Review
Overview of COVID-19 Disease: Virology, Epidemiology,
Prevention Diagnosis, Treatment, and Vaccines
Iman Salahshoori 1, *, Noushin Mobaraki-Asl 2, *, Ahmad Seyfaee 3, *, Nasrin Mirzaei Nasirabad 2 , Zahra Dehghan 4 ,
Mehrdad Faraji 5 , Mina Ganjkhani 4 , Aziz Babapoor 4, *, Seyede Zahra Shadmehr 6 and Ali Hamrang 6






Citation: Salahshoori, I.;
Mobaraki-Asl, N.; Seyfaee, A.;
Mirzaei Nasirabad, N.; Dehghan, Z.;
Faraji, M.; Ganjkhani, M.; Babapoor,
A.; Shadmehr, S.Z.; Hamrang, A.
Overview of COVID-19 Disease:
Virology, Epidemiology, Prevention
Diagnosis, Treatment, and Vaccines.
Biologics 2021, 1, 2–40. https://
doi.org/10.3390/biologics1010002
Academic Editors:
Vasso Apostolopoulos and
Majid Hassanzadeganroudsari
Received: 10 February 2021
Accepted: 23 April 2021
Published: 12 May 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
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iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Biologics 2021, 1, 2–40. https://doi.org/10.3390/biologics1010002
1 Department of Chemical Engineering, Science and Research Branch, Islamic Azad University,
Tehran 14778-93855, Iran
2 Department of Obstetrics and Gynecology, School of Medicine and Allied Medical Sciences, Alavi Hospital,
Ardabil University of Medical Sciences, Ardabil 56189-85991, Iran; nasrinmirzaeinasirabad@gmail.com
3 School of Mechanical Engineering, University of Adelaide, Adelaide 5005, Australia
4 Department of Chemical Engineering, University of Mohaghegh Ardabili, Ardabil 56199-11367, Iran;
zahradehghan1393@gmail.com (Z.D.); minaganjkhani96@gmail.com (M.G.)
5 Micro and Nanotechnology Graduate Program, TOBB University of Economics and Technology,
Sogutozu Caddesi No 43 Sogutozu, Ankara 06560, Turkey; mfaraji@etu.edu.tr
6 Department of Applied Chemistry, Faculty of Science, University of Mohaghegh Ardabili,
Ardabil 56199-11367, Iran; Szahrashadmehrr@gmail.com (S.Z.S.); Alihamrang.1377@gmail.com (A.H.)
* Correspondence: iman.salahshoori@srbiau.ac.ir (I.S.); dr.n.mobaraki@gmail.com (N.M.-A.);
ahmad.seyfaee@adelaide.edu.au (A.S.); babapoor@uma.ac.ir (A.B.)
Abstract: Coronaviruses belong to the “Coronaviridae family”, which causes various diseases,
from the common cold to SARS and MERS. The coronavirus is naturally prevalent in mammals
and birds. So far, six human-transmitted coronaviruses have been discovered. Severe acute res-
piratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019 in Wuhan,
China. Common symptoms include fever, dry cough, and fatigue, but in acute cases, the disease
can lead to severe shortness of breath, hypoxia, and death. According to the World Health Orga-
nization (WHO), the three main transmission routes, such as droplet and contact routes, airborne
transmission and fecal and oral for COVID-19, have been identified. So far, no definitive curative
treatment has been discovered for COVID-19, and the available treatments are only to reduce the
complications of the disease. According to the World Health Organization, preventive measures
at the public health level such as quarantine of the infected person, identification and monitoring
of contacts, disinfection of the environment, and personal protective equipment can significantly
prevent the outbreak COVID-19. Currently, based on the urgent needs of the community to control
this pandemic, the BNT162b2 (Pfizer), mRNA-1273 (Moderna), CoronaVac (Sinovac), Sputnik V
(Gamaleya Research Institute, Acellena Contract Drug Research, and Development), BBIBP-CorV
(Sinofarm), and AZD1222 (The University of Oxford; AstraZeneca) vaccines have received emergency
vaccination licenses from health organizations in vaccine-producing countries. Vasso Apostolopoulos,
Majid Hassanzadeganroudsari
Keywords: coronavirus; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); vaccines
1. Introduction
Small parasitic particles that are unable to reproduce on their own are called viruses.
If they enter the host cell, they can infect the host cell and replicate. Genetic material
(DNA or RNA strand structure), a capsid protein coat (protection of genetic material),
and an outer sheath of lipids are the known components of a virus structure. The funda-
mental particle of an infectious virus composed of nucleic acid and an external protein
shell is called a virion [1]. In the modern world, a record for detecting respiratory infec-
tions caused by the virus in children and adults date back to the 1960s [2]. One of the
essential viruses available that cause respiratory syndromes are coronaviruses. This family
https://www.mdpi.com/journal/biologics
Biologics 2021, 1, FOR PEER REVIEW 2
Biologics 2021, 1 3

viruses available that cause respiratory syndromes are coronaviruses. This family is called
is called Coronaviridae.
Coronaviridae. Many peopleMany arepeople
exposed aretoexposed to the coronavirus
the coronavirus once in theironce in their
lifetime, life-
which
time, which diseases
often causes often causes
suchdiseases such as
as pneumonia or pneumonia or bronchitis. are
bronchitis. Coronaviruses Coronaviruses
single-stranded, are
single-stranded,
enveloped RNAenvelopedviruses with RNA viruses nm
a 120–80 withdiameter
a 120–80andnm diameter
are divided andinto
are four
divided into
groups:
four
Alpha groups: Alpha coronaviruses,
coronaviruses, Beta coronaviruses,
Beta coronaviruses, Gamma coronaviruses,
Gamma coronaviruses, and Delta
and Delta coronaviruses
coronaviruses [3,4]. The four types of coronavirus, HCoV-OC43,
[3,4]. The four types of coronavirus, HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-229E, HCoV-NL63,
and HCoVHKU1
HCoVHKU1 are less
are less pathogenic
pathogenic andand cause
cause onlyonly
mildmild respiratory
respiratory illness
illness [5]. [5]. Neverthe-
Nevertheless,
less, two types of coronavirus, severe acute respiratory syndrome coronavirus
two types of coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV) (SARS-CoV)
and
and Middle
Middle East
East respiratory
respiratory syndrome
syndrome coronavirus
coronavirus(MERS-CoV),
(MERS-CoV),caused causedtwo twodeadly
deadlyepi-
ep-
demics [6]. In 2003, due to the SARS-CoV emergency in southern China
idemics [6]. In 2003, due to the SARS-CoV emergency in southern China and its wide- and its widespread
prevalence, extensive
spread prevalence, research research
extensive was conducted to controltoand
was conducted treat and
control the disease.
treat theAccording to
disease. Ac-
the World Health Organization, more than 8000 people were infected,
cording to the World Health Organization, more than 8000 people were infected, and 774and 774 deaths were
reported
deaths were[7]. reported
In addition,
[7]. in
In2012, another
addition, outbreak
in 2012, of the
another acute respiratory
outbreak of the acutedisease was
respiratory
reported in Saudi Arabia where MERS-COV was identified as the
disease was reported in Saudi Arabia where MERS-COV was identified as the cause of cause of the epidemic.
According to published reports, the mortality rate was over 35% [8]. It was stated that
the epidemic. According to published reports, the mortality rate was over 35% [8]. It was
market civets and dromedary camels were the primary sources of SARS-CoV transmission
stated that market civets and dromedary camels were the primary sources of SARS-CoV
and MERS-CoV transmission to humans [6]. The known animal origins of coronaviruses
transmission and MERS-CoV transmission to humans [6]. The known animal origins of
are demonstrated in Figure 1.
coronaviruses are demonstrated in Figure 1.

Figure 1.
Figure 1. Animal origins of human coronaviruses
coronaviruses (Created
(Created with
with BioRender.com,
BioRender.com.accessed
accessedon
on11August
August2020).
2020).

On
On 1111 March
March2020—The
2020—TheWorld WorldHealth
HealthOrganization
Organization(WHO)(WHO)declared
declared COVID-19
COVID-19 asasa
pandemic
a pandemic caused
caused bybySARS-CoV-2
SARS-CoV-2 [9].[9].
TheThemain effect
main of SARS-CoV-2
effect of SARS-CoV-2 is inishuman respira-
in human res-
tory system
piratory cells.cells.
system However,
However,new new
studies havehave
studies revealed the impact
revealed of theofvirus
the impact on theoncells
the virus the
of theofgastrointestinal
cells tract, kidney
the gastrointestinal system,
tract, kidney liver, pancreas,
system, eyes, and
liver, pancreas, brain
eyes, and[10]. The
brain SARS-
[10]. The
CoV-2 virus isvirus
SARS-CoV-2 about is 79%
aboutand79% 50%,
andsimilar to SARS
50%, similar and MERS
to SARS viruses,
and MERS respectively
viruses, [11].
respectively
Widespread prevalence due to the high transmission strength and complexity
[11]. Widespread prevalence due to the high transmission strength and complexity of of COVID-19
treatment
COVID-19compared
treatmenttocompared
SARS-CoVtoand MERS-CoV
SARS-CoV andhas led to a global
MERS-CoV has crisis
led toand preventing
a global crisis
the
anddisease’s
preventingspread is a necessity.
the disease’s This
spread is study provides
a necessity. anstudy
This overview of allan
provides aspects of theofdis-
overview all
ease,
aspectssuch
of as
thevirology,
disease, modes
such asofvirology,
transmission,
modesand diagnosis. New
of transmission, andtherapeutic
diagnosis.guidelines
New ther-
and vaccines
apeutic approved
guidelines andby the World
vaccines Health Organization
approved by the Worldare also mentioned.
Health Organization are also
mentioned.

2. Virology
Coronaviruses are virions that have viral envelopes. The diameter of these virion
particles is 120 nm. Cloverleaf structures such as glycoproteins and proteins on the virus’s
 Biologics 2021, 1 4

021, 1, FOR PEER REVIEW 3

2. Virology
Coronaviruses are virions that have viral envelopes. The diameter of these virion
surface have created a crown-like structure in it. These viruses are also known as corona-
particles is 120 nm. Cloverleaf structures such as glycoproteins and proteins on the virus’s
viruses becausesurface
of theirhave
crown structure. A section called nucleocapsid is made of capsid-
created a crown-like structure in it. These viruses are also known as coro-
coated proteinsnaviruses
in these viruses
becauseand of is placed
their crown inside the virus’s
structure. geneticcalled
A section material (Figure 2) is made of
nucleocapsid
[12]. The coronavirus has a genomic genus of RNA. This genetic material
capsid-coated proteins in these viruses and is placed inside the virus’s is seen as a spiral
genetic material
or circular in the nucleocapsid
(Figure 2) [12]. The ofcoronavirus
the virus. The has coronavirus
a genomic genus genome consists
of RNA. of a single
This genetic material is seen
strand of positive RNA (ribonucleic acid). This virus’s genomic RNA has
as a spiral or circular in the nucleocapsid of the virus. The coronavirus genome consists a methylated
warhead in its of 5′ aregion
single andstrandis rich in adenine
of positive RNAnucleotide
(ribonucleicatacid).
the end Thisofvirus’s
its ‘3’.genomic
Corona-RNA has a
viruses encode methylated
a protein called warhead in its 50 region
the replicase enzyme andinistheir genome,
rich in adeninewhich functions
nucleotide at theby end of its ‘3’.
transcribing theCoronaviruses
virus genomeencode a protein called
and producing the replicase
new copies using the enzyme in their
host cell’s genome, which func-
capabilities
[13]. Accordingtions by transcribing
to studies, SARS-CoV-2 the virus genome andvirus
is a beta-corona producing
genus newmember.copies using
The SARS-the host cell’s
CoV-2 virus is composed of four structural proteins, including nucleocapsid (N), spike member.
capabilities [13]. According to studies, SARS-CoV-2 is a beta-corona virus genus
(S), membrane The(M),SARS-CoV-2
and envelopevirus is composed
(E) (Figure of four
2). Protein M structural
plays a vital proteins,
role in including
introducing nucleocapsid
(N),
the virus into the spike
body and(S),forming
membrane (M), and[14].
envelopes envelope
Protein (E)E(Figure 2). Protein
is responsible for Mtheplays a vital role in
prolif-
introducing the virus into the body and forming envelopes [14]. Protein E is responsible for
eration, germination, envelope formation, and spread of the virus [15]. Increasing tran-
the proliferation, germination, envelope formation, and spread of the virus [15]. Increasing
scription and assembly of viruses is the responsibility of multipurpose N protein [16]. In
transcription and assembly of viruses is the responsibility of multipurpose N protein [16].
addition, the virus binding to host cells is the responsibility of the Spike (S) protein. There-
In addition, the virus binding to host cells is the responsibility of the Spike (S) protein.
fore, it has a unique rank itinhas
Therefore, pharmaceutical
a unique rank and vaccine research.
in pharmaceutical and It should
vaccine be noted
research. that, be noted
It should
due to the lackthat,
of response
due to thetolack neutralizing
of responseor toimmune
neutralizing antibodies,
or immune proteins
antibodies,N, M, and EN, M, and E
proteins
are not considered as drug targets [17].
are not considered as drug targets [17].
As depicted inAs Figure 2, theinSFigure
depicted glycoprotein
2, the Sofglycoprotein
the newly discovered
of the newly SARS-CoV-2
discovered is SARS-CoV-2
composed of two subunits, S1
is composed of and
two S2, and is commonly
subunits, S1 and S2, and represented
is commonly as a sword-like
representedspike. as a sword-like
The real structure of this
spike. Theprotein, however,
real structure canprotein,
of this be observed via crystallography.
however, can be observed The Pro-
via crystallography.
tein Data Bank The(PDB)Protein
model Data Bank
of this (PDB) model
glycoprotein of thishow
reveals glycoprotein
the subunits reveals how the subunits are
are comprised
comprised
of different regions that areof different
fundamentalregionstothat theare fundamental
infection to the
process. S1infection
and S2 are process.
linkedS1 and S2 are
linked together by a polybasic amino acid bridge,
together by a polybasic amino acid bridge, which may be necessary for studying viral which may be necessary for studying
viral targeting [18]. The virus binds to the host cell
targeting [18]. The virus binds to the host cell with the help of an S-protein and penetrateswith the help of an S-protein and
penetrates
the cell. After the penetrationthe cell. Afterthe
process, thetranscript
penetration process,
process the transcript
begins, and the process begins, and the
virus multi-
virus multiplies until the host cell is wholly infected and destroyed [19].
plies until the host cell is wholly infected and destroyed [19].

.
Figure 2. An in-depth look into the SARS-CoV-2 Spike Glycoprotein (Reprinted from “An In-depth Look into the Structure
Figure 2.Spike
of the SARS-CoV-2 An in-depth look into
Glycoprotein”, by the SARS-CoV-2accessed
BioRender.com, Spike Glycoprotein (Reprinted
on 1 August 2020) [20]. from “An In-depth
Look into the Structure of the SARS-CoV-2 Spike Glycoprotein”, by BioRender, accessed on 1 Au-
gust 2020) [20].
 Biologics 2021, 1 5
021, 1, FOR PEER REVIEW 4

Angiotensin-converting
Angiotensin-converting enzyme
enzyme 2 (ACE2) 2 (ACE2)
receptors receptors in mammalian
in mammalian lung
lung cells act as cells act as
recipients of the S-spike protein, releasing endogenous viral RNA genetic
recipients of the S-spike protein, releasing endogenous viral RNA genetic material into material into
host cells (Figure 3).
host cells (Figure 3).

Figure 3. SARS-CoV-2
Figure 3. SARS-CoV-2 targeting
targeting ACE2 ACE2
receptor receptor
and and
entry in theentry in the
infected infected
cell cellfrom
(Adopted (Adopted from “SARS-
“SARS-CoV-2 Targeting of
CoV-2 Targeting of ACE2 Receptor and Entry in Infected Cell”, by BioRender,
ACE2 Receptor and Entry in Infected Cell”, by BioRender.com, accessed on 1 August 2020) [21].accessed on 1 August
2020) [21].
One of the crucial functions of angiotensin-converting enzymes (ACE2) is to regulate
One of the the
crucial functions of angiotensin-converting
renin–angiotensin system (RAS). In general, enzymes (ACE2) is to regulate enzyme 2
the angiotensin-converting
(ACE2) acts
the renin–angiotensin as a cell
system surface
(RAS). In receptor
general,and thecauses SARS-CoV-2 to enterenzyme
angiotensin-converting host cells2and plasma
(ACE2) acts as a cell surface receptor and causes SARS-CoV-2 to enter host cells and one of the
and is expressed in organs such as the lungs, kidneys, and heart. Moreover,
reasons forin
plasma and is expressed theorgans
development
such asofthe
COVID-19 is the disturbance
lungs, kidneys, and heart. of Moreover,
the ACE/ACE2 Onebalance and
of the reasons for the development of COVID-19 is the disturbance of the ACE/ACE2 bal- cardiovas-
the activation of RAAS by SARS-CoV-2, especially in patients with underlying
cular disease
ance and the activation problems,
of RAAS hypertension,especially
by SARS-CoV-2, and diabetes [22]. Figure
in patients with4 presents
underlying the expression
of ACE2 Receptor in Human Host Tissues. ACE2 expression in alveolar epithelial cells
cardiovascular disease problems, hypertension, and diabetes [22]. Figure 4 presents the
types 1 and 2 in the human lung is much higher than elsewhere in the body [23]. Accord-
expression of ACE2 Receptor in Human Host Tissues. ACE2 expression in alveolar epi-
ing to research, the level of ACE2 expressions in men is much higher than in women in
thelial cells types 1 andcells
alveolar 2 in [24].
the human
Moreover,lungin is much
their higher
alveolar than
cells, elsewhere
ACE2 in the
expression body
levels in Asians are
[23]. Accordingmuch
to research, the level of ACE2 expressions in men is much higher
higher than in whites and African-Americans [25]. It is stated that Increasing than in ACE2
women in alveolar cells [24].
expression dueMoreover,
to SARS-CoV-2in their
virusalveolar
bindingcells, ACE2protein
via spike expression
couldlevels
lead toinalveolar cell
Asians are much higherand
damage than in whites
followed and African-Americans
by systemic reactions and even[25]. deathIt is stated that In-
[26].
creasing ACE2 expression due to SARS-CoV-2 virus binding via spike
Nevertheless, the prerequisite for coronavirus attack on host cells protein could lead binding.
is receptor
to alveolar cell damage
After bindingand followed by systemic
to the receptor, the viralreactions and even
spike protein death
is cleaved by[26].
acid-dependent proteoly-
Nevertheless, theCathepsin,
sis by prerequisite for coronavirus
TMPRRS2, attack onfollowed
or Furin Protease, host cellsbyisfusion
receptor binding.
of the viral coating with
After binding tocell
themembranes.
receptor, the In viral
general, theprotein
spike spike protein is structurally
is cleaved divided into
by acid-dependent two parts of the
prote-
nS1 terminal unit containing a binding site to ACE 2
olysis by Cathepsin, TMPRRS2, or Furin Protease, followed by fusion of the viral coatingreceptor in human cells (RBD) and
with cell membranes. In general, the spike protein is structurally divided into two parts (T.A.) and
the nS2 terminal region containing fusion protein and transmembrane anchor
intercellular
of the nS1 terminal tail (I.T.).aSpike
unit containing protein
binding site has a variable
to ACE aminoinacid
2 receptor sequence
human cells that
(RBD)makes it more
compatible with its host [27].
and the nS2 terminal region containing fusion protein and transmembrane anchor (T.A.)
and intercellular tail (I.T.). Spike protein has a variable amino acid sequence that makes it
more compatible with its host [27].
 Biologics 2021, 1 6
Biologics 2021, 1, FOR PEER REVIEW 5

Figure 4.Figure 4. Multiple

Multiple humanhuman host tissues
host tissues thatthat express
express ACE2receptor
ACE2 receptor highlighting
highlighting lungs, heart,
lungs, and and
heart, vasculature. Note clinical
vasculature. Note clinical
consequences of viral infection in cardiovascular and respiratory tissue. ARDS, acute respiratory distress syndrome
consequences of viral infection in cardiovascular and respiratory tissue. ARDS, acute respiratory distress syndrome (Re-
(Reprinted from “Expression of ACE2 Receptor in Human Host Tissues”, by BioRender.com, accessed on 10 August
printed from “Expression of ACE2 Receptor in Human Host Tissues”, by BioRender, accessed on 10 August 2020) [28].
2020) [28].

3. Symptoms
3. Symptoms
Symptoms
Symptoms of of COVID-19disease
COVID-19 disease vary
varyfromfrom patient to patient.
patient Sometimes
to patient. it may it
Sometimes bemay be
asymptomatic. Typically, in the early stages of COVID-19 infection, the most common
asymptomatic. Typically, in the early stages of COVID-19 infection, the most common
infection symptoms can be fever, dry cough, and tiredness [29]. Less common symptoms
infection symptoms can be fever, dry cough, and tiredness [29]. Less common symptoms
are nausea or vomiting, muscle or joint pain, sore throat, loss of sense of smell or taste or
are nausea or vomiting,
both, nasal congestion,muscle or jointheadache,
conjunctivitis, pain, sore throat,
different lossofofskin
types sense of smell
rashes, or taste or
diarrhea,
both,shivering,
nasal congestion,
and dizziness conjunctivitis, headache,
[30]. In the disease’s differentstages,
progression typestheof patient
skin rashes, diarrhea,
will face
severe shortness of breath, decreased blood oxygen (hypoxia), destruction
shivering, and dizziness [30]. In the disease’s progression stages, the patient will face se- of the lungs,
vere and several organs
shortness dysfunction
of breath, decreased [31]. blood
More severe
oxygenand(hypoxia),
rare neurological complications
destruction of thesuch
lungs, and
as stroke, encephalitis, delirium, and nerve damage are other complications of COVID-19
several organs dysfunction [31]. More severe and rare neurological complications such as
disease [32]. Figure 5 demonstrates the common symptoms of COVID-19.
stroke, encephalitis, delirium,
Acute respiratory and nerve
distress syndrome damage
(ARDS) is theare other
leading complications
cause of COVID-19
of COVID-19 induced
disease [32]. Figure
mortality [33]. One5 of
demonstrates the common
the most influential factors in symptoms
developing ARDSof COVID-19.
with COVID-19 is a
Acute respiratory
cytokine distress storm”
storm [34]. “Cytokine syndrome (ARDS) isinflammatory
is an aggressive the leadingresponse
cause of COVID-19 in-
associated
with the secretion of large amounts of cytokines caused by the
duced mortality [33]. One of the most influential factors in developing ARDS host’s immune response to with
the SARS-CoV-2
COVID-19 virus and
is a cytokine is directly
storm associated with
[34]. “Cytokine lung damage,
storm” multiple organ
is an aggressive failure,
inflammatory re-
and severe COVID-19 prognosis [35].
sponse associated with the secretion of large amounts of cytokines caused by the host’s
immune response to the SARS-CoV-2 virus and is directly associated with lung damage,
multiple organ failure, and severe COVID-19 prognosis [35].
 Biologics 2021, 1 7
ics 2021, 1, FOR PEER REVIEW 6

Figure
Figure 5. The 5. The and
most minor mostmajor
minorsymptoms
and majorofsymptoms
COVID-19of(Created
COVID-19 (Created
with with BioRender.com.
BioRender.com, ac-March 2021).
accessed on 15
cessed on 15 March 2021).
After the virus enters the body through the mouth or nose, SARS-CoV-2 makes its way
After theinto
virustheenters
lungstheandbodyuses through the mouth
its distinctive spikeor nose, SARS-CoV-2
proteins makes
to infect alveolar its In response,
cells.
way into the the
lungsimmune
and usessystem attacks thespike
its distinctive infected area, killing
proteins to infecthealthy alveolar
alveolar cells. cells
In re-in the process.
Reducedsystem
sponse, the immune surfactant
attacksfromthealveolar
infected epithelial type II
area, killing cells, along
healthy withcells
alveolar fluidinaccumulation
the due
to thesurfactant
process. Reduced destructionfromof cells in theepithelial
alveolar alveoli, causes
type IIreduced or severely
cells, along hindered
with fluid accu-gas exchange.
mulation dueHowever, when cytokines
to the destruction of cells inarethe triggered without
alveoli, causes breaks,
reduced they canhindered
or severely cause damage to the
gas exchange.cells’ responses
However, when to the cytokines
cytokines are and shut down
triggered withoutthe organs’
breaks, function. This is known as a
they can cause
damage to the cells’ responses to the cytokines and shut down the organs’ function. ThisThe following
cytokine storm, which mediates severe disease, including COVID19 [36].
is known as asteps describe
cytokine howwhich
storm, a cytokine storm
mediates occurs
severe in the lungs
disease, (Figure
including 6):
COVID19 [36].
The following(1)stepsInfection
describeofhowlunga cells
cytokine storm occurs in the lungs (Figure 6):
by COVID-19.
(1) Infection(2) Cytokine
of lung cells byproduction
COVID-19.through virus detection by immune cells (macrophages).
(2) Cytokine(3) Creating
production a cyclevirus
through of inflammation
detection by in lung cells
immune cellsby further uptake of immune cells
(macrophages).
(3) Creating a cycle (white blood cells) through
of inflammation in lungthe cytokine
cells phenomenon.
by further uptake of immune cells
(4) cells)
(white blood Fibrinthrough
formation theand further
cytokine damage.
phenomenon.
(5) Filling of the
(4) Fibrin formation and further damage.lung cavities due to the infiltration of fluids into the weak blood vessels,
followed by respiratory damage.
(5) Filling of the lung cavities due to the infiltration of fluids into the weak blood vessels,
followed by respiratory damage.
Biologics 2021, 1 8
Biologics 2021, 1, FOR PEER REVIEW 7

Patients
Patients with
with mild
mild symptoms
symptoms improved
improved after
after one
one week,
week, while
while severe
severe cases
cases reported
reported
experiencing progressive respiratory failure due to alveolar damage caused by the virus,
experiencing progressive respiratory failure due to alveolar damage caused by the virus,
which may lead to death [37]. Mortality rates have been assigned averagely between
which may lead to death [37]. Mortality rates have been assigned averagely between mid-
middle-aged and elderly patients with the disease. According to WHO, recovery time for
dle-aged and elderly patients with the disease. According to WHO, recovery time for mild
mild infections is about two weeks, and for severe infections three to six weeks [19].
infections is about two weeks, and for severe infections three to six weeks [19].

Figure 6.
Figure 6. AAcytokine
cytokinestorm
stormininthe lungs
the due
lungs to to
due COVID-19
COVID-19 disease: (1) infection,
disease: (2) Cytokine
(1) infection, pro-
(2) Cytokine
production, (3) Creating a cycle of inflammation in lung cells, (4) Fibrin formation and (5) Fillingthe
duction, (3) Creating a cycle of inflammation in lung cells,(4) Fibrin formation and (5) Filling of of
lung cavities (Reprinted from “Cytokine Storm”, by BioRender, accessed on 3 July 2020) [38].
the lung cavities (Reprinted from “Cytokine Storm”, by BioRender.com, accessed on 3 July 2020) [38].

4. Transmission Routes
Due to the lack of specific treatment and preventing the disease’s outbreak, knowing
the transmission
transmissionmethods
methodscan canreduce
reducethe thedisease’s
disease’sprevalence
prevalence [39]. Epidemiologically,
[39]. Epidemiologically,the
SARS-CoV-2
the SARS-CoV-2 outbreak
outbreakcould
couldbeberelated
related toto
the
thewholesale
wholesalemarket
marketof ofHua
Hua Nan
Nan seafood andand
Wuhan. Communities, health care and the family are
wet animals in Wuhan. are the
the primary
primary setting
setting
of human-to-human transmission of SARS-CoV-2 [40]. SARS-CoV-2 can be detected detected in
in
various organs
organs such as the eye, nasopharynx, saliva, alveolar lavage fluid, blood, intestine,
and feces after infection [41]. Due to the high rate of transmission of SARS-CoV-2 SARS-CoV-2 and and the
the
uncertainty of the main routes of transmission, infection control and prevalence are facing
prevalence are facing
significant challenges. According
According to research, close contact and respiratory droplets are are
one of the
the main
main ways
ways ofof transmission.
transmission. Therefore, the relevantrelevant experts
experts strongly
strongly advised
advised
maintaining social
socialdistance
distanceandandused
used a mask.
a mask. Touching
Touching the the face’s
face’s T-zoneT-zone
afterafter contact
contact with
with contaminated
contaminated surfaces
surfaces is alsoisaalso
mode a mode of transmission
of transmission that emphasizes
that emphasizes the for
the need need for
hand
hand hygiene and handwashing. Other routes of transmission are through
hygiene and handwashing. Other routes of transmission are through contaminated sur- contaminated
surfaces as well
faces as well as airborne,
as airborne, fecal-oral
fecal-oral transmission
transmission [42].
[42]. In In general,
general, droplet droplet and contact
and contact route,
route, airborne transmission, and fecal and oral have been identified to transmit
airborne transmission, and fecal and oral have been identified to transmit the SARS-CoV- the SARS-
CoV-2
2 virusvirus [43] (Figure
[43] (Figure 7). 7).
Biologics 2021, 1 9
Biologics 2021, 1, FOR PEER REVIEW 8

Figure
Figure 7.7.Schematic representation
Schematic of SARS-CoV-2
representation Transmission
of SARS-CoV-2 Routes
Transmission (Created
Routes with BioRender.com.
(Created accessed
with BioRender.com, on 5 Feb-
accessed on
ruary 2021).
5 February 2021).
Droplet and
Droplet and contact
contact routs: As mentioned,
routs: As mentioned, the
the main
main routes
routes of
of transmission
transmission of
of the
the
COVID-19 virus are respiratory droplets and close contact [44]. In general, the transmission
COVID-19 virus are respiratory droplets and close contact [44]. In general, the transmis-
of the COVID-19 virus through droplets and contact can be done in two ways: (1) direct
sion of the COVID-19 virus through droplets and contact can be done in two ways: (1)
contact with infected people and (2) indirect contact with surfaces used by an infected
direct contact with infected people and (2) indirect contact with surfaces used by an in-
person. If the infected person does not observe the social distance (1 m) can make a healthy
fected person. If the infected person does not observe the social distance (1 m) can make
person sick through coughing or sneezing, the virus entering the mucous membranes of the
a healthy person sick through coughing or sneezing, the virus entering the mucous mem-
mouth or nose, or Conjunctiva (eyes). Fomite can also be transmitted through household
branes of the mouth or nose, or Conjunctiva (eyes). Fomite can also be transmitted
items such as clothing, utensils, and furniture around the infected person [45,46]. According
through household items such as clothing, utensils, and furniture around the infected per-
to the Centers for Disease Control and Prevention (CDC) instructions in this section, it is
son [45,46]. According to the Centers for Disease Control and Prevention (CDC) instruc-
necessary to observe the following points [47]:
tions in this section, it is necessary to observe the following points [47]:
(1) Make sure the patient is in a convenient place.
(2) The necessity of proper use of personal protective equipment (PPE).
(3) Restrict the transportation and movement of patients as much as possible.
(4) Utilization of disposable or patient care equipment as much as possible.
Biologics 2021, 1 10

(1) Make sure the patient is in a convenient place.

(2) The necessity of proper use of personal protective equipment (PPE).
(3) Restrict the transportation and movement of patients as much as possible.
(4) Utilization of disposable or patient care equipment as much as possible.
(5) Prioritization disinfection and scouring of rooms.
Airborne transmission: Transmission of the virus through airborne particles is one of
the main transmission routes of COVID-19 disease [48]. According to published research,
if the suspended particles remain in the air for a long time, they will spread the virus [49].
In addition, World Health Organization stated that the virus could also be spread through
aerosols in poorly ventilated indoors [50]. In closed environments (ICU rooms), airborne
droplets or suspended particles in the air may infect the lungs when large doses of aerosols
are inhaled [51]. The CDC’s essential recommendations in this section are as follows [52]:
(1) The necessity of keeping the patient in the air infection isolated room (AIIR).
(2) limitation on the movement of health care personnel to patients’ rooms.
(3) The need for proper use of personal protective equipment (PPE).
(4) Confine movement and transport of patients.
(5) Immunization of people suspected of COVID-19 from unguarded contact.
Fecal and oral: As mentioned, gastrointestinal symptoms are a common symptom
of COVID-19 disease [53]. Some patients with SARS-CoV-2 have the RNA virus in their
stools [54]. Recent research has shown that SARS-CoV-2 in fecal samples from patients
with COVID-19 can be another way of transmitting the virus. This transmission can occur
through contact with food and contaminated water with fecal secretions [55]. Zhang et al.
reported that the molecular diagnostic value of COVID-19 in a stool sample was equivalent
to that of an oropharyngeal swab [56].

5. Prevention
Preventive measures due to lack of definitive treatment are of particular importance to
prevent the spread of COVID-19 [57]. Several preventative measures have been taken at the
public health level that can prevent or delay the transmission of COVID-19. These include
quarantine of the infected person, identification and monitoring of contacts, disinfection of
the environment, and utilization of personal protective equipment [58]. Table 1 reports the
CDC recommendations for avoiding the outbreak of COVID-19 [59]:

Table 1. The CDC recommendations for preventing the spread of COVID-19.

Everyone Should Description

Wash your hands
Stay away from close contact
• Washing hands for at least 20 s with soap and water
• Prior to preparing or consuming the food
• In advance of touching your face
• Posterior to utilization the toilet
• When you leave a public place
• After coughing, blowing your nose, and sneezing
• Posterior to touching your mask
• After changing a diaper
• When caring for a sick person
• Posterior to handling pets and animals
• Use hand sanitizer (at least 60% alcohol) if the soap is not available
• Indoors: prevent close contact with sick people and maintain a distance of 6 feet
between the patient and other members of the home.
• Outdoors: Maintain a 6-foot distance between yourself and people.
• Warning: Asymptomatic disease vectors spread the virus.
Biologics 2021, 1 11

Table 1. Cont.

Everyone Should Description

The necessity of using masks to
cover the mouth and nose in the
face of others
Cover coughs and sneezes
Clean and disinfect
Monitor Your Health Daily
Protect Your Health This
Flu Season
• Prevent the high prevalence and infection of the virus by masks.
• Due to the transmission of COVID-19 disease to others even if there are no symptoms.
• The necessity of wearing masks in public areas and around people in society due to
the difficulty of observing social distancing.
• Do NOT use masks for employees of health centers and hospitals due to the
importance of surgical masks and N95 respirators to prevent disease in staff.
• Everyone should maintain social distancing in society because masks are not a suitable
alternative to social distancing.
• Everyone should cover their mouth and nose with a handkerchief or hand when
coughing or sneezing, and refrain from spitting in public places.
• Never leave used napkins in public places and be sure to put them in the trash bin
• Wash your hands regularly for at least 20 s and in the absence of soap and water, be
sure to disinfect your hands with disinfectant solutions containing at least 60% alcohol.
• Do NOT touch contaminated surfaces AND regularly clean, and disinfect surfaces that
are frequently touched, such as telephones, keyboards, light switches, handles, faucets,
sinks, toilets, tables, door buttons, and countertops.
• Clean dirty surfaces with detergent or soap and water before disinfecting.
• Use a household disinfectant as much as possible.
• Check your symptoms regularly, such as fever, cough, shortness of breath, or other
symptoms of COVID-19, especially when travelling to high-risk areas.
• If your symptoms develop, check your body temperature regularly. Be careful not to
check your body temperature within 30 min of exercising or after taking fever
medications such as acetaminophen.
• If your symptoms develop, try to follow THE CDC guideline.
• The importance of influenza vaccination in winter and autumn months in 2020–2021
for the following reasons:
• Reduction of the risk of influenza, hospitalization, and mortality.
• Saving health resources to care for patients with COVID-19.

Studies have also fulfilled on the prevention of nosocomial infections and the psycho-
logical health issues associated with COVID-19. Nosocomial infections can be controlled
by increasing awareness or prevention via personal protective equipment such as face
and eye protection masks by medical staff at hospitals, disinfection of the tools, and plac-
ing classified protocols based on the infectious environment. Regarding mental health,
some suggested psychological intervention in suspected and confirmed cases and medical
staff [60] Figure 8 demonstrates different safety information about the COVID-19 infectious
disease caused by the SARS-CoV-2 virus.
Biologics 2021, 1 12
Biologics 2021, 1, FOR PEER REVIEW 11

Figure Infographic
8. 8.
Figure of various
Infographic safety
of various information
safety about
information the COVID-19
about infectious
the COVID-19 disease
infectious causedcaused
disease by the by
SARS-CoV-2 virus
the SARS-CoV-2
virus (Adopted
(Adopted from “COVID-19
from “COVID-19 Safety Information”,
Safety Information”, by BioRender,
by BioRender.com, accessed
accessed onMarch
on 18 18 March 2020)
2020) [61].[61].

6.6.Epidemiology
Epidemiology
Epidemiologists’
Epidemiologists’duties dutiesareareessential
essentialwhen
whendiscovering
discoveringa anew newinfectious
infectiousdisease
diseaseinin
collaboration
collaborationwith withother
other scientists
scientists to determine
determine thethereasons
reasonsfor forthe
thespread
spread of of disease.
disease. Ep-
Epidemiologists
idemiologists were wereinitially
initially present
present at
at the
the virus
virus observation
observationsite sitefor
forthe
thefirst
firsttime
time(Wuhan,
(Wuhan,
China)
China)[62].
[62].Then,
Then,theytheyinvestigated
investigated thethe origin
origin of the outbreak,
of the outbreak, control,
control, and andfollow-up
follow-upof
ofthe
thedisease
disease(such
(such as new cases, hospitalizations, deaths, demographic
as new cases, hospitalizations, deaths, demographic information (such information
(such as symptoms,
as symptoms, age,age,
and and gender,
gender, race/ethnicity,
race/ethnicity, andand treatment
treatment methods).
methods). In addition,
In addition, they
they conducted
conducted clinical
clinical studies
studies (including
(including information
information from
from antibody
antibody testing,
testing, risk
risk factorsfor
factors
for severe
severe illness,effective
illness, effectivemedical
medicaltreatments)
treatments)[62].
[62].Finally,
Finally,itittakes
takesnecessary
necessarymeasures
measuresto
toslow
slowthe
thedisease’s
disease’sspread
spread(Supporting
(Supportingand andassisting
assistingpeople
peopleininhigh-risk
high-riskgroupsgroupssuchsuchas
ashealth
healthcare
careworkers
workersor or the
the elderly
elderly to stay safe in environments such as grocery
to stay safe in environments such as grocery stores, stores,
home,
home,ororschool)
school)[62].
[62].AnAnoverview
overviewofofthe various
the various epidemiological
epidemiological statistics
statistics associated
associated
with
with seasonal influenza, SARS, MERS, and COVID-19 outbreaks are reportedininTable
seasonal influenza, SARS, MERS, and COVID-19 outbreaks are reported Table2.2.
According to clinical research, and all ages are sensitive to COVID-19.
According to clinical research, and all ages are sensitive to COVID-19. It should be It should be noted
noted
 Biologics2021,
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1,FOR
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that both
that both symptomatic
symptomatic and and asymptomatic
asymptomatic patients patients could could transmit
transmit the the disease
disease [63]. [63]. Studies
Studies
that
thatboth
that bothsymptomatic
both symptomaticand
symptomatic andasymptomatic
and asymptomaticpatients
asymptomatic patientscould
patients couldtransmit
could transmit
transmit thethedisease
the disease
disease [63].
[63].Studies
[63]. Studies
Studies
have
have shown
shown that
that the
the viral
viral load
load is not significantly different between symptomatic and
have
have shown
shown that
that the the viral
viral load
load isisisnot
not
not significantly
significantly
significantly different
different
different between
between
between symptomatic
symptomatic
symptomatic and
andand
have shown
asymptomatic individualsthat the viral
individuals [64]. load
[64]. is not significantly different between symptomatic and
asymptomatic
asymptomatic
asymptomatic individualsindividuals
individuals [64]. [64].
[64].
asymptomatic
Drops infected
infected with with the the SARS-CoV-2
SARS-CoV-2 virus virus can can be be spread
spread up up to to one
one to to two
two meters
meters
Drops
Drops
Drops infected
infected withwith thethe SARS-CoV-2
SARS-CoV-2 virus can can
virus be spread
be spread
spreadup toup one toto onetwotometers
two meters and
meters
and Drops
can be infected
placed on with
surfaces the SARS-CoV-2
in favorable virus
weather can be
conditions forupmanyto onedays.to twoNeverthe-
and
can can
be
and can can bebe
placed placed
on
be placed
placed on on
surfaces surfaces
on surfaces in
surfaces in in
favorablefavorable
in favorable weather weather
favorable weather conditions
conditions
weather conditions for
conditions for for
many many
for manydays.
many days.days. Neverthe-
Nevertheless,
days. Neverthe-
Neverthe-
and
less, in the
the face
face of of common
common disinfectants such as as sodium
sodium hypochlorite,
hypochlorite, hydrogen peroxide, peroxide,
less,
in theinin
less, face the offace
common of common disinfectants
disinfectants
disinfectants such suchas sodium
such as hypochlorite,
sodium hypochlorite, hydrogenhydrogen
hydrogenperoxide, etc.,
peroxide,
less,itinisthe
etc., face ofeliminated
quickly common disinfectants [65]. According suchtoasasodium study onhypochlorite,
other COVID-19 hydrogen traits, peroxide,
the dis-
dis-
itetc.,
etc., ititisisquickly
is quickly eliminated
quickly eliminated
eliminated [65].
[65]. According
[65]. According to a study
According totoaastudy
on
study on
otheron other
COVID-19
other COVID-19
COVID-19traits,traits,
the the
disease’s
traits, the dis-
etc., it is quickly
ease’s sensitivity
sensitivity eliminated
on people
people [65].
depends According
uponphysical to a study
age, physical
physical on other
health, COVID-19
and biological
biological traits, the
character- dis-
ease’s
sensitivity
ease’s sensitivityon people
sensitivity on on depends
on people
people dependsdepends
upon
depends upon upon
age,
upon age,age, health,
age, physical health,
physical health, and and
biological
health, and and biological character-
characteristics.
biological character-
character-
ease’s
istics. Statistically, mostpatientsadult patients
patients are between
between 3555and 55 years
years oldare andless arecommon
less com-
com-
istics.
istics. Statistically,
Statistically, most adult
Statistically, most
most adult
adult are between
patients are
are 35 and
between 3535 andyears
and 5555 old
years old
andold and
and are
are less
less com-
com-
istics.inStatistically,
mon infants and most
children. adultAmong patients are between
them, people 35 and
with weaker55 years immune old and are less
function, the el-
mon
in mon inininfants
infants infants and
and children.
and children.Among
children. Among them,them,
Among people
them, people
with with
people weaker
with weakerimmune
weaker immune
immune function,
function, the
the elders
function, the el-
el-
monwith
ders in infants
an and children.
average age of 60 Among
years them,
and people
older, people with withweaker
kidney immune
and function,
liver dysfunction the el-
ders
with
ders with
an with an
average
an average
age ofage
average 60 of
age years
of 6060 years
and
years and
older,
and older,
people
older, people with
with kidney
people with kidney
and liver
kidney and
and liver dysfunction
dysfunction
liver dysfunction [60]
dersand
[60] withhypertension,
an average age of 60 years
diabetes, and older,
asthma, chronic people
pulmonarywith kidney obstruction,and liver heart dysfunction
patients,
and[60]hypertension,
[60] andandhypertension,
hypertension, diabetes, asthma,
diabetes,
diabetes, chronic
asthma,
asthma, pulmonary
chronic
chronic pulmonary obstruction,
pulmonary obstruction,heart patients,
obstruction, heart
heartpatients,smok-
patients,
ers[60]
smokers and hypertension,
[63],
[63], pregnant pregnant
women, diabetes,
women,
and people andasthma,
people chronic
with
with disabilities pulmonary
disabilities obstruction,
are
are at higher at higher
risk and heart
risk
more andpatients,
more
likely
smokers
smokers [63],
[63],pregnant
pregnant women,
women, andandpeople
people with
withdisabilities
disabilities are
areatat athigher
higher risk
risk and
and more
more
to smokers
likely to
be exposed [63],
be pregnant
exposed
to the virus to women,
the[66].virus and
[66].
Currently, people
Currently, with
there is there disabilities
there
athere is
highisis a are
high
potential higher
potential
for epidemics risk
for and
epidemics
among more
likely
likely totobebe exposed
exposed totothethe virus
virus [66].
[66]. Currently,
Currently, aahighhigh potential
potential for
for epidemics
epidemics
likely to
among
humans; inbe
humans; exposed
other in other
words, to people
other the
words, virus [66].age
people
ofpeople
any Currently,
ofbecome
any age there
ageinfected
become is with
ainfected
high thepotential
with the
coronavirusthefor epidemics
coronavirus
infection.
among
amonghumans; humans; inin other
other words,
words, people ofofanyany ageagebecome
become infected
infected with
with the thecoronavirus
coronavirus
In among
infection. humans;
older people, In older inpeople,
the averagethe words,
the averagepeople
mortality rate of
mortalityany
was higherwasrate become
was infected
higher
withhigher with
the diseasesthe with
the diseasescoronavirus
than in the than than in
young in
infection.
infection.In Inolder
olderpeople, people, the theaverage
averagemortalitymortalityrate rate was higherwith
was higher with the thediseases
diseases than than in in
infection.
the
people young In
[11].people older
people
There have people,
[11]. There
been no average
have
reportsbeen mortality
ofno reports
pregnant rate
of
womenpregnant with
women
receiving diseases
receiving
prenatal prenatal
transplants
the
the young
young people [11].
[11]. There
There have
have been
been no
no reports
reports of
of pregnant
pregnant women
women receiving
receiving prenatal
prenatal
or the young people
transplants
intrauterine or[63]. [11].
intrauterine
According There [63].have
to the been
According
WHO, nothe reports
to the
the WHO, of pregnant
WHO,
consequences theof women
consequences
not receiving
breastfeeding of not
not prenatal
andbreast-
sep-
transplants
transplants or
or intrauterine
intrauterine [63].
[63]. According
According to
to the WHO, the
the consequences
consequences ofof not breast-
breast-
transplants
feeding
aration and
between or intrauterine
separation
mother between
and [63]. According
child mother
are more and to child
the WHO,
significant are
than the
morethe consequences
significant
risk of COVID-19 than of the
not breast-
risk
infection of
feeding
feedingand andseparation
separationbetween betweenmother motherand andchild childare aremore
moresignificant
significantthan thanthe theriskriskof of
in feeding
COVID-19
infants and
becauseseparation
infection the in between
infants
infection because
in mother the
infants and
is child
infection
usually inare more
infants
mild or is significant
usually
asymptomatic. mildthan or the
WHO risk
asympto- rec- of
COVID-19
COVID-19 infection
infection inininfants
infants because
because the
the infection
infection inininfants
infants isisusually
usually mild
mild oror asympto-
asympto-
COVID-19
matic.
ommends WHO infection
that recommends
mothers in infants
with that because
mothersthe
suspected orwithinfection
suspected
confirmed inCOVID-19
infants is usually
or confirmed
confirmed should mild
COVID-19 or asympto-
be encouraged should
matic.
matic.WHO WHOrecommends
recommendsthat thatmothers
motherswith withsuspected
suspectedor confirmedCOVID-19
or confirmed COVID-19should should
to matic.
beinitiate WHO
encouraged recommends
or continue to initiate
initiate to breast that
or continue mothers
continue
feed. Mothers with
to breast suspected
breastshouldfeed. Mothers or
Mothers
be counselled shouldthat COVID-19
be counselled
counselled
breastfeeding should
that
bebe encouraged
encouraged toto initiate oror continue toto breast feed.
feed. Mothers should
should bebe counselled that
that
be encouraged
breastfeeding
benefits substantially to initiate
benefits outweigh or continue
substantially the to breast
outweigh
potential the
risksfeed. Mothers
potential
for risks
transmission should
for be counselled
transmission
[67–69]. [67–69].
Important that
breastfeeding
breastfeeding benefits benefits substantially
benefits substantially
substantially outweigh outweigh
outweigh the the potential
the potential
potential risksrisks
risks forfor transmission
for transmission
transmission [67–69]. [67–69].
[67–69].
breastfeeding
Important
epidemiological epidemiological
indicators associated indicatorswith associated
COVID-19 withare COVID-19
reportedare are reported
in reported
Table 3. in in Table
Table 3. 3.
Important
Important epidemiological
epidemiological indicators
indicators associated
associated with
with COVID-19
COVID-19 are reported in Table 3.
Important epidemiological indicators associated with COVID-19 are reported in Table 3.
Table2.2.
Table
Table 2.Epidemiological
Epidemiologicalcomparison
comparisonof
ofrespiratory
respiratoryviral
viralinfection
infection[70–73].
[70–73].
Table 2.
Table 2.Epidemiological
Epidemiologicalcomparison
Epidemiological comparisonofof
comparison ofrespiratory
respiratoryviral
respiratory viralinfection
viral infection[70–73].
infection [70–73].
[70–73].
RO
RR CFRCFR
Disease-Causing
Disease-Causing O
ROOO CFR
CFR Incubation Hospitalization
Incubation Hospitalization Community
Community Annual Annual
Infected
Disease Disease-Causing
Disease-Causing Basic
BasicReproductive
Reproductive
R Case
CaseFatality
Fatality
CFR Incubation
Incubation Hospitalization
Hospitalization Community
Community Annual
Annual
Disease Pathogen
Pathogen
Disease-Causing Basic Reproductive
Number Case Fatality
Rate Time
Time
Incubation Rate
Rate
Hospitalization Attack Rate
Attack Rate
Community Global
Infected Global
Annual
Disease Pathogen Basic Reproductive Case Fatality Time Rate Attack Rate Infected
Disease Pathogen
Pathogen
Number
BasicNumber
Reproductive CaseRate
Fatality
Rate Time
Time Rate
Rate Attack Rate
Attack Rate InfectedGlobal
Infected Global
Global
Number
Number Rate
Rate

SARS 33 9.6–11%
9.6–11% 2–7 days
2–7 days Most
Mostcases
cases 10–60%
10–60% 8098
8098(in(in2003)
2003)
SARS
SARS 33 9.6–11%
9.6–11% 2–7
2–7days
days Most
Mostcases
cases 10–60%
10–60% 8098
8098(in(in2003)
2003)
SARS 3 9.6–11% 2–7 days Most cases 10–60% 8098 (in 2003)

SARS-CoV
SARS-CoV
SARS-CoV
SARS-CoV

MERS 0.3–0.8
0.3–0.8 34.4%
34.4% 6 days
6 days Most
Most cases
cases 4–13%
4–13% 420
420
MERS
MERS 0.3–0.8
0.3–0.8 34.4%
34.4% 66days
days Most
Mostcases
cases 4–13%
4–13% 420
420
MERS 0.3–0.8 34.4% 6 days Most cases 4–13% 420

MERS-CoV
MERS-CoV
MERS-CoV
MERS-CoV
MERS-CoV

Flu 1.3 0.05–0.1% 1–4 days 2% 10–20% ~1 billion

Flu
Flu
Flu 1.3
1.31.3 0.05–0.1%
0.05–0.1%
0.05–0.1% 1–4
1–4 days
days
1–4 days 2%2%
2% 10–20%
10–20%
10–20% ~1~1 billion
billion
~1 billion
Flu 1.3 0.05–0.1% 1–4 days 2% 10–20% ~1 billion

Influenza virus
Influenza
Influenzavirus
virus
Influenza
Influenzavirus
virus

COVID-
COVID-
COVID- 2.0–2.5 ~3.4% 4–14 days ~19% 30–40% N/A ongoing
19
COVID- 2.0–2.5
2.0–2.5 ~3.4%
~3.4% 4–14
4–14days
days ~19%
~19% 30–40%
30–40% N/A
N/Aongoing
ongoing
19
COVID-19
19 2.0–2.5
2.0–2.5 ~3.4%
~3.4% 4–14 days
4–14 days ~19%
~19% 30–40%
30–40% N/A ongoing
N/A ongoing
19

SARS-CoV-2
SARS-CoV-2
SARS-CoV-2
SARS-CoV-2
SARS-CoV-2
Biologics 2021,11, FOR PEER REVIEW
Biologics2021, 14
13

Table3.
Table 3. Leading
Leading epidemiological
epidemiological indicators
indicatorsof
ofCOVID-19
COVID-19research
researcharticles
articlesin
inJanuary
January2020.
2020.

Indicators
Indicators Description
Description
• Elderly (over 60 years old) [60].
Biologics 2021, 1, FOR PEER REVIEW • Elderly (over 60 years old) [60]. 13
• Mean • age Mean of 59
ageyears
of 59(research conducted
years (research between
conducted patients
between 50 to 8950years)
patients [74]. [74].
to 89 years)
Biologics 2021, 1, FOR PEER • REVIEW
Risk
• ofRiska severe illness illness
of a severe with increasing age of about
with increasing age of 40 years
about 40[75].
years [75]. 13
• The• low number of patients with mean age 0–49
The low number of patients with mean age 0–49 years [76]. years [76].
Table• Average
3.
• Leading ageepidemiological
Average of patients was 55.5
age of patients years;
indicators
was age
55.5 of distribution:
COVID-19
years; ≤39: 10%;
research
age distribution: 40–49:
articles
≤39: 22%,
in January
10%; 40–49:50–59:
2020.30%;
22%, 50–59:60–69:
30%;22%,
≥70: 15% [77]. 22%, ≥70: 15% [77].
60–69:
Indicators Table Description
• In3. Leading epidemiological indicators of 1%
COVID-19 research8% articles in January 2020.
Biologics 2021, 1, FOR PEER REVIEW
•terms 13
 Age Age of patients
of patients Inofterms
age of age distribution,
distribution, 1% under 1% 10,
under 10, 1% 10–19,
10–19, 8% 20–29, 20–29,
87% 30–79,87% 30–79,
and 3%and >803% >80 [78].
[78].
•• Elderly
• (More
50–60 (over
50–60 than60
(More years
than
half old) [60].
half a million
a million COVID-19 COVID-19
patients patients from different
from different countries
countries participated
participated in this in this
meta-
Indicators Description
• Mean age of 59 years (research
meta-analysis) [79]. conducted between patients 50 to 89 years) [74].
analysis)
•• Elderly [79].
Risk a(over
• ofCases severe60 illness
range years
from old) [60].
2 to
with 72 years [80].
increasing age of about 40 years [75].
••• Mean
Table Cases
• low
The
range
3. Leading
age of from
Increased59 2 to(research
epidemiological
years
number incidence
72 years
of patientswith with
[80].
indicators
conducted of COVID-19
mean agebetween
increasing age
0–49over
research
patients
years50
60 [76].
years
articles in January
to 89 years)
[81]. [74]. 2020.
• • Risk
Increased
of a incidence
severe with
illness increasing
with increasing ageage
overof 60 years
about 40 [81].
years [75].
Indicators •
•Description
Average Theagemedian age of
of patients waswas55.5
74 years
years;[82].
age distribution: ≤39: 10%; 40–49: 22%, 50–59: 30%; 60–69: 22%,
•• The
The median
• low age
number
Cases range of
ofwas 74between
patients
aged years
with[82].
mean
35 andage 55 0–49
yearsyears
[83]. [76].
•• Elderly
≥70: 15%
Cases range [77].
(overaged
60 years
between old) 35
[60].
andyears;
55 years [83].
 Age Sexof of •
patients • Mean
patients Average
In•terms age
More of patients
cases
ofofage were was
males 55.5
[84,85]. age distribution: ≤39: 10%; 40–49: 22%, 50–59: 30%; 60–69: 22%,
 Sex of patients • More age
cases 59 distribution,
were years
males (research 1%
[84,85].
under 10, 1%
conducted 10–19,patients
between 8% 20–29, 87%
50 to 8930–79,
years) and
[74].3% >80 [78].
≥70: 15% [77].than half a million COVID-19 patients from different countries participated in this meta-
• Risk
50–60
• of(More
a severe illness
Increased mortality withbetween
increasing 60 age 80of about 40 years [75].
• Increased mortality between 60 and 80 and
years years [86–88]
1%[86–88]
 Mortality
 AgeMortality raterate •• The
of patients In terms
• low
analysis)Theof age distribution,
[79].
mortality
number rate was
of patients
1% under
significantly
with
10,
mean agehigh
10–19,
0–49in the
years
8%age20–29, 87% 30–79, and 3% >80 [78].
[76].range of >60 years [75,89].
•• The
50–60 mortality
(More ratehalf
than wasasignificantly
million high inpatients
COVID-19 the age from
rangedifferent
of >60 years [75,89].
countries participated in this meta-
• Average
Cases
• range agefrom
Average of 27(2–14
to
of patientsdays72was
years55.5
(2–14 [80].
years;
days) age distribution: ≤39: 10%; 40–49: 22%, 50–59: 30%; 60–69: 22%,
[60,90].
• Average
analysis) of 7
[79]. days days) [60,90].
• ≥70:
• 15%
Increased incidence
Average
[77]. of 10withdaysincreasing
[91]. age over 60 years [81].
•• Average
Cases of 10
range days
from [91].
 Age of patientstime• In
Incubation
Incubation •terms
The 6.4ofdays
median age
age of2was
(95% to CI7274
distribution,
years
5.6–7.7
years [80].
1%days),
[82]. with
under 10, 1%a range
10–19,of8%2.1–11.1
20–29,days
87% [92].
30–79, and 3% >80 [78].
•• 6.4• days
Increased5.0(95%
days CI(95%
incidence 5.6–7.7
with
CI days), with
increasing
4.4–5.6 days), aage
range
over
with a of
602.1–11.1
rangeyears
of days
[81].
2–14 [92].[92].
days
time • 50–60
Cases (More
range aged between
than half 35 and
a million 55 years [83].
COVID-19 patients from different countries participated in this meta-
•• 5.0
• days
The 4.0(95%
median age
days, CIof4.4–5.6
was 74days),ofwith
years a range
[82].days [93].of 2–14 days [92].
 Sex of patients • More cases
analysis) werewith
[79]. males a range
[84,85]. 1–7
•• 4.0 days, with a range of 1–7 days
Cases range aged between 35 and 55 years [83]. [93].
• Increased
Cases range from 2 to
mortality 72 years
between 60[80].
and 80 years [86–88]
Mortality
 Sex rate
of patients • More cases were males [84,85].
• The
Increased 7. Diagnosis
incidence
mortality rate was with increasing high
significantly age over
in the60age
years [81].of >60 years [75,89].
range
• Increased 7. Diagnosis
mortality between 60 and 80 years [86–88]
 Mortality rate • The median
Average of 7age
days of was
(2–14 74 years
days) [82].
[60,90].
Because of the lack of definitive curative treatment for this disease, the most effective
• The mortality ratebetween
Because wasof significantly
the35lack
and of high in[83].
the age
definitive range of
curative >60 yearsfor [75,89].
 Incubation
• Average
Cases range
of 10aged
solution days [91].
after preventing 55
and years
controlling is the treatment
timely diagnosis thisofdisease, the most
the disease effective
and isolating
 Sex of patients •
• MoreAverage
6.4 days of
cases
(95%7
solution days
wereCI (2–14
after
males
5.6–7.7 days)
preventing
[84,85].
days), [60,90].
with and
a controlling
range of 2.1–11.1 is the
days timely
[92]. diagnosis of the disease and isolat-
time the illnesses. There are several ways to diagnose the disease early, such as the RT-PCR
• • Increased
Average
5.0 days ofmortality
ing
(95%10
the days
CI [91].
illnesses.
4.4–5.6
between There
days),60 are
with
and a several
80range
years ofways
2–14
[86–88] to
daysdiagnose
[92]. the disease early, such as the RT-PCR

 Incubation method, CT-Scan, Serological antibody blood test, and Artificial intelligence.
Mortality rate •• 6.4 days
4.0 days,
The (95%
with CI
method,
mortality 5.6–7.7
CT-Scan,
a range
rate wasof days),
dayswith
1–7Serological
significantly a range
[93].
high of 2.1–11.1
antibody
in the age blood
range days [92].
test,
of >60 and
yearsArtificial
[75,89]. intelligence.
time
• 5.0 days (95% CI 4.4–5.6 days), with a range of 2–14 days [92].
• Average 7.1.
of 7RT-PCR
days (2–14 Methoddays) [60,90].
• 4.0 days, with a rangeMethod of 1–7 days [93].
• Average7. 7.1. RT-PCR
ofDiagnosis
10 days [91].
One of the most important ways to detect the SARS-CoV-2 virus in upper and lower
 Incubation
• 6.4 daysrespiratory
(95%Because
CI 5.6–7.7
One ofdays),
ofspecimens
the most
the with
lack is of adefinitive
important
the range of 2.1–11.1
ways
Real-Time curative days
toReverse
detect [92].
the SARS-CoV-2
treatment for this
Transcriptase virus inthe
disease,
(RT)–PCR upper
most
Diagnosticand lower
effective
Panel.
time
• 5.0 days7. Diagnosis
(95% CI
respiratory 4.4–5.6 days), with a range of 2–14 days [92].
The basisafter
solution of specimens
thepreventing is the
PCR is copying and Real-Time
the RNAReverse
controlling and DNA
is the Transcriptase
structure
timely of(RT)–PCR
diagnosis theofsample, Diagnostic
whichand
the disease Panel.
canisolat-
diag-
• 4.0 days, Thewith Because
a range
basis of theof 1–7
the
PCR lack
days of
is [93]. definitive
copying the curative
RNA and treatment for this disease,
DNA structure the most
of the sample, effective
which can
nose
ing theinfectious
illnesses.origin
Thereand arevarious
several genetic
ways toand bloodthe
diagnose diseases
disease [94].
early,Figure
such9 as demonstrates
the RT-PCR
solution
diagnoseafter
COVID-19 preventing
infectious
diagnostic origin
testingand
and controlling
various
through is the RT-PCR.
genetic
real-time timely
andandblooddiagnosis
Asdiseases
depicted of thein disease
[94]. Figure9,and
Figure isolat-
9there
demon-are
method, CT-Scan, Serological antibody blood test, Artificial intelligence.
7.
ing Diagnosis
the
strates
five illnesses.
COVID-19
necessary There
steps are
diagnostic
to performseveral
testing ways to
through
the test: diagnose
sample real-timethe
collection, disease
RT-PCR. early, such as
As depictedRT-qPCR
RNA extraction, the RT-PCR
in Figureset 9,
method,
there
up, andare CT-Scan,
Because
five
test of the
results,
7.1. RT-PCR Method Serological
lack
necessary
all ofof
steps
which antibody
definitive
tocanperform
be blood
curativethe
customized test,
treatment
test: and
sample
to Artificial
for
explain this
collection,
both intelligence.
disease,
this RNA
and the most effective
extraction,
other RT-qPCR RT-
solution
diagnostic
qPCR setafter
One up, preventing
ofprotocols.
and
the testThe
most and
steps
results,
important controlling
allfor
of performing
ways which is
can
to detect the timely
bethe RT-qPCR
customized
the diagnosis
SARS-CoV-2 test of the
are
to explain
virus asin disease
follows
both
upper and
andisolat-
this[95]:
and other
lower
7.1.
ing RT-PCR
the Method
illnesses.
Nasopharyngeal
RT-qPCR diagnostic There are
swab
protocols. several
<15
The ways
min:
steps to
for diagnose
Cotton
performing the
swab disease
theis inserted
RT-qPCR early, such
into
test are as
the the RT-PCR
nostril
follows to
[95]:
respiratory specimens is the Real-Time Reverse Transcriptase (RT)–PCR Diagnostic Panel.
method,
absorb One of the most
CT-Scan,
sections.
Nasopharyngeal important
Serological
swab <15 ways
antibody
min: to detecttest,
blood
Cotton the and
swab SARS-CoV-2
is Artificial
inserted virus in upper
intelligence.
into the nostril and
to lower
absorb
The basis of the PCR is copying the RNA and DNA structure of the sample, which can
respiratory
Collected
sections.
diagnose
specimens
specimen
infectious
is the Real-Time
origin0–72 specimen
andhvarious
Reverse
is stored
genetic and at 2–8 ◦diseases
Transcriptase
blood
(RT)–PCR
C for to 72Diagnostic
up[94]. h or proceed
Figure
Panel.
9 demon- to
7.1.
The RT-PCR
RNA basis of Method
extraction.thespecimen
PCR is copying the RNA is and DNAatstructure ℃ ofup the sample, which can
strates COVID-19 diagnostic testing through real-time RT-PCR. As depicted in Figure to
Collected 0–72 h specimen stored 2–8 for to 72 h or proceed 9,
diagnose
RNA RNA infectious
extraction
extraction.
One of the most origin
~45 andpurified
min
important various
ways to genetic
RNAdetect andSARS-CoV-2
the blood
is extracted fromdiseases
thevirus [94].
deactivated
in Figure
upper 9 demon-
virus.
and lower
there are five necessary steps to perform the test: sample collection, RNA extraction, RT-
strates COVID-19
RT-qPCR,
RNA ~1 diagnostic
extraction h per testing
primer, set through
purified real-time
RNA RT-PCR.
is reverse As depicted
transcribed in Figure
to cDNA and 9,
respiratory
qPCR set up, and test ~45
specimens min
is the
results, purified
Real-Time
all of which RNA canisbeextracted
Reverse Transcriptase
customized from the
to(RT)–PCR deactivated
explain thisvirus.
Diagnostic
both andPanel.
other
amplified
there
The basis by
are five
RT-qPCR, qPCR.
of thenecessary
~1
PCR is steps
hprotocols.
per primer,
copying to perform
set the
purified test:
RNA sample collection,
isstructure
reverse RNA extraction,
transcribed to follows
cDNA RT-
and
RT-qPCR diagnostic Thethe RNA
steps and DNA
for performing the RT-qPCR of thetestsample,
are as which[95]:can
qPCR Test
amplified
diagnose set results
up,
by andreal-time
qPCR.
infectious testorigin positive
results,and allvariousSARS-CoV-2
of which can beand
genetic patients
customized
blood cross the threshold
to explain
diseases [94]. both line
this
Figure and
9 within
other
demon-
Nasopharyngeal swab <15 min: Cotton swab is inserted into the nostril to absorb
40.00
RT-qPCR
strates cycles
Test (<40.00
diagnostic
results
COVID-19 Ct).
protocols.
real-time
diagnostic The steps
positive
testing for performing
SARS-CoV-2
through patients
real-time the RT-qPCR
cross the
RT-PCR. Astest are as follows
threshold
depicted line
in [95]:
within
Figure 9,
sections.
This
40.00Collected
there cyclesmethod
Nasopharyngeal
are five(<40.00 aims
necessaryCt). to
swab detect
steps <15
to the
min: nucleic
perform Cotton
the acid
swab
test: present
is
sample in
inserted the
collection, nasal
into the
RNA swab
nostrilsampling
to
extraction, absorb or
RT-
specimen 0–72 h specimen is stored at 2–8 ℃ for up to 72 h or proceed to
the respiratory
sections. tract using theallPCR process in real-time. Ittois confirmed based on the
RNAThis
qPCR method
set up,
extraction. and aims
test to detect
results, the nucleic
of which canacidbe present
customized in the nasal
explain swab both sampling
this and or the
other
reproduction
Collected
respiratory
RT-qPCR function
tract specimen
diagnostic using and
the
protocols. sequence
0–72
PCR h process
The of
specimen
steps thein
for virus
is in
real-time.
performing the
stored atItthe sample
2–8
is ℃ for uptest
[96].
confirmed
RT-qPCR tobased
72
are has or
on proceed
the
follows repro- to
[95]:
RNA extraction ~45 min purified RNA is extracted from the deactivated virus.
RNA Because
duction extraction.the infectious
function
Nasopharyngeal and sequence
swab virus
<15 of infects
the
min: the in
virus
Cotton host’s
the
swab respiratory
sample
is [96].
inserted system,
into thethenostril
necessary
to sam-
absorb
RT-qPCR, ~1 h per primer, set purified RNA is reverse transcribed to cDNA and
ples are
RNA taken
Because
sections. from
extraction
the the ~45
infectiouslower
min and upperRNA
purified
virus infects respiratory
the tract.from
is extracted
host’s respiratory The the swab
system, test
deactivated
the is necessary
sampling
virus. with
sam-
amplified
aples
special
by
swab
qPCR.
from the throat and nose of a person. The sampling of the nasal aspirates
RT-qPCR,
are ~1 h per primer, set purified RNA is reverse
℃ for transcribed to cDNA and
and Testtaken
Collected
lungs results
is
from the lower
specimen
real-time
implementing
0–72 and
positive
by
upper
h specimen respiratory
SARS-CoV-2
injection of
is stored
a saline
tract.
at
patients 2–8 The
solution cross swab
into thethe
test72ishsampling
up threshold
to
nose,
or line
and
proceed with
within
then the
to
amplified
a
RNAspecial by
swab
extraction.qPCR.
from the throat and nose of a person. The sampling of the nasal aspirates
40.00 cycles (<40.00 Ct).
Test results
RNA extraction real-time
~45 positive SARS-CoV-2 patientsfrom cross the threshold virus. line within
This method aims to min
detect purified RNAacid
the nucleic is extracted
present in the thenasal deactivated
swab sampling or the
40.00RT-qPCR,
cycles (<40.00 Ct).
respiratory tract~1 h per
using theprimer,
PCR process set purified RNA isItreverse
in real-time. is confirmed transcribedbased to oncDNA and
the repro-
This method
amplified by qPCR. aims to detect the nucleic acid present in the nasal swab sampling or the
duction function and sequence of the virus in the sample [96].
respiratory
Test tract using
results real-timethe PCRpositiveprocess in real-time. It is confirmed
SARS-CoV-2 based online the within
repro-
Because the infectious virus infects the host’spatients
respiratory cross the threshold
system, the necessary sam-
 Biologics 2021, 1, FOR PEER REVIEW 14
Biologics 2021, 1 15

and lungs is implementing by injection of a saline solution into the nose, and then the
sample
sampleisiscollecting
collectingbyby suction. Finally,
suction. if itifis itnecessary
Finally, to continue
is necessary the sampling,
to continue the lower
the sampling, the
respiratory tract, i.e., Bronchoalveolar lavage or chip aspiration, which is sputum sampling,
lower respiratory tract, i.e., Bronchoalveolar lavage or chip aspiration, which is sputum
is performing [19,63]. The RT-PCR is widely used in the diagnostic field, and the error
sampling, is performing [19,63]. The RT-PCR is widely used in the diagnostic field, and
percentage of the method is meagre [97].
the error percentage of the method is meagre [97].

Figure 9.9. The

Figure The protocol
protocol template
templateCOVID-19
COVID-19diagnostic
diagnostictesting
testingthrough
throughreal-time
real-timeRT-PCR:
RT-PCR:(1)(1)
Nasopharyngeal swab,
Nasopharyngeal (2)
swab,
Collected
(2) Collectedspecimen, (3) (3)
specimen, RNA extraction,
RNA (4) purified
extraction, RNA
(4) purified and and
RNA (5) Test results
(5) Test real-time
results (Adopted
real-time from from
(Adopted “COVID-19 Diag-
“COVID-19
nostic TestTest
Diagnostic through RT-PCR”,
through by BioRender,
RT-PCR”, accessedaccessed
by BioRender.com, on 9 April
on 2020) [98].
9 April 2020) [98].

7.2. CT-Scan
7.2. CT-Scan
Computedtomography
Computed tomography(CT)(CT)isisa asuitable
suitable diagnostic
diagnostic method
method thatthat sheds
sheds light
light on sev-
on several
eral stages of disease diagnosis and development [99]. One way to look at
stages of disease diagnosis and development [99]. One way to look at the morphologicalthe morpholog-
ical patterns
patterns of lung
of lung lesions
lesions associated
associated withwith COVID-19
COVID-19 is through
is through chestchest
scansscans
such such as X-
as X-rays
and computed tomography (CT) scans. It should be noted that the accuracy of diagnosis
depends heavily on specialists [100]. In the early stages of the epidemic in any country,
 Biologics 2021, 1, FOR PEER REVIEW 15

Biologics 2021, 1 16

rays and computed tomography (CT) scans. It should be noted that the accuracy of diag-
nosis depends heavily on specialists [100]. In the early stages of the epidemic in any coun-
the
try,use
theofuse
CTofimaging methods
CT imaging was more
methods critical
was more than RT-PCR
critical due todue
than RT-PCR thetolack
theof RT-PCR
lack of RT-
technology or the lack
PCR technology of kits
or the lackand diagnostic
of kits equipment
and diagnostic suitable for
equipment accurate
suitable forsampling
accurate[101].
sam-
In addition, CT images are a valuable tool to help physicians identify internal
pling [101]. In addition, CT images are a valuable tool to help physicians identify internal structures
and examine
structures their
and shape,their
examine size, shape,
density,size,
anddensity,
texture and[102].texture [102].
Moreover, CT imaging can help to reveal the
Moreover, CT imaging can help to reveal the abnormalities abnormalitiescausedcausedbybyCOVID-19.
COVID-19. In
In about85%
about 85%ofofpatients
patientswithwith superimposed
superimposed irregular
irregular lines
lines and
and interfaces,
interfaces, Chest
Chest CTCTinin
COVID-19
COVID-19pneumonia
pneumoniacases casesshows
showsbilateral,
bilateral,peripheral,
peripheral,and andbasal
basalpredominant
predominantground-
ground-
glass
glass opacities (GGOs) and/or consolidation [103]. In addition, in patience withoutsevere
opacities (GGOs) and/or consolidation [103]. In addition, in patience without severe
respiratory
respiratorydistress
distresswho
who recovered
recovered from coronavirus
from coronavirus disease 2019,2019,
disease chest chest
CT scans
CT revealed
scans re-
that the that
vealed greatest severityseverity
the greatest in lunginabnormalities
lung abnormalitiesoccurred after about
occurred ten days
after about from from
ten days the
initial symptoms [104]. It is essential to pay close attention to asymptomatic
the initial symptoms [104]. It is essential to pay close attention to asymptomatic patience patience as
they can transmit the infection quite easily if they are undetected. CT imaging
as they can transmit the infection quite easily if they are undetected. CT imaging of these of these
patients
patientshashas unique features that
unique features thatcan
canbebedetected
detected even
even in in asymptomatic
asymptomatic patience
patience withwith
neg-
negative nucleic testing [105]. Figure 10 shows the positive and negative
ative nucleic testing [105]. Figure 10 shows the positive and negative COVID-19 CT scan COVID-19 CT
scan results of the patient.
results of the patient.

Figure10.
Figure 10.Examples
ExamplesofofCT
CTimages
imagesthat
thatare
arepositive
positiveforfor COVID-19
COVID-19 (top)
(top) andand non-COVID-19
non-COVID-19 (bot-
(bottom)
tom) from the COVID-CT dataset, reprinted from [106], Copyright 2020, Elsevier.
from the COVID-CT dataset, reprinted from [106], Copyright 2020, Elsevier.

7.3.
7.3.The
TheSerological
SerologicalAntibody
AntibodyBlood
BloodTest
Test
Serology
Serologytesting
testing is
is a diagnostic
diagnostic method
methodfor fordetecting
detectingantibody-mediated
antibody-mediated immune
immune re-
responses againstinfectious
sponses against infectious agents
agents [107].
[107]. The
The European
European Center
Center forfor Disease
Disease Control
Control andandPre-
Prevention (ECDC)has
vention (ECDC) hasapproved
approvedthe theCOVID-19
COVID-19 serological
serological test test for
for epidemiological
epidemiologicaland and
monitoring
monitoring purposes only because it does not detect the early stagesof
purposes only because it does not detect the early stages ofinfection
infection[108].
[108].
Rapid
Rapidserological
serologicaltesting
testingcan
canbe
beconsidered
consideredan analternative
alternativetotomolecular
moleculartesting
testingtotoidentify
identify
COVID-19
COVID-19 patients when access to PCR testing is limited or non-existent. TheThe
patients when access to PCR testing is limited or non-existent. use ofusesero-
of
serological
logical teststests
withwith
lowlow prevalence
prevalence is notis not appropriate
appropriate because
because this this method
method is likely
is likely to
to have
have false-positive results compared to the actual positive [109]. This protocol
false-positive results compared to the actual positive [109]. This protocol template (Figure template
(Figure 11) demonstrates
11) demonstrates COVID-19
COVID-19 serologic
serologic diagnostic
diagnostic testing
testing through
through antibody
antibody detection.It
detection.
Itdepicts
depictssample
sampleloading,
loading,SARS-CoV-2
SARS-CoV-2antibody-antigen
antibody-antigen detection, and qualitative
detection, and qualitative test test
re-
results. This can be customized as a whole to explain other serologic diagnostic
sults. This can be customized as a whole to explain other serologic diagnostic protocols protocols
for
fordifferent
different viral, bacterial,or
viral, bacterial, orparasitic
parasiticpathogens
pathogens [110].
[110]. TheThestepssteps for performing
for performing a
a serol-
serology test shown in Figure 11 are as follows [111]:
ogy test shown in Figure 11 are as follows [111]:
(1) Sample loading: add a drop of blood or serum in the sample well (S).
(1) Sample loading: add a drop of blood or serum in the sample well (S).
(2) Buffer loading: add dilution phosphate saline buffer to sample well.
(2) Buffer loading: add dilution phosphate saline buffer to sample well.
(3) Sample incubation: capillary action moves sample across lateral flow test.
(3) Sample incubation: capillary action moves sample across lateral flow test.
(4) Antibody-antigen recognition: antibodies with specificity for COVID-19 bind to
(4) Antibody-antigen recognition: antibodies with specificity for COVID-19 bind to
gold COVID-19-antigen conjugates in the conjugate pad.
gold COVID-19-antigen conjugates in the conjugate pad.
(5) COVID-19 antibody detection: sample enters testing well (T), and COVID-19 antibody–
antigen complex binds to immobilized anti-human lgG/IgM antibodies.
Biologics 2021, 1, FOR PEER REVIEW 16

Biologics 2021, 1 17

(5) COVID-19 antibody detection: sample enters testing well (T), and COVID-19 anti-
body–antigen complex binds to immobilized anti-human lgG/IgM antibodies.
(6) Control antibody
(6) Control detection: rabbit
antibody detection: rabbit antibody-gold
antibody-gold conjugate
conjugate binds
binds to
to immobilized
immobilized
anti-rabbit lgG antibodies.
anti-rabbit lgG antibodies.
(7) Interpreting results:
(7) Interpreting results: Positive: one strip
Positive: one strip each
each in
in C
C well
well and
and T
T well, Negative == one
well, Negative one
strip in C well.
strip in C well.

Figure 11. Schematic

Figure 11. Schematicofofserological
serologicaltesting
testingsteps: (1)(1)
steps: Sample
Sampleloading, (2) (2)
loading, Buffer loading,
Buffer (3) Sample
loading, incubation,
(3) Sample (4) Antibody-
incubation, (4) Anti-
body-antigen
antigen recognition,
recognition, (5) COVID-19
(5) COVID-19 antibody antibody detection,
detection, (6) Control
(6) Control antibodyantibody
detectiondetection and (7) Interpreting
and (7) Interpreting results:
results: Positive
Positive (Reprinted
(Reprinted from “COVID-19
from “COVID-19 Serologic Serologic Diagnostic
Diagnostic Test through
Test through AntibodyAntibody Detection”,
Detection”, by BioRender,accessed
by BioRender.com, accessed onon
22 January
January 2020)
2020) [112].
[112].

7.4. Artificial Intelligence (AI)

In the COVID-19
COVID-19 pandemic, the development of new technologies technologies to monitor
monitor andand
control the outbreak of COVID-19 (coronavirus) is a significant step taken by medical re-
searchers.
searchers. Artificial
Artificial intelligence
intelligence(AI)(AI)ininmedicine
medicinehas hasrecently
recentlyledled
to to
significant advances
significant advances in
diagnosis,
in diagnosis,biotechnology,
biotechnology, andand
drug production
drug production[113]. AI technology
[113]. AI technology has shown
has shownpromising
prom-
prospects for various
ising prospects epidemics
for various (SARS,
epidemics EBOLA,
(SARS, EBOLA,andandHIV) [114].
HIV) TheThe
[114]. COVID-19
COVID-19 crisis
cri-
and the rapid increase in the number of new and suspected cases have
sis and the rapid increase in the number of new and suspected cases have led to the rise led to the rise in
AI technology used to control and diagnose the disease [99,115]. Artificial
in AI technology used to control and diagnose the disease [99,115]. Artificial intelligence intelligence
can
can quickly
quickly detect
detect the
the symptoms
symptoms of of the
the disease
disease andand alert
alert patients
patients and
and health
health authorities.
authorities.
In this way,
In this way, itit can reduce the
can reduce the decision
decision time
time in
in traditional
traditional disease
disease diagnosis
diagnosis processes
processes [116].
[116].
In
In these studies, artificial intelligence mainly uses medical imaging technologies such as
these studies, artificial intelligence mainly uses medical imaging technologies such as
computed
computed tomography
tomography (CT), (CT), X-ray
X-ray imaging
imaging (X-ray),
(X-ray), and
and magnetic
magnetic resonance
resonance imaging
imaging
(MRI)
(MRI) toto diagnose
diagnoseinfected
infectedcases
cases[117].
[117].Moreover,
Moreover, AIAI
cancantake practical
take practicalsteps in tracking
steps the
in tracking
coronavirus’s spread, identifying high-risk patients, adequately analyzing
the coronavirus’s spread, identifying high-risk patients, adequately analyzing patients’ patients’ previ-
ous data, and
previous data,predicting the riskthe
and predicting of risk
deathof[118].
deathTable
[118].4 demonstrates the mainthe
Table 4 demonstrates applications
main ap-
of AI in Pandemic COVID-19.
plications of AI in Pandemic COVID-19.
 Table
Biologics 2021, 1, FOR PEER 3. Leading epidemiological indicators of COVID-19 research articles in January 2020.
REVIEW 13

Biologics 2021, 1
Indicators Description 18

Biologics 2021, 1, FOR PEER • REVIEW

Elderly (over 60 years old) [60]. 13
Table
• Mean 3. Leading
age of epidemiological
59 years (research indicators
conducted of COVID-19
between patients research 50 articles in January
to 89 years) [74]. 2020.
Indicators •Description
Risk of a severe illness with increasing age of about 40 years [75].
Table 4. Main applications of AI in COVID-19 pandemic.
• The low number of patients with mean age 0–49 years [76].
Biologics 2021, 1, FOR PEER • REVIEW
Table Elderly
3. (overepidemiological
Leading 60 years old) [60]. indicators
13
• Average age of patients was 55.5 years; of ageCOVID-19
distribution: research articles
≤39: 10%; in January
40–49: 2020.30%; 60–69: 22%,
22%, 50–59:
Properties • Mean age of 59 years Description
(research conducted between patients 50 to 89 years) [74].
≥70: 15% [77].
Indicators •Description
Risk of a severe illness • with
Rapidincreasing
analysis of age of about
patients’ 40 yearssymptoms
irregular [75].
 Age Primary
of patients •• Elderly
diagnosis and
In detection
terms of age
(over 60 distribution,
years old) 1% under 10, 1% 10–19, 8% 20–29, 87% 30–79, and 3% >80 [78].
[60].
Table The low
3. Leadingnumber of• patients
epidemiological with
Facilitating mean
indicators to age
identify 0–49
of COVID-19 years
suspected [76].
infection
research casesinthrough
articles January medical
2020. imaging such as
Biologicsof2021, •• REVIEW
the 1,
infection
FOR PEER [119,120]
50–60 (More than half(research
acomputed
million COVID-19 patients from different countries participated in this meta-
Mean
Average ageage of 59 years
of patients was 55.5 conducted
years; agebetween
tomography (CT),patients
distribution: ≤39:5010%;
magnetic to 89 years)
resonance
40–49: [74].
imaging
22%, (MRI).
50–59: 30%; 60–69: 22%, 13
Indicators analysis)
•Description
Risk [79].
of a severe
≥70: 15% [77]. illness • with
Assistincreasing
in automated age of about 40monitoring
outbreak years [75].and prediction
• Cases range from 2• to 72 years [80].
 Age of patientsthe •treatment
Monitoring Elderly
The low(over
In terms number
of age 60distribution,
years
of old)
patients [60].
with
Establish
1% under amean
neural age
10, 0–49
network
1% years
10–19,to 8% [76].
extract
20–29,visual
87%features
30–79, and and3% assist
>80in appropriate
[78].
[121,122] • • Mean
Increased
Average age incidence
of 59 years with increasing
(research
monitoring conducted
andagetreatment
over 60 years
between of [81].
patients
patients 50 to 89 years) [74].
Table
Biologics 2021, 1, FOR PEER 3. Leading epidemiological indicators of COVID-19 research articles in January 2020. in60–69:
50–60
REVIEW (Moreage of
thanpatients
half a was 55.5
million years;
COVID-19 age distribution:
patients from ≤39: 10%;
different 40–49:
countries 22%, 50–59:
participated 30%; 22%, 13
this meta-
•• Risk
The median
≥70: of a severe
15%
analysis)
age of•waswith
[79]. illness
[77]. 74 years
Follow-up [82].
increasing patient ageupdates
of aboutand 40 follow-up
years [75]. solutions for the COVID-19 pandemic.
Indicators
 Age Contact tracing ••Description
of patients Cases
of The
theterms
In
Cases
range
low number
rangeof ageaged
from
between
2• to
of patients 35with
Analyze
distribution,
72 1%
years
and 55 years
mean
infected
under
[80]. age
10, [83].
0–49
surfaces
1% years
and8%
10–19, [76].
hotspots
20–29, 87% 30–79, and 3% >80 [78].
 Sexindividuals •• More
of patients[117,123] Elderly
Average
50–60 cases
(over
(Moreage were
60
of
than males
years
•
patients
half a [84,85].
old)
was[60].
Provide 55.5
million to predict
years;
COVID-19
Increased incidence with increasing age over 60 years [81]. age disease progression
distribution:
patients from ≤39: 10%; countries
different 40–49: 22%, 50–59: 30%;
participated in60–69: 22%,
this meta-
Table
Biologics 2021, 1, FOR PEER 3. Leading
•• REVIEW
Increased
Mean age of epidemiological
mortality
59 years between
(research indicators
60 and
conducted 80 of COVID-19
years [86–88]
between research
patients 50 articles
to 89 in January
years) [74]. 2020. 13
 Mortality rate ≥70: 15%
analysis) [77].
[79]. • Predict
The median age of was 74 years [82]. the nature of the virus through existing data, social media, and media platforms
 Age Projection
Indicators of patients ••Description
of cases The
Risk
and
In
Cases mortality
of a ofsevere
mortality
termsrange age rate
from
aged 2•was
illness significantly
with
distribution,
to 72
between 35increasing
Tracking
1%
years the55high
under
[80].
and age
risks
10,
years in
of1%the
of
[83]. age range
about
infection
10–19, 40
8% years
and of >60
the
20–29, [75]. years
possibility
87% [75,89].
30–79,of and
spread
3% >80 [78].
[124,125]
 Sex of patients • • The
50–60 low
Average number
(More
Increased of 7 days
than
incidence of• patients
(2–14
half a
with days)
Predictwith
million
increasing mean
[60,90].
the number
COVID-19 age age
over 0–49
of
patients
60 years
positivefrom
years [76].
cases and
different
[81]. deaths in
countries different areas in this meta-
participated
• Elderly
More cases (over were malesold)
60 years [84,85].
[60].
• • Average
analysis)
The median age
of 10
[79]. of
agedays
of •
patients
[91].
was Identify
was
74 55.5
years vulnerable
years;
[82]. age areas and
distribution: help the
≤39: people
10%; of
40–49: that
22%,area
50–59: 30%; 60–69: 22%,
 • Increased
Table 3. Leading
Mean of epidemiological
age mortality
59 yearsbetween
(research indicators
60 and 80 years
conducted of COVID-19 research
[86–88]patients
between 50 articles in January
to 89 years) [74]. 2020.
 Incubation
Mortality rate •• 6.4
≥70:
Cases 15%
days
range [77].
(95% CI
from
aged 5.6–7.7
2• to
between72 days),
Analysis
years
35 withof
[80].
and 55 a range
existing
years of
data
[83]. 2.1–11.1
on days
COVID-19 [92].
for pharmaceutical research
time • Risk
The mortality
of a severe rate was with
illness significantly
increasing high age inofthe age range
about 40 years of >60
[75].years [75,89].
Indicators
 patients of•Description • with Provide real-time acceleration of 20–29,
drug
[92].testing
SexDevelopment
 Age ofpatients
of drugs
In
5.0 and
terms
days
Increased
• Average
More
The cases
low
ofincidence
(95%ageCIdistribution,
of 7were
number
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daysmales
of(2–14
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days),
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[84,85].
patients
days)with
under
mean
[60,90].
aage10,
range
over
age
1%of6010–19, 8%
2–14 days
0–49 years
years [81].
[76].
87% 30–79, and 3% >80 [78].
vaccines [126–129] •• Elderly
50–60
4.0 days, (over
(More with 60
than
a •wasof
years
half
range old)
aHelp [60].
identify
million
1–7 days COVID-19
[93]. drugspatients
useful for treating
from COVID-19
different countries patients
participated in this meta-
• Increased
The median
Average of age age
mortality
10ofdaysof
patients
[91]. 74
between years60 and
was 55.5 [82].
years; 80 years [86–88]
age distribution: ≤39: 10%; 40–49: 22%, 50–59: 30%; 60–69: 22%,
 Mortality
Incubation rate •• Mean age
analysis)
Cases range of aged
[79].59 years • Design
(research
between 35
diagnostic
andconducted
55 years
tests
between
[83].
and assist in the production
patients 50 to 89 years) [74]. of vaccines
• The mortality
≥70:days
6.4 15%(95% rate5.6–7.7
[77]. CI was significantly
days), with high a range in the age range
of 2.1–11.1 daysof >60
[92].years [75,89].
 time • More
Risk
Casesofcases
a7.severe
range from illness
2•(2–14
to 72with increasing
Reducing
years [80]. age of about
the workload 40 years workers
of healthcare [75].
 SexReducing
Age of
ofpatients
patients • Average
the workloadIn terms
5.0 of
days ofDiagnosis
(95% 7were
age days males
CIdistribution,
4.4–5.6 [84,85].
days)1%[60,90].
days), under
with 10, 1%of10–19,
a range 8% 20–29,
2–14 days [92]. 87% 30–79, and 3% >80 [78].
• The low number
Increased incidence of• patients
withTraining
withstudents
increasing mean age ageand
over 0–49physicians
60 years [81].
years in early diagnosis and providing early-stage
[76].
healthcare workers •• Increased
[130–133]
Average
50–60
4.0 (More
days, ofmortality
10Because
with adays
than half
range between
[91].
of
atreatment
million
1–7 60
the days
lack and of80
COVID-19
[93]. years
definitive [86–88]
patients curative treatment
from different for thisparticipated
countries disease, the in most effective
this meta-
 Mortality
Incubationrate • Average
Thedays
median ageage of patients
of was 55.5[82].
was significantly
74 years using
years; digital methods
age distribution: ≤39: 10%; 40–49: 22%, 50–59: 30%; 60–69: 22%,
• The6.4 mortality
analysis) (95%
solution rate
[79]. CI was
5.6–7.7
after days),
preventing with and high
a range in the age range
of 2.1–11.1
controlling is days
theof timely
>60
[92].years [75,89]. of the disease and isolat-
diagnosis
•
•• Average
time ≥70:
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range [77].aged between Update
35 and information
55 years
5.0
Casesdays
range
7.of 7the
(95% days
from 2•(2–14
CIillnesses.
4.4–5.6
to 72 days)
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years [60,90].
with
[80]. range[83].
areaseveral of 2–14 days [92].
 Sex
 Age Prevention
of ••• disease
patientsof the
ofpatients In terms
More ofDiagnosis
ing
[117]
cases age
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[84,85]. under sites
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diseaseandearly,
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Average
4.0 days,
Increased of 10
with
method, adays
incidencerange [91].
of
with
CT-Scan,
• 1–7 days
increasing
Serological [93].age over
antibody60 years [81].
blood test, and Artificial intelligence.
 Incubation ••• Increased
50–60 (More Because
than half
mortality
Help
of
a million
between
prevent
the 60lack viruses
of definitive
COVID-19
and
and
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curative in the
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from different future, with the help
for thisparticipated
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disease, the previous
in most data
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this meta-
 Mortality rate 6.4
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median(95% CIof
age 5.6–7.7
was days),
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2.1–11.1 days [92].
time analysis)
•• The solution
[79]. rateafter
mortality was preventing
significantly and controlling is the of timely diagnosis
[75,89]. of the disease and isolat-
5.0
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range
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Diagnosis
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ayears
rangein[83].
the age range
of 2–14 days [92]. >60 years
•• Average
Cases rangeing
8.of The from
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illnesses. 72 years
There [80].are several ways to diagnose the disease early, such as the RT-PCR
 Sex of patients •• More
4.0 days,
cases with aRole
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(2–14 Nanotechnology
days)
1–7 days[60,90].[93]. in Diagnostics and Treatment of COVID-19
•• Average
Increased method, Because
incidence
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ofmortality
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with
the
CT-Scan,
days [91]. the
most lack
increasing of
important
Serological definitive
age over ways
antibody60 curative
years
to [81].
detect
blood treatment
the
test, for
SARS-CoV-2
and this
Artificial disease,
virus inthe most
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intelligence. andeffective
lower
 • Increased Nanotechnology
between 60 andis currently
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 Incubation
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of RNA
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[92]. disease early,
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• Average ofofCOVID-19
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days (2–14 disease.
of days)
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[60,90].
lack of of nanoparticles
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treatment high solubility,
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 Sex of patients •• More
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• Average of 10One
adaptability,
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[91].
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 Incubation • Increased mortality
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 Mortality rate respiratory
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• 4.0 days, diagnose aset
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strates
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Biologics 2021, 1, FOR PEER REVIEW 13

Biologics 2021, 1 19
Table 3. Leading epidemiological indicators of COVID-19 research articles in January 2020.

Indicators Description
• Elderly Table 5.(over
The60 years old)and
advantages [60].disadvantages of nanotechnology in COVID-19.
Biologics 2021, 1, FOR PEER REVIEW 13
• Mean age of 59 years (research conducted between patients 50 to 89 years) [74].
Properties • Risk of a severe Advantagesillness with increasing age of about 40 years [75]. Disadvantages
• The low number • of patientsofwith
Progression meanand
effective agepromising
0–49 years [76].
Table • Average
3. Leadingageepidemiological
ofdisinfection
patients wasprocess indicators
55.5 years; of
ageCOVID-19
(Antimicrobial distribution: research
activity), articles
≤39: 10%; • in Expandability
40–49: January
22%, 50–59:2020.30%;
and60–69: 22%,
≥70: 15% [77]. Development of new materials, expansion of manufacture costs
Indicators Description
 Age Nanomaterials
of patients for • In terms of ageself-cleaning
distribution, properties
1% under 10, of surfaces
1% 10–19, (Release
8% 20–29, of 87% •30–79, Issues
and 3%related to intellectual and
>80 [78].
• Elderly (over 60chemical years old) [60].
surface decontamination• 50–60 (More than half a disinfectants million COVID-19 to increase
patientstheirfromduration of countries
different regulatory characteristics
participated in this meta-
• Mean age of 59action) years (research
[136]. conducted between patients 50 to 89•years) [74]. and environmental
Toxicity
Biologics 2021, 1, FOR PEER REVIEWanalysis) [79]. 13
• Risk of a severe • from illness with
Antiseptic, increasing age
Antimycotic Agent, of about 40 years [75].
and antiviral impacts of these systems [138]
• Cases range 2 to 72 years [80].
• The low number of patients
activity of metal with mean age 0–49
nanoparticles [137]years [76].
• Increased incidence with increasing age over 60 years [81].
• Average age • ofParticipate
patients was in 55.5production
the years; age of distribution:
appropriate ≤39:
masks10%; 40–49: 22%, 50–59: 30%; 60–69: 22%,
• The median age of was 74 years [82].
Table≥70: 3. Leading
15% [77].epidemiological
and gloves [139] indicators of COVID-19 research articles • in Skin
January 2020.
irritation
• Cases range aged between 35 and 55 years [83].
 Age of patients of• In terms of
Development • ageUse equipment
distribution, 1%moreunder efficiently,
10, 1% 10–19, more 8% 20–29, 87% •30–79,
resilient, Allergies
and 3% >80 [78].
 Sex of patients
Indicators •Description
More cases were males [84,85].
nanomaterials for • 50–60 (More than andhalf safely againstCOVID-19
a million biologicalpatientsand chemicalfrom different countries • Toxic effects in humans
participated in this meta-
personal • Elderly
protective Increased (over 60hazards
mortality years old)
between
[140] [60].
60 and 80 years [86–88] • Environmental pollution
 Mortality
Biologics 2021, 1,rate
FOR PEER REVIEWanalysis) [79]. 13
equipment (PPE) • Mean age•of 59rate
The mortality years
Lack wasof(research
significantly
effect conducted
on[80].
texture high andinbetween
the age patients
rangeof
breathability of 50
>60toyears
89 years) [74]. of nanoparticles during
[75,89].
(release
• Cases range from 2 to 72 years
• Average
Risk of a ofsevere
7 days illness
(2–14with
materials dueincreasing
days) to[60,90].
antimicrobialage of activity
about 40and years [75]. washing from clothes) [135]
• Increased incidence with increasing age over 60 years [81].
• Average
The low number of patients
hydrophobicity
of 10 days [91]. with[141]mean age 0–49 years [76].
 Incubation • The median age of was 74 years [82].
Table • 6.4 3. days
Leading
Average • epidemiological
age
(95% ofCIpatients
5.6–7.7 was
Improving days), indicators
the55.5 with
qualityyears;aof of
age
range COVID-19
distribution:
of 2.1–11.1
SARS-CoV-2 research articles
≤39:[92].
days
diagnosis 10%; in January
40–49: 22%, 50–59:2020.30%; 60–69: 22%,
time • Cases range aged between 35 and 55 years [83].
• 5.0 days (95% CI
≥70: 15% [77]. (Reduce
4.4–5.6the duration
days), with of diagnosis
a range anddays
of 2–14 increase[92].the
 Sex of patients
Indicators •Description
More cases were males [84,85].
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Biologics of patients
2021, 1, FOR PEER •for
In terms
4.0
REVIEWdays, of ageascope
with rangeofofdiagnosis)
distribution, 1–7 1% days under[142]10, 1% 10–19, 8% 20–29, 87% 30–79, and 3% >80 [78].
[93]. 13
• Elderly (over 60Ayears old) [60]. • high operating expenses and
virus detection
 Mortality rate and • Increased
50–60 (More •mortality
than useful
half between
a tool
million 60 the
for andproduction
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and development
patients from different countries participated
capital in this meta-
expenditures
disease diagnosis • Mean age of 59rate
The mortality years
of was(research
various significantly
diagnosticconducted high
kits ininbetween
the age patients
COVID-19 range[143] of 50
>60toyears
89 years) [74].
[75,89].
analysis) [79].
Risk of a7.of
• Average Diagnosis
severe
• 7from
daysillness with increasing age of about 40 years [75].
• Cases range 2(2–14
develop to 72ofdays) [60,90].
the sensors
years [80]. for the detection of
Table • Average
The low number
3. Leadingof Becauseof [91].
epidemiological
10 SARS-CoV-2
days of the[135,144]
patients lack
with of definitive
mean
indicators age 0–49 curative
of COVID-19 [76].treatment
yearsresearch articlesfor this disease,
in January 2020. the most effective
 Incubation • Increased incidence with increasing age over 60 years [81].
• 6.4
Average solution
age of after
patients preventing
was 55.5 and
years; controlling
age distribution: is the
≤39: timely
10%; diagnosis
40–49: 22%, of the 30%;
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60–69: isolat-
22%,
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time Thedays
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median • age CI 5.6–7.7
Transfer
of was of 74days),
the
years with
drug[82]. toa the
rangetargetof 2.1–11.1
organ days [92].
• 5.0
≥70: 15%
days [77].
ing•
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days),antiviral
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55ayears
of
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 Age Carriers ••• Elderly
and drug
of patients
Cases
In terms
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of
aged
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effective
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[60].
antiviral
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10,antibody
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 Sex of patients •• More
4.0 days,method,
with
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a CT-Scan,
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delivery systems • Mean age•ofwere
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Reduction of sideCOVID-19
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of thedifferent participated in this meta-
• Increased
Risk •mortality
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with 60 and storm
increasing
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years of[86–88]
[145] about 40 years [75].
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7.1. RT-PCR
Diagnosis Method
Biologics 2021, 1, FOR PEER • REVIEW
The mortality
low •
number rate of was
Increase significantly
patients
the with
half-life mean high
of age
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drug range
years [76].of >60 years [75,89]. 13
• Cases range from 2 to 72 years [80].
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Because
days
of of the
(2–14
patients of most
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days)
was important
lack
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55.5 of
years; definitive
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10%; for
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50–59: in upper
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60–69: lower
effective
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• Increased •incidence Improve withaction and reaction
increasing age over with viral particles
60 years [81].
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solution
of 10 days
[77].
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[91].
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and Real-Time
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strates This
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Testafter
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resultsfrom
real-time and
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of
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The
patients samplingof the
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aspirates
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ing the COVID-19
illnesses. diagnostic
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Biologics 2021, 1 20
Biologics 2021, 1, FOR PEER REVIEW 19

Figure 12.Figure 12. Schematic representation of the nanotechnologies tools to prevent and control COVID-19 (Created with Bio-
Schematic representation of the nanotechnologies tools to prevent and control COVID-19 (Created with BioRender.
Render.com. accessed on 13 February 2021).
com, accessed on 13 February 2021).
It should be noted that nanoparticles (NP) have been widely used in many medical
It should be
applications noted
such that nanoparticles
as biosynthetic (NP)
sensors, drug haveimaging,
delivery, been widely used in many
and antimicrobial ther- medical
applications
apy [149].such
Tableas biosynthetic
6 reports the typessensors, drug
of NPs and delivery,
their imaging,
applications and antimicrobial
in the detection, control, ther-
apy [149]. Table 6 reports
and vaccination the types of NPs and their applications in the detection, control,
against coronaviruses.
and vaccination against coronaviruses.
Table 6. The types of NPs and their applications in the detection, control, and vaccination against coronaviruses.
Table 6. The typesType
Properties of NPs and theirDescription
of NPs applications in the detection, control, and vaccination against coronaviruses.
• Development of a colorimetric assay based on gold nanoparticles (AuNPs) [150].
Properties Type of •NPs
Metal NPs
Description
• Development of the nanoplasmonic pillar arrays (NPA) comprise gold Nano islands [151].
• • Development
Fabrication of nanosensor based on assay
of a colorimetric non-mediated
based on SWCNTs with ACE2. These
gold nanoparticles ACE2- [150].
(AuNPs)
• Metal NPs • SWCNT nanosensors
Development can be turned into
of the nanoplasmonic an optical
pillar arraystool for prompt
(NPA) comprisediagnosis of SARS-
gold Nano islands [151].
• Carbon nano- CoV-2 [152].
tubes • • Fabrication of nanosensor
Use in electrochemical sensorsbased
based on onfunctional
non-mediated SWCNTs
cobalt TiO2 with(Co-TNTs)
nanotubes ACE2.
These ACE2-SWCNT
for prompt nanosensors
diagnosis of SARS-CoV-2 viacan be turned
sensing the spike into an optical tool
(receptor-binding for prompt
domain
• Carbon diagnosis of SARS-CoV-2 [152].
(RBD)) present at the virus surface [153].
Nanoparticle nanotubes • • Use in electrochemical
Antiviral sensors based
effects against SARS-CoV-2 on faceonmasks
functional
[154]. cobalt TiO2 nanotubes (Co-TNTs)
• Silica NPs
for diagnostic • for
Useprompt diagnosis
of silica-coated of SARS-CoV-2
superparamagnetic via sensing
nanoparticles the spike
to detect (receptor-binding
the virus [155]. domain
• (RBD))
Use of QDpresent at the probes
nanoparticle virus surface
to identify[153].
and confirm SARS-CoV-2 Spike and ACE2
• Quantum • receptor binding
Antiviral effectsinhibitors
against in human cells [156].
SARS-CoV-2 on face masks [154].
• Silicadots
NPs(QDs) • • Use
Designation of human IgG and to investigate severe
of silica-coated superparamagnetic acute respiratory
nanoparticles syndrome
to detect corona-
the virus [155].
virus 2 (SARS-CoV-2)-specific IgM and IgG [157].
• Use of QD nanoparticle probes to identify and confirm SARS-CoV-2
• Fabrication of the surface-functionalized magnetic nanoparticles (MNP’s) and viral
Spike and ACE2
Nanoparticle • Quantum receptor binding inhibitors in human cells [156].
RNA-extraction protocol for potential detection of COVID-19 [158].
• (QDs)
dots Magnetic NPs
•
for diagnostic • Designation
Development of human IgG and
of pcMNPs-based viraltoRNA
investigate
elicitationsevere
methodacute
for therespiratory syndrome
sensitive diagno-
coronavirus
sis of COVID-19 2 (SARS-CoV-2)-specific
causing virus, the SARS-CoV-2 IgM and[159].IgG [157].
• Fabrication of the surface-functionalized magnetic nanoparticles (MNP’s) and viral
RNA-extraction protocol for potential detection of COVID-19 [158].
• Magnetic NPs • Development of pcMNPs-based viral RNA elicitation method for the sensitive
diagnosis of COVID-19 causing virus, the SARS-CoV-2 [159].
• The role of graphene-based materials and strategies in fluid biopsy and diagnosis of
viral diseases in the diagnosis of COVID-19 [160].
• Use of graphene effect transistors (GFET) to detect SARS-CoV-2 in human
• Graphene nasopharyngeal swab samples.
• Use of laser engraved graphene for rapid and remote evaluation of COVID-19
biomarkers [161].
Biologics 2021, 1 21

9. Treatment
The treatments available for people with COVID-19 are based on their symptoms,
and there is no exact treatment available for complete recovery in patients with COVID-19.
Researchers and physicians are making efforts to provide proper treatment for COVID-
19 patients [162]. Researchers are testing a wide range of possible therapies, including
antiviral medicines, immunosuppressants, monoclonal antibodies, and vaccines [163].
In the early stages of the disease, the patient’s immune system is challenged to prevent
replication of the SARS-CoV-2 virus; however, in the acute stages, maybe experience
tissue damage due to severe immune/inflammatory reactions [164]. According to clinical
research, antiviral therapies are most effective in the early stages of the disease. In contrast,
immunosuppressive/anti-inflammatory treatments are likely to be most effective in the
severe stages of COVID-19 [165]. It should be noted that anti-SARS-CoV-2 antibody-based
therapies are more effective in the early stages of infection before the patient enters the acute
phase. Therefore, physicians have recommended receiving monoclonal antibodies against
SARS-CoV-2 [166]. The drugs approved by the US Food and Drug Administration (FDA)
are Dexamethasone and Remdesivir. It is recommended for hospitalized patients who
need supplemental oxygen [167]. Remdesivir is an intravenous nucleotide drug from the
adenosine analogue [168]. The mechanism of action of Remdesivir against the SARS-CoV-2
virus is presented in Figure 13. As depicted in Figure 13, Remdesivir binds to RNA-
dependent RNA polymerase and prevents virus replication by premature termination
of RNA transcription [168]. In the acute phase of the disease, when patients need a
ventilator, dexamethasone, a corticosteroid, significantly affects patients’
Biologics 2021, 1, FOR PEER REVIEW 21 recovery [169].

All recommended treatments for COVID-19 are reported in Table 7.

Figure 13. The potential mechanism of action of Remdesivir against coronavirus replication (Re-
Figure 13. The potential mechanism of action of Remdesivir against coronavirus replication
printed from “Remdesivir: Potential Repurposed Drug Candidate for COVID-19 (Portrait)”, by Bi-
(Reprinted fromon
oRender, accessed “Remdesivir: Potential Repurposed Drug Candidate for COVID-19 (Portrait)”,
1 April 2020) [170].
by BioRender.com, accessed on 1 April 2020) [170].
Table 7. All recommended treatments for COVID-19.

Properties Type Description

• Due to its ability to inhibit SARS-CoV-2, one of the promising drugs for COVID-
19 [171,172].
• Adults who are hospitalized and pediatric patients (aged ≥12 years and weighing
≥40 kg).
Biologics 2021, 1 22

Table 7. All recommended treatments for COVID-19.

Properties Type Description

• Due to its ability to inhibit SARS-CoV-2, one of the
promising drugs for COVID-19 [171,172].
• Adults who are hospitalized and pediatric patients
(aged ≥12 years and weighing ≥40 kg).
• Pediatric patients who are hospitalized (aged <12 years and
weighing 3.5 kg to <40 kg) [173].
• Remdesivir • Side effects (gastrointestinal symptoms (e.g., nausea),
increased transaminase levels, increased prothrombin time
and hypersensitivity reactions, control of renal function,
drug interaction with chloroquine or
hydroxychloroquine) [168,174].
• Low side effects in pregnant women [175].
• Favipiravir is a promising drug for COVID-19 that
decreases hospital stay and the need for mechanical
ventilation [176].
• Favipiravir may emerge as a valuable drug in the treatment
of mild to moderate symptomatic SARSCoV-2 infected
• Favipiravir cases [177].
• The recommended dosage of favipiravir for adults is
1800 mg orally twice daily on 1st day, followed by 800 mg
orally twice daily, up to a maximum of 14 days. The 14-day
course in India costs Rs 10,200 [177].
• Chloroquine is an antimalarial drug (manufactured in
1934). Hydroxychloroquine, an analogue of chloroquine
(manufactured in 1934).
• Less toxicity of hydroxychloroquine compared to
chloroquine [178].
• Prevents acute coronavirus 2 (SARS-CoV-2) syndrome by
increasing endosomal pH [179].
• Chloroquine is a suitable inhibitor of
Angiotensin-converting enzyme 2 (ACE2) [180].
Drug treatment • Inhibits the transfer of SARS-CoV-2 from primary
endosomes to end lysosomes and prevents the spread of
viral genomes [181].
• The COVID-19 Treatment Guidelines Panel recommends
against the use of chloroquine or hydroxychloroquine with
• Chloroquine or or without azithromycin for the treatment of COVID-19 in
Hydroxychloroquine hospitalized patients (AI) [182].
• Non-recommendation for use in nonhospitalized
patients [178].
• high-dose chloroquine (600 mg twice daily for ten days).
• Side effects: QTc prolongation, Torsade de Pointes,
ventricular arrhythmia, and cardiac deaths [183],
fluoroquinolone antibiotics [184], Prolongation of QTc
interval with concomitant use of hydroxychloroquine and
azithromycin [179,185], Increased risk of cardiac arrest if
concomitant use of hydroxychloroquine with
azithromycin [186].
• Drug-Drug Interactions: Caution in concomitant use with
drugs metabolized by CYP2D6 (e.g., certain antipsychotics,
beta-blockers, selective serotonin reuptake inhibitors,
methadone) [187].
• Prevent severe acute respiratory syndrome-associated
coronavirus (SARS-CoV-2) IN VITRO condition
[173,188,189].
• No recommendation for use by the COVID-19 Treatment
Guidelines for the treatment of COVID-19, except in a
• Lopinavir/ritonavir clinical trial [190].
• Side effects (Nausea, vomiting, diarrhea (common),
QTc prolongation, Hepatotoxicity) [190].
• Drug and drug interactions (Increased drug concentration
with concomitant use of drugs metabolized by cytochrome
P450 3A enzyme and increased toxicity) [190].
Biologics 2021, 1 23

Table 7. Cont.

Properties Type Description

• Ivermectin, an FDA-approved anti-parasitic
(broad-spectrum anti-viral activity in vitro, an inhibitor of
the causative virus (SARS-CoV-2)) [174,191,192].
• Ivermectin • No recommendation for use by the COVID-19 Treatment
Guidelines for the treatment of COVID-19, except in a
clinical trial [192].
• Use of blood-derived products of people recovered from
SARS-CoV-2 infection(convalescent plasma,
immunoglobulin products) [179] (The Food and Drug
• Blood-derived
Administration (FDA) has issued an Emergency Use
products
Authorization (EUA) for the use of convalescent plasma for
hospitalized patients with COVID-19).
Immune-Based • Neutralizing monoclonal antibodies (clinical trials) [193,194].
Therapy [165]
• Use of drugs to treat immune and/or inflammatory
syndromes such as corticosteroids (e.g., glucocorticoids) [195].
• Immunomodulatory • Targeted anti-inflammatory treatments such as interleukin
therapies inhibitors [184], interferons [196], kinase inhibitors [197].
• Tocilizumab is a suggested anti-inflammatory drug to
treatment COVID-19 [198].
• Baricitinib plus remdesivir was superior to remdesivir
alone in reducing recovery time and accelerating clinical
status improvement among patients with COVID-19,
• Baricitinib notably among those receiving high-flow oxygen or
noninvasive ventilation. The combination was associated
with fewer serious adverse events [199].
• Bamlanivimab and etesevimab are neutralizing monoclonal
antibodies that bind to different but overlapping epitopes
in the receptor-binding domain of the spike protein of
Anti-SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
Antibody Products (SARS-CoV-2). The bamlanivimab plus etesevimab
combination blocks SARS-CoV-2 entry into host cells and is
being evaluated for the treatment of COVID-19 [200].
• Bamlanivimab • On 9 February 2021, the Food and Drug Administration
(FDA) issued an Emergency Use Authorization (EUA) to
make bamlanivimab 700 mg plus etesevimab 1400 mg
available for the treatment of outpatients with mild to
moderate COVID-19 who are at high risk for progressing to
severe disease and/or hospitalization (see the EUA criteria
for use of the products below). The issuance of an EUA
does not constitute FDA approval of a product [200].
• In hospitalized patients with severe COVID-19 who
required oxygen support, using dexamethasone 6 mg daily
for up to 10 days reduced mortality at 28 days, with the
• Dexamethasone [201]
greatest benefit seen in those who were mechanically
ventilated at baseline.
• There was no observed survival benefit of dexamethasone
in patients who did not require oxygen support at baseline.
• If dexamethasone is not available, alternative
Corticosteroids glucocorticoids such as prednisone, methylprednisolone,
or hydrocortisone can be used [202].
• Methylprednisolone: [A total of 102 severe and critically ill
• Methylprednisolone
COVID-19 patients were included in this study. The results
• Prednisone
showed that methylprednisolone treatment did not
• Hydrocortisone
improve the prognosis] [203].
• Hydrocortisone is commonly used to manage septic shock
in patients with COVID-19 (The hydrocortisone dose was
adjusted according to clinical response).
Biologics 2021, 1 24

Table 7. Cont.

Properties Type Description

• Chronic Anticoagulant and Antiplatelet Therapy.
• Not used for non-hospitalized patients with COVID-19.
• Antithrombotic • Undecomposed heparin, low molecular weight heparin,
Therapy [204] and warfarin are not contraindicated in children and
pregnant women.
• Prohibition of oral anticoagulants with direct action.
• The potential designation of high doses of vitamin C in
• Vitamin C [187] ameliorating inflammation and vascular injury in patients
with COVID-19.
• Increased risk of pneumonia in patients with low levels of
Adjunctive Therapy vitamin D [190,206].
• Vitamin D [205] • Use of vitamin D supplementation to protect against acute
respiratory tract infection [207].
• There are insufficient data to recommend either for or
against the use of zinc to treat COVID-19 [208].
• The COVID-19 Treatment Guidelines Panel recommends
against using zinc supplementation above the
• Zinc [208] recommended dietary allowance to prevent COVID-19,
except in a clinical trial (BIII) [208].
• Evaluation in clinical trials of zinc supplement alone or in
combination with hydroxychloroquine for the prevention
and treatment of COVID-19 [209].

10. Vaccines
A vaccine is a biological product that produces an acquired active immunity against
a specific microbial disease [192]. Vaccines are very vital to save the lives of millions of
people every year. The primary function of vaccines is to train and prepare the immune
system to identify and fight the target viruses and bacteria. Common components of
vaccines are as follows (Figure 14):
(1) Active ingredients Viral or bacterial antigens that directly stimulate the immune
system but cannot cause disease.
(2) Adjuvants Aluminum salts in small quantities that help to boost the immune response
to the vaccine.
(3) Antibiotics prevent contamination by bacteria during the vaccine manufacturing
process.
(4) Stabilizers Sugar/gelatin keeps the valuable vaccine until it is administered to
a patient.
(5) Preservatives Thimerosal prevents dangerous bacterial or fungal contamination
(only used for influenza vaccines).
(6) Trace components Residual inactivating ingredients such as formaldehyde, and resid-
ual cell culture materials (present in small quantities that do not pose a safety concern).
Biologics 2021, 1, FOR PEER REVIEW 24

Biologics 2021, 1 25
(6) Trace components Residual inactivating ingredients such as formaldehyde, and re-
sidual cell culture materials (present in small quantities that do not pose a safety concern).

Figure 14.
Figure 14. Common
Commoncomponents
componentsofofVaccines
Vaccines(Adopted from
(Adopted “Common
from Components
“Common of Vaccines”,
Components by BioRender,
of Vaccines”, accessed
by BioRender.com,
on 7 April
accessed on2020)
7 April 2020).
According to the WHO, there are currently more than 50 COVID-19 vaccine candidates
According to the WHO, there are currently more than 50 COVID-19 vaccine candi-
in trials. To accelerate and distribute the vaccine equitably, WHO is working with scientists,
dates in trials. To accelerate and distribute the vaccine equitably, WHO is working with
businesses, and global health organizations through the COVAX (Working for global
scientists, businesses, and global health organizations through the COVAX (Working for
equitable access to COVID-19 vaccines) project (led by WHO, GAVI CEPI). BNT162b2
global equitable access to COVID-19 vaccines) project (led by WHO, GAVI CEPI).
(Pfizer-BioNTech) developed by BioNTech and manufactured and distributed by Pfizer,
BNT162b2 (Pfizer-BioNTech) developed by BioNTech and manufactured and distributed
and Fosun Pharmaceutical is the first EUA-approved COVID-19 vaccine for emergency
by Pfizer, and Fosun Pharmaceutical is the first EUA-approved COVID-19 vaccine for
use. Clinical trials were performed on 44,000 people, which is reported to be more than
emergency use. Clinical trials were performed on 44,000 people, which is reported to be
95% successful [210,211]. It should be noted that the Moderna vaccine was authorized for
more than 95% successful [210,211]. It should be noted that the Moderna vaccine was au-
emergency use on 18 December 2020, by the US Food and Drug Administration (EUA) to
thorized for emergency use on 18 December 2020, by the US Food and Drug Administra-
prevent COVID-19 disease. The AZD1222 vaccine developed by Oxford [212] is another
tion (EUA) to prevent COVID-19 disease. The AZD1222 vaccine developed by Oxford
effective vaccine that has just received an emergency license. The vaccine has been clinically
[212] ison
tested another
65,000effective vaccine
people and that has to
is reported justbereceived
more than an emergency license.
70% effective TheCOVID-
against vaccine
has been clinically tested on 65,000 people and is reported to be more
19 Acute Respiratory Syndrome [213]. Authorized/approved COVID-19 vaccines are than 70% effective
against COVID-19
tabulated Acute
in Table 8. TheRespiratory
mechanismSyndrome
and type of [213]. Authorized/approved
process COVID-19
of the approved BNT162b2,
vaccines are tabulated in Table 8. The mechanism and type
Sinopharm and Oxford/AstraZeneca vaccines are presented in Figure 15. of process of the approved
BNT162b2, Sinopharm and Oxford/AstraZeneca vaccines are presented in Figure 15.
Biologics 2021, 1 26

Table 8. Authorized/approved COVID-19 vaccines.

Name Vaccine Type Primary Developers Country of Origin Authorization/Approval Storage Description
BNT162b2 is a modified nucleoside mRNA-based
vaccine developed by BioNTech and Pfizer.
Fosun Pharma has licensed BNT162b2 in China.
Pfizer, BioNTech; UK, Bahrain, Canada, The vaccine is given as an intramuscular injection in
BNT162b2 mRNA-based vaccine Fosun Pharma Multinational Mexico, US
−70 ◦ C two doses 21 days apart. BNT162b2 generates an
immune response against SARS-CoV-2, the virus that
causes COVID-19, by encoding a mutated form of the
virus’s full spike protein.
A safe and efficacious vaccine with more than 70%
The University of Oxford; impact against severe acute respiratory syndrome
AstraZeneca/Oxford Adenovirus AstraZeneca; IQVIA; The UK 2–8 ◦C coronavirus 2 (SARS-CoV-2).
AZD1222 Serum Institute of India Mechanism: Replication-deficient viral vector
vaccine (adenovirus from chimpanzees)
CoronaVac (formerly PiCoVacc) is a
Inactivated vaccine formalin-inactivated and alum-adjuvanted vaccine
Sinovac CoronaVac (formalin with Sinovac China China 2–8 ◦C developed by the China-based biotechnology
alum adjuvant) company Sinovac Biotech. The vaccine is
administered in two doses 14 days apart.
The Gamaleya Research Institute in Russia and
Gamaleya Research Health Ministry of the Russian Federation evaluates
Sputnik V Non-replicating viral vector Institute, Acellena Contract Russia Russia −18 ◦ C their non-replicating viral vector vaccine, Sputnik V
Drug Research and
Development (formerly Gam-COVID-Vac), in a Phase 3 trial in
Russia and internationally.
Moderna developed mRNA-1273 based on prior
the U.S. Food and Drug studies of related coronaviruses such as those that
Administration’s (FDA) has cause severe acute respiratory syndrome (SARS) and
Moderna mRNA-1273 mRNA-based vaccine Moderna USA authorized the emergency 2–8 ◦ C the Middle East respiratory syndrome (MERS).
use of mRNA-1273, Moderna predicts it will be able to distribute
Moderna’s vaccine 20 million doses to the United States in
December 2020, and 100 m doses globally
Beijing Institute of
Sinopharm is developing a second inactivated
Sinopharm Inactivated vaccine Biological Products; China China China, 2–8 ◦ C
BBIBP-CorV United Arab Emirates COVID-19 vaccine candidate, BBIBP-CorV, with the
National Pharmaceutical Beijing Institute of Biological Products.
Group (Sinopharm)
Biologics 2021, 1
Name
Bharat Biotech BBV152
propiolactone-inactivated
Johnson and Johnson
vaccine (JNJ-78436735)
Table 8. Cont.
Vaccine Type Primary Developers Country of Origin
Bharat Biotech, the Indian
Council of Medical
whole-virion β- Research (ICMR) and
National Institute of
Virology (NIV)
Janssen Pharmaceuticals
Viral vector Companies of
Johnson & Johnson
27
Authorization/Approval Storage Description
COVAXIN is an inactivated vaccine obtained from
the SARS-CoV-2 strain isolated at the NIV, Pune, an
Indian virology research institute.
The vaccine is used along with immune stimulants,
commonly known as vaccine adjuvants
(Alhydroxiquim-II), to improve immune response
and longer-lasting immunity. The vaccine candidate
Bharat Biotech’s is produced through the formulation of the
India ‘COVAXIN™’ by 2–8 ◦ C inactivated virus with Kansas-based ViroVax’s
DCGI-CDSCO, MoH&FW Alhydroxiquim-II adjuvant.
COVAXIN mainly contains 6 µg of whole-virion
inactivated SARS-CoV-2 antigen (Strain:
NIV-2020-770), and the other inactive components
such as 250 µg aluminium hydroxide gel, 15 µg TLR
7/8 agonist (imidazoquinolinone), 2.5 mg TM
2-phenoxyethanol, and phosphate buffer saline up to
0.5 mL.
The J&J/Janssen vaccine was 66.3% effective in
clinical trials (efficacy) at preventing
laboratory-confirmed COVID-19 illness in people
who had no evidence of prior infection 2 weeks after
Johnson & Johnson receiving the vaccine. People had the most protection
COVID-19 Vaccine
USA Authorized by U.S. FDA 2–8 ◦ C 2 weeks after getting vaccinated.
for Emergency Use The vaccine had high efficacy at preventing
hospitalization and death in people who did get sick.
No one who got COVID-19 at least 4 weeks after
receiving the J&J/Janssen vaccine had to
be hospitalized.
Biologics 2021, 1 28

Biologics 2021, 1, FOR PEER REVIEW 27

Figure 15. The mechanism and type of process of the approved (a) BNT162b2, (b) Sinopharm and (c) Oxford/AstraZeneca
Figure 15. The mechanism and type of process of the approved (a) BNT162b2, (b) Sinopharm and (c) Oxford/AstraZeneca
vaccine (Reprinted from “Clinical Phase Vaccine Candidates for COVID-19”, by BioRender, accessed on 15 April 2020)
vaccine
[214]. (Reprinted from “Clinical Phase Vaccine Candidates for COVID-19”, by BioRender.com, accessed on 15 April
2020) [214].
11. The Effect of COVID-19 on Pregnant Women
11. The Effect of COVID-19 on Pregnant Women
Due to the complications of COVID-19, pregnant women are expected to be at risk of
Due
developing to severe
the complications
COVID-19 compared of COVID-19, pregnant women
to non-pregnant women.are expected
It should to be at
be noted risk
that
of developing severe COVID-19 compared to non-pregnant women.
the easy spread of viral respiratory diseases, such as influenza, during pregnancy indi- It should be noted
that
catesthethateasy spreadwomen
pregnant of viral arerespiratory diseases,
more vulnerable such as influenza,
to COVID-19 and require during
morepregnancy
medical
indicates
care [215,216]. Generally, mechanical and physiological changes in pregnancy more
that pregnant women are more vulnerable to COVID-19 and require gained medical
sus-
care [215,216]. Generally, mechanical and physiological changes
ceptibility to COVID-19, significantly when it affects cardiorespiratory and gravida, andin pregnancy gained sus-
ceptibility
it increases the rate of progression in respiratory failure. Due to physiological changes in it
to COVID-19, significantly when it affects cardiorespiratory and gravida, and
increases
the immune the rate
and of progression in respiratory
cardiopulmonary failure. Due
system in pregnant to physiological
women (e.g., improved changes
dia-in
the immune
phragm, and cardiopulmonary
increased oxygen consumption systemandin respiratory
pregnant women mucosal (e.g., improved
oedema), theydiaphragm,
are very
increased
susceptible oxygen consumption
to respiratory and respiratory
pathogens mucosal[217].
severe pneumonia oedema), they are very
Additionally, susceptible
pregnant peo-
to
ple with COVID-19 might be at increased risk of adverse pregnancy outcomes, such with
respiratory pathogens severe pneumonia [217]. Additionally, pregnant people as
COVID-19
preterm births. might be at16increased
Figure demonstratesrisk of
anadverse
overview pregnancy
of pregnant outcomes,
women with suchCOVID-19
as preterm
births.
diseaseFigure 16 demonstrates
in diagnosis, prevention, anand
overview of pregnant
potential treatments. women with COVID-19 disease in
diagnosis, prevention, and potential treatments.
A wide range of vaccines is routinely and safely administered during pregnancy. As
A wideinrange
mentioned of vaccines
the vaccine is routinely
section, and safely
Pfizer-BioNTech administered
vaccines during pregnancy.
are an effective vaccine
As mentioned
against COVID-19.in theHowever,
vaccine section, Pfizer-BioNTech
as clinical vaccines are
trials of the COVID-19 an effective
vaccine vaccine
in pregnant
against
womenCOVID-19.
have not yetHowever, as clinical
been performed, trials
there of the COVID-19
is insufficient vaccine
evidence in pregnant
to recommend women
routine
have
use ofnottheyet been performed,
COVID-19 vaccine to there is insufficient
pregnant women.evidence
However,togivenrecommend routine use
the mechanism andof
the COVID-19
function of thesevaccine to pregnant
vaccines women. However,
(mRNA vaccine), experts believegiventhat
the itmechanism
is unlikely and function
to pose a riskof
these vaccineswomen.
to pregnant (mRNAMoreover,
vaccine), experts
mRNA believe
vaccines that
areit not
is unlikely
expected to pose
to posea risk to pregnant
a risk to the
women.
breastfed infant. It should be noted that mRNA vaccines do not contain a live virus infant.
Moreover, mRNA vaccines are not expected to pose a risk to the breastfed that
Itcauses
should be notedand
COVID-19 thattherefore,
mRNA vaccines do not
cannot give contain
a person a live virus
COVID-19. that causes
In addition, mRNACOVID-19
vac-
and
cinestherefore, cannot give
do not interact with agenetic
personDNA COVID-19.
because InmRNA
addition, mRNA
does vaccines
not enter the do
cellnot interact
nucleus.
with genetic
However, theDNA because
potential risksmRNA
of mRNA doesvaccines
not enterfor thepregnant
cell nucleus.
women However,
and their thefetus
potential
are
risks
unknownof mRNA becausevaccines
they havefor pregnant womeninand
not been studied their fetus
pregnant are According
women. unknown because
to the CDC they
have not been studied
recommendation, in pregnant
Acetaminophen may women.
be offered According to the
as an option forCDC recommendation,
pregnant women ex-
Acetaminophen may be offered as
periencing other post-vaccination an option
symptoms for pregnant
as well [218]. women experiencing other
post-vaccination symptoms as well [218].
Biologics 2021, 1 29
Biologics 2021, 1, FOR PEER REVIEW 28

Figure
Figure An overview
16. overview
16. An of pregnant
of pregnant womenwomen with COVID-19
with COVID-19 disease
disease in in diagnosis,
terms of terms of diagnosis,
prevention,prevention, and
and potential potential
treatments.
treatments.
There is
There is no
no evidence
evidence ofof neonates
neonatesinfection
infectionininwomen
womenwho who have given
have givenvaginal birth.
vaginal birth.
To understand the risk of infection, further studies are required, and guidelines should be
To understand the risk of infection, further studies are required, and guidelines should be
taken for the method and timing of delivery in pregnant women with COVID-19 infection.
taken for the method and timing of delivery in pregnant women with COVID-19 infection.
The previous investigations on the severe acute respiratory syndrome (SARS) virus have
The previous investigations on the severe acute respiratory syndrome (SARS) virus have
Biologics 2021, 1, FOR PEER REVIEW represented that the virus can cause intrauterine fetal demise, premature birth, and intra- 13
represented that the virus can cause intrauterine fetal demise, premature birth, and in-
uterine growth limitation; hence, testing suspected cases and continuous control of the
trauterine growth limitation; hence, testing suspected cases and continuous control of the
patients their infants is importantly necessary [219,220]. Additionally, there is no evidence
patients their infants is importantly necessary [219,220]. Additionally, there is no evidence
of mother-to-child
Table 3. Leading transmission
epidemiologicaltransmission risk through
indicators of COVID-19 cesarean
research andindelivery
articles section [221]. Table 9
of mother-to-child risk through cesarean and January
delivery2020.
section [221]. Table 9
summarizes the published articles on the relationship between pregnancy and COVID-19.
Indicators summarizes
Description the published articles on the relationship between pregnancy and COVID-19.
• Elderly
Table 9. A summary
(over 60 yearsofold)published
[60]. research on pregnant women with COVID-19.
Table 9. A summary of published research on pregnant women with COVID-19.
Title
• Mean age of
Objective
59 years (research conducted between patients 50 to 89 years) [74].
Description
Title • RiskofDetermination
a Objective
severe illness with increasing
of the clinical age
• A caseof about 40obstetrics
study in years [75].
Description and gynecology ward of Tongji Hospital
Biologics 2021, 1, FOR PEER REVIEW 13
• The low number of patients
characteristics of COVID-19 in with mean age 0–49 years
(Huazhong University [76].
• Aof case
Science study in obstetrics
and Technology, and gynecology
Wuhan, China).
 Coronavirus Disease
• Average age of and
pregnancy patients was 55.5 years;
their newborn • age distribution:
Evaluation ≤39:ward
of demographic, 10%; of40–49:
Tongji
clinical, Hospital
22%, and(Huazhong
50–59:
laboratory 30%; 60–69: 22%,
radiological
2019 (COVID-19) Dur-
≥70: infant.
15% [77].
â Determination of the clinical University
characteristics of SARS-CoV-2 of
infection Science
series. and Technology,
ing Pregnancy: A Case
Wuhan, China). tissue, vaginal mucus, and
 Age Coronavirus
Series patients Disease
of [222] Table  Evaluationcharacteristics
• In3.terms
Leadingof age of transmission of
distribution,
epidemiological 1% under•10,
of COVID-19
indicators Sampling:
of in 10–19,
1%
COVID-19 oropharyngeal
8% 20–29,
research
•
swab, placenta
87% 30–79,
articles
Evaluation and 3%2020.
inofJanuary >80 [78].
demographic, clinical,
2019 (COVID-19)• During SARS-CoV-2 virus
pregnancy vertically
and their breast
newbornpatientsmilk of mothers and oropharyngeal
infant. from different countries participated swab, umbilical cord
50–60 (More than half a million COVID-19 laboratory and radiological in this meta- of
characteristics
Pregnancy: A Case
Indicators through
Description â the intrauterine.
Evaluation of transmissionblood,
of and serum of newborns.
Series [222] analysis) [79]. • Sampling: SARS-CoV-2
amniotic fluid, cord blood, and infection series.
neonatal pharyngeal swab.
•• Elderly (overfrom SARS-CoV-2
60 years old) virus vertically
[60]. through • Sampling: oropharyngeal swab, placenta
Cases range the 2intrauterine.
to 72 years [80]. • Clinical evaluation of 116 pregnant women with coronavirus
• Mean
 Coronavirus disease• Increased
age incidence
of 59
 Clinical
yearswith
(research
characteristics
conducted
increasing
of SARS-
between
age pneumonia.
over 60 yearspatients tissue, vaginal mucus, and breast milk of
[81]. 50 to 89 years) [74].
mothers and oropharyngeal swab, umbilical
2019 in pregnant • • Risk ofCoV-2
The mediana severe
age illness
of waswith
infection. increasing
74 years [82]. • age
Theof about
most 40 years
common [75]. fever
symptoms: (50.9%), cough (28.4%); patients
cord blood, and serum of newborns.
•• The
women: a report based low number
Vertical of patients
transmission with
potential mean
of
Cases range aged between 35 and 55 years [83]. age 0–49
presented years
without[76].
symptoms (23.3%).
• Sampling: amniotic fluid, cord blood, and
on 116 cases [223] • Average SARS-CoV-2infection.
age of patients was 55.5 years; • age
Severe pneumonia (6.9%).
distribution: ≤39:neonatal
10%; 40–49: 22%, 50–59:
 Sex of patients • More cases were males [84,85]. pharyngeal swab.30%; 60–69: 22%,
≥70: 15% [77]. • Preterm delivery (21.2%).
• Increased mortality between 60 and 80• years [86–88]
• Clinical evaluation of 116 pregnant women
Negative newborns (86%).
 Age
Mortality
Coronavirus
of patients • In terms â
rate disease of ageClinical characteristics
distribution, 1% underof10, 1% 10–19, 8% 20–29, with coronavirus
87% 30–79, andpneumonia.
3% >80 [78].
• The mortality
2019 in pregnant• 50–60 (More than rate was
SARS-CoV-2 significantly
infection.high in the age range• ofThe
>60 most
yearscommon
[75,89]. symptoms: fever (50.9%),
half a million COVID-19 patients from different countries participated in this meta-
women: a report•based Average â of 7 days (2–14
Vertical days) [60,90].
transmission potential of cough (28.4%); patients presented without
analysis) [79].
on 116 cases [223]• Average of 10 SARS-CoV-2infection.
days [91]. symptoms (23.3%).
 Incubation • Cases range from 2 to 72 years [80].
• 6.4 days (95% CI 5.6–7.7 days), with a range of 2.1–11.1•daysSevere [92]. pneumonia (6.9%).
time • Increased incidence with increasing age over 60 years [81]. • Preterm delivery (21.2%).
• 5.0 days (95% CI 4.4–5.6 days), with a range of 2–14 days [92].
• The median age of was 74 years [82]. • Negative newborns (86%).
• 4.0 days, with a range of 1–7 days [93].
• Cases range aged between 35 and 55 years [83].
 Sex of patients • More cases were males [84,85].
7. Diagnosis
• Increased mortality between 60 and 80 years [86–88]
 Mortality rate
Biologics 2021, 1, FOR PEER REVIEW 13

Biologics 2021, 1 Table 3. Leading epidemiological indicators of COVID-19 research articles in January 2020. 30

Indicators Description
• Elderly (over 60 years old) [60].
• Mean age of 59 years (research conducted Table 9. Cont.between patients 50 to 89 years) [74].
• Risk of a severe illness with increasing age of about 40 years [75].
Title • The low numberObjective of patients with mean age 0–49 years Description [76].
Biologics 2021, 1, FOR PEER • REVIEW
Average age of patients was 55.5 years; age distribution: • ≤39:comprehension
10%; 40–49: 22%, of pathophysiology
50–59: 30%; 60–69: 22%, 13
≥70: 15% [77]. and susceptibility.
• Diagnostic challenges with real-time
 Age Coronavirus
of patients disease • In terms â of ageAdistribution,
comprehensive 1% under
study 10, 1%effects
of the 10–19, 8% 20–29, 87% 30–79, and 3% >80 [78].
reverse transcription-polymerase chain
2019 (COVID-19)• 50–60 (More than of half a million
COVID-19 on COVID-19
pregnant patients from different
women countries participated in this meta-
pandemic andTable 3. Leading epidemiological indicators of COVID-19 research reaction
articles (RT-PCR).
in January 2020.
pregnancy [217] analysis) [79]. and their infants. • Therapeutic controversies.
•Description
Cases range from 2 to 72 years [80]. • Intrauterine transmission.
Indicators
• Maternal-fetal complications.
•• Elderly
Increased incidence
(over 60 years with
old)increasing
[60]. age over 60 years [81].
• Antiviral therapy and vaccine development.
•• Mean
The median
age of age of was
59 years 74 yearsconducted
(research [82]. between patients • 50 topriority
The 89 years) of [74].
caring for pregnant women
•• Risk
Casesofrange aged
a severe between
illness with35increasing
and 55 years age [83].
of about 40 yearswith [75].physiological conditions of
 Sex of patients •• MoreThe low cases were males
number [84,85].
of patients with mean age 0–49 years [76]. immunodeficiency in a higher-level
health center.
• Increased
Average age mortality
of patients between
was 55.5 60 and 80 years
years; [86–88] • ≤39:Treatment
age distribution: 10%; 40–49: and22%, 50–59: 30%; 60–69: 22%, 13
 Mortality
Biologics 2021, 1,rate
FOR PEER REVIEW maintenance of pregnant
• The ≥70: mortality
15% [77]. rate was significantly high in the age range ofwomen >60 years [75,89].
in the prenatal, postpartum or
 Age A of
Review on the•Effect
patients Average
In terms â of age Evaluation
7 days (2–14 days)
distribution, of COVID-19
1%[60,90].
under 10, and 1%its10–19, 8% 20–29, postpartum
87% 30–79, period,
and 3% in an
>80isolated
[78].
of COVID-19 in • Average 50–60 (More severity
of 10than
days ainmillion
[91].
half pregnant women patients
COVID-19 and its from different environment
countries or negative
participated pressure.
in this meta-
 Incubation • Attempts
Pregnant Women
• 6.4
Table [224]
3. days
Leading
analysis) (95% comparison
epidemiological
[79]. CI 5.6–7.7 days), with SARS
indicators
with and MERS.
of COVID-19
a range of 2.1–11.1 research
days [92]. articlesto inprevent
Januarymother-to-child
2020.
time transmission of SARS-CoV-2 or iatrogenic
• 5.0
Casesdays (95%from
range CI 4.4–5.6
2 to 72days), with a range of 2–14 days [92].
years [80]. infection during and after delivery.
Indicators Description
• 4.0 days, with
Increased a range
incidence of 1–7
with days [93].
increasing age over 60 years [81]. • Separation of infants from the mother of
• Elderly (over 60 years old) [60].
• The median age of was 74 years [82]. COVID-19 after postnatal stage.
• Mean age of 59 years (research conducted between patients • 50 to 89
Need to years)
read more [74].about breastfeeding
• Cases range 7. Diagnosis
aged between 35 and 55 years [83].
• Risk of a severe illness with increasing age of about 40 yearshealth [75]. of mothers with COVID-19.
 Sex of patients • More cases were malesof[84,85].
• The low number Becauseof patients thewithlackmeanof definitive years •[76].treatment
age 0–49 curative The studyfor this disease,
conducted on 16 the most women
pregnant effective
•• Increased mortality
Averagesolution
age of patients between
after preventing 60 and
was 55.5 years; 80 years
andage [86–88]
controlling
distribution:is the with
≤39:timely COVID-19
diagnosis
10%; 40–49: and 18 pregnant
of the 30%;
22%, 50–59: disease women
60–69:and isolat-
22%,
 Mortality rate
• The ≥70: mortality was significantly high in the age range ofsuspected >60 years of COVID-19.
15% ing therate
[77]. illnesses. There are several ways to •diagnose the [75,89].
disease early, such
Vaginal delivery (2), Cesarean delivery (32). as the RT-PCR
 Age
Biologics 2021, 1, FOR
andPEER•• REVIEW
Average of age
7 days (2–14 days) 1%[60,90].
Maternal
of patients Neonatal In termsmethod,
of distribution,
CT-Scan, under 10,antibody
Serological 1% 10–19,blood8%• 20–29,
test, 87%
and30–79,
Having Artificial
symptoms and of 3% and cough at the 13
>80 [78].
intelligence.
fever
Outcomes of Pregnant•• Average
50–60 (More of 10
â than days [91].
half a million COVID-19 patients from different time ofcountries
admission, participated
the presence in this meta-
of symptoms
 Incubation A case-control study to compare
Women With • 6.4 days (95% CI 5.6–7.7
clinical days), with aand
characteristics range of 2.1–11.1 daysof[92].
maternal COVID-19 pneumonia in their CT scan.
time
Coronavirus Disease analysis) [79].
7.1. RT-PCR Method
•• 5.0
Casesdays (95%from
range and4.4–5.6
CI 2neonatal
to 72days), outcomes
years of pregnant
with a range
[80]. of 2–14 days • [92]. Lower counts of white blood cells (WBCs),
2019 (COVID-19) Table 3. Leading epidemiological
One
women of the with mostandindicators
important
without of COVID-19
ways to detectresearch the articles
SARS-CoV-2 in C-reactive
January 2020.
virus in upper and lower
Pneumonia: •• 4.0 days, with a range of 1–7 days [93]. neutrophils, protein (CRP),
Increased incidence COVID-19 with increasing
pneumonia. age over 60 years [81]. and alanine aminotransferase on admission
A Case-Control Description respiratory specimens is the Real-Time Reverse Transcriptase (RT)–PCR Diagnostic Panel.
Indicators
Study [225] • The median age of was 74 years [82]. (Patients with COVID-19 pneumonia).
• Elderly
The
7. basis
Diagnosis
(over 60 years
of the PCR
old) 35 [60].
is copying the RNA•andIncrease DNA structure
the levels of the sample,
of WBCs, which can
neutrophils,
Cases range aged between and 55 years [83].
diagnose infectious origin and various genetic and blood
eosinophils, diseases
and CRP [94]. Figure 9 demon-
 Sex of patients • More Mean cases
age ofwere59 years
Becausemales (research
of[84,85].
the lack conducted between
of definitive patients
curative 50 to 89 years)
treatment for this disease, the mostblood
[74]. in postpartum
effective
strates COVID-19 diagnostic testing through tests
real-timeof pneumonia
RT-PCR. patients.
As depicted in Figure 9,
•• Increased
Risk of asolution
severe
mortalityillness with
between increasing
60 and 80 age
years of
after preventing and controlling is• the No about
[86–88] 40 years [75].
timely diagnosis
COVID-19 of the
infection in disease
infants. and isolat-
 Mortality rate lowthere areoffive necessary steps to perform the test:
•• TheThe mortality
number
ing therate patients
was
illnesses. with are
significantly
There mean high age
severalin 0–49
the years
age
ways to •[76].
range >60sample
ofEvaluation
diagnose years collection,
[75,89].
the disease
of clinicalearly,
RNA extraction, RT-
suchlaboratory
records, as the RT-PCR
AverageqPCR
•• Average age7 of
of
method,
set
days up,
patients
(2–14
CT-Scan,
andwas test
days) 55.5 results,
years; age
[60,90].
Serological
all of
antibody
which can≤39:
distribution: beresults
blood test,
customized
10%;
and 40–49:
and to CT
22%,
chest
Artificial
explain
50–59:
scan of both
30%;
intelligence.
this and
60–69:
9 pregnant 22%, other
Biologics 2021, 1, FOR PEER REVIEW≥70: 15%
• Average RT-qPCR
10 daysdiagnostic
[77].
of [91]. protocols. The steps for performing women with the RT-qPCR
COVID-19test are as follows [95]:
pneumonia. 13
 Incubation • Cesarean delivery.
 Age Clinical •• 6.4
characteristics
of patients In terms of age
days7.1.
(95% Nasopharyngeal
CIdistribution,
RT-PCR 5.6–7.7 days),
Method 1%with swab
under <151%min:
10,
a range of10–19,Cotton
8%days
2.1–11.1 swab
20–29, 87%
[92]. is 30–79,
inserted andinto3% >80 the[78].nostril to absorb
time
and intrauterine•vertical • different
Observed symptoms: fever, cough, myalgia,
50–60
• 5.0 days sections.
(More
â than half
Evaluation a million
of COVID-19
clinical features patients
of from countries participated in this meta-
transmission potential of (95%One CI 4.4–5.6 days), with a range of 2–14 days [92].
of thespecimen
most important ways to detect soreSARS-CoV-2
the throat and lethargy. virus in72upper and lower
Table
COVID-19 infection analysis)
• 4.0 indays,
3. Leading [79].
with COVID-19
Collected in
a range of 1–7 days
epidemiological pregnancy 0–72and h the
specimen
[93]. of COVID-19 research
indicators •is stored at
articles
Fetal 2–8
distress ℃ for
in January
control in up to
2020.
two cases.h or proceed to
nine pregnant women: • Cases range respiratory
RNAfrom potential specimens
for vertical
2 to 72 years [80].
extraction. is the Real-Time
intrauterine Reverse
• Transcriptase (RT)–PCR
Observation of lymphopenia in five patients Diagnostic Panel.
of The transmission
basis of COVID-19 infection.
Indicators
a retrospective review •Description
Increased RNA of
incidence
7. Diagnosis
theincreasing
with
extractionPCR is copying
~45 age over
min the RNA
60 years
purified RNA and
[81]. DNA
(<1.0
is extracted× structure
109from
cells per
theofL).the sample,virus.
deactivated which can
medical records ••[226] Elderly
The median diagnose
(overage ofinfectious
60 years wasold)74~1 [60].
years origin and various
[82].primer, genetic
• and blood
Increased diseases
aminotransferase [94]. concentration
Figure 9 demon-in
RT-qPCR,
Because of the hlack
per of definitive setcurative
purified RNA
treatment is reverse
for this transcribed
disease, to cDNA
the most and
effective
•• Mean
Cases age
range of aged
strates59 years
COVID-19 (research
between 35 conducted
diagnostic
and 55 years between
testing
[83]. patients
through three
50 to patients.
real-time 89 years)
RT-PCR. [74]. As depicted in Figure 9,
amplified
solution by
after qPCR.
preventing andage controlling is•years
the No observation
timely diagnosis of neonatal
of the asphyxia
disease and isolat-
 Sex of patients •• MoreRisk ofcases
athere
severeare
were
Test
illness
five
males with
necessary
[84,85].
resultsThere
increasing
real-time steps to of
positive
about 40the
perform
SARS-CoV-2 test:[75].
sample
patients collection,
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ing the illnesses. are several ways tocan in infants.
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≥70:
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 Age An patients •• Model
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7.1. RT-PCR
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embryo
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implantation. based on the repro-
Average of age
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 Incubation
for Peri-conceptual •• 6.4
50–60 duction
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half and sequence
a million COVID-19 of the virus
patients •indifferent
the sample
To resolve [96].
this challenge, recurrent
in thispregnancy
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CI
â Collected
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days),
specimen important
experimental a range
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model hways
offor tofrom
detect
2.1–11.1
specimen days
is the
[92].
stored
loss
countries
SARS-CoV-2
at 2–8 ℃
suggests
participated
for
workable virus toin 72upper
upinterventions
meta-
and
hnecessary
or proceed lower
utilizing to
time analysis) [79].Because the infectious virus infects the host’s respiratory system, the sam-
Loss and Proposed • 5.0 daysRNA respiratory
(95% extraction.
CI specimens
4.4–5.6
COVID-19 days),
infection is loss
with the Real-Time
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and suggest days [92]. Transcriptase
clinical experience, (RT)–PCR
but success Diagnostic
strongly Panel.
Interventions •• 4.0 Cases ples from
range are taken
2 to 72
interventions from
yearsto the lower outcomes.
[80].
optimize and upper respiratory depends tract.
upon The swab test
accurate is sampling with
days, with
The a range
basis
RNA of of 1–7
the
extractionPCR days is [93].
~45 copying
min the RNA
purified RNA andis DNA structure
extracted from the theand
of deactivated prompt
sample, which can
virus.
to Optimize • Increased a special
incidence swabwithfrom the throat
increasing age over and60noseyearsof[81].
a person.
SARS-CoV-2 The sampling
recognition. of However,
the nasal aspirates
Outcomes [227] • The median age diagnose infectious origin and
RT-qPCR, ~1 h per primer, set purified RNA various genetic and blood diseases
is reverse model
this experimental [94].
transcribed Figure
can warrant 9ademon-
to cDNA and
of was 74 years [82].
7. Diagnosis
strates
amplified COVID-19
by qPCR. diagnostic testing through real-time high-risk RT-PCR.
determination As depicted
for such cases,in Figure 9,
• Cases range aged between 35 and 55 years [83].
thereBecause
are five
Test resultsnecessary
of thereal-time
lack of steps to perform
positive
definitive the test:
SARS-CoV-2
curative thepatients
patients
sample
treatment should
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within
effective
 Sex of patients • More cases were males [84,85]. access to treatment and screening resources.
qPCR
solution
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and all of which is
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customized
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• Increased mortality between 60 and 80 years [86–88]
 Mortality rate RT-qPCR
ing theThis diagnostic
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are The
several
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follows or[95]:
RT-PCR
• The mortality rate was significantly high inthe
the nucleic
age range acid present
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[75,89]. swab the
method,Nasopharyngeal
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tract
• Average of 7 days (2–14 days) [60,90]. using swab
Serological
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blood
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real-time. andis Itinserted
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is confirmed into the
intelligence.
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on to
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duction
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[91]. and sequence of the virus in the sample [96].
 Incubation Collected specimen at 2–8 ℃ for
7.1. RT-PCR
Because
• 6.4 days (95% CI 5.6–7.7 Method
the with 0–72
infectious
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a range h specimen
infects
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2.1–11.1 stored
host’s
days respiratory
[92]. up tothe
system, 72 hnecessary
or proceed sam-to
 Table 3. Leading epidemiological indicators of COVID-19 research articles in January 2020.

Indicators Description
Biologics 2021, 1 31
• Elderly (over 60 years old) [60].
• Mean age of 59 years (research conducted between patients 50 to 89 years) [74].
• Risk of a severe illness with increasing age of about 40 years [75].
• The low number of patients with Table mean 9.age 0–49 years [76].
Cont.
• Average age of patients was 55.5 years; age distribution: ≤39: 10%; 40–49: 22%, 50–59: 30%; 60–69: 22%,
Title ≥70: 15% Objective
[77]. Description
 Age Impact • In terms of age distribution, 1% under 10, 1% 10–19, 8% 20–29, 87% 30–79, and 3% >80 [78].
of COVID-19
of patients
infection on pregnancy
• 50–60 (More than half a million COVID-19 patients from
outcomes and the risk of â • different countriesfrom
Swab sampling participated
all threein this meta-
patients using
analysis) [79]. A complete study of three pregnant qRT-PCR.
maternal-to-neonatal
intrapartum • Cases range from women with
2 to 72 COVID-19
years [80]. in Renmin • Vaginal delivery.
Hospital. • One case of premature birth.
transmission of • Increased incidence with increasing age over 60 years [81].
COVID-19 during • The median age of was 74 years [82].
natural birth [228]
• Cases range aged between 35 and 55 years [83].
 Sex of patients • More cases were males [84,85].
12.mortality
• Increased Conclusionsbetween 60 and 80 years [86–88]
 Mortality rate
• The mortality rate was significantly
The prevalence of COVID-19 hasage
high in the recently been
range of >60identified as a global health emergency.
years [75,89].
• Average According to thedays)
of 7 days (2–14 WHO, ~131M people have been infected, of which ~74.4M have recovered,
[60,90].
• Average and unfortunately,
of 10 days [91]. more than ~3M people have died so far. Quarantine alone is not enough
 Incubation
• 6.4 daysto(95%
prevent the outbreak
CI 5.6–7.7 days), with ofaCOVID-19, and the
range of 2.1–11.1 daysglobal
[92]. impact of this viral infection on the
time
• 5.0 dayseconomy
(95% CI 4.4–5.6 days), with
is a significant a rangeAlthough
concern. of 2–14 days [92].
researchers are trying to find an utterly effective
• 4.0 days, withfor
drug a range of 1–7 days
the definitive [93].
treatment of COVID-19, no 100% effective drug has been discovered
for complete recovery. Fortunately, due to researchers and pharmaceutical companies’
7. Diagnosis
efforts, many effective vaccines to prevent the prevalence of this deadly disease have been
approved by of
Because the
theWorld Health
lack of Organization.
definitive However,
curative treatment for it takes
this a long
disease, thetime
mostfor these
effective
effective
solution vaccines to reach and
after preventing all the world’s people
controlling is the and all diagnosis
timely people to be
of vaccinated.
the disease Until then,
and isolat-
all the points recommended by the World Organization to prevent the prevalence
ing the illnesses. There are several ways to diagnose the disease early, such as the RT-PCR of this
disease must be fully observed.
method, CT-Scan, Serological antibody blood test, and Artificial intelligence.

Author Contributions: I.S. Conceptualization, designed the figures, writing original draft, data vali-
7.1. RT-PCR Method
dation, conceived the original idea, and supervised the project; N.M.-A. Data validation, conceived
One ofidea,
the original the most important ways
and investigated to detect the
and supervised the SARS-CoV-2
findings of thisvirus
work; inA.S.
upperTookandthelower
lead
respiratory specimens is the Real-Time Reverse Transcriptase (RT)–PCR Diagnostic
in writing the manuscript, development of methodology, conceived the original idea, and investi- Panel.
The basis
gated of the PCRtheisfindings
and supervised copyingofthe thisRNA
work;and DNA
N.M.N. structure to
Contributed of sample
the sample, which con-
preparation, can
diagnose infectious origin and various genetic and blood diseases [94]. Figure 9 demon-
tributed to the interpretation of the results and development of methodology; Z.D., M.F., M.G., S.Z.S.,
A.H. (contributed
strates COVID-19todiagnostic
sample preparation, aided in
testing through interpreting
real-time the results,
RT-PCR. and worked
As depicted on the
in Figure 9,
manuscript); A.B. Formal data analysis, writing original draft, writing review and
there are five necessary steps to perform the test: sample collection, RNA extraction, RT- editing, conceived
the
qPCRoriginal idea,
set up, andand
testsupervised
results, allthe
of project.
which canAll authors have read
be customized to and agreed
explain to this
both the published
and other
version of the manuscript.
RT-qPCR diagnostic protocols. The steps for performing the RT-qPCR test are as follows [95]:
Nasopharyngeal
Funding: swab <15
This research received min: Cotton
no external funding.swab is inserted into the nostril to absorb
sections.
Institutional Review Board Statement: Not applicable.
Collected specimen 0–72 h specimen is stored at 2–8 ℃ for up to 72 h or proceed to
Informed Consent Statement: Not applicable.
RNA extraction.
RNA extraction
Data Availability ~45 min
Statement: Notpurified
applicable.RNA is extracted from the deactivated virus.
RT-qPCR, ~1 h per primer, set purified RNA is reverse transcribed to cDNA and
Conflicts of Interest: All authors state that there is no conflict of interest.
amplified by qPCR.
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