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Two years of SARS-CoV-2 infection (2019–2021): structural biology, vaccination, and current global situation

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Two years of SARS-CoV-2 infection (2019–2021): structural biology, vaccination, and current global situation

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The deadly SARS-CoV-2 virus has infected more than 259,502,031 confirmed cases with 5,183,003 deaths in 223 countries during the last 22 months (Dec 2019–Nov 2021), whereas approximately 7,702,859,718, vaccine doses have been administered (WHO: https://covid19.who.int/ ) as of the 24th of Nov 2021. Recent announcements of test trial completion of several new vaccines resulted in the launching of immunization for the common person around the globe highlighting a ray of hope to cope with this infection. Meanwhile, genetic variations in SARS-CoV-2 and third layer of infection spread in numerous countries emerged as a stronger prototype than the parental. New and parental SARS-CoV-2 strains appeared as a risk factor for other pre-existing diseases like cancer, diabetes, neurological disorders, kidney, liver, heart, and eye injury. This situation requires more attention and re-structuring of the currently developed vaccines and/or drugs against SARS-CoV-2 infection. Although a decline in COVID-19 infection has been reported globally, an increase in COVID-19 cases in the subcontinent and east Mediterranean area could be alarming. In this review, we have summarized the current information about the SARS-CoV-2 biology, its interaction and possible infection pathways within the host, epidemiology, risk factors, economic collapse, and possible vaccine and drug development.
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Ahmadand Shabbiri
The Egyptian Journal of Internal Medicine (2022) 34:5
https://doi.org/10.1186/s43162-021-00092-7
REVIEW
Two years ofSARS-CoV-2 infection
(2019–2021): structural biology, vaccination,
andcurrent global situation
Waqar Ahmad1,2* and Khadija Shabbiri2
Abstract
The deadly SARS-CoV-2 virus has infected more than 259,502,031 confirmed cases with 5,183,003 deaths in 223
countries during the last 22 months (Dec 2019–Nov 2021), whereas approximately 7,702,859,718, vaccine doses
have been administered (WHO: https:// covid 19. who. int/) as of the 24th of Nov 2021. Recent announcements of test
trial completion of several new vaccines resulted in the launching of immunization for the common person around
the globe highlighting a ray of hope to cope with this infection. Meanwhile, genetic variations in SARS-CoV-2 and
third layer of infection spread in numerous countries emerged as a stronger prototype than the parental. New and
parental SARS-CoV-2 strains appeared as a risk factor for other pre-existing diseases like cancer, diabetes, neurological
disorders, kidney, liver, heart, and eye injury. This situation requires more attention and re-structuring of the currently
developed vaccines and/or drugs against SARS-CoV-2 infection. Although a decline in COVID-19 infection has been
reported globally, an increase in COVID-19 cases in the subcontinent and east Mediterranean area could be alarming.
In this review, we have summarized the current information about the SARS-CoV-2 biology, its interaction and pos-
sible infection pathways within the host, epidemiology, risk factors, economic collapse, and possible vaccine and drug
development.
Keywords: SARS-CoV-2, COVID-19, Structural biology, Epidemiology, Vaccination, Drugs, Risk factors
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Introduction
In late 2019, several cases of humans infected with a
novel coronavirus were first reported in China. is
virus was named severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) and is commonly known
as COVID-19 [1]. Soon after the emergence, this virus
spread throughout the world within a short time period.
e virus was able to be transferred from one person
to another through respiratory droplets or by touch.
Although the genetic structure of SARS-CoV-2 was very
close to the other coronaviruses, the drugs proposed
based on previous experiences were not much effective
for these species. Meanwhile, the ultimate spread of this
virus globally highlighted the urgent need for an effec-
tive vaccine against this pandemic until the remedy/ drug
availability [2]. However, to develop an effective drug or
vaccination against such a pathogen requires compre-
hensive details of the pathogen structure, its interaction
with the host, and mode of action. Unlike a simple patho-
gen, the host, especially humans, has a complex cellular
mechanism and clinical manifestations caused by SARS-
CoV-2 were vibrant within different age groups and eth-
nic groups. Due to the complex nature of the human
cellular system, it is possible that the presence of other
diseases or body abnormalities might enhance the chance
of incidence or severity of SARS-CoV-2 infection [2, 3].
In this study, we tried to summarize the published data
on the biology of SARS-CoV-2 and its interaction with
the host, possible drug and vaccine development, global
Open Access
The Egyptian Journal of
Internal Medicine
*Correspondence: waqar.ahmad@uaeu.ac.ae; waqar.ahmad@uqconnect.edu.
au; waqarchemist123@yahoo.com
2 The University of Queensland, Brisbane, Australia
Full list of author information is available at the end of the article
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Ahmadand Shabbiri The Egyptian Journal of Internal Medicine (2022) 34:5
economic situation, current epidemiology, and associated
risk factors.
SARS‑CoV‑2/ COVID‑19 structural biology
SARS‑CoV2 genome
SARS-CoV-2 was declared as a “novel virus” due to not
completely matched genome with previously found spe-
cies causing similar symptoms based on PCR and next-
generation techniques’ generated results. SARS-CoV-2
belongs to the Betacoronovirus family on the basis of con-
served 1a and 1ab protein-encoding open reading frame
(ORF) sequence. e SARS-CoV-2 reference sequence
submitted to the GISAID (https:// www. gisaid. org/ epiflu-
appli catio ns/ hcov- 19- refer ence- seque nce/) database has
been considered as the official reference sequence and
named hCoV-19/Wuhan/WIV04/2019 (WIV04). is
reference sequence (total length: 29903nt) can also be
downloaded from NCBI accession number NC_045512.
is sequence showed almost an 80% similarity with pre-
viously known SARS-CoV [1] whereas a 96% similarity to
a bat coronavirus at the whole-genome level [2]. Figure1
is adopted from GISAID and depicted a current genome
structure of SARS-CoV-2.
Briefly, ORF1ab is the longest ORF, approximately cov-
ering 2/3 of the whole genome. It has a position from 266
to 21,555 nt with a 21,289-nt length. It contains ORF1ab
polyprotein of 7096AA and could be cleaved into sev-
eral non-structural proteins ranging from NSP1-NSP16.
e second-largest ORF1a is a part of ORF1ab and has
a length of 13,202 nt from 266 to 13,468 nt. e ORF1a
polyprotein could result in several NSPs (NSP1–NSP10)
via proteolytic cleavage. ORF1ab is followed by spike
glycoprotein (position 21,563 to 25,384, length: 3821nt),
ORF3a (position 25,393 to 26,220, length: 827 nt, NS3a
protein of 275AA), ORF3b (position 25,765 to 26,220,
length: 455nt, NS3b protein of 151AA), Envelop pro-
tein (position 26,245 to 26,472, length: 227 nt, 75AA),
membrane protein (position 26,523 to 27,191, length:
668 nt, 222AA), ORF6/NS6 (position 27,202 to 27,387,
length: 185 nt, 61AA), ORF7a/ NS7a (position 27,394 to
27,759, length: 365 nt, 121AA), ORF7b/NS7b (position
27,756 to 27,887, length: 131 nt, 43AA), ORF8/NS8 (posi-
tion 27,894 to 28,259, length: 365 nt, 121AA), nucleocap-
sid protein (position 28,274 to 229,533, length: 1259 nt,
419AA) with overlapped ORF9a/ NS9a (position 28,284
to 28,577, length: 239 nt, 97AA) and ORF9b/NS9b (posi-
tion 28,734 to 28,955, length: 221 nt, 73AA), and at the
end ORF10/ NS10 (position 29,558 to 29,674, length: 116
nt, 38AA).
SARS‑CoV‑2 proteins andoverall structure
e ORFs of SARS-CoV-2 inside the host are translated
into 16 non-structural, 9 accessory, and 4 structural pro-
teins (Fig. 2). For example, ORF1a and 1ab translated
into polyproteins that further cleaved into 16 non-struc-
tural proteins (nps). ese nps are essential for the virus
life cycle into the host and may modulate host cellular
immunity and proteolytic activity and may be involved
in RNA synthesis, proofreading, and modification. In
coronaviruses, the accessory proteins may play a role in
modulating the host immune response such as regulation
of inflammation markers, cell apoptosis, and ion chan-
nel activity. ere are seven accessory protein-encoding
ORFs in SARS-CoV-2, namely 3a, 6, 7a, 7b, 8, 9a, 9b,
and 10. SARS-CoV-2 structural proteins including spike,
envelop, membrane and nucleocapsid are necessary
for viral structure maintenance and stability. A detailed
explanation of these components can be extracted from a
recent review by Kadam etal. [3].
Virus‑ host interaction
Multiple studies had already discussed a detailed mecha-
nism involved in the interaction of SARS-CoV-2 with host
cells [2, 412]. Briefly, the first step in the viral infection is
Fig. 1 Genome structure of SARS-CoV-2. The genome of SARS-CoV2 comprises of 5 and 3 untranslated region (UTR) and several open reading
frames (ORFs) comprising of non-structural and structural proteins including spike, envelop, membrane, and nucleocapsid
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Ahmadand Shabbiri The Egyptian Journal of Internal Medicine (2022) 34:5
the host-receptor recognition. Previous studies [57, 13]
showed a high affinity of SARS-CoV spike protein with
human angiotensin-converting enzyme 2 (hACE2). e
SARS transmembrane spike glycoprotein consists of two
subunits S1 and S2. S1 is responsible for binding to the
host receptor while S2 plays a role in the viral and cellular
membrane fusions. It has been found that the receptor-
binding domain of SARS-CoV-2 has a low affinity with
hACE2 when compared to SARS-CoV. is could be due
to the mutations and the structural difference between
two RBDs. e SARS-CoV-2 spike sequence was aligned
with the already published sequence of RBD from SARS-
CoV (AA 323-502: PDB ID: 2AJF [14]) and this alignment
resulted in a 72.2% identity and an 80% similarity with 1
gap (Fig.3a). Sequence alignment showed a replacement
of many previously determined critical residues [14] with
others that may change SARS-CoV-2-ACE2 RBD struc-
ture-function insights. e following replacements in
SARS-CoV-2 were found when compared to SARS-CoV:
T424S, R425N, I427L, A429S, T430K, S431V, T432G,
K438L, L443F, H445K, G446S, K447N, N457T, V458Em
P459I, F460Y, S461Q, P462A, D463G, G464S, K465T,
T468N, P469G, P470E, A471G, L472F, W476F, N479Q,
D480S, Y484Q, T485P, T487N, and I489V (Fig.3b). To
further explore the role of these amino acid changes in
SARS-CoV-2, a map was constructed representing any
substantial differences between ACE2 and SARS-CoV-2
contact points [15]. is map was constructed using
already published data and a total of 14 spike residues
of the SARS-CoV showed interactions with 18 residues
of the ACE2 receptor protein [14]. ese changes may
alter the hydrophobic association between SARS-CoV-2
and receptor ACE2. ese results showed changes in the
following contacts: Y442L mutation will change interac-
tion from polar to hydrophobic with ACE2-Lys31, there
was no change in polarity at ACE2 H34, Y41, Q42 and
K353 contacted residues with SARS-CoV-2 after muta-
tions at Y479Q, Y484Q, T487N, and L472F, respec-
tively. e mutation at R426N will change interactions
with ACE2 Q325 and E329. ese changes may alter the
interaction between ACE2 and SARS-CoV-2 and could
be used as possible drug targets [15]. Although SARS-
CoV-2 showed a lower affinity with hACE2 when com-
pared to SARS-CoV, hACE2 is still a well-recognized
host receptor for SARS-CoV-2. e other mechanism
involved during host entry is host-protease activation.
Shang etal. [13] found that furin pre-activation induced
SARS-CoV-2 pseudovirus entry into different cell lines
with ACE2 receptors. Moreover, SARS-CoV-2 pseudovi-
rus entry was also activated through the cell-surface pro-
tease TMPRSS2 (transmembrane protease serine 2) and
the lysosomal cathepsins. ese observations make both
hACE2 and TMPRSS2 possible drug targets to inhibit
SARS-CoV-2 entry in human cells.
Fig. 2 SARS-CoV-2 structure. SARS-CoV-2 is a positive-sense RNA virus consisting of four structural proteins namely envelop, membrane,
nucleocapsid, and spike. It also has 16 non-structural proteins and 9 accessory proteins
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Ahmadand Shabbiri The Egyptian Journal of Internal Medicine (2022) 34:5
Mode oftransmission
Generally, there were three phases involved in the
SARS-CoV-2 pandemic, including local outbreak, com-
munity transmission, and large-scale transmission [16].
SARS-CoV-2 has been considered as a respiratory virus
and the infected persons have been found upper respir-
atory symptoms like sneezing and coughing. Below are
given main transmission routes for the SARS-CoV-2 in
humans according to WHO and other sources (https://
www. who. int/ news- room/ comme ntari es/ detail/ trans
missi on- of- sars- cov-2- impli catio ns- for- infec tion- preve
ntion- preca utions).
Person toperson contact andrespiratory droplets
Contamination of the respiratory droplets via a person-
to-person contact has been found as one of the major
infection routes for the SARS-CoV-2. Respiratory drop-
lets are of a 5–10-μm diameter in size and can be trans-
mitted to another person while coughing, sneezing,
talking, or singing [17].
Airborne transmission
Airborne transmission is a spread of an infectious agent
caused by the diffusion of aerosols containing infec-
tion in the air over a long period of time and distance.
e sources or producers of the SARS-CoV-2 airborne
transmission may include generation of aerosols during
a medical procedure of an infected patient, indoor set-
tings with poor ventilation, and inhalation of infected
aerosols by a suspicious person during speech or breath
[18]. Numerous experimental studies have found that
the SARS-CoV-2 RNA could survive in the air from 3
to 16 h. However, results generated from studies per-
formed in true healthcare facilities remain debatable
[19, 20].
Fomite transmission
Fomites are also known as contaminated surfaces con-
taining traces of any infectious agent. Various stud-
ies found detectable traces of SARS-CoV-2 RNA on the
Fig. 3 Sequence alignments and characterization of SARS-CoV-2 RBD. a Amino acid alignment for RBD of SARS-CoV-2 and SARS-CoV. Highlighted
residues: green, conserved Ser/Thr between two sequences; blue, conserved substitution; pink, new Ser/ Thr residues introduced in SARS-CoV-2;
sea green, Ser/Thr residues in SARS-CoV replaced by other amino acids in SARS-CoV-2. b Detailed binding interface of predicted SARS-CoV-2 RBD
with ACE2 N-terminal. Possible changes in AAs are highlighted in yellow
Page 5 of 12
Ahmadand Shabbiri The Egyptian Journal of Internal Medicine (2022) 34:5
surfaces used by infected patients. Although, there are no
specific reports directly demonstrating fomite transmis-
sion, this mode of infection remained a possible way of
transmission in a similar type of infection reported ear-
lier [19, 21, 22].
Biological samples
Biological samples include urine and feces. Although
SARS-CoV-2 has been found in the patient’s urine and
feces samples, no report confirmed them as a possible
transmission route [23].
Blood serum andplasma andblood transfusion
Even though the SARS-CoV-2 has been found in patients’
blood serum and plasma, lower SARS-CoV-2 viral titers
suggest a minor risk of viral spread through serum and
plasma [23, 24].
Breastfeeding
Although the SARS-CoV-2 RNA was found in few breast
milk samples of infected mothers, there is no evidence
that this virus will be able to reach target sites in infants
to start replication. Until this day, WHO recommended
breastfeeding to be continued in infants by the mothers
who are suspected or infected with SARS-CoV-2 [24, 25].
Human topet animals/livestock andviceversa
It is unclear whether the pets are able to transmit and
infect SARS-CoV-2 in humans; however, there could be
a zoonotic possibility of transmission [26]. In a recent
study, an infected cat was able to transmit the SARS-
CoV-2 virus to other cats living in the same cage. ere
are few studies showing that infected humans can trans-
mit the virus and infect other animals including dogs,
cats and farmed mink. Till date, there is no evidence of
the SARS-CoV-2 transmission from humans to horses
or livestock or vice versa. Detailed information about
SARS-CoV-2 spread through animals can be found at the
website of the College of Veterinary Medicine, e Ohio
State University (https:// vet. osu. edu/ about- us/ news/
covid- 19- and- anima ls# Horses% 20Liv estock% 20risk%
20to% 20hum ans) and other online sources.
Possible infection spread scenarios/risk factors/
prevention
WHO has recently published a scientific brief describing
when a person may be able to spread the virus (https://
www. who. int/ news- room/ comme ntari es/ detail/ trans
missi on- of- sars- cov-2- impli catio ns- for- infec tion- preve
ntion- preca utions)? Briefly, the virus can be detected in
people 1–3 days before the appearance of any symptom
with high viral loads at early onset. e viral loads will
start to decline gradually. However, a positive PCR report
does not mean a person is infected and will be able to
transmit the disease. It might take days to detect the via-
ble virus during the early or mild stage.
Close contacts
Nevertheless, nearby and prolonged contact was found
to be a main reason for the SARS-CoV-2 transmission.
ere are more chances of spreading the virus between
family members if proper measures are not taken soon
after the detection of onset infection in one of the fam-
ily or close contact member. Moreover, the close contact
outside at various places like cinema, meal sharing, gym,
praying, or workplace increases the risk of virus trans-
mission [2729].
Asymptomatic contacts
It is also possible for a person without symptoms to trans-
mit the virus to the healthy ones. It is important to know
that which person is virus infected without showing any
symptoms. Recent studies from the globe revealed that
approximately 16–23% of asymptomatic persons did
not develop the symptoms at all, and this range could be
up to 41%. e most furious part is the recent research
showing that there is a 44% (25–69%) chance that the
viral transmission may have occurred before any symp-
tom appearance. Although it is difficult to trace infection
before symptoms appear, early testing and tracing would
help to minimize the virus transmission [2931].
Late SARS‑CoV—diagnosis andquarantine
All the available data show that reducing or limiting
the close contacts is the most effective way to reduce
the transmission of the virus. Moreover, the early and
timely diagnosis will help to trace the possible infection
whereas self or enforced quarantine will minimize the
spread to any secondary contact [32]. WHO has pub-
lished a detailed guidance document for possible quaran-
tine times that usually range from 5 to 6 days to 2 weeks
(https:// www. who. int/ publi catio ns/i/ item/ consi derat
ions- for- quara ntine- of- indiv iduals- in- the- conte xt- of-
conta inment- for- coron avirus- disea se- (covid- 19)?
Avoiding social gatherings
As there are significant chances to contact with the
asymptomatic persons during social gatherings in or out-
side or at workplaces, it is advised to minimize such gath-
erings or take necessary measures before attending such.
Personal protective measures such as masks and gloves,
and maintaining hygiene can reduce the chance of virus
transmission. e use of antimicrobial agents and mini-
mum required force at workplaces or the option to work
from home wherever possible will reduce the chances of
viral spread [32, 33].
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Ahmadand Shabbiri The Egyptian Journal of Internal Medicine (2022) 34:5
Abiding bycommunity regulations
As most of the SARS-CoV-2 infections spread through
traveling of the infected persons from one place to
another, it is recommended to abide by all the laws and
regulations advised by the communities or countries to
reduce the chances of virus spread in non-infected areas
or reduce infection rates in supervised communities
[3234].
Persons diagnosed/pre‑infected withother
diseases
Like other diseases, it is possible that some abnormalities
or pre-existing diseases could be the possible risk factors
for SARS-CoV-2 infection or vice versa. Unfortunately,
there are few studies that addressed this type of risk fac-
tor [3539]. A summary of these coincidences has been
given below.
SARS‑CoV‑2 andcancer
Cancer patients were found to be at increased risk of the
SARS-CoV-2 infection and having an increased death
rate. A recent study by Lee etal. [40] found that the sus-
ceptibility to SARS-CoV-2 infection is different among
patients with different types of tumors. e UK coronavi-
rus monitoring project (UKCCMP) and other researchers
found that the patients with hematological cancers like
leukemia, lymphoma, or myeloma were more vulnerable
to SARS-CoV-2 than other forms of cancers [4143].
Patients withdiabetes orassociated diseases
According to a report from webmed. com (https:// www.
webmd. com/ diabe tes/ diabe tes- and- coron aviru s#: ~:
text= Early% 20stu dies% 20have% 20sho wn% 20tha t,to%
20die% 20from% 20the% 20vir us), about 25% of patients
with severe COVID-19 symptoms had diabetes, and
infection might increase the pre-existed complexities
in the diabetic patients. is risk could be increased in
the presence of other diseases like lung or heart. As per
guidelines/recommendations from the American Dia-
betes Association, there is not enough data showing
that diabetic persons are more likely to be infected with
the SARS-CoV-2. However, diabetes itself worsened the
condition in case of infection (https:// www. diabe tes.
org/ coron avirus- covid- 19/ how- coron avirus- impac ts-
people- with- diabe tes). Similar findings were observed
from the cohort-based studies across the globe [3638,
43]. In a recent study by Dennis etal. [35] in England
found that the type-II diabetes increased the risk of fatal-
ity in persons infected with SARS-CoV-2, especially in
younger patients. It has also been noted that the hyper-
glycemia not only enhanced the SARS-CoV-2 replication
in monocytes but also increased the ACE2 expression.
Moreover, monocytes taken from diabetic patients were
more vulnerable to SARS-CoV-2 than normal [44].
Patients withneuro disorders
ere are few studies describing any possible association
of the SARS-CoV-2 infection with neurological disorders,
including dementia and Alzheimer’s disease [4548]. It
has been found that the cerebral white matter is most
susceptible to SARS-CoV-2 and might increase cognitive
dysfunction [45, 49]. ere is emerging evidence that the
SARS-CoV-2 infection might induce amyloid beta and
tau toxicity in the patients with Alzheimer’s and associ-
ated dementia diseases. is could be due to the depleted
ACE2 and associated RAS activation. Moreover, there
is strong evidence that the ACE2 depletion in APOE 4
individuals increased the cognitive decline [46, 50]. It is
also possible that SARS-CoV-2 might reduce immune
response and increase the death rate in people already
having dementia and worsen psychiatric symptoms and
behavioral disturbances [51].
SARS‑CoV‑2 andkidney disease
It is interesting to note that the SARS-CoV-2 was found
in autopsy samples of the COVID-19 patients whether
they had pre-kidney problems or not [52]. e same
study also found that the highest copies of the SARS-
CoV-2 per cell were detected in the respiratory tract,
whereas lower viral loads were detected in the kidneys,
liver, heart, brain, and blood. In silico analysis showed
that kidneys have high levels of RNA expression respon-
sible for ACE2, TMPRSS2, and cathepsin L that might in
turn induce the SARS-CoV-2 susceptibility for kidneys.
Meanwhile, vulnerability of the podocytes and tubular
epithelial cells to SARS-CoV-2 infection was expected to
induce the chances of renal injury [53]. It is evident from
various studies that the SARS-CoV-2 infection induces
acute kidney injury that might result in disease severity
and premature death within the first 3 weeks of infection
[54].
SARS‑CoV‑2 andliver injury
It has been found that the SARS-CoV-2 infection to the
liver cells is responsible for liver injury [55]. ere is
evidence that high expression of ACE2 receptors in the
liver cells might induce SARS-CoV-2-associated injury
in infected patients [55]. e other possibility could be
an induced inflammatory response (increased cytokines
levels) after infection that may lead to liver injury [56].
Increased levels of liver enzymes and biochemical mark-
ers, including AST, ALT, and bilirubin were observed
in patients with the SARS-CoV-2 infection. However,
Page 7 of 12
Ahmadand Shabbiri The Egyptian Journal of Internal Medicine (2022) 34:5
there are no reports about liver failure in patients with
COVID-19 [57].
Cardiac complications inSARS‑CoV‑2 infected patients
e virus was detected in the cardiac myocardium
autopsy cases of the patients infected with SARS-CoV-2
with a significant viral replication ability. Moreover,
induced cytokine expression in the patients with high
virus copies suggests that cytokine-induced organ dys-
function may worsen the disease [58]. Meanwhile, in
multiple clinical trials, results reviewed by Wu etal. and
Dhakal etal. also found higher ACE2 expression, hypox-
emia, cytokine storm, stress, and cardiotoxicity of the
anti-viral drugs in patients with COVID-19 symptoms
[59, 60]. Overall, SARS-CoV-2 infection in patients with
pre-cardiovascular disease could contribute to high mor-
tality rates [61].
Ophthalmic (eye) manifestation ofSARS‑CoV‑2
SARS-CoV-2 has strong affection with the ACE2 recep-
tors. Lower levels of ACE2 and TMPRSS2 were found in
the human cornea and conjunctival tissues when com-
pared to the heart and lungs [62, 63]. A recent review by
Perez-Bartolome etal. on clinical cases and other reports
regarding the potential ocular manifestations of SARS-
CoV-2 [64] described that virus infection could result
in eye redness, together with erythroderma and fever.
Besides this, there are chances that the SARS-CoV-2
could be present in tears from infected patients. In a
recent case report, the tear samples collected from some
of the patients were positive for COVID-19 presence [65].
Although there are no indications that the viral infection
could lead to blindness, a recent case report showed that
a COVID-19-positive patient with reversible encephalop-
athy syndrome got persistent cortical blindness.
Overall, these observations not only demand high care
of the corona-infected patients but also the persons tak-
ing care of them, including the medical staff and family
members. All of them should regularly test themselves
and take all necessary protective measures.
Current epidemiology andeconomic situation
SARS‑CoV‑2 epidemiology
e World Health Organization is publishing a weekly
global report on the current epidemiology of the COVID-
19 infection that can be accessed through https:// www.
who. int/ publi catio ns/m. On this day of the 24th of Nov
2021, 25.6 million cases were reported that were 15%
low when compared to the previous week. ere was
also around a 3% decline in the number of deaths due to
coronavirus. Until now, there are 259,502,031 cumulative
cases with 5,183,003 deaths globally with a death rate of
2.0%. Table1 adopted from WHO is reporting the cur-
rent global scenario showing a decline in infection as well
as death rates worldwide. Despite “WHO” worldometer
(https:// www. world omete rs. info/ coron avirus/) is also
updating the COVID-19 infections globally on a daily
basis. According to worldometer, there are 261,036,742
coronavirus cases with 5,209,580 deaths globally on the
24th of Nov 2021. e recovered cases were 235,860,474
whereas a total of 19,966,688 were active cases with
83,223 in the serious or critical stage.
SARS‑CoV‑2, global economy, anddisease spread
To ensure better treatment and a healthy environment,
there should be a strong economy to provide fund-
ing to cope with this type of pandemic. A good econ-
omy resulted in more resources to deploy for scientific
research and development. It has been obvious that most
governments misinterpreted the risks of SARS-CoV-2
infection from the beginning of the pandemic and were
not ready to act properly [66]. e intensive SARS-CoV-2
breakdown resulted in a sudden loss of global econo-
mies due to the long-lasting lockdowns, closure of mul-
tiple businesses, reduced productivity, excess labor, and
reduced working hours. According to BBC, there was
Table 1 Recent reported and cumulative COVID-19 cases and deaths, by WHO regions and globally
WHO region New cases in last 7
days (%) Change in new
cases in last 7
days*
Cumulative cases
(%) New deaths in
last 7 days (%) Change in new
deaths in last 7
days*
Cumulative deaths
(%)
Americas 1315480 (48%) 16% 48228712 (45%) 44385 (55%) 2% 1136906 (48%)
Europe 968943 (36%) 18% 36575529 (34%) 28404 (35%) 19% 812410 (34%)
Southeast Asia 154414 (6%) 13% 13188211 (12%) 2340 (3%) 9% 202607 (8%)
Eastern Mediter‑
ranean 170445 (6%) 7% 5998998 (6%) 2519 (3%) 9% 139468 (6%)
Africa 68115 (2%) 20% 2723431 (3%) 2558 (3%) 21% 68294 (3%)
Western Pacic 49577 (2%) 20% 1531366 (1%) 1134 (1%) 13% 27019 (1%)
Global 2726974 (100%) 16% 108246992 (100%) 81340 (100%) 10% 2386717 (100%)
Page 8 of 12
Ahmadand Shabbiri The Egyptian Journal of Internal Medicine (2022) 34:5
approximately 15 to 5% loss of economic growth
in most of the countries whereas the global economy
shrunk by 4.4% in 2020 worst since the great depression
of the 1930s (https:// www. bbc. com/ news/ busin ess- 51706
225).
Vaccination(s) againstSARS‑CoV‑2 infection
Soon after the rise of the pandemic, multiple labs started
the process to create any effective vaccination against
the SARS-CoV-2 infection. More than 200 vaccine can-
didates were reported to be involved in vaccination
development (https:// www. who. int/ publi catio ns/m/
item/ draft- lands cape- of- covid- 19- candi date- vacci nes).
According to this report, there are 69 vaccines in clini-
cal development while 181 in pre-clinical development.
ere are 33% protein subunit-based vaccines while 14%
each non-replicating viral vector, DNA, and inactivated
virus vaccines. e remaining vaccines might contain
replicating viral vector or virus-like particles or some
combinations of the abovementioned products. Till date,
a total of 2,156,384,616 vaccine doses have been admin-
istered (WHO: https:// covid 19. who. int/). In Table 2,
we have mentioned the vaccines currently in phase 3 or
available in the market now for the immunization.
Candidate drugs againstSARS‑CoV‑2 infection
Although multiple vaccines against the SARS-CoV-2
infection are currently in the clinical stage or available
in a limited amount for people, the requirement of the
drug against any infection remains necessary. Unfor-
tunately, till date, there is no effective drug against the
SARS-CoV-2. ere are two types of drug candidates
which might help to cope with this deadly infection in
the future: (i) blocking of virus entry to host and (ii) inhi-
bition of virus replication [67]. Below is a brief outline
about these candidate drugs.
Inhibiting virus entry tohost
Currently, there are two known virus-host interaction
sites/targets in humans namely TMPRSS2 serine pro-
tease and ACE2 receptors [68]. TMPRSS2 is involved in
the cleavage and activation of the SARS-CoV-2 spike pro-
tein whereas ACE2 is required for the SARS-CoV-2 entry
to the human cells. TMPRSS2 inhibition in the human
cell lines showed a reduction in SARS-CoV-2 infection
[68]. Camostat mseilate (N,N-dimethylcarbamoylme-
thyl 4-(4-guanidinobenzoyloxy)-phenylacetate) [39] and
Nafamostat mesylate (6-amidino-2-naphthyl-4-guanid-
ino benzoate-dimethanesulfonate) [69] are potent inhibi-
tors of TMPRSS2 and are under clinical trials against the
SARS-CoV-2 infection.
e other important target to reduce the virus entry
in humans is the inhibition of human ACE2 receptors.
e compounds and drugs that showed ACE2 inhibi-
tion included chloroquine [70] and hydroxychloroquine
[71], cephranthine [72], ivermectin [73], selamectin,
and mefloquine hydrochloride [74]. ese drugs were
previously used to treat Q-fever and malaria and as
prophylaxis and have been known as anti-helminthic,
parasiticide, and anti-viral. Besides these drugs, there are
some drugs in experimental trials, including synthetic
DX600, MLN-4760, and TAPI-2 [50]. ere are some
plant-derived compounds that may inhibit ACE2 and in
turn block SARS-CoV-2 entry into the host cells/ human
[75].
Anti‑ viral drugs
Other proposed drugs are based on the inhibition of viral
replication and assembly in the host cells. ese include
remdesivir, lopinavir, umifenovir, favipiravir, arbidol,
ribavirin, sofosbuvir, ritonavir, nelfinavir, and dolutegra-
vir. Although these drugs showed promising results in
the human cell cultures in the laboratory, the outcome
in actual patients was not so promising. However, recent
clinical trials showed that different combinations of these
drugs with others could be a good therapeutic option in
the future [67, 76].
Antibody neutralization
Another proposed therapy to deal with the SARS-CoV-2
infection was to inject the already recovered (convales-
cent) patient’s plasma into the diseased person [70, 76,
77]. e current clinical trials have not shown any signifi-
cant improvement in the infected persons after plasma
therapy; however, the development of target-specific
monoclonal antibodies against the SARS-CoV-2 spike
proteins is underway.
Natural compounds andimmune therapy
Alongside these synthetic drugs, many natural products
and their derivatives like plant-based steroids and phy-
tochemicals, including flavonoids, seemed to be effective
against various infections in the past [75]. ese products
not only were able to reduce the virus entry and infection
but also were able to boost the immune response. Mul-
tiple studies have found that the SARS-CoV-2 infection
might result in excessive inflammation and uncontrolled
cytokine storm that could lead to severe disease com-
plexities and patient death [78].
Other options
Unfortunately, the available drugs for the TMRSS2 and
ACE2 inhibition or SARS-CoV-2-specific anti-viral
drugs did not show promising results in reducing SARS-
CoV-2 infection, and there is a need to develop some
disease-specific drugs. It has been an established fact
Page 9 of 12
Ahmadand Shabbiri The Egyptian Journal of Internal Medicine (2022) 34:5
Table 2 Details of vaccines against SARS-CoV-2 currently available or in clinical phase 3
No. Platform Type Doses Dose schedule Route Developers
1Inactivated virus SARS-CoV-2 vaccine (inactivated) 2 Day 0 + 14 IM Sinovac Research and Development Co., Ltd
2Inactivated virus Inactivated SARS-CoV-2
vaccine (Vero cell) 2 Day 0 + 21 IM Sinopharm + China National Biotec Group Co + Wuhan
Institute of Biological Products
3Inactivated virus Inactivated SARS-CoV-2
vaccine (Vero cell) 2 Day 0 + 21 IM Sinopharm + China National Biotec Group Co + Beijing Insti-
tute of Biological Products
4Viral vector (non-replicating) ChAdOx1-S—(AZD1222) (Covishield) 1–2 Day 0 + 28 IM AstraZeneca + University of Oxford
5Viral vector (non-replicating) Recombinant novel coronavirus vaccine (adenovirus type 5
vector) 1 Day 0 IM CanSino Biological Inc./Beijing Institute of Biotechnology
6Viral vector (non-replicating) Gam-COVID-Vac adeno-based (rAd26-S+rAd5-S) 2 Day 0 + 21 IM Gamaleya Research Institute ; Health Ministry of the Russian
Federation
7Viral vector (non-replicating) Ad26.COV2.S 1-2 Day 0 or Day 0 +56 IM Janssen Pharmaceutical
8Protein subunit SARS-CoV-2 rS/Matrix M1-adjuvant (full-length recombinant
SARS CoV-2 glycoprotein nanoparticle vaccine adjuvanted
with Matrix M)
2 Day 0 + 21 IM Novavax
9RNA-based vaccine mRNA-1273 2 Day 0 + 28 IM Moderna + National Institute of Allergy and Infectious Dis-
eases (NIAID)
10 RNA -based vaccine BNT162 (3 LNP-mRNAs ) 2 Day 0 + 21 IM Pfizer/BioNTech + Fosun Pharma
11 Protein subunit Recombinant SARS-CoV-2 vaccine (CHO cell) 2-3 Day 0 + 28
or Day 0 + 28 + 56 IM Anhui Zhifei Longcom Biopharmaceutical + Institute of Micro-
biology, Chinese Academy of Sciences
12 RNA-based vaccine CVNCOV vaccine 2 Day 0 + 28 IM CureVac AG
13 Inactivated virus SARS-CoV-2 vaccine (vero cells) 2 Day 0 + 28 IM Institute of Medical Biology + Chinese Academy of Medical
Sciences
14 Inactivated virus QazCovid-in®—COVID-19 inactivated vaccine 2 Day 0 + 21 IM Research Institute for Biological 15Safety Problems, Rep of
Kazakhstan
15 DNA-based vaccine INO-4800 + electroporation 2 Day 0 + 28 ID Inovio Pharmaceuticals + International Vaccine Institute +
Advaccine (Suzhou) Biopharmaceutical Co., Ltd
16 DNA-based vaccine AG0301-COVID19 2 Day 0 + 14 IM AnGes + Takara Bio + Osaka University
17 DNA-based vaccine nCov vaccine 3 Day 0 + 28
+ 56 ID Zydus Cadila
18 DNA-based vaccine GX-19 2 Day 0 + 28 IM Genexine Consortium
19 Inactivated virus Whole-virion inactivated SARS-CoV-2 vaccine (BBV152) 2 Day 0 + 14 IM Bharat Biotech International Limited
20 Protein subunit SCB-2019 + AS03 or CpG 1018 adjuvant plus alum adjuvant
(native like trimeric subunit spike protein vaccine) 2 Day 0 + 21 IM Clover Biopharmaceuticals Inc./GSK/Dynavax
21 Protein subunit UB-612 (Multitope peptide based S1-RBD-protein based
vaccine) 2 Day 0+28 IM COVAXX + United Biomedical Inc
22 Virus-like particle Coronavirus-like particle COVID-19 (CoVLP) 2 Day 0 + 21 IM Medicago Inc.
Page 10 of 12
Ahmadand Shabbiri The Egyptian Journal of Internal Medicine (2022) 34:5
that certain drugs have serious limitations with multiple
side effects. Based on previous findings, in silico results
showed that inhibiting ACE2 phosphorylation at Ser-787
through O-β-GlcNAcylation has the potential not only
to reduce viral-host binding but also virus entry in host
cells [15]. As persons with pre-diabetes and neurological
disorders like dementia are highly vulnerable to SARS-
CoV-2 infection [3538, 41, 44, 4751], it could be pos-
sible that drugs used to treat lower blood glucose levels
and reduce neurological symptoms might be helpful to
reduce the severity of SARS-CoV-2 infection [7982].
Other drugs that fall into this category could be tested
for the SARS-CoV-2 infection severity. Moreover, multi-
ple genes, metabolites, proteins, and extracellular RNAs
were found to be associated with several clinical param-
eters during SARS-CoV-2 infection. ese genes or pro-
teins have been suggested as possible biomarkers and any
change in their expressions could affect the severity of
the SARS-CoV-2 infection as observed in other diseases
like dementia and cancer [8284].
Future perspectiveonly
So far, understanding of the SARS-CoV-2 structure and
its interaction with the host and the currently available
vaccines and drugs helped to decrease the number of
growing infection cases and deaths suffering from the
SARS-CoV-2 infection. However, the current emergence
of the SARS-CoV-2 variants (https:// www. who. int/ csr/
don/ 31- decem ber- 2020- sars- cov2- varia nts/ en/) like
SARS-CoV-2 D614G (a mutation in the spike protein),
SARS-CoV-2 VOC 202012/01, SARS-CoV-2 N501Y,
Alpha (B.1.1.7, +S:484K/ +S:452K), Beta (B.1.351,
+S:L18F), Gamma (P.1, +S:681H), Delta (B.1.617.2,
+S:417N/ +S:484K) and SARS-CoV-2 Omicron
(B.1.1.529, +S:R346K) could be a potential threat against
the global cumulative efforts to combat this deadly dis-
ease (https:// www. who. int/ en/ activ ities/ track ing- SARS-
CoV-2- varia nts/).
Conclusions
Unfortunately, till date, there are no specific drugs or effi-
cient vaccines to treat the SARS-CoV-2 infection. e
current available vaccines are under trial or still under
data collection from the immunized persons. Apparently,
it would take a long time to assess the efficacy of the cur-
rent available vaccines in immunized persons. Although
vaccination is a potent way to reduce infection via immu-
nity development, efforts should be increased in develop-
ing target-specific drugs to combat the SARS-CoV-2 in
the future. Moreover, societies/communities should be
properly informed about the dangers of this deadly dis-
ease, and governments should implicate such laws that
may be helpful in reducing corona infections without
lowering the living standards of ordinary persons.
Acknowledgements
Not applicable
Code availability
Not applicable
Authors’ contributions
W. A. was responsible for the study design and data collection. W. A. and
K. S. analyzed and wrote the data. The authors read and approved the final
manuscript.
Availability of data and materials
Not applicable
Declarations
Ethics approval and consent to participate
Not applicable
Consent for publication
Not Applicable
Competing interests
The authors have no conflicts of interest.
Author details
1 Department of Biochemistry, College of Medicine and Health Sciences,
UAE University, Al Ain, United Arab Emirates. 2 The University of Queensland,
Brisbane, Australia.
Received: 23 October 2021 Accepted: 3 December 2021
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Background and aims We describe the characteristics and short-term prognosis of in-patients with diabetes and COVID-19 admitted to a Belgian academic care center. Methods We retrospectively reviewed the data on admission from patients with known or newly-diagnosed diabetes and confirmed COVID-19. First, survivors were compared to non-survivors to study the predictive factors of in-hospital death in patients with diabetes. Secondly, diabetic patients with SARS-CoV-2 pneumonia were matched for age and sex with non-diabetic patients with SARS-CoV-2 pneumonia, to study the prognosis and predictive factors of in-hospital death related to diabetes. Results Seventy-three diabetic patients were included. Mean age was 69 (±14) years. Women accounted for 52%. Most patients had type 2 diabetes (89.0%), long-term complications of hyperglycemia (59.1%), and hypertension (80.8%). The case-fatality rate (CFR) was 15%. Non-survivors had more severe pneumonia based on imaging (p 0.029) and were less often treated with metformin (p 0.036). In patients with SARS-CoV-2 pneumonia, CFR was 15.6% in diabetic (n = 64) and 25.0% in non-diabetic patients (n = 128), the difference being non-significant (p 0.194). Predictive factors of in-hospital death were elevated white blood cells count (HR 9.4, CI 1.50–58.8, p 0.016) and severe pneumonia on imaging (HR 25.0, CI 1.34–466, p 0.031) in diabetic patients, and cognitive impairment (HR 5.80, CI 1.61–20.9, p 0.007) and cardiovascular disease (HR 5.63, CI 1.54–20.6, p 0.009) in non-diabetic patients. Conclusion In this monocentric cohort from Belgium, diabetic in-patients with COVID-19 had mostly type 2 diabetes, prevalent hyperglycemia-related vascular complications and comorbidities including hypertension. In this cohort, the CFR was not statistically different between patients with and without diabetes.
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Background: The aim of this study was to evaluate clinical outcomes in coronavirus disease 2019 (COVID-19) positive patients with type 2 diabetes compared to those without diabetes in Korea. Methods: We extracted claims data for patients diagnosed with COVID-19 from the National Health Insurance Service database in Korea from January 20, 2020 to March 31, 2020. We followed up this cohort until death from COVID-19 or discharge from hospital. Results: A total of 5,473 patients diagnosed with COVID-19 were analyzed, including 495 with type 2 diabetes and 4,978 without diabetes. Patients with type 2 diabetes were more likely to be treated in the intensive care unit (ICU) (P<0.0001). The incidence of inhospital mortality was higher in patients with type 2 diabetes (P<0.0001). After adjustment for age, sex, insurance status, and comorbidities, odds of ICU admission (adjusted odds ratio [OR], 1.59; 95% confidence interval [CI], 1.02 to 2.49; P=0.0416) and in-hospital mortality (adjusted OR, 1.90; 95% CI, 1.13 to 3.21; P=0.0161) among patients with COVID-19 infection were significantly higher in those with type 2 diabetes. However, there was no significant difference between patients with and without type 2 diabetes in ventilator, oxygen therapy, antibiotics, antiviral drugs, antipyretics, and the incidence of pneumonia after adjustment. Conclusion: COVID-19 positive patients with type 2 diabetes had poorer clinical outcomes with higher risk of ICU admission and in-hospital mortality than those without diabetes. Therefore, medical providers need to consider this more serious clinical course when planning and delivering care to type 2 diabetes patients with COVID-19 infection.