Abstract

There is a new public health crises threatening the world with the emergence and spread of 2019 novel
coronavirus (2019-nCoV) or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The
virus 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 is
transmitted by inhalation or contact with infected droplets and the incubation period ranges from 2 to
14 d. the symptoms are usually fever, cough, sore throat, breathlessness, fatigue, malaise among others.
The disease is mild in most people; in some (usually elderly) 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

Introduction

The 2019 novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome corona virus 2
( SARS-CoV-2) as it is now called, is rapidly spreading from its origin in Wuhan City of Hubei Province of
China to the rest of the world [1]. Until 05/03/2020 around 96,000 cases of coronavirus disease 2019
(COVID-19) and 3300 deaths have been reported [2]. India has reported 29 cases until date. Fortunately,
so far, children have been infrequently affected with no deaths. However, the future course of this virus
is unknown. This article gives a bird’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 sense RNA viruses ranging from 60 nm to 140 nm in diameter with
spike like projections on its surface giving it a crown like appearance under the electron microscope;
hence the name coronavirus [3]. Four corona viruses namely HKU1, NL63, 229E and OC43 have been in
circulation in humans, and generally cause mild respiratory disease.

There have been two events in the past two decades wherein crossover of animal beta corona viruses to
humans has resulted in severe disease. The first such instance was in 2002-2003 when a new
coronavirus of the β 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 people mostly in China and Hong Kong and caused 916 deaths
(mortality rate 11%) before being contained [4]. Almost a decade later in 2012, the Middle East
respiratory syndrome coronavirus (MERS-CoV), also of bat origin, emerged in Saudi Arabia with
dromedary camels as the intermediate host and affected 2494 people and caused 858 deaths (fatality
rate 34%) [5].

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 with severe pneumonia of unknown cause. Many of the initial
cases had a common exposure to the Human wholesale seafood market that also traded live animals.
The surveillance system (put into place after the SARS outbreak) was activated and respiratory samples

1
of patients were sent to reference labs for etiologic investigations. On December 31st 2019. China
notified the outbreak to the World Health Organization and 1 January the Huanan seafood market was
closed. On 7 January the virus was identified as a coronavirus that had >95% homology with the bat
coronavirus ad >70% similarity with the SARS-CoV. Environmental samples from the Huanan seafood
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 human-to-human transmission was occurring [8]. The first fatal case was
reported on 11th Jan 2020. The massive migration of Chinese during the Chinese New Year fueled the
epidemic. Cases in other provinces of China, other countries (Thailand, Japan and South Korea in quick
succession) were reported in people who were returning from Wuhan. Transmission to healthcare
workers caring for patients was described on 20th Jan, 2020. By 23rd January, the 11 million population
of Wuhan was placed under lock down.

The case fatality rate is estimated to range from 2 to 3%. Diagnosis is by demonstration of the virus in
respiratory secretions by special molecular tests. Common laboratory findings include normal/ low
white cell counts with elevated Creative protein (CRP). The computerized tomographic chest scan is
usually abnormal even in those with no symptoms or mild disease.

Treatment is essentially supportive role of antiviral agents is yet to be established. Prevention entails
home isolation of suspected cases and those with mild illnesses and strict infection control measures at
hospitals that include contact and droplet precautions. The virus spreads faster than its two ancestors
the SARS-CoV 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 had reported only 3 cases till 2/3/2020, has also seen a sudden spurt in cases.
By 5/3/2020, 29 cases had been reported; mostly in Delhi, Jaipur and Agra in Italian tourists and their
contacts. One case was reported in an Indian who traveled back from Vienna and exposed a large
number of school Children in a birthday party in a city hotel. Many of the contacts of these cases have
been quarantined.

These numbers are possibly an underestimated of the infected, dead due to limitations of surveillance,
and testing. Though the SARS-CoV-2 originated from bats, the intermediary extended to other cities of
Hubei province. Cases of COVI-19 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 putting screening mechanisms to detect symptomatic
people returning from China and placed them in isolation and testing them for COVID-19. Soon it was
apparent that the infection could be transmitted from asymptomatic people and also before onset of
symptoms. Therefore, countries including India who evacuated their citizens from Wuhan through
special flights or had travelers returning from China placed all people symptomatic or otherwise in
insolation for 14 days and tested them for the virus.

Case continued to increase exponentially and modelling studies reported an epidemic doubling time of
1.8 d [10]. In fact, on February 12, China changed its definition of confirmed cases to include patients
with negative/ pending molecular tests but with clinical, radiology of COVID-19 leading to an increase in
cases by 15,000 in a single day [6]. As of 15/03/2020, 96,000 cases worldwide (80,000) in China, 87 other
countries, and 1 international conveyance (696, in the cruise ship Diamond Princess parked off the coast
of Japan) have been reported [2]. It is important to note that while the number of new cases has

2
reduced in China lately, they have increased exponentially in other countries including South Korea, Italy
and Iran.

Epidemiology and Pathogenesis [10,11]

All ages are susceptible. Infection is transmitted through large droplets generated during coughing and
sneezing by symptomatic patients but can also occur from asymptomatic people and before onset of
symptoms [9]. Studies have shown higher viral loads in the nasal cavity as compared to the throat with
no difference in viral burden between symptomatic and asymptomatic people [12]. Patients can be
infectious for as long as the symptoms last and even on clinical recovery. Some people may act as super
spreaders; a UK citizen who attended a conference in Singapore infected 11 other people while staying
in a resort in French Alps and upon return to the UK [6]. These infected droplets can spread 1-2m and
deposit on surfaces. The virus can remain viable on surfaces for days in favorable 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 inhalation of theses droplets or touching
surfaces contaminated by them or then touching the nose, mouth and eyes. The virus is also present in
the stool and contamination of the water supply and subsequent transmission via aerosolization/feco
oral route is also hypothesized [6]. As per current information, Trans placental transmission from
pregnant women to their fetus has not been described [14].

However, neonatal disease due to post-natal transmission is described [14]. The incubation period varies
from 2 to 14 d [median 5 d]. Studies have identified angiotensin receptor 2 as the receptors through
which including 1L2, 1L7, 1L10, GCSF, 1P10, MCP1, M1P1A, and TNFα [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 series.
Complications witnessed included acute lung injury.

Recovery started in the 2nd or 3rd wk. the median duration of hospital stay in those who recovered was
10 d. Adverse outcomes and death are common in the elderly and those with underlying co-morbidities
(50-75% of fatal cases). Fatality rate in hospitalized adult patients ranged from 4 to 11%. The overall case
fatality rate is estimated to range between 2 and 3% [2].

Interestingly, disease in patients outside Hubei province has been 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 various modelling studies
[11]. In comparison, the BCR of SARS was 2 and 1.3 for pandemic flu H1N1 2009 [2].

Clinical Features [8, 15-18]

The clinical features of COVID-19are varied, ranging from asymptomatic state to acute respiratory
distress syndrome and multi organ dysfunction. The common clinical features include fever (not in all),
cough, sore throat, headache, fatigue, myalgia and breathlessness. Conjunctivitis has also been
described. Thus, they are indistinguishable from other respiratory infections.

Disease in neonates, infants and children has been also reported to be significantly milder than their
adult counterparts. In a series of 34 children admitted to a hospital in Shenzhen, China between January
19th and February 7th, there were 14 males and 20nfemales. The median age was 8 years and 11 month

3
and in 28 children the infection 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 (38%). All patients recovered with symptomatic therapy and there were no deaths. One case of
severe pneumonia and multiorgan dysfunction in a child has also been reported [19]. Similarly, the
neonatal cases that have been reported have been mild [20].

Diagnosis [21]

A suspect case is defined as one with fever, sore throat and cough who has history of travel to China or
other areas 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.

Specific diagnosis is by specific molecular tests on respiratory samples (throat swab/ nasopharyngeal
swab/ sputum/ endotracheal aspirates and bronchoalveolar lavage). Virus may also be detected in the
stool and in severe cases, the blood. It must be remembered that the multiplex PCR panels currently
available do not include the COVID-19. Commercial tests are also not available at present. In a suspect
case in India, the appropriate sample has to be sent to designated reference labs in India or the National
Institute of Virology in Pune. As the epidemic progresses, commercial tests will become available.

Other laboratory investigations are usually nonspecific. The white cell count is usually normal or low.
There may be lymphopenia; a lymphocyte count, 1000 has been associated with 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, COK and LDH may be elevated and high levels are associated
with severe disease.

The chest X-ray (CXR) usually shows bilateral infiltrates but may be normal in early disease. The CT is
more sensitive and specific. CT imaging generally shows infiltrates, ground 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 diagnose COVID-19
in suspect case with negative molecular diagnosis; many of these patients had positive molecular tests
on repeat testing [22].

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 be either due to selection bias wherein the cases reporting from Wuhan included
only the severe cases or due to predisposition of the Asian population to the virus due to higher
expression of ACE2 reporters on the respiratory mucosa [11].

Disease in neonates, infants and children has been also reported to be significantly milder than their
adult counterparts. In a series of 34 children admitted to a hospital in Shenzhen, China between January
19th and February 7th, there were 14 males and 20 females. The median age was 8 y 11 mo. and in 28
children the infection was linked to a family member and 26 children had history of travel/residence to
Hubei province in 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 (38%). All patients

4
recovered with symptomatic therapy and there were no deaths. One case of severe pneumonia and
multiorgan dysfunction in a child has also been reported [19]. Similarly, the neonatal cases that have
been reported have been mild [20].

Diagnosis [21]

A suspect case is defined as one with fever, sore throat and cough who has history of travel to China or
other areas of persistent local transmission or contact with patients with similar history. It is also
abnormal 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 case with
negative molecular diagnosis; many of these patients had positive molecular tests on repeat testing.

Differential Diagnosis [21]

[The differential diagnosis includes all types of respiratory viral infections [influenza, parainfluenza,
respiratory syncytial virus (RSV), adenovirus, human metapneumovirus, and non COVID-19 coronavirus],
atypical organisms (mycoplasma, chlamydia) and bacterial infections. It is not possible to differentiate
COVID-19 from these infections clinically or through routine lab tests. Therefore, travel history become
important. However, as the epidemic spreads, the travel history will become irrelevant.

Treatment [21, 23]

Treatment is essentially supportive and symptomatic

The first step is to ensure adequate isolation (discussed later) to prevent transmission to other contacts,
patients and healthcare workers. Mild illness should managed at home with counseling about danger
signs. The usual principles are maintain hydration, nutrition, and controlling fever and cough. Routine
use of antibiotics and antivirals such as oseltamivir should be avoided in confirmed cases. In hypoxic
patients, provision of oxygen through nasal prongs, facemask, 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-infections are suspected or proven. The role of corticosteroids is unproven; while
current international consensus and WHO advocate against their use, Chinese guidelines do recommend
short-term therapy with low-to-moderate dose corticosteroids in COVID-19 ARDS [24, 25]. The WHO
[26] has published detailed guidelines for critical care management for COVID-19. There is, as of now, no
approved treatment for COVID-19. Antiviral drugs such as ribavirin, lopinavir-ritonavir have been used
based on the experience with SARS and MERS. In historical control study in patients with SARS, patients
treated with lopinavir-ritonavir had better outcomes as compared to those given ribavirin alone [15].

In case series of 99 hospitalized patients with COVID-19 infection from Wuhan, oxygen was given to
76%, non-invasive ventilation in 13%, mechanical ventilation in 4%, extracorporeal membrane
oxygenation (ECMO) in 3%, continuous renal replacement therapy (CRRT) in 9%, antibiotics in 71%,
antifungals in 15%, glucocorticoids in 19% and intravenous immunoglobulin therapy in 27% [15].
Antiviral therapy consisting of oseltamivir, ganciclovir and lopinavir-ritonavir was given to 75% of the
patients. The duration of non-invasive ventilation was 4-22 d [median17 d]. In the case series of children
discussed earlier, all children recovered with basic treatment and did not need intensive care [17].

5
There is anecdotal experience with use of remdesivir, a board spectrum anti RNA drug developed for
Ebola in management of COVID-19 [27]. More evidence is needed before these drugs are
recommended. Other drugs proposed for therapy are arbidol (an antiviral drug available in Russia and
China), intravenous immunoglobulin, interferons, chloroquine and plasma of patients recovered from
COVID-19 [21, 28, 29]. Additionally, recommendations about using traditional Chinese herbs fid place in
the Chinese guidelines [21].

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-specific features of the disease, the
infectively even before onset of symptoms in the incubation period, transmission from asymptomatic
people, long incubation period, tropism for mucosal surfaces such as the conjunctive, prolonged
duration of the illness and transmission even after clinical recovery.

Isolation of confirmed or suspected cases with mild illness at home is recommended. The ventilation at
home should be good with sunlight to allow for destruction of virus, patients should be asked to wear
simple surgical mask and practice cough hygiene. Caregivers should be asked to wear a surgical mask
when in the same room as the patients and use hand hygiene every 15-20 min.

The greatest risk in COVID-19 is transmission to healthcare workers. In the SARS outbreak of 2002, 21%
of those affected were healthcare workers in China have been infected with 6 deaths. The doctor who
first warned about the virus has died too. It is important to protest healthcare workers to ensure
continuity of care and to prevent transmission of infection to other patients. While COVID-19 transmits
as a droplet pathogen and is placed in Category B of infectious agent (highly pathogenic H5N1 and
SARS), by China National Heath Commission, infection control measures recommended are those for
category A agents (cholera, plague). Patients should be placed in separate rooms or cohosted together.
Negative pressure rooms are not generally needed. The rooms, surfaces, and equipment should undergo
regular decontamination preferably with sodium hypochlorite. Healthcare workers should be provided
with fit tested N95 respirators and protective suits and goggles. Airborne transmission precautions
should be taken during aerosol generating procedures such a intubation, suction and tracheostomies. All
contacts including healthcare workers should be monitored for development of symptoms of COVID-19.
Patients can be discharged from isolation once they are afebrile for at least 3 d and have two
consecutive negative molecular tests at 1 d sampling interval. This recommendation is different from
pandemic flu where asked to resume works/school once afebrile for 24 h or by day 7 of illness. Negative
molecular tests were not a prerequisite for discharge.

At the community level, people should be asked to avoid crowded areas and postpone non-essential
travel to places with ongoing transmission. They should be asked to practice cough hygiene by coughing
in sleeve/ tissue rather than hands and practice hand hygiene frequently every 15-20 min. patients with
respiratory symptoms should be asked to use surgical masks. The use of mask by healthy people in
public places has not shown to protect against respiratory viral infections and is currently not
recommended by WHO> however, in China, the public has been asked to wear masks in public and
especially in crowded places and large scale gatherings are prohibited (entertainment parks etc). China
is also considering introducing legislation prohibit selling and trading of wild animals [32].

6
The international response has been dramatic. Initially, there were massive travel restrictions to China/
evaluated from China being evaluated for clinical symptoms, isolated and tested for COVID-19 for 2
weeks even if asymptomatic. However, now with rapid worldwide spread of the virus there travel
restrictions have extended to other countries. Whether these efforts will lead to slowing of viral spread
is not known.

A candidate vaccine is under development.

Therapeutics

To date, there are no generally proven effective therapies for COvid-19 or antivirals against SARS-CoV-2
although some treatment have shown some benefits in certain subpopulations of patients or for certain
ends. Researchers and manufactures are conducting large-scale clinical trials to evaluate various
therapies for COVID-19. As of 2 October 2020, there were about 405 therapeutic drugs in development
for COVID-19, and nearly 318 in human clinical trials (COVID-19 vaccine and therapeutics tracker). In the
following sections, we summarize potential therapeutics against SARS-CoV-2 on the basic of published
clinical data and experience.

Chloroquine and hydroxychloroquine are other potential but controversial drugs that interfere with the
entry of SARS-CoV-2. They have been used in the prevention and treatment of malaria and autoimmune
diseases, including systemic lupus erythematosus and rheumatoid arthritis. They can inhibit the
glycosylation or cellular receptors and interfere with virus-host receptor binding, as well as increase the
endosomal pH and inhibit membrane fusion. Currently, no scientific consensus has been reached for
their efficacy in the treatment of COVID-19. Some studies showed they can inhibit SARS-CoV-2 infection
in vitro, but clinical data are insufficient 128, 129. Two clinical studies indicated no association with death
rates in patients receiving chloroquine or hydroxychloroquine compared with those not receiving the
drug and even suggest it may increase the risk of dying as a higher risk of cardiac arrest was found in the
treated patients 130,131. On 15 June 2020, owing to the side effects observed in clinical trials, the US Food
and Drug Administration (FDA) revoked the emergency use authorization for chloroquine and
hydroxychloroquine for the treatment pf COVID-19. Another potential therapeutic strategy is to block
binding of the S protein to ACE2 through soluble recombinant hACE2, specific monoclonal antibodies or
fusion inhibitors that target the SARS-CoV-2 S protein132, 134. The safety and efficacy of these strategies
need to be assessed in future clinical trials. 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.

However, this study did not include a control arm, and most of the trials of favilavir were based on a
small sample size. For more reliable assessment of the effectiveness of favilavir for the treating COVID-
19, large-scale randomized controlled trials should be conducted.

Lopinavir and ritonavir were reported to have in vitro inhibitory activity against SARS-CoV-2 and MERS-
CoV. Alone the combination of lopinavir and ritonavir had little therapeutic benefit in patients with
COVID-19, but appeared more effective when used in combination with other drugs, including ribavirin
and interferon beta-1b. The randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, a national

7
clinical trial programme in the UK, has stopped treatment with lopinavir and ritonavir as no significant
beneficial effect was observed in a randomized trial established in March 2020 with a total of 1,596
patients.

Vaccines

Vaccination is the most effective method for a long-term strategy for prevention and control of COVID-
19 in the future. Many different vaccine platforms against SARS-CoV-2 are in development, the
strategies of which include recombinant vectors, DNA, mRNA in lipid Nano-particles, inactivated viruses,
live attenuated viruses and protein subunits159, 160. As of 2 October 2020, 174 vaccine candidates for
COVID-19 had been reported and 51 were in human clinical trials (COVID-19 vaccine and therapeutic
tracker). Many of these vaccine candidates are in phase 1 testing, and some have already advanced to
phase 111 trials. A randomized double-blinded phase 11 trials of an adenovirus type vectored vaccine
expressing the SARS-CoV-2 S protein, developed by CanSino Biologicals and the Academy of Military
Medical Sciences of China, was conducted in 603 adult volunteers in Wuhan. The vaccine has proved to
be safe and induced considerable humoral and cellular immune response in most recipients after a
single immunization162. Another vectored vaccine, ChAdOx1, by the University of Oxford. In a
randomized controlled phase 1/11 trial, induced neutralizing antibodies against SAS-CoV2 in all 1,077
participants after a second vaccine dose, while its safety profile was acceptable as well 163. The NIAID and
Moderna co-manufactured mRNA-1273, a lipid nanoparticle-formulated mRNA vaccine candidate that
encodes the stabilized perfusion SARS-CoV-2 S protein. Its immunogenicity has been confirmed by a
phase 1 trial in which robust neutralizing antibody responses were induced in a dose-dependent manner
and increased after a second dose164. Regarding inactivated vaccines, a successful phase 1/11 trial
involving 320 participants has been reported in China. The whole virus COVID-19 vaccine had a low rate
of adverse reactions and effectively induced neutralizing antibody production165. The verified safety and
immunogenicity support advancement of these vaccine candidates to phase 111 clinical trials, which will
evaluate their efficacy in protecting healthy populations from SARS-CoV-2 infections.

Immunoglobulin therapy. Convalescent plasma treatment is another potential adjunctive therapy for
COVID-19. Preliminary findings have suggested improved clinical status after the treatment 153, 154. The
FDA has provided guidance for the use of COVID-19 convalescent plasma under an emergency
investigational new drug application. However, this treatment may have adverse effects by causing
antibody-medicated enhancement of infection, transfusion-associated acute lung injury and allergic
transfusion reactions.

The interferon response is one of the major innate immunity defenses 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 1 interferons as a promising therapeutics candidate for
SARS 149. In vitro data showed SARS-CoV-2, is even more sensitive to type 1 interferons than SARS-CoV,
suggesting the potential effectiveness of type 1 interferons in the early treatment of COVID-19 150. In
China, vapor inhalation of interferon-α is included in the COVID-19 treatment guideline 151. Clinical trials
are going across the world to evaluate the efficacy of different therapies involving interferons either
alone or in combination with other agents152.

Monoclonal antibody therapy is an effective immuno-therapy for the treatment of some viral infections
in select patients. Recent studies reported specific monoclonal antibodies neutralizing SARS-CoV-2
infection other clinical trials in different phases are still ongoing elsewhere.

8
Immunomodulatory agents. SARS-CoV-2 triggers a strong immune response, which may cause cytokine
storm syndrome60, 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 support146.

Tocilizumab and sarilumab, two types of interleukin-6(1L-6) receptor-specific antibodies previously used
to treat various types of arthritis, including rheumatoid arthritis, and cytokine release syndrome,
showed effectiveness in the treatment of severe COVID-19 by attenuating the cytokine storm in a small
uncontrolled trial147. Bevacizumab is an anti-vascular endothelial growth factor (VEGF) medication that
could potentially reduce pulmonary edema in patients with severe COVID-19. Eculizumab is a specific
monoclonal antibody that inhibits the proinflammatory complement protein C5. Preliminary results
showed that it induce a drop of inflammatory markers and C-reactive protein levels, suggesting it is
potential to be an option for the treatment of severe COVID-19[REF.148].

Inhibition of virus replication. Replication inhibitors include remdesivir (GS-5734), favilavir (T-705),
ribavirin, lopinavir and ritonavir. Except for lopinavir and ritonavir, which inhibit 3CLpro, the other three
all target RdRp128, 135 (FIG.5). Remdesivir has shown activity against SARS-CoV-2 in vitro and in vivo 128, 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 difference in mortality was not
statistically significant138. The FDA has issued an emergency use authorization for remdesivir for the
treatment of hospitalized patients with severe COVID-19. It is also the first approved option by the
European Union for the treatment of adults and adolescents with pneumonia requiring supplement
oxygen. Several international phase 111 clinical trials are continuing to evaluate the safety and efficacy
of remdesivir for the treatment of COVID-19.

Favilavir (T-705), which is an antiviral drug developed in Japan to treat influenza, has been approved in
China, Russia and India for the treatment of COVID-19. A clinical study in China showed that favilavir
significantly reduced the signs of improved disease signs in chest imaging and shortened the time to viral
clearance139. A preliminary report in Japan showed rates of clinical improvement of 73.8% and 87.8%
from the start of favilavir therapy in patients with mild COVID-19 at 7 and 14 days, respectively, and
40.1% and 60.3% in patients with severe COVID-19 at 7 and 14 days, respectively140. However, this
study did not include a control arm, and most of trials of favilavir were based on small sample size. For
more reliable assessment of the effectiveness of favilavir for treating COVID-19, large-scale randomized
controlled trials should be conducted.

Lopinavir and ritonavir were reported to have in vitro inhibitory activity against SARS-CoV and MERS-
CoV141, 142. Alone, the combination of lopinavir and ritonavir had little therapeutic benefit in patients with
COVID-19, but appeared more effective when used in combination with other drugs, including ribavirin
and interferon beta-1b143, 144. The Randomized Evaluation of COVID-19 Therapy(RECOVERY) trials, a
national clinical trial programme in the UK, has stopped treatment with lopinavir and ritonavir as on

9
significant beneficial effect was observed in a randomized trial established in March 2020 with total of
1,596 patients145.

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 [RIG.5]. In vitro
experiments showed that it has activity against SARS-CoV-2, and current clinical data rivaled it may be
more effective than lopinavir and ritonavir in treating COVID-19 (REFS124, 125). Yet some ongoing
clinical trials are evaluating its efficacy for COVID-19 treatment. Camostat mesylate is approved in Japan
for the treatment of pancreatitis and postoperative reflux esophagitis. Previous studies showed that it
could prevent SARS-CoV from entering cells by blocking TMPRSS2 activity and protect mice from lethal
infection with SARS-CoV in a pathogenic mouse model (wild-type mice infected with a mouse-adapted
SARS-CoV-2 into human lung cells47. Thus, it can be a potential antiviral drug against SARS-CoV-2
infection, although so far there are not sufficient clinical data to support its efficacy.

Future perspective

COVID-19 is the third highly pathogenic human coronavirus disease to date. Although less deadly the
SARS and MERS, the rapid spreading of this highly contagious disease has posed the severest threat to
global health in this century. The SARS-CoV-2 outbreak has lasted for more than half a year now, and it is
likely that this emerging virus will established n niche in humans and coexist with us for a long time 166.
Before clinically approved vaccines are widely available, there is no better way to protect us from SARS-
CoV-2 than personal preventive behaviors such as social distancing and wearing masks, and public
health measures, including active testing, case tracing and restrictions on social gatherings. Despite a
flood of SARS-Co-V-2 research published every week, current knowledge of this novel coronavirus is just
the tip of the iceberg.

The animal origin and cross-species infection route of SARS-CoV-2 are yet to be uncovered. The
molecular mechanisms of SARS-CoV-2 infection pathogenesis and virus host interactions remain largely
unclear. Intensive studies on these virological profiles of SARS-CoV-2 will provide the basis for the
development of preventive and therapeutic strategies against COVID-19. Moreover, continued genomic
monitoring of SARS-CoV-2 in new cases is needed worldwide, as it is important to promptly identify and
mutation that may result in phenotypic changes of the virus. Finally, COVID-19 is challenging all human
beings. Tackling this epidemic is a long-term job, which requires efforts of every individual and
international collaborations by scientists, authorities and the public.

Animal host and spillover

Bats are important natural hosts of alpha coronaviruses and beta coronaviruses. The closet relative to
SARS-CoV-2 known to date is a bat coronavirus detected in Rhinolophus affine from Yunnan province,
China, named `RaTG13`, whose full-length genome sequence is 96.2% identical to that of SARS-CoV-2.
This bat virus shares more than 90% sequence identity with SARS-CoV-2 in all ORFs throughout the

10
genome, including the highly variable S and ORF8. Phylogenetic analysis confirms that SARS-CoV-2
closely clusters with RaTG13. The high genetic similarity between SARS-CoV-2 and RaTG13 supports the
hypothesis that SARS-CoV-2 likely originated from bats. Another related coronavirus has been reported
more recently in a Rhinolophus Malayans bat sampled in Yunnan.

The assess the genetic variation of different SARS-CoV-2 strains, the 2019 Novel Coronavirus Resource of
China National Center for Bio information aligned 77,801 genome sequence of SARS-CoV-2 detected
globally and identified a total of 15,018 mutations, including 14,824 single- nucleotide polymorphisms
(BIGD). In the S protein, four amino acid alterations, V483A, L4551, F456V and G476S, are located near
the binding interface in 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, SRS-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. Pseudo typed viruses carrying the S protein with G614 generated higher infectious titers than
viruses carrying the S protein with D614, suggested the alteration may have increased the infectivity of
SARS-CoV-2.

However, the results of in vitro experiments based on pseudo virus models may not exactly reflect
natural infection. This preliminary finding should be validated by more studies using wild type SARS-CoV-
2 variants to infect different target cells and animal models. Whether this amino acid change enhanced
virus transmissibility is also to be determined. Another marker mutation for SARS-CoV-2 evolution is the
single-nucleotide a polybasic cleavage site (RRAR), which enables effective cleavage by furin and other
proteases. Such an S1-S2 cleavage site is not observed in all related viruses belonging to the subgenus
Sarbecovirus, except for a similar three amino acid insertion (PAA) in RmYN02, a bat-derived coronavirus
newly reported from Rhinolophus malayanus in China. Although the 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 fruin-cleavage site could reduce the stability of SARS-CoV-2 S protein and facilitate
the conformational adaptation that is required for the binding of the RBD to its receptor. Whether the
higher transmissibility of SARS-CoV-2 compared with SARS-CoV-2 is a gain of function associated with
acquisition of the furin like cleavage site is yet to be demonstrated.

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 not contain a motif that triggers intercellular stress pathways. Notably, a SARS-CoV-2 variant with a
382-nucleotide deletion covering the whole of ORF8 has been discovered in a number of patients in
Singapore, which resembles the 29 or 415 nucleotide deletions in the ORF8 region observed in human
SARS-CoV variants from the late phase of 2002-2003 outbreak. Such ORF8 deletion may be indicative of
human adaptation after cross-species transmission from an animal host. Using sequence of five
conserved replicative domains in pp1ab (3C-like protease), (3CLpro), norovirus RNA- dependent RNA
polymerase (RdRp) associated nucleotidyltransferase (NiRAN), RdRp, zinc-binding domain (ZBD) and
HEL1, the Coronaviridae Study Group of International Committee on Taxonomy of viruses estimated the
pairwise patristic distance between SARS-CoV-2 and known coronaviruses, and assigned SARS-CoV-2 to

11
the existing species SARS-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 (1,255 amino
acids) and known bat SARSr-CoVs (1,245-1,269 amino acids). It is distinct from the S proteins of most
members in the subgenus Sarbecovirus, sharing amino acid sequence similarities 0f 76.7-77.0% with
SARS-CoVs from civets and human’s length to the corresponding proteins in SARS-CoV. Of the four
structural genes, SARS-CoV-2 shares more than 90% amino acid identity with SARS-CoV except for the S
genes, which diverges. The replicate gene covers two thirds of the 5` genome, and encodes a large
polyprotein (pp1ab), which is proteolytic ally cleaved into non-structural proteins that are involved in
transcription and virus replication. Most of these SARS-CoV-2 non-structural proteins have greater the
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 Beta coronavirus. Within this clade, SARS-CoV-2 is grouped in a distinct lineage together with four
horse-shoe bat coronavirus isolates (RaTG13, RmYN02, ZC45 and ZXC21) as well as novel coronaviruses
recently identified in pangolins, which group parallel to SARS-CoV in 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 initial source of human infection with SARS-CoV-2. One study from France
detected SARS-CoV-2 by PCR in a sorted sample from a patient who had pneumonia at the end of 2019,
suggesting SARS-CoV-2 might have spread there much earlier than generally known starting time of the
outbreak in France. However, this individual early report cannot give a solid answer to the origin of
SARS-CoV-2 and contamination, and thus a false positive result cannot be excluded. To address this
highly controversial issue, further retrospective investigations involving a larger number of banked
samples from patients, animals and environments need to be conducted worldwide with well-validated
assays.

Genomics, phylogeny and taxonomy

As a novel beta coronavirus, SARS-CoV-2 shares 79% genome sequence identity with SARS-CoV and 50%
with MERS-CoV. Its genome organization is shared with other beta coronaviruses. The six functional
open reading frames (ORFs) are arranged in order from 5` to 3`: replicate (ORF1a/ORF1b), spike (S),
envelope (E), membrane (M) and nucleocapsid (N). In addition, seven putative ORFs encoding accessory
proteins are interspersed between the structural genes. Most of the proteins encodes by SARS-CoV-2
have a similar 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 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’.

12
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 newly confirmed cases per day. To control COVID-19, China
implemented unprecedentedly strict public health measures. The city of Wuhan was shut down on 23
January, and all travel and transportation connecting the city was blocked. In the following couple of
weeks, all outdoor activities and gatherings were restricted, and public facilitates were closed in most
cities as well as in countryside. Owing to these measures, the daily number of new cases in China started
to decrease steadily.

However, despite the declining trend in China, the international spread of COVID-19 accelerated from
late February. Large clusters of infection have been reported from an increasing number of countries.
The high transmission efficiency of SARS-CoV-2 and the abundance of international travel enabled rapid
worldwide spread of COVID-19. On 11 March 2020, the WHO officially characterized the global COVID-
19 outbreak as a pandemic. Since March, while COVID-19 in China has become effectively controlled, the
case numbers in Europe, the USA and other regions have jumped sharply. According for system Science
and Engineering at Johns Hopkins University, as of 11 august 2020. Hence, knowledge and
understanding of S protein-based vaccine development in SARS-CoV will help to identity potential S
protein vaccine candidates in SARS-CoV-2. Therefore, vaccine strategies based on the whole S proteins,
S protein subunits, or specific potential epitopes of S protein appear to be the most promising vaccine
candidates against coronaviruses. The RBD of S1 subunit of S protein has a superior capacity to induce
neutralizing antibodies. This property of the RBD can be utilized for designing potential SARS-CoV
vaccines by either using RBD-containing recombinant proteins or recombinant vectors that encode RBD
(175).

Hence, the superior genetic similarity existing between SARS-CoV-2 and SARS-CoV can be utilized to
repurpose vaccines that have proven in vitro efficacy against SARS-CoV to be utilized for SARS-CoV-2.
The possibility of cross-protection in COVID-19 was evaluated by comparing the S protein sequence of
SARS-CoV-2 with that of SARS-CoV. The comparative analysis confirmed that the variable residues were
found concentrated on the S1 subunit of S protein, an important vaccine target of the virus. Hence, the
possibility of SARS-CoV specific neutralizing antibodies providing cross-protection to COVID-19 might be
lower. Further genetic analysis is required viruses in nasal washes, saliva, urine and faces for up to 8
days after infection, and a few naïve 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 fecal samples were also documented. 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. These findings explain the rapid geographic reduce transmission will provide
benefits to mitigate the epidemic, as has proved successful in China and several other countries, such as
South Korea.

Diagnosis

Early diagnosis is crucial for controlling the spread of COVID-19. Molecular detection of SARS-CoV-2
nucleic acid is the gold standard. Many viral nucleic acid detection kits targeting ORF1b (including RdRp),
N, E or S genes are commercially available. The detection time ranges from several minutes to hours
depending on the technology. The molecular detection can be affected by many factors. Although SARS-
CoV-2 has been detected from a variety of respiratory sources, including throat swabs, posterior

13
oropharyngeal saliva, nasopharyngeal swabs, sputum and bronchial fluid, the viral load is higher in lower
respiratory tract samples. In addition, viral nucleic acid was also found in samples from the intestinal
tract or blood even when respiratory samples were negative. Lastly, viral load may already drop from its
peak level on disease onset. Accordingly, false negatives can be common when oral swabs and used, and
so multiple detection methods should be adopted to confirm a COVID-19 diagnosis. Other detection
methods were therefore used to overcome this problem. Chest CT was used quickly identify a patient
when the capacity of molecular detection was overloaded in Wuhan. For example, a cohort study in
London reveals 44% of the frontline health-care workers from a hospital were infected with SARS-CoV-2.

The high transmissibility of SARS-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. However, the SARS-CoV-2 viral load in upper respiratory tract samples was already highest
during first week of symptoms, and thus the risk of pharyngeal virus shedding was very high at the
beginning of infection. 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 CPVID-19 spreads viruses in liquid droplets during speech.
However, smaller and much more numerous particles known as aerosol particles can also be visualized,
which could linger in the air for long time and then penetrate deep into the lungs when inhaled by
someone else. Airborne transmission was also observed in the ferret experiments mentioned above.

SARS-CoV-2 infected ferrets shed or even die, whereas most young people and children have only mild
diseases (non-pneumonia or mild pneumonia) or are asymptomatic. Notably, the risk of disease was not
higher for pregnant women. However, evidence of transpalcental transmission of SARS-CoV-2 from an
infected mother to a neonate was reported, although it was an isolated case. On infection, the most
common symptoms are fever, fatigue and dry cough. Less common symptoms include sputum
production, headache, hemoptysis, diarrhea, anorexia, sore throat, chest pain, chills, nausea, and
vomiting in studies of patients in China. Self-reported olfactory and taste disorders were reported by
patients in Italy. Most people showed signs of diseases after an incubation period of 1-14 days (most
commonly around 5 days), and dyspnea and pneumonia developed within a median time of 8 days from
illness onset.

In a report of 72,314 cases in China, 81% of the cases were classified as mild, 14% were severe cases that
required ventilation in an intensive care unit (ICU) and a 5% were critical (that is, the patients had
respiratory failure, septic shock and/or multiple organ dysfunction or failure). On admission, ground-
glass opacity was the most common radiology findings on chest-computed tomography (CT). Most
patients also developed marked lymphopenia, similar to what was observed in patients with SARS and
MERS, and non-survivors developed severer lymphopenia over time. Compared with non-ICU patients,
ICU patients had higher levels of plasma cytokine, which suggests an immunopathological process
caused by a cytokine storm. In this cohort of patients, around 2.3% people died within a median time of
16 days from disease onset. Men older than 68 years had higher risk of respiratory failure, acute cardiac
injury and heart failure that led to death, regardless of a history of cardiovascular disease [FIG 4]. Most
patients recovered enough to be released from hospital in 2 weeks [FIG 4].

Early transmission of SARS-CoV-2 in Wuhan in December 2019 was initially linked to the Huanan Seafood
Wholesale Market, and it was suggested as the source of the outbreak. However, community
transmission might have happened before that. Later, ongoing human-to-human transmission

14
propagated the outbreak. It is generally accepted that SARS-CoV and MERS-CoV. However,
determination of an accurate reproduction number (R0) for COVID-19 is not possible yet, as many
asymptomatic infections cannot be accurately accounted for at this stage. An estimated R0 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 of the SARS-CoV-2 human-to-human transmission early in China occurred in family
clusters, and in other countries large outbreaks also happened in other settings, such as migrant worker
communities, slaughterhouses and meat packing plants, indicating the necessity of isolating infected
people. Nosocomial transmission was not the main source of transmission in China because of the
implementation of infection control measures in clinical settings. By contrast, a high risk of nosocomial
transmission was reported in some other lower respiratory tracts. Acute viral interstitial pneumonia and
humoral and cellular immune responses were observed. Moreover, prolonged virus shedding peaked
early in the course of infection in asymptomatic macaques, and old monkeys showed severe intestinal
pneumonia than young monkeys, 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.

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 response 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. In other animal models, including cats and
ferrets, SARS-CoV-2 could efficiently replicate in the upper respiratory tract but did not induce severe
clinical symptoms. As transmission by direct contact and air was observed in infected ferrets and
hamsters, these animals could be used to model different transmission modes of COVID-19 [REFS 77-79].
Animal models offer important information for understanding the pathogenesis of SARS-CoV-2 infection
and transmission dynamics of SARS-CoV-2, and are important to evaluate the efficacy of antiviral
therapeutics and vaccine.

Clinical and epidemiological features

It appears that all ages of the population are susceptible to SARS-CoV-2 infection, and the median age of
infection is around 50 years. However, clinical manifestations different with age. In general, older men
(>60 years old) with co-morbidities are more likely to develop severe respiratory disease that requires
hospitalization. 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 entire and enters alveolar epithelial cells in 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 (FIG 4). Multiple organ failure has also been reported in some COVID-19 cases.

Histopathological changes in patients with COVID-19 occur mainly in the lungs. Histopathology analyses
showed bilateral diffused alveolar damage, hyaline membrane formation, desquamation of
pneumocystis and fibrin deposits in lungs of patients with severe COVID-19. Exudative inflammation was
also shown in some cases. Immunohistochemistry assays detected SARS-CoV-2 antigen in the upper

15
airway, bronchiolar epithelium and submucosal gland epithelium, as well as in type 1 and type 2
pneumocystis, alveolar macrophages and hyaline membranes in the lungs.

Animal models used for studying SARS-CoV-2 infection pathogenesis include non-human primates
(rhesus macaques, cynomolgus monkeys, marmosets and African green monkeys), mice (wild-type mice
with mouse-adapted virus) and human ACE2-transgenic or human ACE2-knock in mice, ferrets and
golden hamsters. In non-human primate animal models, most species display clinical features similar to
those of patients with COVID-19, including virus shedding, virus replication and host responses to SARS-
CoV-2 infection. For example, in the rhesus macaque model, high viral loads were detected in the upper
appeared asymptomatic. Another serological study detected SARS-CoV-2 neutralizing antibodies in cat
serum samples collected in Wuhan after the COVID0-19 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.

Receptor use and pathogenesis

SARS-CoV-2 uses the same receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2). Besides
human ACE2 (Hace2), SARS-CoV-2 also recognizes ACE2 from pig, ferret, rhesus monkeys, civet, cat,
pangolin, rabbit and dog. The board receptor usage of SARS-CoV-2 implies that it may have a wide host
range, and varied efficiency of ACE2 usage in different animals may indicate their different
susceptibilities to SARS-CoV-2 infection. The S1 subunit of a coronavirus is further divided into two
functional domains, an N-terminal domain and a C-terminal domain. Structural and biochemical analyses
identified a 211 amino acid region (amino acid 319-529) at the S1 C-terminal domain of SARS-CoV-2 as
the RBD, which has a key role in virus entry and is the target of neutralizing antibodies. The RBM
medicates contact with the ZCE2 receptors (amino acids 437-507 of SARS-CoV-2 S protein), and this
region in SARS-CoV-2 differs from that in SARS-CoV in the five residues.

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 could not 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 related viruses in China, Southeast Asia and other regions targeting
bats, wild and captured pangolins and other wildlife species will help us to better understand the
zoonotic origin of SARS-CoV-2.

Besides wildlife, researchers investigated the susceptibility of domesticated and laboratory animals to
SARS-CoV-2 infection. The study demonstrated experimentally that SARS-CoV-2 replicates efficiently in
cats and in the upper respiratory tract of ferrets, whereas dogs, pigs, chickens and ducks were not
susceptible to SARS-CoV-2. The susceptibility of minks was documented by a report from the
Netherlands on an outbreak of SARS-CoV-2 infection in farmed minks. Although the symptoms in most
infected minks were mild, some developed severe respiratory distress and died of interstitial
pneumonia. Both virological and serological testing found evidence for natural SARS-CoV-2 infection in
two dogs from households with human cases of COVID-19 in Hong Kong, but the dog’s residues for
receptor bindings. In comparison with the Guangdong strains, pangolin coronaviruses reported from

16
Guangxi are less similar to SARS-Cov-2, with 85.5% genome sequence identity. The repeated occurrence
of SARS-CoV-2 related coronavirus infection 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 natural hosts.

An intermediate host usually plays an important role in the outbreak of bat-derived emerging
coronaviruses, for example, palm civets for SARS-CoV and dromedary camels for MERS-CoV. The virus
strains carried by these two intermediate hosts were almost genetically identical to the corresponding
viruses in humans (more than 99% genome sequence identity). Despise an RBD that is virtually identical
to that of SARS-CoV-2, the pangolin coronaviruses known to date have no more than 92% genome
identity with SARS-CoV-2 [REF42]. The available data are insufficient to interpret pangolins as the
intermediate host of SARS-CoV-2. So far, no evidence has shown that pangolins were directly involved in
the emergence of SARS-CoV-2. In the long 1ab gene, it exhibits 97.2% identity to SARS-CoV-2, which is
even higher than for RaTG13. 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. The discovery of diverse bat
coronaviruses closely related to SARS-CoV-2. Nevertheless, on the basis of current findings, the
divergence between SARS-CoV-2 and related bat coronaviruses likely represents more than 20 years of
sequence evolution, suggesting that these bat coronaviruses can be regarded only as the likely
evolutionary precursor of SARS_CoV-2 but not as direct progenitor of SARS-CoV-2.

Beyond bats, pangolins are another wildlife host probably linked with SARS-CoV-2. Multiple SARS-CoV-2
related viruses have been identified in tissues of Malayan pangolins smuggled from Southeast Asia into
Southern China from 2017 to 2019. These viruses from pangolins independently seized by Guangxi and
Guangdong provincial customs belong to two distinct sub lineages. The Guangdong strains, which were
isolated or sequenced by different research groups from smuggled pangolins, have 99.8% sequence
identity with each other. They are very closely related to SARS-CoV-2, exhibiting 92.4% sequence
similarity. Notably, the RBD of Guangdong pangolin coronaviruses is highly similar to that of SARS-CoV-2.
The receptor-bonding motif (RBM which is part of the RBD) of these viruses has only one amino acid
variation from SARS-CoV-2, and it is identical to that of SARS-CoV-2 in all five critical differs that in SARS-
CoV in the five residues critical for ACE2 binding, namely Y455L, L486F, N493Q, D494S and T501N. Owing
to these residue stabilizes the two virus-binding hotspots on the surface of Hace2. 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 h ACE2-binding ridge than in SARS-CoV and enables better contact with the N-
terminal helix of h ACE2 features of the SARS-CoV-2 RBD has strengthened its h ACE2 binding affinity
compared with that of SARS-CoV.

Similarly, to other coronaviruses SARS-CoV-2 needs proteolytic processing of the S protein to activate
the endocytic route. It has been shown that host proteases participate in the cleavage of the S protein
and activate the entry of SARS-CoV-2, including transmembrane protease serine protease 2 (TMPRSS2),
cathepsin L and furin. Single-cell RNA sequencing data showed that TMPRSS2 is highly expressed in
several tissues and body sites and is co-expressed with ACE2 in nasal epithelial cells, lungs and bronchial
branches, which explains some of the tissue tropism of SARS-CoV-2. SARS-CoV-2 pseudovirus entry

17
assays revealed that TMPRSS2 and cathepsin L have cumulative effects with furin on activating virus
entry. Analysis of the cryo-electron microscopy structure of SARS-CoV-2 S protein revealed that its RBD
is mostly in the lying-down state, whereas the SARS-CoV S protein assumes equally standing-up and
lying-down conformation states. A lying-down conformation of the SARS-CoV-2 S protein may not be in
favor of receptor binding but is helpful for immune evasion.

Antiviral Therapy

COVID-19 is an infectious disease caused by 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 in treating the patients with novel coronavirus. The remaining
two drugs were effective in treating malaria.

Likewise, a study carried out in the United States by the National Institute of Health proved that
remdesivir is effective in treating the Middle East respiratory syndrome coronavirus (MERS-CoV), which
is also a type of coronavirus that was transmitted from monkeys. The drug remdesivir was also used in
the United States for treating the patients with COVID-19. There has been a proposal to use the
combination of protease inhibitors lopinavir-ritonavir for treating the patients affected by COVID-19. 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 treat its efficacy.

A metacentric study was conducted in China to test the effectiveness of remdesivir in treating the
patients with COVID-19. Thus, the results of the clinical trial proved that remdesivir has a considerably
acceptable level of efficacy for treating the patients with COVID-19. Therefore, the National Health
Commission of the People`s Republic of China decided to include remdesivir in the Guidelines for the
Prevention, Diagnosis and Treatment of Pneumonia caused by COVID-19.

Chloroquine and hydroxychloroquine are existing anti-malaria drugs also given to more than 30 patients
infected with COVID-19 in Guangdong province and Hunan province to test their effectiveness and
efficacy. Thus, the 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 hydroxyl chloroquine. 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 was suggested by preclinical data, but additional data has failed to
confirm it. Tocilizumab is an immunomodulation agent used as adjunct therapy in some protocols based
on a theoretical mechanism and limited preliminary data.

18
HOME CARE

Home management may be appropriate for patients with mild infection who can be adequately isolated
in the outpatient setting. Management of such patients should focus on prevention of transmission to
others, and monitoring for clinical deterioration, which should prompt hospitalization. Interim
recommendations on home management of patients with COVID-19 can be found on the WHO and CDC
websites.

Potential Therapeutic Agents

Potent therapeutics to combat SARS-coV-2 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, short interfering RNA (siRNA), neutralizing antibodies, MAbs against the host receptors, MAbs
interfering with the S1 RBD, antiviral peptide aimed at S2, and natural drugs/medicines. 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 of the fusion core, and proteases.

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 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 (ACE1) and angiotensin type-1 receptor (AT1R).

Several investigations have suggested the use of small-molecule inhibitors for the potential control of
SARS-CoV- infections. Drugs of the FDA-approved compound library were screened to identify four
small-molecule inhibitors of MERS-CoV (chlorpromazine, chloroquine, loperamide, and lopinavir) that
inhibited viral replication. These compounds also hinder SARS-CoV and human CoVs. Therapeutic
strategies involving the use of specific antibodies or compounds that neutralize cytokines and their
receptors will help to restrain the host inflammatory responses. Such drugs acting specifically in the
respiratory tract will help to reduce virus-triggered immune pathologies in COVID-19. The later stages of
coronavirus induced inflammatory cascades are characterized by the release of proinflammatory
interleukin-1 family members, such as 1L-1 and 1L-33. Hence, there exists a possibility that the
inflammation associated with coronavirus can be inhibited by utilizing anti-inflammatory cytokines that
belong to the 1L-1 family. 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.
The plasma angiotensin 2 level was found to be markedly elevated in COVID-19 infection and was
correlated with viral load and lung injury. Hence, drugs that block angiotensin receptors may have
potential for treating COVID-19 infection. A scientist from Germany, named Rolf Hilgenfeld, has been
working on the identification of drugs for the treatment of coronavirus infection since the time of the
first SARS outbreak.

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Animal Models and Cell Cultures

For evaluating the potential of vaccines and therapeutics against CoVs, including SARS-CoV, MERS-CoVs,
and the presently emerging SARS-CoV-2, suitable animal models that can mimic the clinical disease are
needed. Various animal models were assessed for SARS and MERS-CoVs, such as mice guinea pigs,
golden Syrian hamsters, ferrets, rabbits, nonhuman primates like rhesus macaques and marmosets, and
cats. The specificity of the virus to hACE2 (receptor of SARS-CoV) was found to be a significant barrier in
developing animal models. Consequently, a SARS-CoV transgenic mouse model has been developed by
inserting the hACE2 gene into the mouse genome. 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. 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, H DPP4-transduced mice, and H DPP4-Tg mice (transgenic for expressing).
These findings suggest that primary infection with SARS-CoV-2 could protect from later exposures to the
virus, which could help in defining disease prognosis and crucial inference for designing and developing
potent vaccines against COVID-19.

Prevention, Control and Management

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. 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 surroundings provinces as well as to several other
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. The current
scenario demands effective implementation of vigorous prevention and control strategies owing to the
prospect of COVID-19 for nosocomial infections. Follow-ups of infected patients by telephone on day 7
and day 14 are advised to avoid any further unintentional spread or nosocomial transmission. The
availability of public data sets provided by independent analytical teams will act as robust evidence that
would guide us in designing interventions against the COVID-19 outbreak. Newspaper reports and social
media can be used to analyze and reconstruct the progression of an outbreak. They can help us to
obtain detailed patients level data in the early stages of an outbreak. Immediate travel restrictions
imposed by several countries might have contributed significantly to preventing the spread of SARS-CoV-
2 globally. Following the outbreak, a temporary ban was imposed on the wildlife trade, keeping in mind
the possible role-played by wild animal species in the origin of SARS-CoV-2/COVID-19. Making a
permanent and bold decision on the trade of wild animal species is necessary to prevent the possibility
susceptible individuals. Hence, 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.

Medical staff are in the group of individuals most at the 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

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protect themselves and others from this deadly disease. As a preventive measure, health care workers
caring for infected patients should take extreme precautions against both contact and airborne
transmission. They should use PPE such as facemasks (N95 or FFP3), eye protection (goggles), gowns,
and gloves to nullify the risk of infection.

The human-to-human transmission reported in SARS-CoV-2 infection occurs mainly through droplet or
direct contact. Due to this finding, frontline health care workers should follow stringent infection control
and preventive measures, such as the use of PPE, to prevent infection. The mental health of the
medical/health workers who are involved in the COVID-19 outbreak is of great importance, because the
strain on their mental well-being 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.

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. The total
numbers of COVID-19 confirmed cases is on a continuous rise and cure rate is relatively low, making
disease control very difficult to achieve. The Chinese government is making continuous efforts to contain
the disease by taking emergency control and prevention measures. They have already built a hospital for
patients affected by this virus and are currently building several more for accommodating the
continuously increasing infected population. The effective control of SARS-CoV-2/COVID-19 requires
high-level interventions like intensive contact tracing, as well as the quarantine of people with suspected
infection and the isolation of infected individuals. The implementation of rigorous control and
preventive measures together might control the R0 number and reduce the transmission risk. The
number of confirmed cases around the 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. 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 after lockdown relaxation. Lockdown should be
imposed only to slow down disease progression among the population so that the health care system is
not overload.

The reputation number (R0) of COVID-19 infection was earlier estimated to be in the range of 1.4 to 2.5
(70); recently, it was estimated to be 2.24 to 3.58. Compared to its coronavirus predecessors, COVID-19
has an R0 value that is greater than that of MERS (R0<1) but less than that of SARS (R0 value of 2 to 5).
Still, to prevent further spread of disease at mass gatherings, functions remain canceled in the affected
cities, and it is a relief that the current outbreak of COVID-19 infection can be brought under control
with the adoption of strategic preventive and control measures along with the early isolation of
subsequent cases in the coming days. Studies also report that since air traffic between China and African
countries increased many times over in the decade after the SARS outbreak, African countries need to
be vigilant to prevent the spread of novel coronavirus in Africa. Due to fear of virus spread, Wuhan city
was completely shut down. The immediate control of the ongoing COVID-19 outbreak appears a
mammoth task, especially for developing countries, due to their inability to allocate quarantine stations
that could screen infected individuals movements. Such underdeveloped countries should divert their
resources and energy to enforcing the primary level of preventive measures, like controlling the entry of

21
individuals from China or countries where the disease has flared up, isolating the infected individuals,
and quarantining individuals with suspected infection. Most of the sub-Saharan African countries have a
fragile health system that can be crippled in the event of an outbreak. Effective management of COVID-
19 would be difficult for low-income countries due to their inability to respond rapidly due to lack of an
efficient health care system. Controlling the imported cases is critical in preventing the spread of COVID-
19 to 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 onset of symptoms to hospitalization and
can only be made possible by using intense disease surveillance systems. 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 who traveled out of the city just before the imposition of the ban might
have remained undetected and resulted in local outbreaks. Emerging novel disease like COVID-19 are
difficult to contain within the country of origin, since globalization has led to a world without borders.
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. However, the real question is, how are we planning to
counter the next zoonotic CoV epidemic that is likely to occur within the next 5 to 10 years or perhaps
sooner? Our knowledge of most of the bat CoVs is scarce, as these viruses have not been isolated and
studied, and extensive studies on such viruses are typically only conducted when they are associated
with specific disease outbreaks. The next step following the control of the COVID-19 outbreak in China
should be focused on screening, identification, isolation, and characterization of CoVs present in wildlife
species of China, particularly in bats. Both in vitro and in vivo studies (using suitable animal models)
should be conducted 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 and vaccines against several other emerging diseases will help develop suitable
therapeutic agents against COVId-19 in a short time. Until then, we must rely exclusively on various
control and prevention measures to prevent this new disease from becoming a pandemic.

Virology

Coronaviruses, a family of viruses within the noroviruses superfamily, are further classified according to
their genera, alpha-, beta-, and gamma- and delta coronaviruses (α-, β-, у-, δ-). Among those, alpha and
beta species are capable of contaminating only mammals, whereas the other two genera can infect birds
and could infect mammals. Two of these genera belong to human coronavirus (HCoVs): α-coronaviruses,
which comprise human coronavirus 229E (hcov229E) and human coronavirus NL63 (hcovNL63), and β-
coronaviruses, which are human coronavirus HKU1, human coronavirus OC43, MERS-COV (known as
Middle East respiratory syndrome coronavirus) and SARS-CoV (referred to as severe acute respiratory
syndrome coronavirus).

The severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is now named novel COVID-19 (coronavirus
disease 2019). Genome sequencing and phylogenetic research revealed that the COVID-19 causing

22
coronavirus is a beta-coronavirus that belongs to the same subtypes as SARS virus, but still exist in a
variant group. The receptor-binding gene region appears to be very similar to that of the SARS-CoV and
it is believed that the same receptor would be used for cell entry.

Vision structure and its genome

Coronaviruses are structurally enveloped, 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 ends, it remains identical to the
cellular mRNAs. The structure is comprised of hemagglutinin esterase (HE) (present only in some beta-
coronaviruses), spike (S), small membrane €, membrane (M) and nucleocapsid (N). The envelope
containing glycoprotein is responsible for attachment to the host cell, which possesses the primary anti-
genic epitopes mainly those recognized by neutralizing antibodies. The spike S-protein being in a spike
from is subjected to a structural rearrangement process so that fusing the outer membrane of the virus
with the host cell membrane becomes easier. Recent SARS-CoV work has also shown that the
membrane exopeptidase ACE enzyme (angiotensin-converting system) functions as a COVID-19 receptor
to enter the human cell.

Viral replication

Usually replication of coronavirus occurs within the cytoplasm and is closely associated with
endoplasmic reticulum and other cellular 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 features 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 produced. The shortest
mRNAs codes and the others can express the synthesis of another genome segment for nucleoprotein.
At the cell membrane, these proteins are collected and genomic RNA is initiated as a mature particle
type by burgeoning from internal cell membranes.

Pathogenesis

Coronaviruses are tremendously precise and mature in most of the airway epithelial cells as observed
through both in vivo and in vitro experiments. There is an enhanced nasal secretion observed along with
along edema because of the damage of the host cell, which further stimulates the synthesis of
inflammatory mediator. In addition, these reactions can sneezing, difficulty breathing by causing airway
inhibition and elevate mucosal temperatures. These viruses, when released, chiefly affect the lower
respiratory tract, with the signs and symptoms existing clinically. Also, the virus further affects the
intestinal lymphocytes, renal cells, liver cells and T-lymphocytes. Furthermore, the virus induces T-cell
apoptosis, causing the reaction of the T-cell to be erratic, resulting in the immune system`s complete
collapse.

23
Mode of Transmission

In fact, it was accepted that the original transmission originated from a seafood market, which had a
tradition of selling live animals, where the majority of the patients had either worked or visited,
although up to now the understanding of the COVID-19 transmission risk remains incomplete. In
addition, while the newer patients had no exposures to the market and still got the virus from humans
present there is an increase in the outbreak of this virus through human-to-human transmission, with
the fact that it has become widespread around the globe. This confirms the fact similar to the previous
epidemics, including SARS and MERS, that this coronavirus exhibited potential human-to-human
transmission, as WHO recently declared it.

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 differ by both location and interaction with involvement in
infection control. It is stated that even asymptomatic individuals or those individuals in their incubation
period can act as carrier of SARS-CoV-2. With the data and evidence provided by the CDC, the usual
incubation period is probably 3 to 7 days, sometimes being prolonged up to even 2 weeks, and typical
symptom occurrence from incubation period to infection takes an average of 12.5 days.

Clinical Diagnosis

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 hospitalized in the intensive care unit. Comorbid patients showed a more severe
clinical course than predicted from previous epidemic. Diagnosis of COVID-19 includes the complete
history of travel and touch, with laboratory testing. It is more preferable to choose serological screening,
which can help to analyze even the asymptomatic infections; several serological tests are in progress for
SARS-CoV-2.

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
epidemiological factors. The screening protocols must be prepared and followed per the native context.
Collecting and testing of specimen samples from the suspected individual is considered one of the main
principles for controlling and managing the outbreak of the disease in a country. The suspected cases
must be screened thoroughly in order to detect the virus with the help of nucleic acid amplification tests
such as reverse transcription polymerase chain reaction (RT-PCR). If a country or a particular region does
not have the facility to test the specimens, the specimens of the suspected individual should be sent to
nearest reference laboratories per the list provided by WHO.

24
It is also recommended that the suspected patients be tested for the other respiratory pathogens by
performing the routine laboratory investigation per the local guidelines, mainly to differentiate from
other viruses that include influenza virus, parainfluenza virus, adenovirus, respiratory and syncytial virus.
The one Health approach may play a vital role in the prevention and control measures being followed to
restrain this pandemic virus. The substantial important of COVID-19 presymptomatic cases from Wuhan
has resulted in independent, self-sustaining outbreak across major cities both within the country and
across the globe. The majority of Chinese cities are now facing localized outbreaks of COVID-19. Hence,
deploying efficient public health interventions might help to cut the spread of this virus globally.

The occurrence of COVID-19 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. 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 Princess, Celebrity Apex, and Ruby Princess.

Personal protective equipment (PPE), like face masks, will help to prevent the spread of respiratory
infections like COVID-19. Facemasks not only protect from infectious aerosols but also prevent the
transmission of disease to other susceptible individuals while travelling through public transport
systems. 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 virus is transmitted through the formation of large
droplets. Hence, it is better not to overemphasize that hand hygiene will prevent the transmission of
SARS-CoV-2, since it may produce a false sense of safety among the general public that further
contributes to the spread of COVID-19. Even though airborne spread has not been reported in SARS-
CoV-2 infection, transmission can occur through droplets and fomites, especially when there is close,
unprotected contact between infected and susceptible individuals.

The exploration of fully human antibodies (human single-chain antibodies; HuscFvs) or humanized Nano
bodies (single-domain antibodies; sdAb, VH/VHH) could aid in blocking virus replication, as these agents
can traverse the virus-infected cell membrane (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. Producing similar transbodies against intracellular
proteins of coronaviruses, such as papain-like proteases (PLpro), cysteine-like protease (3CLpro), or
other nsps, which are essential for replication and transmission of the virus, might formulate a practice
move forward for a safer and potent passive immunization approach for virus-exposed persons and
rendering therapy to infected patients.

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. 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 sites, make up crucial entry
tasks of S protein. Passive immunization employing weaker and strongly neutralizing antibodies

25
provided considerable protection in mice against a MERS-CoV lethal challenge. Such antibodies may play
a crucial role in enhancing protective humoral responses against the emerging CoVs by aiming
appropriate epitopes and functions of all s protein. The cross-neutralization ability of SARS-CoV RBD-
specific neutralizing MAbs considerably relies on the resemblance between their RBD; therefore, SARS-
CoV RBD-specific antibodies could cross-neutralized SL CoVs, i.e., bat-SL-CoV strain W1V1 (RBD with
eight amino acid differences from SARS-CoV) but not bat-SL-CoV strain SHC014 (24 amino acid
differences.

Appropriate RBD-specific MAbs can be recognized by a relative analysis of RBD of SARS-CoV-2 to that
SARS-CoV, and cross-neutralizing SARS-CoV RBD- specific MAbs could be explored for their effectiveness
against COVID-19 and further need to be assessed clinically. The U.S. biotechnology company Regeneron
is attempting to recognize potent and specific MAbs to combat COVID-19. An ideal therapeutic option
suggested for SARS-CoV-2 is the combination therapy comprised of MAbs and the drug remdesivir
(COVID-19). The SARS-CoV-specific human MAbs CR3022 is found to bind with SARS-CoV-2 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.
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 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 and nosocomial spread of COVID-19, the post procedure risk
management program should not be neglected. Development of broad-spectrum inhibitors against the
human coronaviral pathogens will help to facilitate clinical trials on the effectiveness of such inhibitors
against endemic and emerging coronaviruses. A promising animal study revealed the protective effect of
passive immunotherapy with immune serum from MERS-immune camels on mice infected with MERS-
CoV. Passive immunotherapy using convalescent plasma is another strategy that can be used for treating
COVID-19 infected, critically ill patients. 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 1gM and 1gG
antibodies can be used as a high-throughput alternative. At present, there is no diagnostic kit available
for detecting the SARS-CoV-2 antibody. The specific antibody profiles of COVID-19 patients were
analyzed, and it was found that the IgM level lasted more than 1 month, indicating a prolonged stage of
virus replication in SARS-CoV-2 infected patients. These findings can be utilized for the development of
specific diagnostic tests against COVID-19 and can be used for rapid screening. Even though diagnostic
test kits are already available, that can detect the genetic sequence of SARS-CoV-2, their availability is a
concern, as the number of COVId-19 cases is skyrocketing. A major problem associated with this
diagnostic kit is that its works only when the test subject has an active infection, limiting its use to earlier
stages of infection. Several laboratories around the world are currently developing antibody-based
diagnostic tests against SARS-CoV-2.

Chest CT is an ideal diagnostic tool for identifying viral pneumonia. The sensitivity of chest CT is far
superior to that of X-rays screening. The chest CT findings associated with COVID-19 infected patients
include characteristic patchy infiltration that later progresses to ground-glass opacities. Early
manifestations of COVID-19 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

26
pneumonia. Those patients having COVID-19 pneumonia will exhibit the typical ground-glass opacity in
their chest CT images. 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. The chest CT imaging abnormalities associated with COVID-19
pneumonia have also been observed even in asymptomatic patients. These abnormalities progress from
the initial focal unilateral to diffuse progress to or coexist with lung consolidation changes within 1 to 3
weeks. 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. Even though chest CT is considered an essential diagnostic
tool for COVID-19. The extensive use of CT for screening purposes in the suspected individuals might be
associated with a disproportionate risk-benefit ratio due to increased radiation exposures as well as
increased risk of cross-infection. Hence, the use of CT for early diagnosis of SARS-CoV-2 infection in high-
risk groups should be done with great caution.

Vaccines, Therapeutics and Drugs

Recently emerged viruses, such as Zika, Ebola and Nipah viruses, and their grave threats to humans have
begun a race in exploring the designing and developing of advanced vaccines, prophylactics,
therapeutics, and drug regimens to counter emerging viruses. Several attempts are being infection,
mostly by targeting the spike glycoprotein. Nevertheless, owing to extensive diversity antigenic variants,
cross-protection rendered by the vaccines is significantly limited, even within the strains of the
phylogenetic sub cluster. 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. Recently, the receptor for SARS-CoV-2 was established as the
human angiotensin-converting enzymes 2 (hACE2), and the virus was found to enter the host cell mainly
through endocytosis. It was also found that the major components that have a critical role in viral entry
include PIkfyve, TPC2, and cathepsin L. These findings are critical, since the components described above
might act as candidates for vaccines or therapeutic drugs against SARS-CoV-2.The majority of the
treatment options and strategies that are being evaluated for SARS-CoV-2 (COVID-19) have been taken
from our previous experiences in treating SARS-CoV, MERS-CoV, and other emerging viral disease.

Vaccines

The protein plays a significant role in the induction of protective immunity against SARS-CoV by
mediating T-cell responses and neutralizing antibody production. In the past few decades, we have seen
several attempts to develop a vaccine against human coronaviruses by using S protein as the target.
However, the developed vaccines have minimal application, even among closely related strains of the
virus, due to a lack of cross-protection. That is mainly because of the extensive diversity existing among
the different antigenic variants of the virus. The contributions of the structural proteins, like spike (S),
matrix (M), small envelope (E), and nucleocapsid (N) proteins, of SARS-CoV to induce protective
immunity has been evaluated by expressing them in a recombinant parainfluenza virus type 3 vector. Of
note, the result was conclusive that the expression of M, E, or N proteins without the presence of S
protein. 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

27
will be helpful in the scenario of an outbreak; sine 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 immunoinformatic, tools can be used to develop
multiepitope subunit vaccines. The vaccines that are engineered by this technique can be further
evaluated using docking studies and, if found effective, and then can be further evaluated in animal
models. Identifying epitopes that have the potential to become a vaccine candidate is critical to
developing an effective vaccine against COVID-19.the immunoinformatics approach has been used for
recognizing essential epitopes of cytotoxic T lymphocytes and B cells from the surface glycoprotein of
SARS-CoV-2. Recently, a few epitopes have been recognized from the SARS-CoV-2 surface glycoprotein.
The selected epitopes explored targeting molecular dynamic stimulations, evaluating their interaction
with corresponding major histocompatibility complex class 1 molecules. They potentially induce immune
responses. 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) article vector-
based vaccine. However, the latter can induce a very high antibody response at lower doses. Hence, the
degree of humoral and cellular immune responses produced by such vaccines depends upon the vector
used.

Dual vaccines have been getting more popular recently. Among them, the rabies virus-based vectored
vaccine platform is used to develop vaccines against emerging infectious diseases. The dual vaccine
developed from inactivated rabies virus particles that express the MERS-CoV S1 domain of S protein was
found to induce immune responses for both MERS-CoV and rabies virus. The vaccinated mice were
found to be completely protected from challenge with MERS-Cov. Immunoinformatics methods have
been employed for the genome-wide screening of potential vaccine targets among the different
immunogens of MERS-CoV. The N protein and the potential have been suggested as immunoprotective
targets inducing both T-cell and neutralizing antibody responses.

The collaborative effort of the researchers of Rocky Mountain Laboratories and Oxford University is
designing a chimpanzee adenovirus-vectored vaccine to counter COVID-19. The Coalition for Epidemic
Preparedness Innovations (CEPI) has initiated three programs to design SARS-CoV-2 vaccines. CEPI has a
collaborative project with Inovio for designing a MERS-CoV DNA vaccine that could potentiate effective
immunity. CEPI and the University of Queensland are designing molecular clamp vaccine platform for
MERS-CoV and other pathogens, which could assist in the easier identification of antigens by immune
system. 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 Institute of Health (NIH). 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. 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 first research group to launch small clinical trials of vaccine against
COVID-19. Their study is evaluating their vaccine’s safety and ability to trigger immune responses.

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 Scientists from all over the world are trying hard to develop working vaccines with robust protective
immunity against COVID-19. Vaccine candidates like mRNA-1273 SARS-CoV-2 vaccine, INO-4800 DNA
coronavirus vaccine, and adenovirus type 5-vector vaccine candidate (Ad5-nCoV), are a few examples
under phase 1 clinical trials, while self-amplifying RNA vaccine, oral recombinant COVID-19 vaccine,
BNT162, plant-based COVID-19 vaccine, and li-key peptide COVID-19 vaccine are under preclinical trials.
Similarly, the WHO on its official website, has mentioned a detailed list of COVID-19 vaccine agents that
are under consideration. Different phases of trials are ongoing for live attenuated virus vaccines,
formaldehyde alum inactivated vaccine, adenovirus type 5-vector vaccine, LNP-encapsulated mRNA
vaccine, DNA plasmid vaccine, and S protein, S-trimer, and Li-Key peptide as a subunit protein vaccine,
among others. 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. The
development of an effective vaccine against COVID-19 with high speed and precision is the combined
result of advancements in computational biology, gene synthesis, protein engineering, and the invention
of advanced manufacturing platforms.

The recurring nature of the coronavirus outbreaks calls for the development of a pan-coronavirus
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. Even though several vaccines 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 due to alterations in the immune system and other physiological
systems that are associated with pregnancy. Therefore, in the event of successful vaccine development,
pregnant women will not get access to the vaccine. Hence, it is recommended that pregnant women be
included in the ongoing vaccine trials, since successful vaccination in pregnancy will protect the mother,
fetus, and newborn.

The heterologous immune effects induces by Bacillus Calmette Guerin (BCG) vaccination is a promising
strategy for controlling the COVID-19 pandemic and requires further investigations. BCG is a widely used
vaccine against tuberculosis in high-risk regions. It is derived from a live attenuated strain of
Mycobacterium bovis. At present, three new protective role of BCG vaccination against SARS-CoV-2.
Recently, a cohort study was conducted to evaluate the impact of childhood BCG vaccination in COVID-
19 PCR positivity rates. However, childhood BCG vaccination was found to be associated with a rate of
COVId-19 positive test results similar to that of the nonvaccinated group. 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%). 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 the L and S types are very small and may not
affect the immune response. However, we can expect further genetic variations in the coming days that
could lead to the emergence of new strains.

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Therapeutics and Drugs

There is no currently licensed specific antiviral treatment for MERS- and SAS-CoV infections, and the
focus in clinical settings remains on lessening clinical signs and providing supportive care. Effective drugs
to manage COVId-19 patients include remdesivir, lopinavir/ritonavir alone or in a blend with interferon
beta, convalescent plasma, and monoclonal antibodies (MAbs); however, efficacy and safety issues of
these drugs require additional clinical trials. A controlled trial of ritonavir-boosted lopinavir and
interferon alpha 2b treatment was performed on COVID-19 hospitalized patients. 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
foolproof clinical trials have been published. Recently, a clinical trial conducted on adult patients
suffering from severe COVID-19 revealed no benefit of lopinavir-ritonavir treatment over standard care.

The efforts to control SARS-CoV-2 infection against utilize defined strategies as followed against MERS
and SARS, along with adopting and strengthening a few precautionary measures owing to the unknown
nature of this novel virus. 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 ShuFenJieDu capsules) could aid in
COVID-19 treatment. However, further clinical trials are being carried out concerning their safety and
efficacy. It might require months to a year(s) to design and develop effective drugs, therapeutics, and
vaccines against COVID-19, with adequate evaluation and approval from regulatory bodies and moving
to the bulk production of many millions of doses at commercial levels to meet the timely demand of
mass populations across the globe. Continuous efforts are also warranted to identify and assess viable
drugs and immunotherapeutic regimens that revealed proven potency in combating other viral agents
similar to SARS-CoV-2.

COVID-19 patients showing severe signs are treated symptomatically along with oxygen therapy. In such
cases where the patients progress towards respiratory failure and become refractory to oxygen therapy,
mechanical ventilations is necessitated. The COVID-19 induced septic shock can be managed by
providing adequate hemodynamic support. 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 that virus entry into the host cell,
drugs that block viral replication as well as its survival within the host cell, and drugs that attenuated the
exaggerated host immune response. An inflammatory cytokine storm is commonly seen in critically ill
COVID-19 patients. Hence, they may benefit from the use of timely anti-inflammation treatment. Anti-
inflammatory therapy using drugs like glucocorticoids, cytokine inhibitors, JAK inhibitors, and
chloroquine/hydroxychloroquine should be done only after analyzing the risk/benefit ration in COVID-19
patients. There have not been any studies concerning the application of nonsteroidal anti-inflammatory
drugs (NSAID) to COVID-19 infected patients. However, reasonable pieces of evidence are available that
link NSAID uses with the occurrence of respiratory and cardiovascular adverse effects. Hence, as a
cautionary approach, it is better to recommend the use of NSAIDs as the first-line option for managing
COVId-19 symptoms. The use of corticosteroids in COVID-19 patients is still a matter of controversy and
requires further systematic clinical studies. The guidelines that were put forward to manage critically ill
adults suggest the use of systemic corticosteroids in mechanically ventilated adults with ARDS. The

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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
different types of MSCs, expanded umbilical cord MSCs can be considered a potential therapeutic agent
that requires further validation for managing critically ill COVID-19 patients.

Repurposed broad-spectrum antiviral drugs having proven uses against other viral pathogens can be
employed for SARS-CoV-2 infected patients. These possess benefits of easy accessibility and recognized
pharmacokinetic and pharmacodynamics activities, stability, doses, and side effects. Repurposed drugs
have been studied for treating CoV infections, like lopinavir/ritonavir, and interferon-1β 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. A combination of these drugs is being evaluated to treat
MERS in humans (MIRACLE trial). These two protease inhibitors (lopinavir and ritonavir), in combination
with ribavirin, gave encouraging clinical outcomes in SARS patients, suggesting their therapeutic values.
However, in the current scenario, due to the lack of specific therapeutic agents against SARS-CoV-2,
hospitalized patients confirmed for the diseases are given supportive care, like oxygen and fluid therapy,
along with antibiotic therapy for managing secondary bacterial infections. Patients will novel
coronavirus or COVID-19 pneumonia who are mechanically ventilated often require sedatives,
analgesics, and even muscle relaxation drugs to prevent ventilator-related lung injury associated with
human-machine incoordination. 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. 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 control studies should be performed with a sufficient
study population.

Antiviral Drugs

Several classes of routinely used antiviral drugs like oseltamivir (neuraminidase inhibitor), acyclovir,
ganciclovir, and ribavirin, do not have any effect on COVID-19 and, hence, are not recommended.
Oseltamivir, neuraminidase inhibitors, has been explored in Chinese hospitals for treating suspected
Covid-19 cases, although proven efficacy against SARS-CoV-2 is still lacking for this drug. The in vitro
antiviral potential of FAD-approved drugs, viz., ribavirin, penciclovir, nitazoxanide, nafamostat, and
favipiravir (broad-spectrum antiviral drugs) revealed remdesivir and chloroquine to be highly effective
against SARS-CoV-2 infection in vitro. Ribavirin, penciclovir, 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 effectiveness
in COVID-19 patients.

Several therapeutics agents, such as lopinavir/ritonavir, chloroquine, and hydroxychloroquine, have

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RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 using different commercially available
antipolymerase drugs, identified that drugs such as ribavirin, remdesivir, galidesivir, tenofovir, and
sofosbuvir bind RdRp tightly, indicating their vast potential to be used against COVID-19. A broad-
spectrum antiviral drug that was developed in the United States, tilorone didydrochloride, was
previously found to possess potent antiviral activity against MERS, Marburg, Ebola, and chikungunya
viruses. Even though it had broad-spectrum activity, it was neglected for an extended period. Tilorone is
another antiviral drug that might have activity against SARS-CoV-2.

Remdesivir, a novel nucleotide analog prodrug, was developed for treating Ebola virus disease (EVD),
and it was found to inhibit the replication of SARS-CoV and MERS-CoV in primary human airway
epithelial cell culture systems. Recently, in vitro study has proven that remdesivir has better antiviral
activity than lopinavir and ritonavir. Further, in vivo studies conducted in mice also identified that
treatment with remdesivir improved pulmonary function and reduced viral loads and lung pathology
both in prophylactic and therapeutic regimens compared to lopinavir/ritonavir-IFN-y treatment in
MERS-CoV infection. Remdesivir also inhibits a diverse range of coronaviruses, including circulating
human CoV, zoonotic bat CoV, and prepandemic zoonotic CoV. Remdesivir is also considered the only
therapeutic drug that significantly reduces pulmonary pathology. All these findings indicate that
remdesivir has to be further evaluated for its efficacy in the treatment of COVID-19 infections in
humans. The broad-spectrum activity exhibited by remdesivir will help control the spread of disease in
the event of a new coronavirus outbreak.

Practice Points from an Indian Perspective

At the time of writing this article, the risk of coronavirus in Indian is extremely low. However, that may
change in the next few weeks. Hence, the following is recommended:

Healthcare providers should take travel history of all patients with respiratory symptoms, and any
international travel in the past 2 week as well as contact with sick people who have travelled
internationally.

They should set up a system of triage of patients with respiratory illness in the outpatient department
and give them a simple surgical mask to wear. They should use surgical masks themselves while
examining such patients and practice hand hygiene frequently.

Suspected cases should be referred to government designated centers for isolation and testing (in
Mumbai, at this time, it is Kasturba hospital). Commercial kits for testing are not yet available in India.

Patients admitted with severe pneumonia and acute respiratory distress syndrome should be 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 patients if logistics permit and if no pathogens is identified, refer the samples for testing for SARS-
CoV-2.

All clinicians should keep themselves updated about recent developments including global spread of the
diseases.

Non-essential international travel should be avoided at this time.

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People should stop spreading myths and false information about the disease and try to allay panic and
anxiety of the public.

Conclusion

This new virus outbreaks has challenged the economic, medical and public health infrastructure of China
and to some extent, of other countries especially, its neighbours. Time alone will tell how the virus will
impact our lives here in India. More so, future outbreaks of viruses and pathogens of zoonotic origin are
likely to continue. 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 changes in the climate, and ecological conditions may be associated with human-animal contact. Live-
animal markets, such as the Huanan South china Seafood Market, represent ideal conditions for
interspecies contact of wildlife with domestics birds, pigs, and mammals, which substantially increases
the probability of interspecies transmission of CoV infection and could result in high risks to humans due
to adaptive genetic recombination in these viruses.

The COVId-19 associated symptoms are fever, cough, expectoration, headache, and myalgia or fatigue.
Individuals with asymptomatic and atypical. We also predict the possibility of another outbreak, as
predicted by Fan et al. indeed, the present outbreak caused by SaRS-CoV-2 (COVID-19) was expected.
Similar to previous outbreaks, the current outbreaks also will be contained shortly. However, the real
issue is how we are planning to counter the next zoonotic CoV epidemic that is likely to occur within the
next 5 to 10 years or even sooner.

The coronavirus (COVID-19) spreads at an 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.
In addition, attempts have to be made to formulate systematic strategies to prevent such future
zoonotic outbreaks.

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