Ind J Clin Biochem (Oct-Dec 2020) 35(4):385–396

https://doi.org/10.1007/s12291-020-00919-0

REVIEW ARTICLE

The Pathophysiology, Diagnosis and Treatment of Corona Virus

Disease 2019 (COVID-19)
Subir Kumar Das1

Received: 2 June 2020 / Accepted: 4 August 2020 / Published online: 13 August 2020
Ó Association of Clinical Biochemists of India 2020

Abstract Since the beginning of this century, beta coron- Introduction

aviruses (CoV) have caused three zoonotic outbreaks.
However, little is currently known about the biology of the Coronaviruses (CoVs) is accountable for mixture of ail-
newly emerged SARS-CoV-2 in late 2019. There is a ments in human and animals that include respiratory,
spectrum of clinical features from mild to severe life enteric, renal, and neurological diseases [1]. These are
threatening disease with major complications like severe categorized into four genera, for instance alpha-CoV, beta-
pneumonia, acute respiratory distress syndrome, acute CoV, gamma-CoV, and delta-CoV2. Seven coronaviruses
cardiac injury and septic shock. The genome of SARS- (CoVs) of beta-CoVs have been isolated from human
CoV-2 encodes polyproteins, four structural proteins and beings till date [2]. There have already been three zoonotic
six accessory proteins. SARS-CoV-2 tends to utilize outbreaks in this century. Severe acute respiratory syn-
Angiotensin-converting enzyme 2 (ACE2) of various drome coronavirus (SARS-CoV) with about 10% case
mammals. The imbalance between ACE/Ang II/AT1R fatality rate (CFR) was initially witnessed from China in
pathway and ACE2/Ang(1–7)/Mas receptor pathway in the 2002, while Middle East respiratory syndrome coronavirus
renin-angiotensin system leads to multi-system inflamma- (MERS-CoV) infection with about 34.4% CFR was origi-
tion. The early symptoms of COVID-19 pneumonia are nally detailed from Saudi Arabia in June 2012 [2]. This
low to midgrade fever, dry cough and fatigue. Vigilant third outbreak coronavirus disease 19 (COVID-19) is
screening is important. The diagnosis of COVID-19 should indisputably the most frightening compared to the previous
be based on imaging findings along with epidemiological epidemics, which has spread from a marketplace in Wuhan,
history and nucleic acid detection. Isolation and quarantine China in December 2019 to more than 213 countries and
of suspected cases is recommended. Management is pri- territories, infecting more than 1.5 crore people with death
marily supportive, with newer antiviral drugs/vaccines toll more than 6 lakhs of the world within nine months.
under investigation. With nearly 4% CFR, we have never thought anything like
this highly contagious and pathogenic COVID-19, caused
Keywords Angiotensin
Angiotensin converting enzyme
by severe acute respiratory syndrome coronavirus 2
Chloroquine
Corona virus
COVID-19
Cytokine storm
(SARS-CoV-2) since the Spanish flu [3].
RNA-dependent
RNA polymerase
Spike protein
However, pathogenesis of SARS-CoV-2 is yet to decode
SARS-CoV2 and as result there is no appropriate management for
COVID-19 patients. This article focuses on understanding
the structure of the virus, pathogenesis for disease pro-
gression, diagnosis of the disease with pros and cons of
& Subir Kumar Das different treatment strategies.
[email protected]
1
Department of Biochemistry, College of Medicine and JNM
Hospital, WBUHS, Kalyani, Nadia, West Bengal 741235,
India

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Structure subunit (Fig. 3). Every monomer of trimeric S protein is

approximately 180 kDa, and is liable for attachment and
SARS-CoV-2 is positive-sense, single-stranded RNA con- membrane fusion. In the structure, N- and C- terminal parts
nected to a nucleoprotein surrounded by a matrix protein of S1 fold acts as two autonomous domains: N-terminal
based capsid (Fig. 1) [4]. Among the RNA viruses, the domain (NTD) and C-terminal domain (CTD) (Fig. 3).
human CoV has the biggest viral genome [27–32 kilobase Based on the virus, either NTD or CTD can function as the
pairs (kb)] with 80–160 nm in diameter [2]. A classic CoV receptor-binding domain (RBD) [1]. In adiition, a polyba-
has no less than six open reading frames (ORFs) in its sic (furin) fragmenting site at the junction of the S1 and S2
genome. All the structural and accessory proteins of CoVs subunits in the Spike protein of the SARS-CoV-2 was
are translated from it’s single guide RNAs (sgRNAs) [4]. reported, which is absent in the other SARS-like CoVs [8].
Two big overlapping ORFs, ORF 1a and ORF 1b, reside in Data suggests that SARS-CoV-2 is intimately shared with
two-thirds of the genome at the 50-terminus, and a third of SARS-CoV structural proteins having only 12.8% of dif-
the genome at the 30-terminus encodes for four conven- ference in S protein and has 83.9% similarity in minimal
tional structural proteins in the sequential arrangement of RBD [9].
spike (S), envelope (E), membrane (M), and nucleocapsid
(N) (50–30) (Fig. 2a). The genome of SARS-CoV-2 Genomic Analysis
encodes polyproteins pp1ab, four structural proteins and
six accessory proteins (3a, 6, 7a, 7b, 8, and 10), which is Using all accessible genomic information, the phylogenetic
comparable to the structure of SARSCoV and MERS-CoV tree investigation has ascertained the high sequence simi-
(Fig. 2b) [2]. The viral ORFs are produced through puri- larity ([ 99%) between all the existing sequenced SARS-
fying selection. The most restricted sequences corre- CoV-2 genomes, with the closest as Bat coronavirus
sponded to a few non-structural proteins (nsps) and (BCoV) sequence resembling 96.2% sequence identity
membrane protein [5] (Fig. 2). [10], while pangolin-CoV shares 85.98% identity [11],
Different proteins of human CoVs play important roles authenticating the conception of a zoonotic origin of
for viral infection and/or pathogenesis (Table 1) [2]. Sur- 2019-nCoV [10]. Other studies including full genome
face glycoprotein of the virus displayed five cytotoxic T sequencing of strains from China, Japan, USA, Finland and
lymphocyte (CTL) epitopes, three sequential B cell epi- Korea showed more than 99.9% sequence homology
topes and five discontinuous B cell epitopes [6]. B cell [12, 13]. Sequence homology of SARS-CoV-2 with SARS-
mediated humoral immune response causes the clearance CoV, and MERS-CoV was accounted 77.5% and 50%,
of SARS-CoV-2, while T cells play a fundamental role in respectively [12]. One study on the sequences of SARS-
viral infections [7]. The CTL epitopes attach to the major CoV-2 from India illustrated high (* 99.98%) identity
histocompatibility complex (MHC) Class I peptide-binding with Wuhan seafood market pneumonia virus (accession
grooves with uninterrupted hydrogen bonds and salt bridge number: NC 045512) [14].
anchors, which is accountable for immune responses, Analysing the 15 obtainable whole genome sequences of
leading to the development of subunit vaccines [6]. SARS-CoV-2, 12 whole genome sequences of SARS-CoV-
The S protein can be fragmented into two functional 2 and 12 extremely related whole genome sequences
subunits, N-terminal S1 subunit and a C-terminal S2 available in gene bank (five from the SARS-CoV, two from

Fig. 1 Schematic structure of

virion of SARS-CoV, MERS- Spike (S) protein
CoV, and 2019-nCoV (SARS-
CoV2) and its major structural
proteins
Nucleocapsid (N) RNA
Membrane (M) Protein
Lipid bilayer

Genomic RNA
Envelop (E) Protein

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Fig. 2 Schematic diagram of

genomic organization of SARS- A
5’-UTR 3’-UTR
CoV, MERS-CoV, and SARS-
CoV.2. a The genomic regions S E M N
or open-reading frames (ORFs)
are compared. b Structural B
proteins, including spike (S),
SARS-CoV E N
envelope (E), membrane
(M) and nucleocapsid
(N) proteins, as well as non-
structural proteins translated
from ORF 1a and ORF 1b and MERS-CoV E N
accessory (A) proteins are A
indicated for SARS-CoV,
MERS-CoV and SARS-CoV2

SARS-CoV2 A E N A

Table 1 Functions of different parts of SARS-CoV2 proteins

Protein Function

Non-structural proteins (nsps) Viral RNA replication and/or transcription

accessory proteins interact with host cells that help the viruses to evade the immune system and enhances their virulence
Membrane (M) and Envelop (E) proteins virus assembly and promote virulence
Spike (S) protein mediates viral entry into host cells and thereby membrane fusion, facilitating viral infection

Fig. 3 Diagram of full-length

SARS-CoV2 Spike (S) protein; S protein
S1 receptor binding subunit; S2
membrane fusion subunit; TM, S1 S2
transmembrane domain; HR-N,
heptad repeat-N; HR-C, heptad TM
repeat-C
NTD
Furin
cleavage site

MERS-CoV, and five from bat SARS-like CoV) explained in the coding region [17]. The nonsynonymous substitu-
the mutation in spike glycoprotein and nucleocapsid pro- tions resulting into 57 amino acid changes were reported to
tein [15]. It has been suggested that C-to-U conversion be distributed over different human CoV proteins with
mediated by C deamination played a significant role in the maximum on spike protein [17].
evolution of the SARS-CoV-2 [16]. These outcomes Out of 3617 available complete genome sequences of
implied that SARS-CoV-2 could have been evolving for a SARS-CoV2 from across the world maintained in the
relatively long period in humans following the transfer National Center for Biotechnology Information (NCBI)
from animals before spreading worldwide. database, the E protein possesses several non-synonymous
One study identified 12 novel recurrent mutations in mutations [18]. In another study, analysis of 10 SARS-
South American and African viral genomes, among which CoV2 sequences by genome alignment from the NCBI
3 were exclusively in South America, 4 in Africa and 5 database, did not report difference in amino acid sequences
were present in-patient isolates from both populations [11]. within M and N proteins, while two amino acid variances
Phylogenetic and alignment study of 591 novel coron- in the S protein region were reported. Two possible ‘‘L’’
aviruses of different clades from Group I to Group V and ‘‘S’’ SNPs were found in ORF1ab and ORF8 regions
identified several mutations and related amino acid chan- [19]. A third study, utilising genomes of twenty-nine
ges. Detailed analysis on nucleotide substitution revealed 2019-nCoV and thirty b-coronavirus, it was found that E
43 synonymous and 57 non-synonymous type substitutions genes were extremely conserved (99.56%), while S genes

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had lowest identity (92.87%), suggesting that S gene was suggested the chance of SARS-CoV-2 transmission
of a rapid evolutionary rate [13]. through the fecal–oral route [28]. SARS-CoV-2 may also
Analysis of the spike protein sequences from all five be noticed within the tears and conjunctival secretions in
identified isolates from the state of West Bengal (Eastern another study [31]. Airborne diffusion of SARS-CoV-2
India), two mutations were reported at position 723 and may also take place if patient respiratory activity or med-
1124 in the S2 domain. This mutation decreases the flex- ical processes generate respiratory aerosols [32].
ibility of S2 domain. Another mutation at the downstream
of the receptor binding domain (RBD) at position 614 in S1 Pathogenesis
domain was found similar with the sequence reported from
Gujarat (a state of western India). These mutations may be SARS-CoV-2 primarily targets the lungs, the vasculatures,
responsible for the affinity or avidity of receptor binding and the immune system [33]. The initial step of the viral
[20]. multiplication is the binding to the surface of respiratory
In another study, analysis of thirty-two genomes of cells mediated by the spike (S) viral protein [34]. It had
Indian COVID 19 patients revealed that ORF3a gene been speculated that SARS-CoV-2 likely utilize angio-
possesses single and double point mutations. The phylo- tensin- converting enzyme 2 (ACE2, EC 3.4.17.23) of
genetic analysis revealed that the parental origin of the various mammals, except murines and a few birds, such as
ORF3a gene over the genomes of SARS-CoV2 and Pan- pigeon [35]. The affinity of SARS-CoV-2 for ACE2 is
golin-CoV is same [21]. 10–20-higher than that of SARS- CoV [36].
All these investigations reliably suggested that ACE2 is a metalloproteinase and shares about 60%
2019-nCoV is most narrowly related to BatCoV RaTG13 homology with the carboxypeptidase angiotensin- con-
and belongs to subgenus Sarbecovirus of Betacoronavirus, verting enzyme (ACE, EC 3.4.15.1). ACE2, which is made
together with SARS CoV and Bat-SARS-like Cov [22]. up of 805 amino acids, is type I transmembrane glyco-
Evolutionary scrutiny using ORF1a/1b, S and N genes also protein having a single extracellular catalytic domain [37].
implied that 2019-nCoV is probably a novel CoV, which is Its expression is reported in the lungs, cardiovascular sys-
independently introduced to humans from animals [23]. tem, gut, kidneys, CNS and adipose tissue [38]. It is the key
active peptide of the renin-angiotensin system (RAS) or
Symptoms renin–angiotensin–aldosterone system (RAAS) [38].
Angiotensin II (Ang II) is the major effector of the
The incubation phase of COVID-19 is 3–7 days globally. RAAS that advances hypertension partly by decreasing
Approximately 80% of infectious cases remain mild or baroreceptor sensitivity to maintain heart rate, and
asymptomatic, 15% are severe and 5% infectious cases turn increasing vasoconstriction, sodium retention, oxidative
to critical, who require ventilation [24]. Three major stress, inflammation and fibrosis. Evidence from various
courses of infection include mild disease with upper res- studies favors a crucial function of ACE2 to efficiently
piratory symptoms, non-severe pneumonia, and severe degrade Ang II to Ang-(1-7), which antagonizes the effects
pneumonia complicated by acute respiratory distress syn- of Ang II (Fig. 4) [38]. Ang-(1–7) acts on the Mas receptor
drome (ARDS) and multi organ failure [25]. that modestly reduces blood pressure through vasodilation,
Fever and cough are the foremost common symptoms, promoting excretion of sodium and water by the kidney,
whereas dyspnea, fatigue, shortness of breath and chest and also attenuate inflammation through the nitric oxide
distcomfort are observed in moderate to severe cases [26]. production (Fig. 4) [36]. On the contrary, ACE converts
Olfactory and taste disorders also are reported in COVID- Ang I into Ang II, which acts at the type 1 angiotensin
19 patients, who may not have nasal indications [27]. receptor (AT1R) and increase blood pressure by inducing
Patients may further suffer from extra-pulmonary mani- vasoconstriction, increasing kidney reabsorption of sodium
festations, including those influencing the liver and GI and water by the kidney, and generating oxidative stress to
tract, with indications like diarrhoea, vomiting and promote inflammation and fibrosis (Fig. 4) [36].
abdominal pain [28]. The S1 domain of the SARS-CoV attaches to its cellular
receptor ACE2 on the host cells [39]. Binding of the
Transmission SARS- CoV-2 spike protein to ACE2, followed by a con-
formational change in the S-glycoprotein permitting pro-
Infection by droplets contaminating hands and surfaces are teolysis of ACE2 by transmembrane serine protease 2
the foremost means of dispersal of the virus [29]. GI tract is (TMPRSS2) to generate the S1 and S2 subunits is a critical
also a plausible spreading pathway and target organ of step for S2-induced membrane fusion and virus internal-
SARS-CoV-2 [30]. One study demonstrated the presence ization by endocytosis in the pulmonary epithelium. The
of SARS-CoV-2 RNA in feces of COVID-19 patients, and entry of the virus into cells further facilitates virus

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Fig. 4 Functional scheme of

the renin-angiotensin system.
The protease renin converts the
precursor angiotensinogen to
Angiotensin I (Ang I) and
subsequently converted to Ang
II by dipeptidyl
carboxypeptidase angiotensin
converting enzyme (ACE). Ang
II binds to the AT1 receptor
(AT1R) to stimulate
inflammation, fibrosis, oxidative
stress and an increase in blood
pressure. Ang II are converted
to Ang-(1-7) via endopeptidases
(NEP) and the
monocarboxypeptidase ACE2,
respectively. Ang-(1-7) binds to
the Mas-R to exert anti-
inflammatory and anti-fibrotic
actions, stimulate the release of
nitric oxide and reduce blood
pressure. SARS-CoV-2 binds to
ACE2 to stimulate
internalization of both the virus
and peptidase causing
deleterious effects. Angiotensin-
converting enzyme inhibitors
(ACEIs)/Angiotensin receptor
blockers (ARBs) regulate the
metabolic pathway

multiplication and cell- to- cell transmission [39], and is damage [40]. Furthermore, SARS-CoV-2 induced activa-
thought to suppress expression of ACE2. This suppression tion of apoptosis and p53 signaling pathway in lympho-
of ACE2 causes decrease in tissue level and reduces Ang- cytes causes lymphopenia in such patients [41].
(1–7) formation, and correspondingly increase in Ang II SARS-CoV-2 demonstrates neurotropic behaviour and
levels. ACE further converts Ang-(1–7) to less biologically may also cause neurological diseases. It is reported that
active peptides. This process can drive an Ang II–AT1R- CoV are often found in the brain or cerebrospinal fluid
mediated inflammatory response in the lungs and [42]. Another feature of severe COVID-19 is coagulopathy,
prospectively stimulate parenchymal injury [36]. which is determined by elevated plasmin(ogen) in such
The pathogenesis involves two interconnected pro- patients. Plasmin and other proteases, may cleave furin site
cesses: lung inflammation and immune deficiency, both of in the S protein of SARS-CoV-2 extracellularly, which
which are related to an improper immunologic response increases its infectivity and virulence, and is related to
and over-production of proinflammatory cytokines [33], hyperfibrinolysis [43].
Additionally, altered redox balance in infected cells
through alteration of NAD? biosynthesis, poly (ADP-ri-
bose) polymerase (PARP) function along with changeing
proteasome and mitochondrial function further exacerbate
inflammation and lipid peroxidation resulting in cell

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Factors Associated with Pathogenesis- age, Gender manifesting as acute respiratory distress syndrome (ARDS)
and Co-morbidities [50].
One meta-analysis comprising 1558 patients with
Studies have shown that SARS-CoV-2 causes worse out- COVID-19 from 6 studies revealed no association between
comes and a higher mortality rate in older people (more the increased risk of COVID-19 with liver disease,
than 60 years of age) and those with comorbidities such as malignancy, or renal diseases [52].
hypertension, cardiovascular disease, diabetes mellitus,
chronic respiratory disease, and chronic kidney disease Diagnosis
[43, 44]. The COVID-19 virus appears to cause mild
infections in children. Though the reasons for this tolerance Viral serological test is an efficient investigative means to
is unknown, some researchers suggested that non-suscep- determine the prevalence for SARS-CoV-2 infection
tibility of children to coronavirus may be due to separate among the population [53]. COVID-19 infection stimulates
ACE activity [45], and active innate immune response IgG antibodies against N protein that can be noticed in
caused by trained immunity (secondary to live-vaccines serum as early as day 4 after the onset of disease, and in
and frequent viral infections). Adult patients are believed most patients seroconversion take place by day 14 [24].
to have suppressed adaptive immunity and dysfunctional IgG illustrated higher positive rate and titer variance than
innate immune response [46]. that of IgM in COVID-19 [53]. Detection of IgM and IgG
It is believed that women, compared to men, are less against SARS-CoV-2 is a fast and easy monitoring method
vulnerable to viral diseases due to dissimilar innate [54]. Combined examination of the IgM-IgG proved better
immunity, steroid hormones and factors related to sex efficacy and sensitivity compared to a single antibody [55].
chromosomes. The immune regulatory genes encoded by X A decreased lymphocyte count and an increased high-
chromosome in female category causes lower viral load, sensitivity C-reactive protein (hs-CRP) level are the most
and less inflammation than in man, while CD4? T cells are common laboratory findings [56]. As the infection advan-
higher with better immune response. Higher TLR7 in ces, white blood cell count (WBC), neutrophil count, pla-
women and its biallelic expression is responsible for better telet count, red blood cell distribution width-coefficient of
immune responses and enhances the fighting to viral variation (RDW-CV), and RDW-standard deviation
infections in comparison to men [47]. (RDW-SD) parameters elevates with severity of the dis-
Myocardial injury is one of the important pathogenic eases; while, lymphocyte count, eosinophil count, red
features of COVID-19, possibly due to direct damage to the blood cell count (RBC), hemoglobin, and hematocrit
cardiomyocytes, systemic inflammation, myocardial inter- parameters decreases. The combined neutrophil-to-lym-
stitial fibrosis, interferon mediated immune response, phocyte ratio and RDW-SD parameter is the best hema-
exaggerated cytokine response by Type 1 and Type 2 tology index [57].
helper T cells, in addition to coronary plaque destabiliza- The assenting diagnosis of COVID-19 is dependent on
tion, and hypoxia [48]. the viral isolation by polymerase chain reaction (PCR)
COVID-19 may augment complications in individuals from sputum, or nasal swab, or throat swab for the cate-
with diabetes through an imbalance in ACE2 activation gories of those with symptoms or potentially exposed [58].
pathways leading to an inflammatory response and b-cell The real-time-reverse transcription (RT)-PCR detection of
dysfunction in the pancreas, which may deteriorate viral nucleic acid test (NAT) is considered as sensitive,
COVID-19 complications including vasculopathy, coagu- specific and able to process large batches of samples [59].
lopathy and psychological stress [49]. The chronic low The RT-PCR results generally become positive after
grade inflammation in diabetes and obesity can also lead to 2–8 days [60]. However, the commonly used RT-PCR
an enhanced ‘cytokine storm’ in COVID-19 patients [50]. method shows false-negative in some cases, such as
Respiratory epithelium cells of smokers and patients mutations of the SARS-CoV-2 genome, variable viral load
with COPD express higher ACE2 receptor. Nicotine binds kinetics or laboratory errors [61]. It may lack sensitivity,
and enhances nicotinic acetylcholine receptors (nAChR), particularly in the advanced phase of infection, and
specifically the a7subtype (a7-nAChR) in lungs and vari- depends closely on the samples’ quality [62]. As turn-
ous other tissues, particularly in central nervous system. around time of RT-PCR is long, molecular point of care
Increased expression of ACE2 receptors is mediated by tests (POCT) should be considered in situations where
stimulation of a7-nAChR, and facilitates the SARS-CoV-2 quick results are critical [59].
entry of into the respiratory epithelium [51]. ACE2 This rapid PCR by cartridge system (CBNAAT: car-
expression on endothelial cells is associated with virus tridge-based nucleic acid amplification test or GeneXpert
mediated endothelitis and precipitate vascular dysfunction polymerase chain reaction test) reduces response times
[62], demonstrated equal performance compared to routine

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in-house RT-PCRs [59], but is not suitable for laboratories vital element; but it is just one component of a shielding
with high throughput of requests [62]. system from COVID-19 infection [32]. Quarantine or
Computed tomography (CT) can be considered as an physical segregation is vital to confirm effectiveness,
essential supplemental investigative tool for the detection including short- to medium-term lockdowns, voluntary
of COVID-19 pneumonia in this pandemic context. In home curfew, curb on the gathering of people, cessation of
severe cases, CT plays an important role in identifying social and public events and closure of mass transit systems
viral lung infection, examining the nature and extent of [71].
pulmonary lesions, and scrutinizing the disease severity
[63]. Known features of COVID-19 on initial CT consist of Treatment
bilateral multilobar with an usual of three lung segments,
ground-glass opacification (GGO) with a peripheral or As extracorporeal membrane oxygenation (ECMO) is
posterior distribution, principally in the lower lobes and considered as an efficient remedy in the treatment of severe
some times inside the right middle lobe. Consolidative COVID-19 [72].
opacities superimposed on GGO may be reported in a few No valdated medicine is available till date against
elderly population. Other uncommon findings include COVID-19. Some drugs that are indicated for other
septal thickening, bronchiectasis, pleural thickening, and afflictions are being tested, although without unambiguous
subpleural involvement, which are rarely reported in the evidence. Lipophilic antibiotics tetracyclines (e.g. tetracy-
later stages of the disease [64]. The imaging pattern readily cline, doxycycline, and minocycline) can chelate zinc (Zn)
change over a short period of time [65]. compounds on matrix metalloproteinases (MMPs).
However, CT decontamination is essential after scan- Coronaviruses are believed to depend on host MMPs for
ning COVID-19 patients, which may disarray radiological survival, cell infiltration, cell to cell adhesion, and repli-
service accessibility and advocates that chest radiography cation; many of those have Zn as a part of their MMP
may lessen the risk of cross-infection [66]. In COVID-19, complex. It is possible that the Zn-chelating characteristic
chest X-ray (CXR) shows patchy or diffuse reticular- of tetracyclines may be responsible to inhibit SARS-CoV-2
nodular opacities and consolidation, with basal, peripheral infection in humans, and controlling their capacity to
and bilateral predominance [67]. The consideration of CXR multiply within the host [73]. Ivermectin, an FDA-ap-
for early detection may contribute an important role in the proved anti-parasitic drug that was previously shown as
regions around the world with limited access to RT-PCR broad-spectrum anti-viral activity in vitro, was reported as
COVID testing [66]. an inhibitor of the causative virus (SARS-CoV-2) in Vero-
Increased cytokine levels (IL-6, IL-10 and TNFa), hSLAM cells [74].
lymphopenia (in CD4? and CD8? T cells), and decreased The spike (S) protein on the viral envelope, is believed
IFN-c expression in CD4? T cells are linked with severe as a major intention of vaccine development for the pre-
COVID-19, illustrating the ‘‘cytokine storm’’ [68]. vention of coronavirus infection. The choices to block viral
Some patients are detectd with definite disseminated ingress include the employment of natural neutralizing
intravascular coagulation (DIC) [69]. This DIC is primarily antibodies from convalescent plasma (discussed elsewhere
pro-thrombotic with high venous thromboembolism rate, within the manuscript) and engineered antibodies. Engi-
increased D-dimer and fibrinogen levels, reduced anti- neered antibodies or neutralizing fragments are often uti-
thrombin levels, pulmonary congestion with microvascular lised in various formats. The antibody/Fc-receptor complex
thrombosis and occlusion on pathology besides high rates imitates viral receptor to intervene viral entry. Antibody-
of central line thrombosis and vascular occlusive events dependent enhancement (ADE) of viral entrance has been
(e.g. ischemic limbs, strokes, etc.) [69]. observed for several viruses. In such cases, antibodies mark
There is no study exclusively in asymptomatic partici- one serotype of viruses and subneutralize another, causing
pants. Combination of clinical presentation, imaging fea- to ADE of the second virus. A unique mechanism for the
tures and laboratory findings could help early diagnosis of ADE is that a neutralizing antibody attaches to the S pro-
COVID-19 pneumonia. tein of coronaviruses like a viral receptor, triggers a con-
formational change of the spike, and mediates viral entry
Preventive Measures into IgG Fc receptor-conveying cells through canonical
viral-receptor-dependent pathways [75].
Infection can spead only in the existence of contact. Angiotensin-converting enzyme inhibitors (ACEIs) and/
Nosocomial spread is usually controlled through prelimi- or angiotensin receptor blockers (ARBs) might possibly
nary infection control measures, including wearing of face alleviate the RAS-induced lung injury, and restrict heart
masks, respiratory etiquette, hand and environmental and renal damage. It was reported that ACEIs and/or ARBs
hygiene [70]. Personal protective equipment (PPE) is a increases the ACE2 expression, and also inhibit

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angiotensin-converting enzyme 1 (ACE1) or stops angio- controlling the T lymphocyte activation [85]. Azithromycin
tensin II type 1 receptor (Fig. 4). Considering that ACE2 together with HCQ was reported considerably more effi-
expression might be associated with the vulnerability to cient for virus elimination [86]. However, there is inade-
SARS-CoV-2, intake of ACEIs and/or ARBs might pre- quate proof to establish the safety and effectiveness of CQ/
dispose patients to the infection of SARS-CoV-2 [76]. HCQ to treat COVID-19.
However, due to the functional complexity of the RAAS A few broad-spectrum antiviral drugs were tested
and the lack of strong information on the activities of against COVID-19 in clinical trials. RNA-dependent RNA
ACE2 expression in various tissues following the use of polymerase (RdRp) is an essential protease that mediates
ACE inhibitors or angiotensin receptor blockers, it is dif- the replication of RNA from RNA template for coron-
ficult to speculate on the relevance of those ACE modu- aviruses and is an important therapeutic target. Some
lators [76, 77]. clinical assessments against viral RdRp inhibitors had been
Viral S-glycoprotein, TMPRSS2 and ACE-2 inhibition conducted. Favipiravir, a purine nucleic acid analogue and
are important objectives of therapy and probably vaccine effective RdRp inhibitor, which is endorsed against
development [39]. Subunit vaccines are commenced influenza, is additionally being considered in different
depending on the full-length S protein, receptor-binding clinical trials [87]. Remdesivir, an analogue of adenosine
domain (RBD), non-RBD S protein fragments, and non-S with broad-spectrum antiviral agent has shown a high
structural proteins [2]. Using structure-based drug screen- capacity to block infection and viral replication in vitro and
ing to detect SARS-CoV-2 protease blockers, macrolides in animals with attainable concentrations in human plasma
(MAC) were believed to be effective for COVID-19 [78]. against SARS-CoV and MERS-CoV. It seems that
E proteins of SARS-CoV2 form ion channels. Result remdesivir may be one amongst the few antiviral drugs
revealed that a-helix and loops present in this protein is with proven efficacy against SARS-CoV2 [88] possibly by
associated with the random movement under optimal delayed RNA chain termination [89].
condition, which successively alter ion channel activity; Recently, the mixture of three drugs, lopinavir, oselta-
and thereby developing the disease. Inhibition of those ion mivir and ritonavir has been proposed to mitigate the vir-
channels after binding with three phytochemicals, such as, ulence to a good extent in COVID-19 affected patients.
belachinal, macaflavanone E, and vibsanol B, reduces the Hence, these drugs are often explored further for drug
random motion of the human ‘‘SARS-CoV-2 E’’ protein, repurposing against the successful inhibition of COVID-19
inhibit its function and controlling the disease [79]. [90]. A randomized controlled experiment of lopinavir/ri-
The main protease (Mpro) of SARS CoV-2 is an tonavir showed no visible clinical or virologic benefit, and
important component of this viral replication. Three drug–drug interactions and consequences further limit its
polyphenols (epigallocatechin gallate, epicatechingallate utility [91]. Oseltamivir demonstrated limited activity
and gallocatechin-3-gallate) of green tea [80] and com- against SARS-CoV-2 [91].
pounds from Curcuma longa L. (Zingiberaceae family) Prevention of the cytokine storm may be one of the
[81] interact strongly with one or both catalytic residues solution to save the patients with severe COVID-19
(His41 and Cys145) of Mpro, and are considered as pneumonia. Limited pre-clinical data suggested that sys-
potential inhibitors against SARS CoV-2 Mpro. Famo- temic mesenchymal stem cells (MSCs) administration
tidine, a class A G protein-coupled receptor antagonist used could cure or significantly improved the functional out-
for the treatment of gastroesophageal reflux, is reported to comes in seven SARS-CoV2 patients without any adverse
interact within the catalytic site of the three proteases effect [92]. Addition of anticytokinic biological agents, like
associated with SARS-CoV2 replication [82]. anti-IL-1 (anakinra) [93] or anti-IL-6 (tocilizumab (TCZ))
There has been growing interest in the use of anti- [94] are also recommended.
malaria and anti-amebiasis drugs chloroquine (CQ, N4-(7- Anti-complement C5 therapy with eculizumab is
Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine) reported to be a potential key player in treatment of severe
and hydroxychloroquine (HCQ), as potential treatments for cases of COVID-19 [95]. Some studies reported that the
COVID-19. Chloroquine inhibits quinone reductase 2, use of corticosteroids might speed up improvement from
which is involved in the biosynthesis of sialic acids [83]. COVID-19 [96]. However, it is also reported that non-
CQ (or it’s active derivative HCQ) inhbits attachment of steroidal anti-inflammatory drugs (NSAIDs) and corticos-
the viral spike to the gangliosides [34]. Further study teroids may worsen conditions in SARS-CoV2 patients
suggested that both CQ and HCQ stall the movement of [97]. Therefore, use of corticosteroids or Janus kinase
SARS-CoV-2 from endosomes to endolysosomes, which (JAK) blockers need to be reconsidered in cases with
seems to be critical to discharge the viral genome [84]. hyperinflammation [98]. One study indicated that Lian-
HCQ probably reduce the progression of COVID-19 huaqingwen, a conventional Chinese medicine formula
severity, by hindering the ‘cytokine storm’ through significantly inhibited SARS-CoV-2 replication in Vero E6

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cells and markedly reduced pro-inflammatory cytokines Conclusion

[99].
Memantine, an antagonist of a7-nAChR and NMDA Given the high infection rate of this virus between humans
receptors may lessen ACE2 receptors expression and and its pandemics, it is essential to understand the structure
reduce oxidative stress and inflammation [51]. Early and basis of its pathogenicity for the advancement to the
treatment with anti-oxidants such as N-acetyl cysteine special treatment or the prevention. Due to the greater
during COVID-19 can be a way to control the excessive resemblance of the virus to its families, attempts have been
inflammation and cell damage [40]. Various randomized made to expolore the medicines and vaccines for COVID-
controlled trials, pilot studies, case reports and in vitro and 19. Identification of the specific molecular details of the
in vivo studies confirmed that Nigella sativa (black cumin virus is helpful in achieving treatment goals. It is also
seeds) that showed antiviral, antioxidant, anti-inflamma- important to monitor any changes in phenotype as the virus
tory, immunomodulatory, bronchodilatory, antihistaminic, spreads.
antitussive activities, could be considered as an adjuvant
therapy along with repurposed conventional drugs for Compliance with Ethical Standards
management of COVID-19 patients [100]. It further ren- Conflict of interest None.
ders the importance of homocysteine-dependent trans-sul-
furation pathway in COVID-19 infection. Hence, Vitamin
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