coronaviruses reported from Guangxi are less similar to SARS-CoV-2, with 85.5%
genome sequence identity?®
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. The repeated
occurrence of SARS-CoV-2-related coronavirus infections in pangolins from different
smuggling events suggests that these animals are possible hosts of the viruses. However,
unlike bats, which carry coronaviruses healthily, the infected pangolins showed clinical signs
and histopathological changes, including interstitial pneumonia and inflammatory cell
infiltration in diverse organs*. These abnormalities suggest that pangolins are unlikely to be
the reservoir of these coronaviruses but more likely acquired the viruses after spillover from
the

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such instance was in 2002-2003 when a
new coronavirus of the ® genera and with origin in bats crossed over to humans via the
intermediary host of palm civet cats in the Guangdong province of China. This virus,
designated as severe acute respiratory syndrome coronavirus affected 8422

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216 countries and regions from all six continents had reported more than 20 million cases of
COVID-19, and more than 733,000 patients had died". High mortality occurred especially
when health-care resources were overwhelmed. The USA is the country with the largest
number of cases so far.
Although genetic evidence suggests that SARS-CoV-2 is a natural virus that likely originated
in animals, there is no conclusion yet about when and where the virus first entered humans.
As some of the first reported cases in Wuhan had no epidemiological link to the seafood
market?
, it has been suggested that the market may not be the initial source of human infection with
SARS-CoV-2.
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being closely related to contact with both animals and humans at the market (284). In January
2020, China imposed a temporary ban on the sale of live-dead animals in wet markets.
However, now hundreds of such wet markets have been reopened without optimizing
standard food safety and sanitation practices (286).
With China being the most populated country in the world and due to its domestic and
international food exportation policies, the whole world is now facing the menace of COVID-
19, including China itself. Wet markets of live-dead animals do not maintain strict food
hygienic practices. Fresh blood

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Recently, 95 full-length genomic sequences of SARAS-CoV-2 strains available in the
National Center for Biotechnology Information and GISAID databases were subjected to
multiple-sequence alignment and phylogenetic analyses for studying variations in the viral
genome (260). All the viral strains revealed high homology of 99.99% (99.91% to 100%) at
the nucleotide level and 99.99% (99.79% to 100%) at the amino acid level. Overall variation
was found to be low in ORF regions, with 13 variation sites recognized in la, 1b, S, 3a, M, 8,
and N regions. Mutation rates of 30.53% (29/95) and 29.47% (28/95) were observed at nt
28144 (ORF8)

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health emergency on 31 January 2020; subsequently, on 11 March 2020, they declared it a
pandemic situation. At present, we are not in a position to effectively treat COVID-19, since
neither approved vaccines nor specific antiviral drugs for treating human CoV infections are
available (7-9). Most nations are currently making efforts to prevent the further spreading of
this potentially deadly virus by implementing preventive and control strategies.
In domestic animals, infections with CoVs are associated with a broad spectrum of
pathological conditions. Apart from infectious bronchitis virus, canine respiratory CoV, and
mouse hepatitis virus,
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and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. The
global impact of this new epidemic is yet uncertain.
Keywords: 2019-nCOV, SARS-CoV-2,
COVID-19, Pneumonia, Review

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including bilateral multilobar ground-glass opacities with a peripheral or posterior
distribution. Thus, it has been suggested that CT scanning combined with repeated swab tests
should be used for individuals with high clinical suspicion of COVID-19 but who test
negative in initial nucleic acid screening's. Finally, SARS-CoV-2 serological tests detecting
antibodies to Nor S protein could complement molecular diagnosis, particularly in late phases
after disease onset or for retrospective studies 16,120,121. However, the extent and duration
of immune responses are still unclear, and available serological tests differ in their sensitivity
and specific-ity, all of which need to be taken into account when one is deciding on
serological tests and interpreting
ne natantialla

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results similar to that of the nonvaccinated group
(364). Further studies are required to analyze whether BCG vaccination in childhood can
induce protective effects against COVID-19 in adulthood.
Population genetic studies conducted on 103 genomes identified that the SARS-CoV-2 virus
has evolved into two major types, L and S. Among the two types, L type is expected to be the
most prevalent (~70%), followed by the S type (~30%)
(366). This finding has a significant impact on our race to develop an ideal vaccine, since the
vaccine candidate has to target both strains to be considered effective. At present, the genetic
differences between

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ritonavir had little therapeutic benefit in pati
COVID-19, but appeared more effective when t mbination with other drugs, including
ribavirin feron beta-1b 43,144
. The Randomized Evaluatio
IMG 211
MID-19 Therapy (RECOVERY) trial, a national trial programme in the UK, has stopped
treatn lopinavir and ritonavir as no significant benef it was observed in a randomized trial
establishe ch 2020 with a total of 1,596 patients!45. Neverthe

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In such cases where the patients progress toward respiratory failure and become refractory to
oxygen therapy, mechanical ventilation is necessitated. The COVID-19-induced septic shock
can be managed by providing adequate hemodynamic support (299).
Several classes of drugs are currently being evaluated for their potential therapeutic action
against SARS-CoV-2. Therapeutic agents that have anti-SARS-CoV-2 activity can be
broadly classified into three categories: drugs that block virus entry into the host cell, drugs
that block viral replication as well as its survival within the host cell, and drugs that attenuate
the exaggerated host immune response

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and SARS, along with adopting and strengthening a few precautionary measures owing to the
unknown nature of this novel virus (36, 189). Presently, the main course of treatment for
severely affected SARS-CoV-2 patients admitted to hospitals includes mechanical
ventilation, intensive care unit (ICU) admittance, and symptomatic and supportive therapies.
Additionally, RNA synthesis inhibitors (lamivudine and tenofovir disoproxil fumarate),
remdesivir, neuraminidase inhibitors, peptide (EK1), anti-inflammatory drugs, abidol, and
Chinese traditional medicine (Lianhuaqingwen and ShuFenolieDu cansules) could aid in
COVID-19
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route warrants the introduction of negative fecal viral nucleic acid test results as one of the
additional discharge criteria in laboratory-confirmed cases of
COVID-19 (326).
The COVID-19 pandemic does not have any novel factors, other than the genetically unique
pathogen and a further possible reservoir. The cause and the likely future outcome are just
repetitions of our previous interactions with fatal coronaviruses.
The only difference is the time of occurrence and the genetic distinctness of the pathogen
involved.
Mutations on the RBD of CoVs facilitated their capability of infecting newer hosts.
thereby

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this emerging virus will establish a niche in human and coexist with us for a long time'6.
Before clinicall approved vaccines are widely available, there is no bet ter way to protect us
from SARS-CoV-2 than persona preventive behaviours such as social distancing anc wearing
masks, and public health measures, including active testing, case tracing and restrictions on
socia gatherings. Despite a flood of SARS-CoV-2 research published every week, current
knowledge of this nove coronavirus is just the tip of the iceberg. The anima origin and cross-
species infection route of SARS-CoV-2 are yet to be uncovered. The molecular mechanisms
o SARS-CoV-2 infection pathogenesis and virus-hos

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on surfaces. The virus can remain viable on surfaces for days in
favourable atmospheric conditions but are destroyed in less than a minute by common
disinfectants like sodium
hypochlorite, hydrogen peroxide etc.
[13]. Infection is acquired either by
IMG 217
nidoviruses superfamily, are further classified according to their genera, alpha, beta-, gamma-
and deltacoronaviruses (a-, B-, y- and o-).
Among those, alpha and beta species are capable of contaminating only mammals, whereas
the other two genera can infect birds and could also infect mammals. 13, 14 Two of these
genera belong to human coronaviruses (HCoVs): a-coronaviruses, which comprise human
coronavirus 229E (hcov229E) and human coronavirus NL63 (hcovNL63), and B-
coronaviruses, which are human coronavirus

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therapeutics, and drug regimens to counter emerging viruses (161-163, 280). Several attempts
are being made to design and develop vaccines for CoV infection, mostly by targeting the
spike glycoprotein.
Nevertheless, owing to extensive diversity in antigenic variants, cross-protection rendered by
the vaccines is significantly limited, even within the strains of a phylogenetic subcluster
(104). Due to the lack of effective antiviral therapy and vaccines in the present scenario, we
need to depend solely on implementing effective infection control measures to lessen the risk
of possible nosocomial transmission
(68). Recently, the receptor for SARS-CoV-2 was

END