Journal of

Clinical Medicine

Review
Multi-Organ Involvement in COVID-19: Beyond
Pulmonary Manifestations
Vikram Thakur 1 , Radha Kanta Ratho 1, *, Pradeep Kumar 2 , Shashi Kant Bhatia 3 , Ishani Bora 1 ,
Gursimran Kaur Mohi 1 , Shailendra K Saxena 4 , Manju Devi 5 , Dhananjay Yadav 6, * and Sanjeet Mehariya 7, *

1 Department of Virology, Postgraduate Institute of Medical Education and Research (PGIMER),

Chandigarh 160012, India; vik5atif@gmail.com (V.T.); ishanibora16@gmail.com (I.B.);
gkmohi@gmail.com (G.K.M.)
2 Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management
Sciences, Solan 173229, India; pradeep.kumar@shooliniuniversity.com
3 Department of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, Korea;
shashikonkukuni@konkuk.ac.kr
4 Centre for Advanced Research, Faculty of Medicine, King George’s Medical University,
Lucknow 226003, India; shailen@kgmcindia.edu
5 Department of Oral Pathology and Microbiology, RUHS College of Dental Sciences (Government Dental
College), RUHS University of Rajasthan, Jaipur, Rajasthan 302016, India; bajiyamanju45@gmail.com
6 Department of Medical Biotechnology, Yeungnam University, Gyeongsan 712-749, Korea
7 Department of Engineering, University of Campania ‘Luigi Vanitelli’, Real Casa dell’ Annunziata,
Via Roma 29, 81031 Aversa, Italy
* Correspondence: rathopgi@yahoo.com (R.K.R.); dhanyadav16481@gmail.com (D.Y.);
sanjeet.mehariya@unicampania.it (S.M.); Tel.: +91-947-808-8899 (R.K.R.)



Abstract: Coronavirus Disease 19 (COVID-19), due to severe acute respiratory syndrome coronavirus-


2 (SARS-CoV-2) has become an on-going global health emergency affecting over 94 million cases with
Citation: Thakur, V.; Ratho, R.K.; more than 2 million deaths globally. Primarily identified as atypical pneumonia, it has developed
Kumar, P.; Bhatia, S.K.; Bora, I.; Mohi, into severe acute respiratory distress syndrome (ARDS), a multi-organ dysfunction with associated
G.K.; Saxena, S.K; Devi, M.; Yadav, D.; fatality. Ever since its emergence, COVID-19 with its plethora of clinical presentations has signalled its
Mehariya, S. Multi-Organ
dynamic nature and versatility of the disease process. Being a disease with droplet transmission has
Involvement in COVID-19: Beyond
now assumed the proportion of a suspected airborne nature which, once proved, poses a Herculean
Pulmonary Manifestations. J. Clin.
task to control. Because of the wide distribution of the human angiotensin-converting enzyme-2
Med. 2021, 10, 446. https://doi.org/
(hACE2) receptors, known for its transmission, we envisage its multiorgan spread and extensive
10.3390/jcm10030446
disease distribution. Thus, an extensive review of the extrapulmonary organotropism of SARS-CoV-2
Academic Editor: Jihad Mallat with organ-specific pathophysiology and associated manifestations like dermatological complications,
Received: 16 December 2020 myocardial dysfunction, gastrointestinal symptoms, neurologic illnesses, hepatic and renal injury is
Accepted: 20 January 2021 needed urgently. The plausible mechanism of site-specific viral invasion is also discussed to give
Published: 24 January 2021 a comprehensive understanding of disease complexity, to help us to focus on research priorities
and therapeutic strategies to counter the disease progression. A note on the latest advancements in
Publisher’s Note: MDPI stays neutral vaccine research will enlighten the scientific world and equip it for better preparedness.
with regard to jurisdictional claims in
published maps and institutional affil- Keywords: SARS-CoV-2; COVID-19; ACE-2; neurological; hepatic; dermatological; pathogenesis;
iations. therapeutics; vaccines

Copyright: © 2021 by the authors. 1. Introduction

Licensee MDPI, Basel, Switzerland.
Coronavirus disease 2019 (COVID-19) is a novel emerging human infectious disease
This article is an open access article
due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first reported in
distributed under the terms and
Wuhan, China, in December 2019. Having been present for one year, SARS-CoV-2 had
conditions of the Creative Commons
infected more than 94 million individuals with 2,031,875 deaths from 218 countries globally
Attribution (CC BY) license (https://
as of 17 January 2021 [1]. COVID-19 spread quickly across the world until a global
creativecommons.org/licenses/by/
4.0/).
emergency and pandemic were declared by the World Health Organization (WHO) on

J. Clin. Med. 2021, 10, 446. https://doi.org/10.3390/jcm10030446 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2021, 10, 446 2 of 19

30 January and 11 March 2020, respectively [2]. Untiring efforts are being invested to
understand the origin, transmission, and pathogenesis of COVID-19 so that effective
therapeutic agents, as well as an effective vaccine, can be developed. The R (reproductive
number) for SARS-CoV-2 is estimated between 1.5–3.5 in comparison to 2.0 of SARS 2002,
however, the case fatality rate (CFR) is around 2–3% in SARS-CoV-2 in comparison to 10%
for SARS 2002 [3,4].
Of the seven coronaviruses (CoVs), 229E, NL63, OC43, and HKU1 are known for self-
limiting upper respiratory tract infections [5], whereas Middle East respiratory syndrome
coronavirus (MERS-CoV), SARS-CoV, and the novel SARS-CoV-2 end up with life-threatening
respiratory failure and multi-organ dysfunction [6,7]. SARS-CoV-2 through spike (S) glyco-
proteins recognizes and binds specifically to the human angiotensin-converting enzyme 2
(hACE2) receptors expressed on type-II alveolar epithelial cells for its entry [8]. SARS-CoV-2
has a stronger binding affinity with ACE2 along with cellular transmembrane serine protease 2
(TMPRSS2) imparting virulence and aggressive properties. Following the SARS-CoV-2 binding
to alveolar epithelial cells, the innate and adaptive immune system is activated leading to
cytokine-release syndrome (CRS) or macrophage activation syndrome (MAS). Increased produc-
tion of interleukin (IL-1, IL-6, IL-8) cytokines in plasma resulting in dyspnea, acute respiratory
distress syndrome (ARDS), and death [9]. High levels of SARS-CoV-2 shedding in the upper
respiratory tract, even among presymptomatic patients, is a key factor in the transmissibility
of COVID-19.

2. Clinical Presentation and Transmission of Coronavirus Disease 2019 (COVID-19)

Because of the novel nature of the virus and lack of immunity, the presentations are
dynamic and frequently changing. Being an unknown cause of atypical pneumonia, the
infection gradually progressed affecting the population in Hubai province, China and
thereafter, spread to different countries, the presentations varied from mild respiratory
tract infection to severe pneumonia and ARDS or multi-organ dysfunction with increased
mortality [10]. Other typical presentations like fever, cough, diarrhea, hemoptysis, rhin-
orrhea, shortness of breath, myalgia, fatigue and severe dyspnoea, lymphopenia, chest
radiographic findings like ground-glass opacity are observed in COVID-19 [11]; 20% of
COVID-19 patients in an older age group with pre-existing morbidities present with severe
respiratory illness and ARDS whereas children and young adults have a milder illness and
better prognosis [12].
The asymptomatic cases contributed to a major source of the virus and resulted in a
high rate of community transmission, and thus extensive screening was required [13]. It
has been estimated that up to 86% of cases with unusual presentations might have been
missed in China [14]. In the beginning, COVID-19 was suspected with unusual respiratory
symptoms, whereas over the progression of the pandemic involving different countries
the extra-pulmonary symptoms like the neurological, cardiac, renal, gastrointestinal tract,
ocular, vascular, olfactory including anosmia and ageusia were reported. The multior-
gan manifestations may be correlated due to the abundancy of the ACE2 receptors in
various organs [15–18] and observed with symptoms including diarrhea, poor appetite,
nausea, vomiting (digestive); headache, and confusion (nervous), palmus, chest distress
(cardiovascular) [19]. SARS-CoV-2 is commonly transmitted from person-to-person mainly
by respiratory droplets and fomites through cough, sneeze, or by droplet inhalation and
contact transmission with oral, nasal and eye, mucous membrane, including saliva.
COVID-19 diagnosis is mainly made on radiological settings like X-ray, chest com-
puted tomography (CT) scan, and laboratory findings like lymphopenia and elevated
Lactate Dehydrogenase (LDH) [12]. Nasopharyngeal and oropharyngeal swabs help in
virus identification through nucleic acid detection by real-time polymerase chain reaction
(RT-PCR) which is the method of choice for lab diagnosis as isolation in cell lines requires
BSL-3/4 facilities [20]. Such labs are highly specialized to deal with potentially deadly
infectious and exotic agents requiring the most stringent containment. The classical char-
J. Clin. Med. 2021, 10, 446 3 of 19

acteristics of BSL-4 is a full-body, air-supplied, positive pressure suit, class III biological
safety cabinet, and rooms with negative pressure facility.

3. Cutaneous Manifestations of Severe Acute Respiratory Syndrome Coronavirus-2

(SARS-CoV-2)
Skin rashes and purpuric plaques are an interesting clinical presentation of classical
coronavirus infections. The first report of the cutaneous manifestations was reported from
Italy, where 20.4% (18/88) hospitalized COVID-19 patients developed an erythematous
rash (14), widespread urticaria (3), and chickenpox-like vesicles (1) distributed in the trunk
area [21]. In severe cases, erythematous rash, and localized or widespread urticarial rashes
seem to be the most common cutaneous manifestation whereas in China only 0.2% (2/1099)
confirmed COVID-19 cases had skin rashes [22].
Fernandez et al. [23] had reported a skin biopsy of a 32-year-old woman from France
with COVID-19 having urticariform rash with perivascular infiltration of lymphocytes,
eosinophils, and upper dermal edema on histopathology. Urticaria (1.4%) is also reported as
cutaneous symptoms. A rare COVID-19 associated varicella-like papulovesicular exanthem
was first observed in Italian patients by Marzano et al. [24]. Lesions were varied from
scattered to diffuse with vesicular predominance in 12 (54.5%) patients with trunk and
limbs involvement generally appearing 3 days after systemic symptoms. Fever, cough,
headache, weakness, coryza, dyspnea, hyposmia, and hypogeusia were common systemic
symptoms reported. However, SARS-CoV-2 detection in skin lesional was not performed
but still represents a useful clue to suspect COVID-19 in asymptomatic patients. A dengue-
like petechial rash with thrombocytopenia was reported by Joob and Wiwanitkit [25] in a
COVID-19 patient from Thailand. Unusual skin manifestations like confluent erythematous-
yellowish papules on both heels of a 28-year-old COVID-19 infected woman with symptoms
of diarrhea, ageusia, and anosmia has been reported [26].
In a few COVID-19 patients, atopic dermatitis, and psoriasis has been aggravated
as pre-existing skin disease. Joob and Wiwanitkit [27] presented an 84-year-old woman
with arterial hypertension history having COVID-19 related bilateral pneumonia, later
developed mild pruriginous rashes in the peri-axillary area and coalescing macules in
flexural regions. Thus, various studies have reflected the possibilities of potential skin
lesions of COVID-19.

4. Hepatic Manifestations of SARS-CoV-2

Though primarily a respiratory pathogen, shreds of evidence indicate the liver as an
extra-pulmonary site for SARS-CoV-2 infection causing liver injury ranging between 14.8%
to 78% [28,29]. The possible mechanism of hepatic injury in COVID-19 could either be virus
related cytopathic effect or infection-induced cytokine storm. Two independent studies on
healthy cohorts by single RNA sequencing data demonstrated significant ACE2 expression
(59.7%) in cholangiocytes. SARS-CoV-2 binds to the ACE2 expressed cholangiocytes and
being facilitated its entry by TMPRSS2 [30]. Higher coexpression of ACE-2 and TMPRSS2
in human trophoblast cell surface antigen 2 (TROP2high ) cholangiocyte progenitor cells
of the liver has been reported [31]. The human liver ductal organoid model revealed that
cholangiocyte permissiveness for SARS-CoV-2 causes direct liver injury leading to the
accumulation of bile acids [32]. In 54% of COVID-19 patients, the ACE2 expression was
found to be high in bile duct cells as evidenced by elevated gamma-glutamyl transferase
(GGT) levels [33]. Ablation of tight junction protein claudin 1 and down-regulation of
apical sodium-dependent bile acid transporter (ASBT) and cystic fibrosis transmembrane
conductance regulator (CFTR) might be the contributing factors towards liver injury in
COVID-19 [32] (Figure 1).
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 4 of 20

J. Clin. Med. 2021, 10, 446 and macrophages secretes inflammatory IL-6, IL-10, IL-2, and IFN-c causing CRS and he- 4 of 19
patic injury [35].

Bile duct

SARS-CoV-2 Liver
TMPRSS2
ACE2 Inflammatory cytokine
(IL-6) mediated liver
injury
Hepatic bile

Direct liver injury, breaks the

Hepatocyte Claudin1 junction protein

Cholangiocyte Deregulate liver function

Accumulation of bile acids
Down-regulate ASBT & CFTR

Figure Figure
1. Mechanism of hepatic
1. Mechanism ofinjury:
hepaticin injury:
coronavirus disease 2019
in coronavirus (COVID-19)
disease patients, hepatic
2019 (COVID-19) patients, hep-
injury attributed
atic injuryby (i) direct virus-induced
attributed cytopathic effect;
by (i) direct virus-induced (ii) virus-mediated
cytopathic infection-induced
effect; (ii) virus-mediated infection-
cytokine storm. cytokine
induced Severe acute respiratory
storm. syndrome
Severe acute coronavirus-2
respiratory syndrome (SARS-CoV-2)
coronavirus-2 binds to the angi-binds to
(SARS-CoV-2)
otensin-converting enzyme 2 (ACE2),
the angiotensin-converting expressed
enzyme on hepatocytes
2 (ACE2), expressed and cholangiocytes
on hepatocytes and in the bile
cholangiocytes in the
duct cells causing ablation of tight junction protein claudin 1 and down-regulation of apical so-
bile duct cells causing ablation of tight junction protein claudin 1 and down-regulation of apical
dium-dependent bile acid transporter (ASBT) and cystic fibrosis transmembrane conductance reg-
sodium-dependent bile acid transporter (ASBT) and cystic fibrosis transmembrane conductance
ulator (CFTR), leading to the accumulation of bile acids and contributing towards liver injury.
regulator
Inflammatory (CFTR),(interleukin-6,
cytokines leading to theIL-10,
accumulation
and IL-2)of bile acids
secretion by and contributing
lymphocytes and towards
macro- liver injury.
Inflammatory cytokines (interleukin-6, IL-10, and IL-2) secretion by lymphocytes
phages aggravate inflammatory responses causing hepatic injury. Black dotted square frame and macrophages
in the
aggravate inflammatory responses causing hepatic
figures denotes the selected area for the magnified portion. injury. Black dotted square frame in the figures
denotes the selected area for the magnified portion.
5. Cardiac Manifestations of SARS-CoV-2
A liver biopsy of a COVID-19 positive deceased patient revealed portal inflammation
Viral pathogens, especially SARS, are well-known for contributing to cardiovascular
with microvesicular steatosis [34]. Virus-mediated persistent activation of lymphocytes and
disease like acute myocarditis, acute myocardial infarction, and rapid-onset heart failure
macrophages secretes inflammatory IL-6, IL-10, IL-2, and IFN-c causing CRS and hepatic
[36]. A wide range of cardiovascular events such as myocardial injury, acute coronary
injury [35].
syndromes, cardiac arrhythmias, and heart failure are associated with COVID-19 [37,38].
In a study comprising
5. Cardiac 138 hospitalized
Manifestations COVID-19 patients, cardiac injury was reported in
of SARS-CoV-2
7.2% of patients [12]. An investigation
Viral pathogens, especially SARS, on 273 COVID-19 positive
are well-known forpatients revealed
contributing that the
to cardiovascular
higher disease
concentration of creatine kinase isoenzyme- myocardial band (CK-MB), myohemoglo-
like acute myocarditis, acute myocardial infarction, and rapid-onset heart fail-
bin, cardiac troponin
ure [36]. A wide I, and N-terminal
range pro-brain events
of cardiovascular natriuretic
suchpeptide (NT-proBNP)
as myocardial injury,inacute
venous
coronary
blood are the hallmark of heart injury [39]. A COVID-19 associated Brugada type
syndromes, cardiac arrhythmias, and heart failure are associated with COVID-19 [37,38]. I electrocar-
diographic patterncomprising
In a study in a 61-year-old Hispanic maleCOVID-19
138 hospitalized presented with a history
patients, of substernal
cardiac injury was chest
reported
pain, elevated CRP (150.7 mg/L) and BNP (19 pg/mL) were reported by Vidovich
in 7.2% of patients [12]. An investigation on 273 COVID-19 positive patients revealed [40]. Sor-
gente etthat
al. [41]
the observed an episode ofof
higher concentration supraventricular
creatine kinasetachycardia
isoenzyme- in myocardial
patients withbandBrugada
(CK-MB),
syndrome, mostly due to plaque rupture, myocarditis, or microvascular thrombosis,
myohemoglobin, cardiac troponin I, and N-terminal pro-brain natriuretic peptide (NT- resulting
in virus-induced
proBNP) in myocardial
venous blood ischemia, inflammation,
are the hallmark ofand ST injury
heart elevation.
[39].Therefore,
A COVID-19 abnormal
associated
myocardial-associated fatalities necessitate careful
Brugada type I electrocardiographic patternmonitoring of the myocardial
in a 61-year-old Hispanic male enzyme pro- with
presented
files toareduce
history theofCOVID-19-associated
substernal chest pain, complications
elevated CRP in (150.7
patients.
mg/L) and BNP (19 pg/mL) were
reported by Vidovich [40]. Sorgente et al. [41] observed an episode of supraventricular
Possibletachycardia
Mechanisminofpatients
Cardiac Manifestations
with Brugada syndrome, mostly due to plaque rupture, myocarditis,
or microvascular thrombosis, resulting in virus-induced myocardial ischemia, inflamma-
tion, and ST elevation. Therefore, abnormal myocardial-associated fatalities necessitate
careful monitoring of the myocardial enzyme profiles to reduce the COVID-19-associated
complications in patients.
 J. Clin. Med. 2021, 10, 446 5 of 19

J. Clin. Med. 2021, 10, x FOR PEER REVIEW 5 of 20

Possible Mechanism of Cardiac Manifestations

Single nuclear transcriptome analysis of the adult human heart identified the car-
Single nuclearendothelial
diomyocyte, transcriptome cellanalysis of the adult
(ECs), fibroblast, humanand
pericyte, heart identified cell
neuron-like the (Neu)
cardi- to be
omyocyte, endothelial cell (ECs), fibroblast, pericyte, and neuron-like cell (Neu)
crucial for the proper functioning of the heart [42]. Moreover, the higher ACE2 expression to be cru-
cial for
inthe
theproper
cardiac functioning
pericytes of the heartthe
illustrates [42].potential
Moreover,of the higher ACE2
SARS-CoV-2 expression
to affect heartinreflectory,
the
cardiac pericytes an
indicating illustrates
intrinsicthesusceptibility
potential of SARS-CoV-2
of the hearttotoaffect heart reflectory,
SARS-CoV-2 indicating
infection [43]. There-
an intrinsic susceptibility
fore, during of the infection
COVID-19 heart to SARS-CoV-2
in the heart,infection [43]. Therefore,
SARS-CoV-2 mediated during
injuryCOVID-
to pericytes
19 infection in the heart, SARS-CoV-2 mediated injury to pericytes and, capillary
and, capillary ECs dysfunction might induce microvascular myocardial microcirculation ECs dysfunc-
tion might induce
disorder [44]microvascular
(Figure 2). myocardial microcirculation disorder [44] (Figure 2).

Vessel
Heart SARS-CoV-2

ACE2
Capillaries

Pericytes

Endothelial Cardiomyocyte
cells
Injury to pericytes
and endothelial cells

Capillary ECs Dysfunction

Microvascular myocardial
micro-circulation disorder

FigureFigure
2. Mechanism of cardiac
2. Mechanism of injury:
cardiacIninjury:
COVID-19 patients, SARS-CoV-2
In COVID-19 mediated injury
patients, SARS-CoV-2 to injury to
mediated
cardiomyocyte, pericytes, and, capillary endothelial cells by expressing ACE2 receptor and elevat-
cardiomyocyte, pericytes, and, capillary endothelial cells by expressing ACE2 receptor and ele-
ing thevating
heart susceptibility to SARS-CoV-2
the heart susceptibility infection, which
to SARS-CoV-2 induce
infection, microvascular
which myocardial myocardial
induce microvascular mi-
crocirculation disorder and other cardiac abnormalities.
microcirculation disorder and other cardiac abnormalities.

6. Neurological Manifestations
6. Neurological of SARS-CoV-2
Manifestations of SARS-CoV-2
SARS-CoV and MERS-CoV
SARS-CoV and MERS-CoV havehave
neuro-invasive
neuro-invasiveproperties thatthat
properties can can
assist the the
assist virus
virus to
to spread from the respiratory tract to the central nervous system CNS resulting
spread from the respiratory tract to the central nervous system CNS resulting in neurologi- in neu-
rological manifestations in
cal manifestations in the
the form
form of of febrile
febrile seizures,
seizures, convulsions,
convulsions, and and encephalitis
encephalitis[45].
[45]. From
From thetheepidemiological
epidemiologicalsurveys,
surveys,a latency
a latency period
period of 7ofdays
7 days for SARS-CoV-2
for SARS-CoV-2 may may be
be enough to
enough to enter
enter and destroy
and destroy the medullary
the medullary neurons.
neurons. SevereSevere destructions
destructions manifested
manifested with
with involuntary
involuntary
breathing,breathing,
hyposmia,hyposmia,
ageusia, ageusia,
hypoxia, hypoxia, symptomatic
symptomatic seizures,
seizures, status epilep-
status epilepticus, nausea,
ticus, and vomiting
nausea, accompanied
and vomiting by chronicbyrespiratory
accompanied distress [17].
chronic respiratory Patients
distress with
[17]. COVID-19
Patients
have been have
with COVID-19 reported
beenwith mild with
reported (anosmia
mild and ageusia)
(anosmia andto severe to
ageusia) (encephalopathy)
severe (encepha-neuro-
logical
lopathy) features being
neurological featuresexacerbated by smoking,
being exacerbated by due to co-expression
smoking, of hACE2 and
due to co-expression of the
hACE2 nicotinic
and theacetylcholine receptor (nAChR)
nicotinic acetylcholine [46].
receptor Recent [46].
(nAChR) reports of SARS-CoV-2
Recent detection in
reports of SARS-
CoV-2CSF of the COVID-19
detection in CSF of patient
the COVID-19reasonably validate
patient the assumption
reasonably validate of CNS
the being affected
assumption of by
SARS-CoV-2
CNS being affected[47]. A COVID-19 positive
by SARS-CoV-2 patient manifested
[47]. A COVID-19 with necrotizing
positive patient manifested hemorrhagic
with
encephalopathy
necrotizing hemorrhagic evidenced through a evidenced
encephalopathy brain CT scan [48]. Viral
through encephalitis,
a brain CT scan [48].infectious
Viral toxic
encephalitis, infectious toxic encephalopathy, and acute cerebrovascular disease are somemani-
encephalopathy, and acute cerebrovascular disease are some of the important CNS
of thefestations
importantrelated to COVID-19. Viral
CNS manifestations encephalitis
related to COVID-19.characterized by acute onset,
Viral encephalitis headache,
character-
ized byfever,
acutevomiting, convulsions,
onset, headache, fever, and consciousness
vomiting, disorders
convulsions, andspeculation
consciousness wasdisorders
clinically sup-
ported was
speculation by the detection
clinically of SARS-CoV-2
supported by theindetection
the CSF of ofCOVID-19
SARS-CoV-2 patients
in the[49].
CSFInfectious
of
toxic encephalopathy, a reversible brain dysfunction syndrome
COVID-19 patients [49]. Infectious toxic encephalopathy, a reversible brain dysfunction due to systemic toxemia,
and hypoxia
syndrome were reported
due to systemic toxemia,in andCOVID-19 patients
hypoxia were [50].inAdditionally,
reported COVID-19 patientsbrain [50].
autopsies
Additionally, brain autopsies showed tissue edema and partial neuronal degeneration in
J. Clin. Med. 2021, 10, 446 6 of 19

showed tissue edema and partial neuronal degeneration in deceased patients of COVID-19
infection. The SARS-CoV-2 infection has been widely reported to cause CRS, leading to
acute cerebrovascular disease. Also, elevated levels of D-dimer and reduced platelet count
in critically ill SARS-CoV-2 patient predispose to acute cerebrovascular events. Recent case
series from China and the US describe ischaemic or hemorrhagic stroke, Guillain-Barré
syndrome (GBS), or acute necrotizing encephalopathy (ANE), as neurological symptoms
among COVID-19 patients [51,52] (Table 1).

Table 1. COVID-19 cases with neurological signs and manifestations.

Case/Study Symptoms (Neurological)

Fever, acute loss of consciousness, and bilateral
extensor plantar reflexes.
79-year-old man
Intracerebral hemorrhage in the right brain
(Positive-Oropharyngeal swab) [53]
hemisphereIntraventricular and subarachnoid
hemorrhage.
Generalized fatigue and fever, transient
The first case of SARS-CoV-2 associated generalized seizures, and neck stiffness.
meningitis. Convulsion accompanied by unconsciousness.
Absence of SARS-CoV-2 RNA in Hyperintense signal in the right mesial
nasopharyngeal swab.Positive in CSF [54] temporal lobe in the brain along with
significant paranasal sinusitis.
Fever, shortness of breath, lymphopenia,
multiple subpleural ground-glass opacities in
SARS-CoV-2 positive male with encephalitis,
the chest, and myalgia. Progression of
however, CSF is negative [55]
consciousness towards the confusion with
signs of meningeal irritation.

Mechanisms of Neurotropism and Neuroinvasion

Brain infiltration through the olfactory nerves following intranasal administration
could be a possibility as with SARS-CoV and MERS-CoV in the transgenic mice model.
There are numerous predicted pathways for CNS invasion by SARS-CoV-2 to cause neu-
ronal damage (Figure 3).
In the hematogenous route, SARS-CoV-2 binds to the ACE2 expressing capillary
endothelium and enters the CNS by a breach in the blood–brain barrier (BBB) resulting in
high blood pressure with the risk of cerebral hemorrhage. Through dynein and kinesin
motor proteins, SARS-CoV-2 infects sensory or motor nerve endings by retrograde or
anterograde neuronal transport as a neuronal pathway [56,57]. In the olfactory neuron
transport, SARS-CoV-2 can enter the CNS/brain through the olfactory tract by olfactory
nerves in the nasal cavity/epithelium and the olfactory bulb in the forebrain, causing
inflammation and demyelinating reactions. Moreover, diffusion of alveolar and interstitial
inflammatory exudation, results in anabolic metabolism in brain cells, leading to hypoxia
and ischemic stroke. Circumventricular organs and cerebrovascular endothelial cells
expressing ACE2 receptors regulate multiple neurological functions including regulation
of hormone formation, the sympathoadrenal system, vascular autoregulation, and cerebral
blood flow [58,59]. COVID-19 results in a large number of fatalities, mostly due to multiple
organ failure induced systemic inflammatory response syndrome (SIRS). The persistence
and ability of SARS-CoV-2 to infect and activate macrophages, microglia, astrocytes, and
glial cells in the CNS induces a pro-inflammatory state by secretion of IL-6, IL-12, IL-15,
and tumor necrosis factor-α (TNF-α) [60]. The IL-6 mediated cytokine storm, results in
acute necrotizing encephalopathy (ANE) causing neuroinflammation in addition to a surge
in interleukin IL-2, IL-7, interferon-γ, monocyte chemoattractant protein 1, and TNF-α
leading to hyper inflammation, encephalopathy, and even stroke [61].
 Mechanisms of Neurotropism and Neuroinvasion
Brain infiltration through the olfactory nerves following intranasal administration
could be a possibility as with SARS-CoV and MERS-CoV in the transgenic mice model.
There are numerous predicted pathways for CNS invasion by SARS-CoV-2 to cause neu-
J. Clin. Med. 2021, 10, 446 ronal damage (Figure 3). 7 of 19

Brain Hippocampus
Olfactory bulb
Neurons

Medulla
oblongata
SARS-CoV-2 Oligodendrocyte
Blood stream 3 SARS-CoV-2
1
Vagus nerve Infected nerve cells
SARS-CoV-2
• Neuroinflammation and demyelination
• Acute cerebrovascular disease
• Acute necrotizing encephlopathy
• Necrotizing hemorrhagic encephalopathy

Lungs

Direct pathways:
1. Through olfactory nerve
2. Blood circulation
3. Neuronal pathway
SARS-CoV-2
infected CSF

Figure 3. Predictable model for SARS-CoV-2 induced neurological manifestations: Numerous pathways predicted for central
nervous system CNS invasion by SARS-CoV-2 to cause neuronal damage. In the olfactory neuron transport, SARS-CoV-2
can infiltrate the CNS/brain through the olfactory tract by olfactory nerves in the nasal cavity/epithelium and the olfactory
bulb in the forebrain, causing inflammation and demyelinating reactions. In the hematogenous route, SARS-CoV-2 binds to
the receptor ACE2 expressed in the capillary endothelium and enters the CNS by a breach in the blood–brain barrier (BBB)
resulting in high blood pressure with the risk of a cerebral hemorrhage. Infected and activated macrophages, microglia,
astrocytes, and glial cells in the CNS induce a pro-inflammatory state by secretion of IL-6, IL-12, and IL-15 resulting in acute
necrotizing encephalopathy (ANE), hyper inflammation, and encephalopathy.

7. Renal Manifestations
Renal injury is the commonly reported COVID-19 associated renal manifestations
reflecting the renal tropism of SARS-CoV-2 [62]. The burden of acute kidney injury (AKI)
with COVID-19 infection was relatively low, ranging from 3–9% to as high as 15% [63,64].
Further evidence supported the renal tropism of SARS-CoV-2 by the isolation of viral RNA
from urine and albuminuria and hematuria in COVID-19 infection [65,66]. Puelles et al. [67]
quantified the SARS-CoV-2 viral load in autopsy tissue samples obtained from 22 COVID-
19 positive deceased patients; 17 (77%) had more than two coexisting conditions, which
was associated with SARS-CoV-2 tropisms for the kidneys, even in patients without a
history of chronic kidney disease. Three out of six patients on autopsy had a detectable
SARS-CoV-2 viral load preferentially in glomerular cells as shown in Table 2.
J. Clin. Med. 2021, 10, 446 8 of 19

Table 2. COVID-19 positive cases showing renal manifestations.

Case/Study Symptoms (Renal)

High risk of AKI associated with age >60 years,
85 COVID-19 positive patients coexisting hypertension, and coronary
Acute kidney injury (AKI) in 27% of artery disease.
patients [68] Severe acute tubular injury with macrophage
infiltration, and detection of viral antigen (6)
Proteinuria (44%), Haematuria (27%), and
701 hospitalized patients [63]
Acute kidney injury (3.2%)
Diarrhea as common presenting symptoms
(4/5), fever (3/5), fatigue (3/5), dyspnoea
201 maintenance hemodialysis (MHD) patients.
(2/5), and abdominal pain (2/5), lymphopenia
Five had COVID-19 pneumonia [69]
(5/5), with ground-glass opacity.
Fever, cough, and dyspnoea were absent.
230 haemodialysis patients; 16.1% (37) Lymphopenia, lower levels of inflammatory
diagnosed with COVID-19 [70] cytokines, and mild clinical disease

The Potential Mechanisms of Renal Manifestations

In silico analysis of single-cell RNA sequencing revealed the enriched RNA expression
of ACE2, TMPRSS2, and cathepsin L (CTSL) in podocytes and tubule epithelial cells which
might facilitate the SARS-CoV-2 associated kidney injury [71,72]. ACE2 is expressed on
the renal epithelial and bladder cells which counter the activation of the renin-angiotensin-
aldosterone system (RAAS) [73]. SARS-CoV-2 can bind and injure the renal epithelial cells,
thereby disrupting the body fluid and electrolyte homeostasis in addition to the erythropoi-
etin and vitamin D production. Organ crosstalk (lung-kidney and heart-kidney), cytokine
damage by IL-6, and systemic effects could be the underlying mechanisms for renal injury.
During lung–kidney crosstalk, tubular epithelium enhances the IL-6 upregulation in serum
resulting in increased alveolar-capillary permeability and pulmonary hemorrhage [74].

8. Gastrointestinal (GIT) Manifestations

Gastrointestinal (GIT) manifestations are revealed in 10.6% of patients with SARS and
30% of patients with MERS had diarrhea as the clinical symptoms [75]. The first case of
SARS-CoV-2 infection with nausea, vomiting, and abdominal discomfort was reported
from the U.S. where viral RNA was detected from the stool and respiratory specimen of a
COVID-19 patient on day 7 of illness [76]. Clinically diarrhea was reported in 1–3.8% cases,
diarrhea, and nausea in 10.1%, and vomiting in 3.6% [12].
Lin et al. [77] observed diarrhea and abdominal pain as evidenced in 20–50% of
COVID-19 patients, which sometimes preceded respiratory symptoms. A 25-year-old
female with respiratory symptoms was negative for SARS-CoV-2 in the pharyngeal aspirate
but positive in the fecal sample. This might indicate feces as a source of virus transmission
and the GIT region as an extrapulmonary site for virus replication [78]. Thus, early
monitoring of viral RNA in the fecal specimens might benefit the disease prediction even
before respiratory symptoms (Table 3).
J. Clin. Med. 2021, 10, 446 9 of 19

Table 3. Case studies showing gastrointestinal (GIT) manifestations in COVID-19 patients.

Case/Study Symptoms (GIT/others)

Headache, myalgia, fatigue, cough, sputum
26/84 COVID-19 patients with diarrhea [79]
production, nausea, vomiting
204 COVID-19 patients
Anorexia (83.8%)
GIT symptoms in 99 (48.5%)
Diarrhea (29.3%)
Cross-sectional study, China [80]
651 COVID-19 patients
11.4% (74) patients with GI symptoms Diarrhea, nausea, and vomiting
28% lack respiratory symptoms [81]
95 COVID-19 patients Diarrhoea (24.2%),
61.1% cases with GI symptoms Nausea (17.9%),
52.4% (22) positive faecal samples [77] Elevated transaminases (32.6%)
1141 COVID-19 patients
Anorexia, nausea, vomiting, diarrhea,
GIT symptoms in 16% of patients
abdominal pain
A retrospective study, China [82]

The presence of SARS-CoV-2 in stool samples even after 11 days of viral clearance
from respiratory tract samples in over half of patients indicates the alternative route of
excretion of the virus [83]. Similarly, Xu et al. [84] reported 8 of the 10 infected children
having persistent positive SARS-CoV-2 in rectal swabs, where nasopharyngeal swabs were
negative for the virus. In a multicentric study with 1992 patients, 34% of them experienced
diarrhea whereas 53% experienced one of the GIT symptoms. However 74% of the cases
were mild and not associated with severe clinical course [85]. Despite the ability of SARS-
CoV-2 to establish a robust infection in GIT; it might be inactivated by human colonic
fluids in the intestinal lumen, hence the viral RNA transiting through GIT and shedding
through the feces may not be infectious [86]. However, live SARS-CoV-2 was detected
using electron microscopy in stool samples from two patients, which might focus on the
potentiality of fecal transmission [87]. Even though there is evidence of GI symptoms due
to SARS-CoV-2, its role in the disease process is yet to be demonstrated.

Possible Mechanism for GIT Manifestations

The causative mechanism for GIT manifestation in COVID-19 positive patients is
not well studied. Single-cell transcriptomic analysis of GIT (stomach, colon, ileum, and
esophagus) indicated high ACE2 expression in absorptive intestinal epithelial cells (IECs)
in the ileum and colon [88]. The ACE2 receptor indirectly regulates intestinal inflammation
whereas TMPRSS2 is crucial for viral fusion [89]. Various hypothetical models were
predicted: Higher co-expression of ACE2 and TMPRSS2 and stronger binding efficiency of
SARS-CoV-2 for ACE2, located on the mature enterocytes in the ileum and colon, triggers
epithelial cell fusion by TMPRSS2 and TMPRSS4 (inducing S cleavage and enhancing the
fusogenic activity of the virus) suggesting the viral invasion of enterocytes of the digestive
tract and stratified epithelial cells of the esophagus, resulting in oesophageal erosion [90]
(Figure 4).
 SARS-CoV-2 for ACE2, located on the mature enterocytes in the ileum and colon, triggers
epithelial cell fusion by TMPRSS2 and TMPRSS4 (inducing S cleavage and enhancing the
fusogenic activity of the virus) suggesting the viral invasion of enterocytes of the digestive
tract and stratified epithelial cells of the esophagus, resulting in oesophageal erosion [90]
(Figure 4).
J. Clin. Med. 2021, 10, 446 10 of 19

Surface epithelium

Oesophagus Gastric pit

Enterocytes
Duodenum
Goblet cells Gastric gland

Intestinal
epithelial cells
SARS-CoV-2 Ileum Parietal cell
ACE-2 Colon
TMPRSS2
Chief cell

Invasion to upper Unbalanced intestinal Enteroendocrine

stratefied epthelial cell secretion and malabsorption cells
causing oesophagus leading to diarrhea
SARS-CoV-2 infected
erosion Gastric and
enterocytes
Duodenum
Diarrhea

Figure 4. A predictive model for gastrointestinal (GIT) manifestations: High ACE2 expression and stronger binding
efficiency of SARS-CoV-2 for ACE2 in absorptive intestinal epithelial cells (IECs), enterocytes in the ileum and colon,
indirectly regulate intestinal inflammation and oesophageal erosion suggested the viral invasion to enterocytes of the
digestive tract and stratified epithelial cells of the esophagus. High-expression of ACE2 receptors in the glandular cells
of the gastric and duodenal epithelium, or proximal and distal enterocytes, leads to unbalanced intestinal secretion and
mal-absorption resulting in diarrhea as a common GIT manifestation. Red dotted square frame in the figures denotes the
selected area for the magnified portion.

High expression and possible interaction of ACE2 receptors with SARS-CoV-2 in the
glandular cells of gastric and duodenal epithelial cells, or in proximal and distal enterocytes,
leads to unbalanced intestinal secretion and malabsorption resulting in diarrhea [91]
The abundant and ubiquitous presence of ACE2 in human epithelial (small intestine)
and endothelial cells might provide possible routes of transmission accounting for high
transmission capacity.

9. Hematological Manifestations of SARS-CoV-2

Hematological parameters like alterations in immune cell population and coagulation
factors in COVID-19 patients could suggest disease progression [92]. Lymphocytopenia
seems to be the most common characteristic in adult patients with severe COVID-19
infection possibly due to the destruction of lymphoid organs [93]. Platelets are important
in modulating inflammatory responses. A meta-analytical study showed the association of
reduced platelets with COVID-19 severity, resulting in thrombocytopenia due to increased
destruction or decreased platelet production [94,95]. Elevation in the levels of D-dimer
is commonly observed in severe patients. Such patients are at high risk of developing
thrombosis, endothelium damage, and hemorrhagic complications [96]. SARS-CoV-2
mediated endothelium injury, initiates the protective clotting cascade to minimize the
internal injury, which subsequently forms undesirable internal blood clots resulting in
thrombosis [97]. Angiogenesis associated ARDS was reported in the lung autopsies of 7
COVID-19 patients. It was marked by diffuse alveolar damage with perivascular T-cell
infiltration and microthrombosis. Also, the severe endothelial injury was associated with
intussuscepted vascular angiogenesis in the lungs [98]; 5% of large-vessel stroke incidences
were reported among hospitalized patients in a single-centric study from China where
coagulopathy and vascular endothelial dysfunction was the crucial presentation [52].
J. Clin. Med. 2021, 10, 446 11 of 19

10. Unusual Manifestations of SARS-CoV-2

Subacute thyroiditis, oral lesions, large vessel stroke, rheumatologic skin disease, im-
mune thrombocytopenia, endothelitis, pulmonary thromboembolism, pedo, and angiogenesis
associated ARDS were also reported with SARS-CoV-2 as depicted in Table 4. Irregular oral
lesions have been described as an early COVID-19 symptom, which needs to be proven with
more pieces of evidence. Self-limited subacute thyroiditis (SAT) is characterized by neck pain,
and thyroid dysfunction is usually preceded by an upper respiratory tract infection [99,100].

Table 4. Unusual manifestations of SARS-CoV-2.

Manifestation Type Case and Studies Presentation/Symptoms

Irregular oral ulcer on the dorsal side of
45-year-old female; SARS-CoV-2 positive the tongue, painful inflammation of
Oral
Nasopharyngeal swab (NPA) [101] tongue papilla, macular erythematous
lesion, vasculitis
18-year-old female positive for Thyroid enlargement
Thyroid
SARS-CoV-2; The bilateral and diffuse hypoechoic area
(Subacute thyroiditis)
(Oropharyngeal swab) [102] around the neck
New-onset symptoms of severe
large-vessel ischemic stroke with the
mean National Institutes of Health Stroke
Scale (NIHSS) score of 17. Partial
5 SARS-CoV-2 positive patients
Large-vessel stroke infarction of the right middle cerebral
(<50 years of age) [103]
artery with a partially occlusive
thrombus in the right carotid artery.
Patchy ground-glass opacities in bilateral
lung apices
71-year-old male renal transplant
Viral inclusion structures in endothelial
recipient with coronary artery disease
cells. Inflammatory cells and apoptotic
Endothelitis and arterial hypertension diagnosed
bodies accumulation in the heart and
COVID-19 positive on post mortem
lungs
analysis of transplanted kidney [104]
Mouth: Development of purple lesions.
Petechiae concentrated on lower
10-year-old SARS-CoV-2 positive patient extremities, chest and neck and
with severe thrombocytopenia and wet ecchymoses in the popliteal regions and
purpura [105] shins. Fatigue, fever, cough, and
Immune thrombocytopenia
65-year-old SARS-CoV-2 positive woman abdominal discomfort.
with hypertension and autoimmune Developed lower-extremity purpura,
hypothyroidism [106] epistaxis, subarachnoid
microhemorrhage, and intracranial
hemorrhage
Gait alteration of red-violet lesions,
itching, pain with mild swelling of both
feet, nausea, dizziness, headaches, and
dry eyes.
Neuropathic involvement of peripheral
16-year-old COVID-19 positive female nervous system (neuralgia)
from Ciudad Real [107] Limb ischemic symptoms: acrops,
Pedo/axillary manifestation
21% (7) critically ill COVID-19 patients cyanosis, plantar plaques, dry gangrene,
with acromegaly [22] and blood blisters on the feet and hands.
Significant increase in D-dimer,
fibrinogen, prothrombin time,
hypercoagulation, and or disseminated
intravascular coagulation causing micro
thrombosis
J. Clin. Med. 2021, 10, 446 12 of 19

Previous studies showed cross-reaction of SARS-CoV-2 antigen and antibodies in

patients with rheumatoid arthritis, systemic sclerosis, and systemic lupus erythemato-
sus (SLE) [108] so there is the possibility of viral arthritis and musculoskeletal pain in
COVID-19 patients, possibly due to posttranslational modification of peptides, or molec-
ular mimicry activating T cells or epitope spreading due to T-cell associated damage by
the virus leading to autoreactive T cells. SARS-CoV-2 through the ACE2 receptor directly
infects the endothelial cell and facilitates the induction of endothelitis in several organs.
Diffuse endothelial inflammation by host inflammatory response results in the recruitment
of immune cells causing widespread endothelial dysfunction associated with apoptosis
and pyroptosis. This results in shifting of vascular endothelium equilibrium towards
vasoconstriction (microvascular dysfunction), resulting in inflammation with associated
tissue edema, and a procoagulant state explaining the systemic impaired microcirculatory
function in different vascular beds [109].
SARS-CoV-2 also directly attacks human epithelial cells of alveoli, large and small
arteries, small intestine, and vascular endothelial cells. Counteracting the innate immune
system activates and induces cytokine storms (IL-6) damaging the microvascular system. It
activates the coagulation system while inhibiting fibrinolysis and anticoagulation systems
that stimulate the liver to synthesize more thrombopoietin, fibrinogen leading to extensive
thrombosis in microvessels [110]. Antiphospholipid antibodies result in endothelial injury,
platelet activation, and thrombosis, with hypercoagulation. COVID-19 patients with high
D-dimer levels and hypercoagulable state were associated with sudden onset of oxygen
deterioration, respiratory distress, and reduced blood pressure resulting in pulmonary
thromboembolism (PTE) [111].

11. COVID-19 in Immunocompromised Solid-Organ Transplant Recipients

Solid-organ transplant (SOT) recipients are high-risk individuals, usually on im-
munosuppressive therapy. Interestingly, in 2003 SARS-CoV in 2003 and 2012 MERS-CoV
pandemic, SOT recipients did not appear to be associated with adverse outcomes. The
role of different immunosuppressive agents such as calcineurin inhibitors and intravenous
immunoglobulin (IVIG) in COVID-19 disease has not been established due to limited
data on COVID-19 in transplant recipients. The typical presentation of COVID-19 in SOT
recipients is the classic triad of fever, fatigue, and dry cough. A 75-year-old male and
a 52-year-old female at 120 and 8 months post-transplant, respectively were diagnosed
with stable graft function in males and AKI in females respectively. Extensive bilateral
ground-glass opacities were the common lung abnormality reported in both cases [112].
A case of a 50-year-old COVID-19 positive man with 3rd kidney transplant recipient
with IgA nephropathy induced end-stage renal disease manifested with the gastrointestinal
viral disease (3–5%) and fever, further progressing to respiratory symptoms in 48 h [113]. A
39-year-old diabetic dual-organ (heart/kidney) transplant recipient positive for COVID-19
had a mild clinical course with minimal supportive care with no evidence of any graft
rejection despite being on three immunosuppressive agents. The patient had additional
risk factors of hypertension, diabetes mellitus, and morbid obesity, lymphopenia, elevated
CRP, IL-6, D-dimer, and troponin I levels [114]. Li et al. [115] reported two heart transplant
recipients with COVID-19 from Wuhan, were successfully treated, and survived.

12. Co-Infections with COVID-19: Viral, Bacterial, and Fungal

Diagnosing co-infections is complex owing to the clinical conditions of the infected
patients [116]. During the 2003 SARS-CoV outbreak, invasive pulmonary aspergillosis
was reported in only 4 among the 8422 probable SARS cases [117]. The risk of develop-
ing invasive pulmonary aspergillosis in COVID-19 patients is high as described in France
where 9 out of 27 (33%) COVID-19 patients with invasive pulmonary aspergillosis admitted
to an intensive care unit (ICU) [118] and 5 in Germany (26% of 19 admitted) proved in
histopathology of autopsy [119]. Zhou et al. [120] showed that 50% of patients with COVID-
19 died due to secondary bacterial infections. Patients with chronic obstructive pulmonary
J. Clin. Med. 2021, 10, 446 13 of 19

disease (COPD) will have underlying chronic bacterial infections before SARS-CoV-2 in-
fection. Wang et al. [121] reported a case of a 37-year-old man, from Wuhan infected by
SARS-CoV-2 and human immunodeficiency virus (HIV) simultaneously, highlighting the
co-infection might damage T lymphocytes, impairing the immune system, B-cell dysfunc-
tion resulting in abnormal polyclonal activation and prolongation of the disease process
(2 months). Chest CT showing multiple infiltrations in both lungs while nasopharyngeal
swab positivity confirmed the SARS-CoV-2 infection, accompanied by dyspnea, chest pain,
and palpitation. The significant decrease in the total number of immune cells i.e., B cells,
T cells, and NK cells were also correlated with COVID-19 severity.

13. Advancements in Vaccine Research

As per the draft landscape of COVID-19 [122] dated 15 January 2021; 63 candidate
vaccines are in line with clinical evaluations with 13 vaccines currently at phase 3 trial. Two
mRNA vaccines i.e., 3LNP-mRNA by Pfizer-BioNTech and RNA LNP encapsulated mRNA
vaccine jointly by Moderna and National Institute of Health (NIH) demonstrated an efficacy
of 95% and were recently approved for the emergency use under the Emergency Use
Authorization (EUA) by the US Food and Drug Administration (FDA). Another promising
vaccine i.e., ChAdOx1 (chimpanzee adenovirus vaccine vector) with comparable efficacy
has been developed by AstraZeneca with Oxford University, which is a non-replicating
version of adenovirus containing the genetic sequence of surface spike protein which is
produced after vaccination and prime the immune system to attack against the SARS-CoV-2
viral infection.
The other important vaccine candidates undergoing clinical trials are the inactivated
SARS-CoV-2 vaccines (Vero cells) developed by Sinopharm in collaboration with China
National Biotec Group Corporation and Wuhan Institute of Biological Products, inactivated
SARS-CoV-2 vaccines by Sinovac Research and Development Co. Ltd., Beijing, China
and Gam-COVID-Vac Adeno-based (rAd26-S+rAdS-S) by Gamaleya Research Institute,
Moscow, Russia etc. and these are depicted in Figure 5. Recently, two vaccine candidates
were approved in India for clinical trials. Bharat Biotech International Limited devel-
oped an indigenous inactivated BBV152 (COVAXIN) COVID vaccine candidate with the
collaborative work of the National Institute of Virology and Indian Council of Medical
Research. The other one is ZyCov-D from Zydus Cadila, Ahmedabad, India which is
also promising. India is also working with FluGen, Madison, USA and the University of
Wisconsin-Madison, Madison, USA on an intranasal vaccine called CoroFlu with the S
gene of SARS-CoV-2 insertion, built on the backbone of M2sr, a self-limiting version of
influenza virus that induces immunity against COVID-19 and influenza (expressing H
protein), lacking the M2 gene by restricting the replication with one cycle only. Besides,
more than 173 vaccine candidates are in the pre-clinical stage. Considering the efforts, and
the preliminary results from the various studies, hopefully by early 2021 we may have an
approved effective vaccine available for human use to control the pandemic.
 consin-Madison, Madison, USA on an intranasal vaccine called CoroFlu with the S gene
of SARS-CoV-2 insertion, built on the backbone of M2sr, a self-limiting version of influ-
enza virus that induces immunity against COVID-19 and influenza (expressing H pro-
tein), lacking the M2 gene by restricting the replication with one cycle only. Besides, more
J. Clin. Med. 2021, 10, 446
than 173 vaccine candidates are in the pre-clinical stage. Considering the efforts, and the
14 of 19
preliminary results from the various studies, hopefully by early 2021 we may have an
approved effective vaccine available for human use to control the pandemic.

EUA Approval

CoronaVac
NVX CoV2373 (NCT04456595)
(NCT04368988) BNT 162
(NCT04368728)
AZD1222
(ISRCTN89951424
)
INO-4800
GX19 (NCT04336410)
(NCT04445389)

Inactivated
(ChiCTR2000034780)
BBIBP-CorV
mRNA-1273
SCB-2019 (ChiCTR2000034780)
(NCT04470427)
(NCT04405908)
Ad5-nCOV
(ChiCTR2000031781
LNP-nCoV SaRNA )
(ISRCTN17072692)
EUA Approval
Phase III

Figure 5. Landscape representation of COVID-19 vaccine candidates in phase III clinical trials: BNT162b2 and mRNA 1273
vaccines are in the forefront and have been granted the Emergency Use Authorization (EUA) status. Adeno based vaccine
by AstraZeneca is also the promising vaccines that may be soon approved for emergency use. Other COVID-19 vaccine
players are Sinovac Biotech. Ltd (Beijing, China), CasSin Biologics Inc. (Tianjin, China), Novavax (Maryland, US), Inovio
(San Diego, CA, US), Clover Biopharmaceuticals (Zhejiang, China), and GenNBio Inc. (Daegu, South Korea).

14. Conclusions
Since the emergence of COVID-19, the understanding of the clinical presentation of
this disease is that it evolves with extrapulmonary involvement. Limited but unusual
clinical cases involving the eyes, central nervous system, kidney, and liver suffice the
organotropism of SARS-CoV-2. The probable explanation is the ubiquitous presence of
ACE2 receptors in the various specialized cells of different organs which facilitates the
binding and entry of SARS-CoV-2 inside the different cells. Unrestricted viral replication
inside the cell releases the infectious virions from the cell resulting in cellular damage and
eliciting the cytokine storm. The COVID-19 extra-pulmonary manifestations such as acute
encephalitis in the brain, rashes on the dermis, acute renal and hepatic injury, conjunctivitis
in the eyes, blood clots in the blood vessels, and loss of smell and taste are attributed by
SARS-CoV-2. Understanding the different mechanisms causing organ-specific injury by
SARS-CoV-2 and the route through which the virus transfers to the different locations will
help the clinicians and scientists to design the treatment modality considering the critical
situation of the severe COVID-19 patients. Such patients admitted to ICUs need critical
monitoring of the functioning of different organs in addition to supportive oxygen therapy
and antiviral administration. This will ultimately help to reduce the mortality related to
COVID-19 induced acute respiratory distress syndrome and multiorgan failure until the
world finds an effective and FDA-approved COVID-19 vaccine.

Author Contributions: Conceptualization, V.T. and R.K.R.; Collection of information, V.T., R.K.R.,
P.K. and S.KS.; Planning, V.T., R.K.R., P.K., S.K.B. and S.M.; Writing-original draft preparation, V.T.,
R.K.R., I.B. and G.K.M.; Formal analysis, V.T., R.K.R., S.K.B., M.D., D.Y., and S.M.; Writing—review
and editing, V.T., R.K.R., S.KS., P.K., I.B., G.K.M., S.K.B., M.D., D.Y., and S.M.; Supervision, R.K.R.,
S.KS. and S.K.B. All authors have read and approved the final submitted version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: The authors’ would like to thank the administrative support from the Depart-
ment of Virology, PGIMER, Chandigarh.
J. Clin. Med. 2021, 10, 446 15 of 19

Conflicts of Interest: The authors declare no conflict of interest in the submitted manuscript.

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