Send Orders for Reprints to reprints@benthamscience.

net

Coronaviruses, 2021, 2, e030821190295

REVIEW ARTICLE
ISSN: 2666-7967
eISSN: 2666-7975

A Coadunation of Biological and Mathematical Perspectives on the Pan-

demic COVID-19: A Review
BENTHAM
SCIENCE

1 1 2 2 1,*
Sahar Qazi , Kayenat Sheikh , Mo Faheem , Arshad Khan and Khalid Raza

1
Department of Computer Science, Jamia Millia Islamia, New Delhi-110025, India; 2Department of Mathematics,
Jamia Millia Islamia, New Delhi-110025, India

ARTICLE HISTORY
Received: June 30, 2020
Revised: November 03, 2020
Accepted: November 08, 2020
Abstract: Background: Coronavirus disease 2019 (COVID-19) outbreak has created an emergen-
cy globally, and social distancing and isolation are the only solution to prevent its spread. Several
countries have announced a full lockdown to tackle this pandemic. The coronavirus family is inclu-
sive of pathogens of both- animal species and humans, encapsulating the isolated severe acute respi-
ratory syndrome coronavirus (SARS-CoV). Researchers around the globe have been dexterously
working to decode this lethal virus. Many mathematical frameworks have also been depicted,
which have helped to understand the dynamics of the COVID-19.
Methods: This systematic review highlights the virus genomic composition, preliminary phyloge-
netic analysis, pathogenesis, symptomatology, diagnosis, and prognosis along with mathematical
models of disease transmission and dynamics.

DOI:
10.2174/2666796702666210114110013
Results: Our preliminary phylogenetic analysis of the novel coronavirus sequence discerns that al-
though shares its lineage with SARS, BAT-CoV, Beta-BAT-SARS, however, this protein is highly
dissimilar to its ancestors. The widely prominent amino acid residues found in the protein are ala-
nine (ALA), aspartic acid (ASP), phenylalanine (PHE), leucine (LEU), aspartic acid (ASP), threo-
nine (THR), valine (VAL), tyrosine (TYR) and asparagine (ASN) that are responsible for its repli-
cation process.

Conclusion: Research on coronaviruses continues towards developing a strong understanding of

the rapidly evolving viral replication and its transmission between individuals.

Keywords: SARS-CoV-2, COVID-19, coronavirus, viral pandemic, nCoV-19, mathematical modeling.

1. INTRODUCTION Latin American countries. The number of cases of

A novel coronavirus (nCoV), named -2019-nCoV”, is
causing the deadliest pandemic since late 2019 to mid-2020,
defined as the coronavirus disease 2019 (COVID-19) by the
World Health Organization (WHO) and is known as severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It
is responsible for the recent sequential spread which began
in Wuhan, China, in early December 2019) [1-4]. This out-
burst has been affiliated with the humongous scale of the sea-
Coronaviruses
th
COVID-19 has drastically grown up since 16 March 2020
outside China. It is said that the carriers and reservoirs of
this virus are bats and snakes [2, 6]. Fig. (1) depicts the trans-
mission of COVID-19 from Wuhan, China to the globe.
Coronaviruses belong to the Nidovirales order and are
enveloped single-stranded positive-strand RNA virus with a
genome of ~30kb. The order includes- Coronaviridae,
Arteriviridae, and Roniviridae families, wherein, the Coron-

food and animal market in Wuhan, which has been the poten-
tial site of the spread of the virus infection. According to the
Chinese Center for Disease Control and Prevention reports
[5], the number of infected people has grown from hundreds
to thousands not only in China but around the globe. During
February-March, 2020, the apex spread of this viral disease
has latched itself to people and is growing rapidly in Europe,
North America, Asia, and the Middle East, while the first
confirmed cases were identified in African and
* Address correspondence to this author at the Department of Computer Sci-
ence, JamiaMilliaIslamia, Jamia Nagar, New Delhi-110025, India;
Tel/Fax: +91-11-26981717; E-mail: kraza@jmi.ac.in
avirinae encapsulates the Coronaviridae family and the
Torovirinae families respectively [7]. The coronavirus fami-
ly is inclusive of pathogens of both- animal species and hu-
mans, encapsulating the isolated severe acute respiratory syn-
drome coronavirus (SARS-CoV). Human coronaviruses
were first described in the 1960s and are said to have the
onus for severe respiratory tract infections [7]. The coron-
aviruses are responsible for leading to serious respiratory
and gastrointestinal tract infections. They further have bifur-
cations in general, namely- α-coronavirus, β-coronavirus, γ-
coronavirus, and δ-coronavirus [8]. Alpha and Betacoron-
aviruses infect mammals while Gamma and Deltacorona
viruses infect birds [9]. Few human infecting coronaviruses

2666-7975/21 $65.00+.00 © 2021 Bentham Science Publishers

1
Coronaviruses, 2021, Vol. 2, No. 9 e030821190295
Fig. (1). Diagrammatic representation of COVID-19 spread from Wuhan City, China to the globe. (A higher resolution / colour version of
this figure is available in the electronic copy of the article).
have been identified lately- for Alphacoronaviruses (HCoV-
-NL63 and HCoV229E) whereas, Betacoronaviruses are in-
clusive of HCoV-OC43, HCoVHKU1, Middle East respira-
tory syndrome coronavirus (MERS-CoV) severe acute respi-
ratory syndrome coronavirus (SARS-CoV), and more recent-
ly, SARS-CoV-2 (COVID-19) [10]. A comparison among
MERS-CoV, SARS-CoV, and SARS-Cov-2 is shown in
Table 1 [11, 12].
The rationale behind the execution of the current study is
to understand the dynamics of the evolving novel coron-
avirus (nCoV). Although, the genomic size of the virus is
very small, yet it has the potential to cause lethality in hu-
mans. Previous studies executed on the coronavirus strain
have revealed that it is responsible for severe respiratory
tract infections but does not hold any potential of morbidity
and mortality. Henceforth, it becomes crucial to understand
what has been altered in this coronavirus strain, which
2
Qazi et al.
makes it so different from its ancestral lineage. We have exe-
cuted a systematic literature review on the global pandemic
caused by this petite novel coronavirus (nCoV), which will
surely aid in understanding the genomic organization, its life
cycle, pathophysiology in both animals and humans, its
symptomatology, along with the latest detection and diagno-
sis and treatment strategies, which are being currently de-
ployed for clinical trials. Also, our study aims to depict the
evolutionary spectra of the novel coronavirus strain and why
it differs from its ancestor's combination with previously de-
scribed mathematical models predicted for the novel coron-
avirus (nCoV-19) bat-to-human and human-to-human
spread elicited from China. This systematic literature review
will be helpful for researchers working in decoding the un-
derlying mysteries of this novel coronavirus (nCoV) and to
apprehend its plausible genetic modifications, which lead to
its anarchistic functioning in humans leading to infection
and mortality at a wide scale.
A Coadunation of Biological and Mathematical e030821190295 Coronaviruses, 2021, Vol. 2, No. 9

Table 1. A comparison among MERS-CoV, SARS-VoV and SARS-CoV-2.

Comparison Parameters MERS-CoV SARS-CoV SARS-CoV-2 (COVID-19)

Host Dromedary camels Bats, Civet cats Bats, Civet cats, Snakes
Guangdong province of Southern Chi-
Outbreak source/year Saudi Arabia (2012) Hubei province, Wuhan, China (2019)
na (2002)
Zoonotic transmission, Human-to-human, Respiratory droplets Human-to-human,
Mode of transmission Limited human-to-human, Respiratory from sneezing or coughing, faecal Respiratory droplets from coughs or
droplets from coughs or sneezes transmission sneezes
Fever
Cough
Respiratory infection
Pneumonia
Shortness of breath
Symptoms Runny nose X
Diarrhoea X
Nausea/vomiting X
Persistent pain or pressure in the chest, Ina-
The weakened immune system, kidney Malaise, Myalgia, Headache, Shiver-
Others bility to arouse,
failure ing, Loss of appetite, Extreme fatigue
Bluish lips or face
Diabetes, Renal failure, Chronic lung Diabetes, Hepatitis, Immuno-compro- Diabetes, Heart disease, Lung disease, Im-
Severe illness risk factors
disease, Immuno-compromised mised muno-compromised
2% (might change as the reported cases are
Case Fatality Ratio (CFR) 35% 11%
not final)
Lung radiography,
Diagnostic methods Lung radiography Lung radiography, RT-PCR, CT-scan
RT-PCR

2. MODUS OPERANDI FOR THE SYSTEMATIC LIT-
ERATURE REVIEW
We selected to pen down a Systematic Literature Re-
view (SLR) on the worldwide outbreak caused by the novel
coronavirus nCoV-19. Our basic motive was to provide a
critical, synthesized, evaluative, and a summarized presenta-
tion of the current status of the pandemic. Thus, we re-
trieved 100+ research articles from various literature reposi-
tories namely- PubMed (PMC), Scopus, Google Scholar,
Lazy Scholar, and My Science Work. We also utilized the of-
ficial websites of the World Health Organization (WHO),
Centers for Disease Control and Prevention (CDC) [12], and
the Indian Council of Medical Research (ICMR). For the
progression of this review, we used keywords such as -hu-
man coronavirus”, -novel coronavirus”, -nCoV-19”, and -
SARS-coronavirus”, -MERS-coronavirus”, -Beta-BAT-
SARS-coronavirus”, and -coronavirus mathematical
models”. Our inclusion criterion of research and review pa-
pers was based on the origin of the virus, i.e., the articles
must have these SARS/MERS/Beta-bat-SARS origins,
whereas we excluded articles that reported animal coron-
avirus infections as we have stringently highlighted the po-
tential of human coronavirus.
3. GENOMIC COMPOSITION
It has been observed that RNA viruses encompass a se-
lective packaging of their genomes. The first coronavirus
packaging signal was studied thirty years back [13] howbeit;
its preliminary functioning is still unknown. It is being reiter-
ated here that these zoonotic viruses are composed of a lin-
ear positive-sense RNA genome of about 30 kb, which is in-
clusive of a 5’ cap entity in combination with a 3’ poly (A)
tail used as an mRNA for the translation of the replicase po-
lyproteins [7]. The Non-Structural Proteins (NSP) take up
the majority of the genome than the accessory proteins. The
5’ end includes - a preliminary sequence and an Untranslat-
ed Region (UTR) having many stem-loop structures. More-
over, many transcriptional sequences are attached at the initi-
ation point of every structural gene required for their expres-
sion. The 3’ UTR is composed of RNA structures used for
replication and production of the viral RNA (Fig. 2). The ac-
cessory proteins have an important role in viral proliferation
even though not in replication [7].
There are three important parameters for coronavirus
genome architecture arrangement - a) viral infection in-
cludes replication of gRNA and the formation of subgenom-
ic (sg) RNAs, which act as mRNAs for genes present down-
stream, b) coronaviruses have helically symmetric icosahe-
dral nucleocapsids [14-16], which is simply not common for
a positive-strand RNA virus, and c) the arrangement of the
nucleocapsid into the virion is initiated via interactions be-
tween the -C terminal of multiple monomers of N and M pro-
teins [17, 18]. The packaging of coronavirus is quite a chal-
lenge to obtain a specific recognition and selection of gR-
NAs and other RNA species [18]. Fig. (2) represents the ge-
nomic composition of the novel coronavirus strain inclusive
of initial primary ORFs and various accessory proteins.

3
Coronaviruses, 2021, Vol. 2, No. 9
Fig (2). Genomic composition of the virus. (A higher resolution / colour version of this figure is available in the electronic copy of the arti-
cle).
4. PRELIMINARY PHYLOGENETIC ANALYSIS
The complete genomic sequence of Wuhan coronavirus
has been available, one with accession ID: MT019531.1,
th
which was previously isolated on 11 Feb 2020 while the
other with accession ID: NC_045512.2 has been recently
th
uploaded on 30 March 2020. The complete genome con-
sists of 29,903 base pairs while beta-CoV has 29899 bp on-
ly. The complete RNA-dependent RNA polymerase [Severe
acute respiratory syndrome coronavirus 2] accession ID:
YP_009725307.1, has been available online on GenPept,
th
NCBI since 30 March, 2020. We executed a preliminary
phylogenetic and statistical analysis on this SARS-protein,
which has a length of 932 amino acids. We ran a protein
BLAST and retrieved 100 best matching sequences to our
query protein which had E-value 0.0, query coverage of
100%, and identity percentage of 100%. These sequences
were then subjected to MEGA 5.0 software for further analy-
sis. On identification of conserved residues, we figured out
that not a single residue matches its similar proteins. Al-
though it is similar to SARS, BAT-CoV, Beta-BAT-SARS,
this protein is highly dissimilar to its ancestors. The widely
4
e030821190295 Qazi et al.
prominent amino acid residues found in this protein are
namely- alanine (ALA), aspartic acid (ASP), phenylalanine
(PHE), leucine (LEU), aspartic acid (ASP), threonine
(THR), valine (VAL), tyrosine (TYR) and asparagine (AS-
N), respectively, which could be responsible and involved in
the replication process. Table 2 represents the essential align-
ment information about conserved residues, Mark Parsim in-
formative residues, variable sites, and singleton sites, respec-
tively. We also executed a neutrality test namely Tajima’s
test to assess the equality of the evolutionary rate between se-
quences A (YP009725307) and B (YP009724389), with se-
quence C (QH282463) used as an outgroup in Tajima's rela-
2
tive rate test. The χ test statistic was 0.00 (P = 1.00000)
with 1 degree[s] of freedom. Moreover, Tajima’s neutrality
analysis involved 100 amino acid sequences; there were a to-
tal of 932 positions in the final dataset. Our results have
been phylogenetic analysis portrayed in Tables 2-4. Our pre-
liminary phylogenetic analysis discerns that the common an-
cestral group of coronavirus has no similarities with the nov-
el coronavirus sequence (YP009725307) and shows differ-
ing nature.
A Coadunation of Biological and Mathematical
Table 2. Important alignment information of 100 sequences.
Description
Conserved Residues
Mark Variable Sites
Mark Parsim Informative Sites
Mark Singleton Sites
Table 3. Results from the Tajima's test for 3 sequences.
S.No. Configuration
1. Identical sites in all three sequences
2. Divergent sites in all three sequences
3. Unique differences in Sequence A
4. Unique differences in Sequence B
5. Unique differences in Sequence C
Table 4. Results from Tajima's neutrality test.
m S ps Θ π
100 46 0.049356 0.009533 0.016110
5. VIRUS STRUCTURE
Coronaviruses are large (diameter= ~150-160 nm),
round, bulbous structures. The viral structure can be classi-
fied into two parts: the viral envelope, and the nucleocapsid
[19].
5.1. The Viral Envelope
It is the outermost part of a virus, providing strength,
rigidity, and a definite shape. It includes Spike (S), Enve-
lope (E), and Membrane (M). The subgroup of coronavirus-
es like Betacoronavirus subgroup A has protein structures
embedded in the membrane known as Hemagglutinin Es-
terase (HE). SARS-CoV-2 differs from other viruses be-
cause it expresses Hemagglutinin esterase [19].
5.1.1. Glycosylated Spike (S)
For an easy entry inside the host cell, the virus uses a
densely glycosylated spike protein. Spike (S) protein is a
class I fusion protein. It exists in a metastable prefusion con-
formation. This conformation undergoes a substantial struc-
tural rearrangement for fusion between the viral membrane
and host cell membrane. The 3D structure of the spike de-
monstrates that there exists a single Receptor Binding Do-
main (RBD) in the up conformation. RBD undergoes a
hinge-like movement. The S1 subunit becomes visible along
with the S2 unit (more stable). The S1 subunit decides the
virus-host range and cellular tropism by RBD. The S2 subu-
nit carries out the membrane fusion of virus and cell by HR1
and HR2. This stochastic RBD movement is found in close-
ly related beta-coronaviruses such as SARS-CoV and MER-
S-CoV and distantly related alpha-coronaviruses (PEDV).
e030821190295 Coronaviruses, 2021, Vol. 2, No. 9
This mechanism in 2019-CoV indicates a similar trigger sys-
tem in Coronaviridae, where a receptor (ACE2) that binds
Number to the RBDs forms 3 RBD up conformations (unstable) that
5646/7105 result in the shredding of S1 and S2 refolding. Fig. (3) de-
monstrates the RBD of a spike complexed with the ACE2 re-
1454/7105
ceptor (Protein Data Bank).
1114/7105
The overall spike structure of 2019-nCoV is similar to
340/7105 SARS-CoV spike. The minor difference between the two is
the position of RBD in their respective down conformations.
The spike of SARS-CoV-2 has a higher affinity for the
ACE2 receptor on the host, approximately 10 times more
Count than the SARS-CoV affinity [19-23]. Polypeptide 1(in blue
932
color) is ACE2 (Angiotensin-converting Enzyme 2, Homo
sapiens). It has four binding sites for spike protein namely,
0 6LZG_A_AC3_4, 6LZG_A_AC2_4, 6LZG_A_AC4_2, and
0 6LZG_A_AC1_4. Catalytic activity: (angiotensin II + H2O
= angiotensin-1-7 + L-phenylalanine). Microbial infection in-
0
teracts with Human coronavirus NL63/HCoV-NL63 spike
0 glycoprotein. Polypeptide 2 (in red color) is the Spike pro-
tein of nCoV-19. It is the site of attachment to the ACE2 re-
ceptor of the host human cell for entry. Small molecules like
NAG (N-acetyl-D-glucosamine) are found on both the
D chains whereas Zn ion is found only on the ACE2 receptor.
2.179389
5.1.2. Envelope Protein (E)
These are very short and integral membrane proteins
with a length of 76-109 amino acids approximately, from
8.4 to 12 kDa in size. Within the envelope, there is a short
and hydrophilic amino terminus with about 7-12 amino
acids. Also, a large hydrophobic TMD of 25 amino acids
that end with a long, hydrophilic carboxyl terminus is pre-
sent. The amphipathic alpha-helix of the hydrophobic region
of TMD undergoes oligomerizations to form pores for ionic
movements in membranes. The TMD comprises 2 neutral
and non-polar amino acids (valine and leucine) that impart
strong hydrophobic character to the E protein. The overall
net charge is zero. The middle region is not charged and
flanks on one side by N terminus and on another side by C
terminus (exhibits some hydrophobicity) of variable charge.
Postsynaptic Density Protein 95 (PSD95) (PDZ)-binding-mo-
tif (PBM) is the bonding motif known in E protein. The
PDZ domain (protein-protein interaction module) can bind
to the C-terminus for target proteins such as cellular adapter
proteins involved in host-cell processes important for viral
infection [19]. The PBM region can either be deleted or mu-
tated but it reverts to a pathogenic state. PBM mutations can
be tolerated but a reasonably intact PBM domain is still ne-
cessary to avoid revertant mutants. The viral envelope is
formed by the interaction between E protein and M protein
[19].
5.1.3. Membrane Protein (M)
The integral protein, membrane protein (M) is a region
where the assembly for virus occurs. It is responsible for the
transmembrane transport of nutrients, bud release and enve-
lope formation, which determine the shape too. There are
two functionally distinct forms of coronavirus M protein.
Both types of M visible on viral particles are larger than
5
Coronaviruses, 2021, Vol. 2, No. 9 e030821190295
Fig. (3). Diagramatic representation of ACE2 and RBD of spike and their binding interface (PDB). (A higher resolution / colour version of
this figure is available in the electronic copy of the article).
assumed for a single M protein. MLONG protein type deter-
mines the formation of a convex, rigidified viral envelope.
The spike incorporation is related to the size of particle and
spike clusters in regions where generally MLONG is present. It
is statistically evident now [20].
5.1.4. Hemagglutinin Esterase (HE)
The Hemagglutinin Esterase (HEs), a homodimer class I
membrane protein, is a family of viral envelope glycopro-
teins that causes reversible attachment to O-acetylated sialic
acids by acting both as lectins and as Receptor-Destroying
Enzymes (RDEs). Enzymatic activity is associated with the
Hemagglutinin-Esterase (HE), CoV HEs lacking membrane
fusion activity and, in the virion, they are accessory to the
spike protein S [21].
5.2. The Nucleocapsid
It is protected by the viral envelope by strong surround-
ings. N protein is bound to the RNA genome to form a nucle-
ocapsid. The role of N protein is its potential ability to coun-
ter host immune responses as a viral suppressor protein of
RNAi (VSR). The VSRs suppress the RNAi to overcome
the host defense to establish infection [22].
6. THE LIFE CYCLE OF CORONAVIRUS
The novel Coronavirus is unique in its replication strate-
gy. The exact pathway for its interaction with the host cell
6
Qazi et al.
and duplication is fully not known yet. However, based on
the current literature, we discern its probabilistic life cycle.
The stages of SARS-CoV-2 life cycle can be divided as:
6.1. The Entry of the Virus
According to Hoffmann et al. 2020 [23], SARS-CoV-2
can attack the host cell in two ways: via fusion with the plas-
ma membrane (cell-surface or early endosome pathway) or
through endosomal pathway using cathepsins to activate
spike protein. The spike protein (S) of the virus has the Re-
ceptor Binding Domain (RBD) that comes in contact with
the Angiotensin-converting enzyme 2 (ACE2 entry receptor)
(Fig. 3). The spike protein gets activated by the cellular
serine protease TMPRSS2 that is present very close to the
ACE2 receptor. It initiates the fusion of the viral membrane
with the plasma membrane (Fig. 4) [23]. The plasma mem-
brane fusion entry is less provocative in activating the cell
immunity, rather it becomes easy for the virus particle to re-
plicate [24].
6.2. Translation of Viral Machinery and Replication
After the virus enters the host cell, the RNA of the virus
is released into the cell, and the polyproteins start to trans-
late. The coronavirus genomic RNA encodes Non-Structural
Proteins (NSPs) that have an essential role in viral RNA syn-
thesis, and structural proteins which are important for the as-
sembly of the virion. Polyproteins pp1a and pp1ab are trans-
A Coadunation of Biological and Mathematical
lated first, which are later cleaved by the Papain-like pro-
tease (Pl pro) and 3C-like protease (3CL pro) to form func-
tional NSPs as Helicase or the RNA replicase-transcriptase
complex (RdRp) [25].
Fig. (4). Interaction between S protein and the ACE2 receptor for
viral entry. (A higher resolution / colour version of this figure is
available in the electronic copy of the article).
6.3. Translation of Viral Structural Proteins and Assem-
bly
RdRp is responsible for the replication of structural pro-
tein RNA. Structural proteins (S), Envelope (E), and Mem-
brane (M) are translated by ribosomes that are bound to the
endoplasmic reticulum (ER) and presented on its surface as
preparation of virion assembly [7]. The nucleocapsid (N) re-
mains in the cytoplasm and is assembled from genomic
RNA. They fuse with the virion precursor, which is then
transported from the ER through the Golgi apparatus to the
cell surface via small vesicles [7].
6.4. Release
Virions are transported to the cell surface in small bag--
like structures called vesicles. By the process of exocytosis,
virions are released from the cell into the extracellular re-
gion. It either follows the traditional method of transporta-
tion, through the Golgi body, or it has its unique exit path-
way that is not known yet. In most of the Coronaviruses, the
S protein does not assemble into virions but transits to the
surface of the cell to mediate cell-cell fusion between the in-
fected and uninfected cells. As a result of such interaction,
multinucleated huge cells are formed that allow the spread-
ing of the virus in the infected organism without any detec-
tion and neutralization by the specific antibodies [7].
7. PATHOGENESIS: ANIMAL AND HUMAN
7.1. Animal Coronaviruses
Coronaviruses are responsible for causing myriad diseas-
es in animals. Feline enteric coronavirus (FCoV) has been
discerned to lead a mild or asymptomatic infection in domes-
tic cats, which later on develops into a highly virulent strain
of FCoV (Feline Infectious Peritonitis Virus, FIPV) and the
disease is known as - feline infectious peritonitis (FIP),
which is of both the forms-wet and dry, quite similar to the
sarcoidosis, which is a human disease. This virus is said to
e030821190295 Coronaviruses, 2021, Vol. 2, No. 9
be lethal as it disturbs the cytokine and the chemokine ex-
pression leading to lymphocyte depletion [26]. Howbeit, this
hypothesis is still not confirmed yet. On the other hand,
bovine CoV, rat CoV, and infectious bronchitis virus (IBV)
lead to benign to acute respiratory tract infections in cows,
rats, and chickens respectively. Bovine CoV has been held
responsible for an apex loss in the cattle industry as it infects
cattle and spreads to other animals such- camel, deer, and
elk, causing winter dysentery (diarrhea), dehydration, weight
loss, animal depression, lackadaisical attitude and also re-
duced milk production. IBV strains, namely- γ-coronavirus,
are the causative agents that affect the urogenital tract of
chickens causing kidney disorders. Moreover, it reduces egg
production in chicken and abnormal weight gain in chick-
ens, which is a significant loss in the poultry industry annual-
ly [26]. Researchers [27] have identified a type of coron-
avirus from the liver of Beluga whales enduring respiratory
infection namely- SW1, howbeit, electron microscopy failed
to confirm whether it belonged to the coronavirus family.
There has always been much interest to study bat-based coro-
naviruses. The novel coronavirus (nCoV-19) is also said to
be a BAT-SARS-Coronavirus, especially, Beta-BAT-SARS
coronavirus. SARS and MERS coronaviruses and many
other bat-based novel coronaviruses have been identified pre-
viously. Another coronavirus, Mesoniviridae, has been iden-
tified to infect insects [28, 29]. The most widely studied ani-
mal coronavirus is the murine hepatitis virus (MHV) respon-
sible for neurological, respiratory, hepatic, and enteric dis-
eases in mice. For instance, MHV-1 leads to serious respira-
tory disease in A/J and C3H/HeJ mice, A59, while MHV-3
causes serious hepatitis. JHMV leads to encephalitis [30].
7.2. Human Coronaviruses
Before SARS-CoV epidemic, coronaviruses were consid-
ered to be not-so-serious respiratory infections in humans. It
is being reiterated that two major coronaviruses in humans
are- Alpha- coronaviruses (HCoV-229E and HCoV-NL63)
and are Beta-coronaviruses (HCoV-OC43 and HCoV-
-HKU1). HCoV-229E and HCoV-OC43 were retrieved 50
years ago [31-33]. HCoV-NL63 and HCoV-HKU1 have
been determined during the previous SARS-CoV outbreak
[34, 35]. These viruses lead to respiratory tract infections in
15-30% of the human populace and have been observed to
be very serious in the elderly population as well as in individ-
uals who endure cancer or any other immunological disorder
[7]. HCoV-NL63 has the onus of causing laryngotracheitis
[36]. One interesting aspect of these viruses is the variance
in their genetic variability [7].
A group 2b β-coronavirus namely - SARS-CoV was first
determined, which was responsible for Severe Acute Respira-
tory Syndrome (SARS) spread in China during the year
2002-2003. During this outburst, around 8098 cases were ob-
served with 774 lethality leading to a death rate of 9%. Elder-
ly people were morbid and mortality was also high in this
section of individuals. This virus often attacks the epithelial
cells within the lung and has the potential to penetrate the
macrophages and dendritic cells [37, 38]. The novel coron-
avirus which has now become a pandemic around the globe
7
Coronaviruses, 2021, Vol. 2, No. 9 e030821190295
is also said to belong to the beta-BAT-SARS-coronavirus
family [39].
Another novel human CoV emerged in the Middle East
back in 2012 whose nomenclature is-Middle East Respirato-
ry Syndrome-CoV (MERS-CoV). It was observed to lead to
sequential zoonotic-based respiratory infections in Saudi
Arabia and other countries in the Middle East [40]. With its
rapid spread, it was assumed that it would lead to an apex
and a very serious outburst, however, in 2013, newer cases
never showed up. In 2014, an unpredictable outshoot of al-
most 200 cases and 40 mortalities from human-to-human
transmission was reported.
8. SIGNS AND SYMPTOMS OF COVID-19
The most common mode of transmission is via inhala-
tion of contaminated/infectious aerosols. The incubation peri-
od of the pathogen is around 3-14 days [41]. The disease
caused by COVID-19 may range from asymptomatic to fatal
disease. Pre-medical health conditions such as hypertension,
chronic obstructive pulmonary disease, diabetes, and cardio-
vascular disease enhance the susceptibility to getting infect-
ed by COVID-19 [42]. Severe complications that might
arise in COVID-19 patients are respiratory distress syn-
drome, septic shock, metabolic acidosis, coagulation dys-
function, and multiple organ failure. Besides, Cytopathic Ef-
fect (CPE) and cytokine storm or sustained inflammatory re-
sponses, hypoxia, septic shock, etc. may be related to the
critical conditions of COVID-19 infected patients (http-
s://www.mayoclinic.org/).
The severity of infection varies from person to person
and even from one age group to another age group [42]. Peo-
ple are more prone to getting serious infection and reestab-
lishment of health might be difficult if they already possess
chronic illnesses and inefficient organs such as kidney or liv-
er dysfunctionalities, heart and blood disorders, poor im-
mune system, endocrine, and metabolic disorders, lung dis-
eases, neurological conditions, and a recent pregnancy, etc.
and people belonging to older age groups, lacking efficient
immune responses also have hazardous effects [42]. With
the changing environment in hand, people get confused with
common cold or allergy to be infected with coronavirus in-
fection since the signs and symptoms are quite similar.
9. DETECTION, DIAGNOSIS AND PROGNOSIS
To diagnose COVID-19, like other viral diseases, it is
composed of techniques that help to determine the presence
of the virus and antibodies which develop in response to the
infection. Because of limited screening, no countries had
trustworthy data on the spread of the virus in their populace
[43].
9.1. Detection and Diagnosis Approaches
9.1.1. Imaging Investigations
A chest CT scan is one of the most prominent imaging in-
vestigations which is aiding medical consultants to screen
for the disease, helping to understand lung pathology. A re-
8
Qazi et al.
cent study, on 919 patients defined the typical early growth
of COVID-19 as -bilateral multilobar ground-glass opacifi-
cation (GGO) along with a posterior spread” [44]. Another
pivotal study discerns that the CT imaging investigation
proves to be better than the RT-PCR method for CVD-19 in-
fection with a sensitivity of 98%, but, since this was per-
formed in China, it cannot be generalized for all [45]. In one
of the recent studies, it was established that Chinese radiolo-
gists showcased about 72-94% sensitivity and 24-94% in
distinguishing nCoV-19 from other viral infections using CT
imaging [46].
9.1.2. rRT-Polymerase Chain Reaction for Virus Detection
Deploying real-time Reverse Transcription-Polymerase
Chain Reaction (rRT-PCR) is the easiest way to figure out
infection in patients which can be done by taking the pa-
tients' respiratory samples such as - nasopharyngeal swab or
sputum sample (CDC, 2020) [12]. These results are avail-
able within a frame of either a few hours from the test to 2
days. This molecular biochemistry examination helps to
identify genomic composition. The initial PCR tests were
produced at Charité in Berlin at the beginning of 2020 using
real-time reverse transcription-polymerase chain reaction (r-
RT-PCR), which has now the main examination for
CVD-19. Around 250,000 kits have been distributed by the
WHO [47]. These PCR-based kits are being deployed by the
Indian Council of Medical Research (ICMR) as well to diag-
nose infected patients. The most reliable diagnostic kits have
proved to have a high sensitivity and specificity, namely- Re-
alStar SARS-CoV-2 RT-PCR kit 1.0, Real-Time Fluores-
cent RT-PCR Kit for detecting 2019-nCoV and TaqMan
2019-nCoV Control Kit v1 (ICMR, https://www.icmr.nic.in/-
content/covid-19#strategy). A research group conducted
[48] tests and discerned that kits namely-R-Biopharm AG,
BGI, KH Medical, and Seegene performed better and must
be deployed for COVID positive cases. In another research
group, some researchers [49] deployed a multidisciplinary re-
search approach to evaluate the performance of the devel-
oped SARS-CoV2 diagnostic test. Their study reveals the ro-
bustness of their kit as it performed well with a 384-well for-
mat qRT-PCR on the QuantStudio 5 instrument using an
RUO Promega one-step master-mix and has a 10 μL vol-
ume. They were able to screen many samples in one go effi-
ciently and the kit also provided specific results in a much
short time of 5 days.
9.1.3. Antibody Identification
Infections can also be diagnosed by determining the anti-
body production in an infected individual, which mainly in-
cludes- antibody IgM and IgG. These are useful in identify-
ing the immunity of a populace in the examination. Anti-
body identification tests can be performed by point of care
testing (PoCT). For identification by PoCT, a single blood
sample is taken using puncturing the skin. It has been proph-
esized that the United States will launch an all-time PoCT
by the 30th March 2020 (FDA, 2020). As the case of the In-
dian Council of Medical Research is concerned, they have
employed MY LAB company’s PathoDetect assay, which
A Coadunation of Biological and Mathematical e030821190295 Coronaviruses, 2021, Vol. 2, No. 9

aids in identifying the coronavirus pathogens in the infected but none of them are approved yet. Conventionally, it has
patients (ICMR, https://www.icmr.nic.in/content/covid-19#s- been considered that live attenuated vaccines would be effi-
trategy). cacious in targeting the coronaviruses. Vaccine generation
Table 5. Current drug leads subjected to clinical trials against for coronaviruses is an apex challenge and has seen many up-
COVID-19. s-downs in the past [51].
Since March 2020, many drug candidates have been sub-
Name of Lead Number of Administration Duration jected to clinical trials for their development of vaccines and
Trials treatments. These drugs mainly include compounds that are
Stem Cell Therapy (SCT) 23 N/A 5-7 days used to treat flu, malaria, and Ebola disease [52]. Table 5
summarizes the conventional drug leads, which have been
Lopinavir/Ritonavir 15 Oral 7-14 days
subjected to clinical trials for COVID-19 [53].
Chloroquine phosphate 11 Oral 10days
Umifenovir 9 Oral 14 days 10. MATHEMATICAL MODELS OF COVID-19
TRANSMISSION AND DYNAMICS
Hydroxychloroquine 7 Oral 14 days
COVID-19 has spread rapidly worldwide, and WHO and
Plasma treatment 7 Intravenous -
CDC have labeled it as a -pandemic”. Therefore, it becomes
Favipiravir 7 Oral 10-14 days necessary to develop and use the mathematical approach to
Methylprednisolone 5 Intravenous 3-7 days study the pathogenesis of SARS-CoV-2 in humans. There is
scarce literature available that is inclined towards the mathe-
Remdesivir 5 Intravenous 5-10 days
matical modeling for this virus [54-57]. The motive of these
Oseltamivir 2 Oral 14 days researches was to calculate the basic reproduction number ()
Baloxavirmarboxil 2 Oral/ Intravenous 7 days by using Ordinary differential equations (ODEs), Markov
Chain Monto Carlo methods (MCMC) [57], or using intrin-
Thalidomide 2 Oral 14 days
sic growth rate and serial intervals [54, 58, 59]. In this sec-
Darunavir/cobicistat 2 Oral N/A tion, we discuss nine major models that exist in the literature
Thymosin 2 Subcutaneous 5 days that can help us understand the transmissibility of the
SARS-CoV-2 from its natural reservoirs to humans.
PD-1 blocking antibody 2 Intravenous N/A
Tocilizumab 2 N/A N/A 10.1. The Bats-Hosts-Reservoir-People (BHRP) Trans-
Intravenous Immunoglobulin 2 Intravenous 3-5 days
mission Network Model
Ozonated autohemotherapy 2 N/A N/A Researchers [13] developed a mathematical model for si-
mulating the phase-based transmissibility of the SARS-
Type 1 Interferon injection 1 N/A N/A
CoV-2. They used the data from the published literature
Interferon nebulization 1 N/A N/A [59-63]. The assumption was that the virus first spreads
Losartan N/A N/A N/A among the bats and then is transmitted to some wild ani-
mals, which were hunted and lastly delivered to the seafood
9.2. Prognosis market. These were now the ‘reservoir of the viruses. People
Since the outbreak of nCoV-19 worldwide, pharmacists visited the market and therein got infected. The model is
and researchers are working towards determining the poten- based on the following parameters:
tial drugs, which can be used as an efficient treatment for 1) The bats (B) and hosts (H) had been divided into
COVID-19. The entire globe is desperate to find effective quadrants namely - susceptible bats (Bs), exposed bats (Be),
treatments for this treacherous viral disease. Although, viral infectious bats (Bi), removed bats Br and susceptible hosts
diseases have affected mankind in the past, however, we still (Hs), exposed hosts (He), infectious hosts (Hi), and removed
lack anti-viral therapeutics. Traditionally, interferons (IFNs) hosts Hr respectively; while the people into five categories -
are not much effective against coronaviruses [50]. IFNs suspicious people (Ps), exposed people (Pe), symptomatic in-
along with ribavirin have showcased to increase the efficacy
fected people (Pi), symptomatic infected people (Pa), and re-
when IFNs were employed individually against coronavirus-
es. The previous outbreaks of the SARS-CoV and MERS-- moved people.
CoV have allowed determining the humongous number of 2) The SARS-CoV-2 in a reservoir (the seafood mar-
potential anti-viral drug leads namely- viral proteases, poly- ket) was taken as W. The retail purchase rate of the hosts in
merases, and entry proteins. Unfortunately, much work yet the market was assumed as ah. The transmission rate of infec-
remains in this domain of research. Approved vaccines are tion through symptomatic infected people and asymptomatic
present for IBV, TGEV, and Canine CoV, however, they are infected people into W was denoted by μP and μP'.
not much effective in preventing the disease. As far as
SARS-CoV is concerned, several potential vaccines such as- 3) nb, nh and np denoted the birth rate of bats, hosts, and
recombinant attenuated viruses, live virus vectors, or mono people, respectively, whereas mb, mh and mp were taken as
viral proteins expressed from DNA plasmids, are available the death rate of the latter. The birth and death rates of peo-

9
Coronaviruses, 2021, Vol. 2, No. 9 e030821190295
ple during the outbreak were quite less. However, people
who traveled, either from migration or immigration across
the Wuhan city reason being a bar, thus, np and mp was taken
as the rate of people coming into the city of Wuhan and go-
ing out of the city of Wuhan accordingly. Nb, Nh and Npwere
taken as the total number of bats, hosts, and people, respec-
tively.
4) ∆b, ∆h and ∆p denoted the newborn bat, newborn
host, and newborn people, respectively and were defined by:
, and (1)
(1)
5) The incubation period of the bat infection, host in-
fection and human infection was denoted by 1/wb, 1/wh and
1/wp respectively, and the infectious period of bat infection,
host infection and human infection was denoted by 1/Yb,
1/Yh and 1/Yp, respectively. The transmission rate of infec-
tion through sufficient contact, from Bi to Bs, Hi to Hs and Pi
to Bswas defined by βB, βH and βP, respectively. The latent pe-
riod of human infection was denoted 1/wp by and the trans-
mission rate of infection through sufficient contact from PI
to W was denoted by βW.
The dynamic and transmissibility of this disease are mod-
eled by the following system of first-order differential equa-
tions [13].
(2)
(3)
(4)
(5)
(6)
(7)
The transmissibility of asymptomatic infection was tak-
en as ½ times of transmissibility of symptomatic infection,
i.e. k = 0.5, which was the same as influenza [59]. Since
2.87 million people moved out from Wuhan city between
January 10-24, 2020, therefore the moving rate was 0.2 mil-
lion per day and the total population of Wuhan city at the
end of 2018 was about 11 million (CBN, 2020 &Wuhan
Govt, 2020). Therefore, np = mp = 0.1 x = 0.0018. The
relative shedding rate of Ap in contrast Ip to was also taken as
0.5. Initially, the prevalence of the virus in the market was
taken as 1/100000. Since it is a positive single-stranded
RNA virus, it cannot sustain in the external environment for
long, howbeit, could stay in an unknown host for 10 days
(i.e.= 0.1). The estimated value of R of SARS-CoV-2 was
10
Qazi et al.
2.2, where Li et al. [53] applied intrinsic growth rate and se-
rial intervals-based method.
10.2. Susceptible-Exposed-Infectious-Recovered (SEIR)
Model
The SEIR model was proposed [64], and the group
studied the practical intercession of people’s health, and mea-
sures were also included. The data used in this model has
been taken from the WHO situation report, the National
Health Commission of the People’s Republic of China, and
the Health Commission of Wuhan City and Hubei Province
[65, 66]. This research wasbased on the determination of the
dynamic and epidemiology status of the disease by calculat-
ing the basic reproduction number. Let the susceptible popu-
lation beSp, exposed population is Ep, the pre-symptomatic
population is Ap, the infected population is Ip, the hospital-
ized population is Hp and the recovered population is Rp. The
quarantined susceptible, isolated exposed and isolated infect-
ed population are denoted by SQ, EI and II respectively. The
transmission and dynamic of the virus are modeled by the
following system of differential equations:
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
In simulation, the initial guess is taken as the data given
on 10th January, 2020 from the Health Commission of Hubei
Province, R is the number of subsequently recovered popula-
tion which is 2.0, the number of quarantine population SQ
was 739 and set Hp (0) = 2. The estimated reproduction num-
ber considered was 6.47 [64].
10.3. Time-Dependent Dynamic Model (TDDM)
Tang and collaborators updated their SEIR model using
the latest available data on January 23, 2020 [67] and called
this model TDDM. In the TDDM model, it has been as-
sumed that the contact rate is time dependent variable and is
given by,
(16)
A Coadunation of Biological and Mathematical e030821190295
Where c initial contact is the rate on January 23, 2020, cb
is the minimum contact rate by applying restrictions and con-
trol strategies, and r1 denotes the exponential decreasing rate
of contact rate.
The transition rate of symptomatic infected individuals
to the quarantined infected class δi(t) has been taken as an in-
creasing function with respect to time,
(17)
The governing differential equation of this model is the
same as the governing differential equation of the previous
model, the only difference is the term δi replaced by and δi(t)
and c is replaced by c(t).
The effective daily reproduction number is defined by
(18)
The same techniques and methods as in the SEIR model
[65] had been applied for simulating the TDDM model. The
estimated reproduction number in this study is 6.47.
10.4. Conceptual Model
Researchers [68] proposed the conceptual model where
individual behavioral reactions and governmental actions
were also included. Susceptible-Exposed-Infectious-Re-
moved (SEIR) model had been carried out with two extra
compartments, namely ‘D’ mimicking the public perception
of risk regarding the 54 number of severe and critical cases
and deaths, and ‘C’ representing the number of cumulative
cases.
The following system of differential equations is used
for modeling [69].
(19)
(20)
(21)
(22)
(23)
(24)
(25)
Where N is the total population, S, E, I, Rdenote the sus-
ceptible, exposed, infected and removed population respec-
tively, and β(t) is the transmission rate that can be computed
using the following relation,
Coronaviruses, 2021, Vol. 2, No. 9
(26)
The basic reproduction number is calculated by employ-
ing the next-generation matrix approach and is given by,
(27)
In this model, the estimated value of R is 2.8.
10.5. Migration & Emigration Model
The migration and emigration model is based on the data
from December 31, 2019, to January 28, 2020 [56]. In this
study, they assumed that the virus transmission occurred due
to the migration and emigration of people from Wuhan city,
China. Hence, the virus can be exported internationally. Fol-
lowing SEIR model is used for the Wuhan epidemic,
(28)
(29)
(30)
The rate of international case exportation is defined by,
(31)
The expected number of exportation case on day ‘d’ is
calculated by,
(32)
The maximum likelihood estimation for reproduction
number is given by,
(33)
Markov Chain Monte Carlo method was applied for cal-
culating the basic reproductive number. They simulated the
SEIR model by putting the value of R [57].
10.6. SIR Model on Euclidean Network
The SIR model works on the Euclidean network in
which random long-range links between nodes at a
Euclidean distance l have been added with probability
[69]. They used the data from January 21, 2020 to
March 11, 2020. In this model, the total population has been
divided into three categories namely Susceptible populations
(S), Infected population (I) and Removed population (R),
with = . In this model, they assume that the infected peo-
ple either recover or die therefore they both belong to the
same categories while in other models, the death factor has
11
Coronaviruses, 2021, Vol. 2, No. 9 e030821190295
been also taken into account which makes the model more
complicated. The numerical data can be fitted as Khaleque
et al. [70].
(34)
Where a,c and T depend on q (infection probability)and
δ (range of contact), having values 1.15698 × 10-6,
0.0201529 and 5.22 respectively. To fit the model, they cal-
culated the number of cases R(d), where d denotes the Haver-
sine distance in Km from the epicenter. Wuhan and Berga-
mo have been taken as the epicenter for China and Italy, re-
spectively. For large values of d, both show consistency
with the power-law decay
(35)
with γ = 1.85 ± 0.1. The important achievement of this
model is a good agreement with real data. According to this
model, the disease can have control at later stages if the sus-
ceptible people live in quarantine, and mobility is not al-
lowed. Another advantage of this model is that there is no
need to count death as an additional factor, which makes the
model easy to simulate and understand.
10.7. The SEIR Model with Social Distancing Through
Differential Evolution
. In this proposed model [71], the spreading of Covid-19
in Italy and two of its regions, Lombardy and Campania was
extended with Social Distancing (SEIR-SD) model. Re-
searchers [71] have extended the SEIR-SD model using the
definition of social distancing function, which varies over
time. To make the model work properly, one should have
the exact value of the parameter so that it can describe the re-
al-world situation. In this model, the Differential Evolution
technique has been adopted for finding the values of the pa-
rameter. The following system of differential equation is
formed by this model
(36)
(37)
(38)
(39)
Where is the additional parameter in this model. The da-
ta which is used for simulation has been taken from the
Italian Ministry for Health free repository [72], updated on
March 29, 2020. For optimization, the Root Mean Square Er-
rors (RMSE) between the number of infectious cases estimat-
ed by the SEIR-SD model (Ie) and the actual number of in-
fectious people (Ia) has been taken as:
12
Qazi et al.
(40)
Where Nd is the total number of days from the official
onset of Covid-19 in Italy to the last day for which the actu-
al data is available. Using the Differential Evolution tech-
nique, the values of parameters have been estimated as α =
0.33, β = 2.11, γ = 0.50 with RMSE = 9.12-10 and the estimat-
ed basic reproduction number (R) for Italy is 4.2. For Lom-
bardy, the estimated values of parameters are as follows:
α = 0.33, β = 1.96, γ = 0.50 with RMSE = 7.9-9 and R =
3.9. For Campania, the values are as follows α = 0.33, β =
2.25, γ = 0.50 with RMSE = 1.18-10 and R = 4.5.
10.8. A Bayesian Logistic Growth Model
This model has been proposed [73] to study the dynamic
of Covid-19 in the state of New York. The author used Baye-
sian Estimation for the logistic growth model to study the dy-
namics of this virus. This model is based on the data from
March 4, 2020 to March 31, 2020, which is publicly avail-
able at https://github.com/nytimes/covid-19-data/blob/mas-
ter/us-states.csv. The differential equation for this model is
given by:
(41)
Where C denotes the cumulative number of infected indi-
viduals, r denotes the infection rate and k denotes the upper
limit of the infected individual during the epidemic. The ex-
act solution of the equation is given by:
(42)
where the value of coefficient A can be calculated using
the initial condition. The Bayesian estimates give a more ac-
curate approximation as compared to others existing in the
literature such as Least Squares and Maximum Likelihood
approaches. The advantage of this model is that it is capable
to describe the dynamic of Covid-19 even when the number
of data rows is relatively small and the upper asymptote
seems not to have been approached yet.
10.9. Generalized SEIR Model
This model is based on public data of the National
Health Commission of China from Jan 20, 2020 to Feb 9,
2020 [74]. They generalized the SEIR model by introducing
seven different states namely susceptible cases (S(t)) , insus-
ceptible cases (P(t)), exposed cases (E(t)), infectious cases
(I(t)), quarantined cases (Q(t)), recovered cases (R(t)) and
death cases (D(t)). The basic reproduction number in this
model has been calculated by:
BRN = βδ-1 (1 - α)T, where T denotes the number of days
-1
α,β, and δ denote the protection rate, infection rate, and aver-
age quarantine day, respectively. This model predicts the dy-
A Coadunation of Biological and Mathematical e030821190295
namics of the disease in five different regions of China
namely Mainland, Hubei, Wuhan, Beijing, and Shanghai.
Sensitivity analysis has been adopted for the estimation of a
fitting parameter for the long-term forecast. This model pre-
dicts that the Covid-19 in Beijing and Shanghai would end
up within two weeks (since Feb 15) while for most of Main-
land, it would be no longer than the middle of March. How-
ever, the condition of Wuhan is still critical and severe.
There is a need for more effective policies and more efforts
in medical care.
The SEIR model [64] and TDDM model [67] give a bet-
ter prediction. The reproduction number (R) estimated by th-
ese two models is the highest among all the models which
suggests that this outbreak could be more serious than pre-
dicted in other models.
11. DISCUSSION
The deadliest pandemic of severe acute respiratory syn-
drome coronavirus 2 (SARS-CoV-2), also called coron-
avirus disease (COVID-19), began in early December 2019
from the Wuhan city of China and spread to the world dur-
ing January-March, 2020. During February-March 2020, the
apex spread of this viral disease has latched itself to people
and is growing rapidly in Europe, North America, Asia, and
the Middle East. Although it originated from China, the sta-
tistical analysis of the period January 22 to March 25, 2020,
states an exponential growth of COVID-19 cases outside
China as well, which is most likely to further grow shortly.
Coronaviruses lead to acute respiratory tract infections in
15-30% of the infected human populace and have been ob-
served to be very serious in the elderly population and in in-
dividuals who endure cancer or any other immunological dis-
order. Severe complications may arise due to its infection in-
cluding respiratory distress syndrome, septic shock,
metabolic acidosis, coagulation dysfunction, and multiple or-
gan failure. Further, cytopathic effect, cytokine storm, sus-
tained inflammatory response, hypoxia, septic shock and so
on may be related to critical conditions of SARS-CoV-2 in-
fected patients. Furthermore, severe pneumonia symptoms
with abnormal chest CT, haemoptysis, and lymphopenia as-
sociated with SARS, acute cardiac injuries and kidney fail-
ure may eventually lead to death.
CONCLUSION
We conducted a basic phylogenetic analysis of the novel
coronavirus sequence (accession id: YP_009725307) and dis-
cerned that even though it comes from the coronavirus fami-
ly sharing links of lineage with SARS, BAT-CoV, Beta--
BAT-SARS, howbeit, the novel coronavirus protein is high-
ly dissimilar to its ancestors and even peers. The widely
prominent amino acid residues found in the protein are-
alanine (ALA), aspartic acid (ASP), phenylalanine (PHE),
leucine (LEU), asparagine (ASP), threonine (THR), valine
(VAL), tyrosine (TYR) and asparagine (ASN) that are re-
sponsible for its replication process. Moreover, the novel
coronavirus does not have a single amino acid residue match-
ing to similar proteins of its lineage, which hints at the fact
Coronaviruses, 2021, Vol. 2, No. 9
of adaptive divergence of the virus. The virus has undergone
some changes, which make it different from its ancestors
and peers. Research is ongoing as to how does this virus in-
fect the human genome and leads to lethality.
As far as the diagnosis of COVID-19 is concerned, chest
CT imaging, rRT-PCR, etc. are mostly used. Research
suggests that the CT imaging investigation is better than the
RT-PCR method for COVID-19 detection having a sensitivi-
ty of 70-98%. However, rRT-PCR is a widely applied
method to diagnose COVID-19. Also, the Indian Council of
Medical Research (ICMR) has also developed PCR-based
kits for diagnosis. The most reliable diagnostic kits with
high sensitivity and specificity are RealStar SARS-CoV-2
RT-PCR kit 1.0, Real-Time Fluorescent RT-PCR Kit for de-
tecting 2019-nCoV and TaqMan 2019-nCoV Control Kit v1.
Moreover, diagnosis can also be done using the antibody pro-
duction in an infected individual encapsulating antibody
IgM and IgG. Such diagnosis is done using a point of care
testing (PoCT) that requires a single punctured blood sam-
ple. ICMR deployed MY LAB company’sPathoDetect as-
say, which aids in identifying the coronavirus pathogens in
the infected patients.
Coronaviruses are large, round, bulbous, and pleiomorph-
ic structures belonging to the Nidovirales order. They are en-
veloped single-stranded positive-strand RNA virus with a
genome of ~30kb. The packaging of coronavirus is quite a
challenge to obtain a specific recognition and selection of
gRNAs and other RNA species.
To comprehend the pandemic dynamics, researchers
have applied many mathematical models wherein the basic
reproduction number (R) is computed by using Ordinary dif-
ferential equations (ODEs), Markov Chain Monto Carlo
methods (MCMC), intrinsic growth rate and serial intervals.
Some of the models covered in the review are the Bats-Host-
s-Reservoir-People (BHRP) transmission network model
[13], the Susceptible-Exposed-Infectious-Recovered (SEIR)
model [65], Time-Dependent Dynamic Model (TDDM)
[68], conceptual model [69] and Migration & Emigration
Model [57]. Out of these models, the SEIR model and TD-
DM model provide a better prediction. Further, the two mod-
els prophesize that this outbreak could be more serious than
predicted in other models. Owing to the pandemic transmis-
sion, researchers have been on their tenterhooks working
hard to devise drugs that would combat COVID-19 effective-
ly. Till date, there is no specific medicine to prevent or treat
COVID-19, however, antivirals such as interferon α (IFN-
α), lopinavir/ritonavir, chloroquine phosphate, ribavirin, and
arbidol are added in recent version of guidelines by the Na-
tional Health Commission (NHC) of China as a tentative
drug for the treatment of COVID-19 [75, 76]. The efficacy
and safety of these tentative drugs for COVID-19 are subject-
ed to clinical trials. For SARS-CoV-2, several potential
vaccines, including recombinant attenuated viruses, live
virus vectors, or mono viral proteins expressed from DNA
plasmids, are available but none of them are yet approved.
Vaccine generation for coronaviruses is an apex challenge to
date. Since March 2020, many drug candidates have been
subjected to clinical trials.
13
Coronaviruses, 2021, Vol. 2, No. 9 e030821190295
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
SQ is supported by DST-Inspire Fellowship by the De-
partment of Science & Technology (DST), MF is supported
by CSIR-Junior Research Fellowship by the Council of Sci-
entific and Industrial Research (CSIR), Government of In-
dia. KS and KR acknowledge the Bioinformatics Infrastruc-
ture Facilities (BIF) at the Department of Computer Science,
Jamia Millia Islamia funded by the Department of Biotech-
nology (DBT), Government of India.
REFERENCES
[1] Huang C, Wang Y, Li X, et al. Clinical features of patients infect-
ed with 2019 novel coronavirus in Wuhan, China. Lancet 2020;
395(10223): 497-506.
http://dx.doi.org/10.1016/S0140-6736(20)30183-5 PMID:
31986264
[2] Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associ-
ated with a new coronavirus of probable bat origin. Nature 2020;
579: 270-3.
http://dx.doi.org/10.1038/s41586-020-2012-7
[3] Zhu N, Zhang D, Wang W, et al. China novel coronavirus investi-
gating and research team. A novel coronavirus from patients with
pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727-33.
http://dx.doi.org/10.1056/NEJMoa2001017 PMID: 31978945
[4] Wu P, Hao X, Lau EHY, et al. Real-time tentative assessment of
the epidemiological characteristics of novel coronavirus infections
in Wuhan, China, as at 22 January 2020. Euro Surveill 2020;
25(3): pii=2000044.
http://dx.doi.org/10.2807/1560-7917.ES.2020.25.3.2000044
PMID: 31992388
[5] CCDC weekly. Tracking the epidemic (2021). Available from:
http://weekly.chinacdc.cn/news/TrackingtheEpidemic.htm
[6] Leung C. The difference in the incubation period of 2019 novel
coronavirus (SARS-CoV-2) infection between travelers to Hubei
and nontravelers: The need for a longer quarantine period. Infect
Control Hosp Epidemiol 2020; 41(5): 594-6.
http://dx.doi.org/10.1017/ice.2020.81 PMID: 32183920
[7] Fehr AR, Perlman S. Coronaviruses: an overview of their replica-
tion and pathogenesis. In: Maier H, Bickerton E, Britton P, Eds.
Coronaviruses Methods in molecular biology. New York, NY: Hu-
mana Press 20. 2015; pp. 1-23.
http://dx.doi.org/10.1007/978-1-4939-2438-7_1
[8] Li F. Structure, function, and evolution of coronavirus spike pro-
teins. Annu Rev Virol 2016; 3(1): 237-61.
http://dx.doi.org/10.1146/annurev-virology-110615-042301
PMID: 27578435
[9] Tang Q, Song Y, Shi M, Cheng Y, Zhang W, Xia XQ. Inferring
the hosts of coronavirus using dual statistical models based on nu-
cleotide composition. Sci Rep 2015; 5: 17155.
http://dx.doi.org/10.1038/srep17155 PMID: 26607834
[10] Wu A, Peng Y, Huang B, et al. Genome composition and diver-
gence of the novel coronavirus (2019-nCoV) originating in China.
Cell Host Microbe 2020; 27(3): 325-8.
http://dx.doi.org/10.1016/j.chom.2020.02.001 PMID: 32035028
[11] Peeri N C, Shrestha N, Rahman MS, et al. The SARS, MERS and
novel coronavirus (COVID-19) epidemics, the newest and biggest
14
Qazi et al.
global health threats: what lessons have we learned? Int J Epidemi-
ol 2020; 49(3): 717-26.
http://dx.doi.org/10.1093/ije/dyaa033
[12] CDC. Real-Time RT-PCR panel for detection 2019-novel coron-
avirus. Available from: https://www.cdc.gov/coronavirus/2019-n-
cov/summary.html
[13] Chen TM, Rui J, Wang QP, Zhao ZY, Cui JA, Yin L. A mathemat-
ical model for simulating the phase-based transmissibility of a nov-
el coronavirus. Infect Dis Poverty 2020; 9(1): 24.
http://dx.doi.org/10.1186/s40249-020-00640-3 PMID: 32111262
[14] Masters PS. The molecular biology of coronaviruses. Adv Virus
Res 2006; 66: 193-292.
http://dx.doi.org/10.1016/S0065-3527(06)66005-3 PMID:
16877062
[15] Neuman BW, Adair BD, Yoshioka C, et al. Supramolecular archi-
tecture of severe acute respiratory syndrome coronavirus revealed
by electron cryomicroscopy. J Virol 2006; 80(16): 7918-28.
http://dx.doi.org/10.1128/JVI.00645-06 PMID: 16873249
[16] Gui M, Liu X, Guo D, et al. Electron microscopy studies of the
coronavirus ribonucleoprotein complex. Protein Cell 2017; 8(3):
219-24.
http://dx.doi.org/10.1007/s13238-016-0352-8 PMID: 28044277
[17] Escors D, Ortego J, Laude H, Enjuanes L. The membrane M pro-
tein carboxy terminus binds to transmissible gastroenteritis coron-
avirus core and contributes to core stability. J Virol 2001; 75(3):
1312-24.
http://dx.doi.org/10.1128/JVI.75.3.1312-1324.2001 PMID:
11152504
[18] Masters PS. Coronavirus genomic RNA packaging. Virology
2019; 537: 198-207.
http://dx.doi.org/10.1016/j.virol.2019.08.031 PMID: 31505321
[19] Schoeman D, Fielding BC. Coronavirus envelope protein: current
knowledge. Virol J 2019; 16(1): 69.
http://dx.doi.org/10.1186/s12985-019-1182-0 PMID: 31133031
[20] Neuman BW, Kiss G, Kunding AH, et al. A structural analysis of
M protein in coronavirus assembly and morphology. J Struct Biol
2011; 174(1): 11-22.
http://dx.doi.org/10.1016/j.jsb.2010.11.021 PMID: 21130884
[21] Zeng Q, Langereis MA, van Vliet AL, Huizinga EG, de Groot RJ.
Structure of coronavirus hemagglutinin-esterase offers insight into
corona and influenza virus evolution. Proc Natl Acad Sci USA
2008; 105(26): 9065-9.
http://dx.doi.org/10.1073/pnas.0800502105 PMID: 18550812
[22] Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the
2019-nCoV spike in the prefusion conformation. Science 2020;
367(6483): 1260-3.
http://dx.doi.org/10.1126/science.abb2507 PMID: 32075877
[23] Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2
cell entry depends on ACE2 and TMPRSS2 and is blocked by a
clinically proven protease inhibitor. Cell 2020; 181(2):
271-280.e8.
http://dx.doi.org/10.1016/j.cell.2020.02.052 PMID: 32142651
[24] Shirato K, Kawase M, Matsuyama S. Wild-type human coron-
aviruses prefer cell-surface TMPRSS2 to endosomal cathepsins
for cell entry. Virology 2018; 517: 9-15.
http://dx.doi.org/10.1016/j.virol.2017.11.012 PMID: 29217279
[25] Zhavoronkov A, Aladinskiy V, Zhebrak A, et al. Potential
COVID-2019 3C-like protease inhibitors designed using genera-
tive deep learning approaches. ChemRxiv Cambridge: Cambridge
Open Engage; 2020 (pre-print) Available from: https://chem-
rxiv.org/engage/chemrxiv/article-details/60c7486cbb8c1ac5453-
dac67
[26] Perlman S, Netland J. Coronaviruses post-SARS: update on repli-
cation and pathogenesis. Nat Rev Microbiol 2009; 7(6): 439-50.
http://dx.doi.org/10.1038/nrmicro2147 PMID: 19430490
[27] Mihindukulasuriya KA, Wu G, St Leger J, Nordhausen RW,
Wang D. Identification of a novel coronavirus from a Beluga
whale by using a panviral microarray. J Virol 2008; 82(10):
5084-8.
http://dx.doi.org/10.1128/JVI.02722-07 PMID: 18353961
[28] Nga PT, Parquet MdelC, Lauber C, et al. Discovery of the first in-
sect nidovirus, a missing evolutionary link in the emergence of the
largest RNA virus genomes. PLoS Pathog 2011; 7(9): e1002215.
A Coadunation of Biological and Mathematical e030821190295
http://dx.doi.org/10.1371/journal.ppat.1002215 PMID: 21931546
[29] Lauber C, Ziebuhr J, Junglen S, et al. Mesoniviridae: A proposed
new family in the order Nidovirales formed by a single species of
mosquito-borne viruses. Arch Virol 2012; 157(8): 1623-8. [47]
http://dx.doi.org/10.1007/s00705-012-1295-x PMID: 22527862
[30] Levy GA, Liu M, Ding J, et al. Molecular and functional analysis
of the human prothrombinase gene (HFGL2) and its role in viral [48]
hepatitis. Am J Pathol 2000; 156(4): 1217-25.
http://dx.doi.org/10.1016/S0002-9440(10)64992-9 PMID:
10751347
[31] McIntosh K, Becker WB, Chanock RM. Growth in suckling-- [49]
mouse brain of -IBV-like” viruses from patients with upper respi-
ratory tract disease. Proc Natl Acad Sci USA 1967; 58(6):
2268-73.
http://dx.doi.org/10.1073/pnas.58.6.2268 PMID: 4298953
[32] Bradburne AF, Bynoe ML, Tyrrell DA. Effects of a -new” human [50]
respiratory virus in volunteers. BMJ 1967; 3(5568): 767-9.
http://dx.doi.org/10.1136/bmj.3.5568.767 PMID: 6043624
[33] Hamre D, Procknow JJ. A new virus isolated from the human res-
piratory tract. Proc Soc Exp Biol Med 1966; 121(1): 190-3.
http://dx.doi.org/10.3181/00379727-121-30734 PMID: 4285768 [51]
[34] Woo PC, Lau SK, Chu CM, et al. Characterization and complete
genome sequence of a novel coronavirus, coronavirus HKU1,
from patients with pneumonia. J Virol 2005; 79(2): 884-95.
http://dx.doi.org/10.1128/JVI.79.2.884-895.2005 PMID: [52]
15613317
[35] van der Hoek L, Pyrc K, Jebbink MF, et al. Identification of a new
human coronavirus. Nat Med 2004; 10(4): 368-73. [53]
http://dx.doi.org/10.1038/nm1024 PMID: 15034574
[36] van der Hoek L, Sure K, Ihorst G, et al. Croup is associated with
the novel coronavirus NL63. PLoS Med 2005; 2(8): e240.
http://dx.doi.org/10.1371/journal.pmed.0020240 PMID: 16104827 [54]
[37] Peiris JSM, Chu CM, Cheng VCC, et al. HKU/UCH SARS study
group. Clinical progression and viral load in a community out-
break of coronavirus-associated SARS pneumonia: a prospective
study. Lancet 2003; 361(9371): 1767-72.
http://dx.doi.org/10.1016/S0140-6736(03)13412-5 PMID:
12781535 [55]
[38] Spiegel M, Schneider K, Weber F, Weidmann M, Hufert FT. Inter-
action of severe acute respiratory syndrome-associated coron-
avirus with dendritic cells. J Gen Virol 2006; 87(7): 1953-60.
http://dx.doi.org/10.1099/vir.0.81624-0 PMID: 16760397
[39] Xu Y, Li X, Zhu B, et al. Characteristics of pediatric SARS-CoV- [56]
-2 infection and potential evidence for persistent fecal viral shedd-
ing. Nat Med 2020; 26(4): 502-5.
http://dx.doi.org/10.1038/s41591-020-0817-4 PMID: 32284613
[40] Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD,
Fouchier RA. Isolation of a novel coronavirus from a man with
pneumonia in Saudi Arabia. N Engl J Med 2012; 367(19): [57]
1814-20.
http://dx.doi.org/10.1056/NEJMoa1211721 PMID: 23075143
[41] CDC. Community Mitigation. 2020. Available from: http-
s://www.cdc.gov/coronavirus/2019-ncov/downloads/communi-
ty-mitigation-strategy.pdf [58]
[42] Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and
clinical therapies on coronavirus disease 2019 (COVID-19) out-
break-an update on the status. Mil Med Res 2020; 7(1): 1-10.
http://dx.doi.org/10.1186/s40779-020-00240-0 PMID: 31928528
[43] Ioannidis John PA. A fiasco in the making? As the coronavirus [59]
pandemic takes hold, we are making decisions without reliable da-
ta. Available from: https://www.statnews.com/2020/03/17/a-fias-
co-in-the-making-as-the-coronavirus-pandemic-- [60]
takes-hold-we-are-making-decisions-without-reliable-data/
[44] Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coron-
avirus disease 2019 (covid-19): A systematic review of imaging [61]
findings in 919 patients. AJR Am J Roentgenol 2020; 215(1):
87-93.
http://dx.doi.org/10.2214/AJR.20.23034 PMID: 32174129 [62]
[45] Ai T, Yang Z. Correlation of chest CT and RT-PCR testing in
coronavirus disease 2019 (COVID-19) in China: A report of 1014
Cases. Radiology 2020; 296(2): E32-40. [63]
http://dx.doi.org/10.1148/radiol.2020200642
[46] Bai HX, Hsieh B, Xiong Z, et al. Performance of radiologists in
Coronaviruses, 2021, Vol. 2, No. 9
differentiating COVID-19 from Non-COVID-19 viral pneumonia
at chest CT. Radiology 2020; 296(2): E46-54.
http://dx.doi.org/10.1148/radiol.2020200823 PMID: 32155105
Sheridan C. Coronavirus and the race to distribute reliable diagnos-
tics. Nat Biotechnol 2020; 38(4): 382-4.
http://dx.doi.org/10.1038/d41587-020-00002-2 PMID: 32265548
van Kasteren PB, van der Veer B, van den Brink S, et al. Compari-
son of seven commercial RT-PCR diagnostic kits for COVID-19.
J Clin Virol 2020; 128: 104412.
http://dx.doi.org/10.1016/j.jcv.2020.104412 PMID: 32416600
Nelson AC, Auch B, Schomaker M, et al. Analytical validation of
a COVID-19 qRT-PCR detection assay using a 384-well format
and three extraction methods. bioRxiv 2020, 04.02.022186 (pre-
print).
http://dx.doi.org/10.1101/2020.04.02.022186
Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr
HW. Treatment of SARS with human interferons. Lancet 2003;
362(9380): 293-4.
http://dx.doi.org/10.1016/S0140-6736(03)13973-6 PMID:
12892961
Khan FN, Qazi S, Tanveer K, Raza K. A review on the antagonist
Ebola: A prophylactic approach. Biomed Pharmacother 2017; 96:
1513-26.
http://dx.doi.org/10.1016/j.biopha.2017.11.103 PMID: 29208326
Li G, De Clercq E. Therapeutic options for the 2019 novel coron-
avirus (2019-nCoV). Nat Rev Drug Discov 2020; 19(3): 149-50.
http://dx.doi.org/10.1038/d41573-020-00016-0 PMID: 32127666
Li Q, Guan X, Wu P, et al. Early transmission dynamics in
Wuhan, China, of novel coronavirus-infected pneumonia. N Engl
J Med 2020; 382(13): 1199-207.
http://dx.doi.org/10.1056/NEJMoa2001316 PMID: 31995857
Chan JFW, Yuan S, Kok KH, et al. A familial cluster of pneumo-
nia associated with the 2019 novel coronavirus indicating person--
to-person transmission: a study of a family cluster. Lancet 2020;
395(10223): 514-23.
http://dx.doi.org/10.1016/S0140-6736(20)30154-9 PMID:
31986261
Bogoch II, Watts A, Thomas-Bachli A, Huber C, Kraemer MUG,
Khan K. Pneumonia of unknown aetiology in Wuhan, China: po-
tential for international spread via commercial air travel. J Travel
Med 2020; 27(2): taaa008.
http://dx.doi.org/10.1093/jtm/taaa008 PMID: 31943059
Wu JT, Leung K, Leung GM. Nowcasting and forecasting the po-
tential domestic and international spread of the 2019-nCoV out-
break originating in Wuhan, China: a modelling study. Lancet
2020; 395(10225): 689-97.
http://dx.doi.org/10.1016/S0140-6736(20)30260-9 PMID:
32014114
Zhao S, Lin Q, Ran J, et al. Preliminary estimation of the basic re-
production number of novel coronavirus (2019-nCoV) in China,
from 2019 to 2020: A data-driven analysis in the early phase of
the outbreak. Int J Infect Dis 2020; 92: 214-7.
http://dx.doi.org/10.1016/j.ijid.2020.01.050 PMID: 32007643
Zhao S, Musa SS, Lin Q, et al. Estimating the unreported number
of novel coronavirus (2019-nCoV) cases in China in the first half
of January 2020: a data-driven Modelling analysis of the early out-
break. J Clin Med 2020; 9(2): 388.
http://dx.doi.org/10.3390/jcm9020388 PMID: 32024089
Longini IM Jr, Nizam A, Xu S, et al. Containing pandemic influen-
za at the source. Science 2005; 309(5737): 1083-7.
http://dx.doi.org/10.1126/science.1115717 PMID: 16079251
WHO. Novel coronavirus – China. Available from: http-
s://www.who.int/csr/don/12-january-2020-novel-coronavirus-chi-
na/en/
Japan-MoH. Development of patients with pneumonia associated
with new coronavirus. Available from: https://www.mhlw.go.jp/st-
f/newpage_08906.html
WHO. Novel Coronavirus – Thailand (ex-China). Available from:
https://www.who.int/csr/don/14-january-2020-novel-coron-
avirus-thailand/en/
WHO. Disease outbreak news - Japan. Available from: http-
s://www.who.int/csr/don/17-january-2020-novel-coronavirus-ja-
pan-ex-china/en/
15
Coronaviruses, 2021, Vol. 2, No. 9 e030821190295
[64] Tang B, Wang X, Li Q, et al. Estimation of the transmission risk
of the 2019-nCoV and its implication for public health interven-
tions. J Clin Med 2020; 9(2): 462.
http://dx.doi.org/10.3390/jcm9020462 PMID: 32046137
[65] WHO. COVID-19 – China. Available from: https://www.who.in-
t/csr/don/12-january-2020-novel-coronavirus-china/en/
[66] WHO. Novel Coronavirus (2019-nCoV) Situation Report – 3, 23
January 2020. Available from: https://www.who.int/docs/default--
source/coronaviruse/situation-reports/20200123-sitrep-3-2019-n-
cov.pdf
[67] Tang B, Bragazzi NL, Li Q, Tang S, Xiao Y, Wu J. An updated es-
timation of the risk of transmission of the novel coronavirus
(2019-nCov). Infect Dis Model 2020; 5: 248-55.
http://dx.doi.org/10.1016/j.idm.2020.02.001 PMID: 32099934
[68] Lin Q, Zhao S, Gao D, et al. A conceptual model for the outbreak
of Coronavirus disease 2019 (COVID-19) in Wuhan, China with
individual reaction and governmental action. Int J Infect Dis 2020;
93: 211-6.
http://dx.doi.org/10.1016/j.ijid.2020.02.058 PMID: 32145465
[69] Biswas K, Khaleque A, Sen P. Covid-19 spread: Reproduction of
data and prediction using a SIR model on Euclidean network.
arXiv: 2020, 2003.07063 (pre-print).
[70] Khaleque A, Sen P. The susceptible infected recovered model on
16
Qazi et al.
a Euclidean network. J Phys A Math Theor 2013; 46(9): 095007.
http://dx.doi.org/10.1088/1751-8113/46/9/095007
[71] De Falco I, Della Cioppa A, Scafuri U, Tarantino E. Coronavirus
Covid-19 spreading in Italy: optimizing an epidemiological model
with dynamic social distancing through differential evolution.
arXiv: 2020, 2004.00553 (preprint).
[72] Github. Covid–19 - italia - monitoraggio - situazione. Available
from: https://github.com/pcm-dpc/COVID-19/blob/master/dati-re-
gioni/dpc-covid19-ita-regioni.csv
[73] Bliznashki S. A bayesian logistic growth model for the spread of
COVID-19 in New York. medRxiv 2020, 2020.04.05.20054577
(pre-print).
[74] Peng L, Yang W, Zhang D, Zhuge C, Hong L. Epidemic analysis
of COVID-19 in China by dynamical modeling. medRxiv 2020,
2020.02.16.20023465 (pre-print).
[75] Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus dis-
ease 2019 (COVID-19). Drug Discov Ther 2020; 14(1): 58-60.
http://dx.doi.org/10.5582/ddt.2020.01012 PMID: 32147628
[76] Saif LJ, Wang Q, Vlasova NA, Jung K, Xiao S. Coronaviruses. In:
Zimmerman JJ, Karriker LA, Ramirez A, Schwartz KJ, Stevenson
GW, Zhang J, Eds. Diseases of Swine. US: John Wiley & Sons,
Inc 2019; pp. 488-523.