Expert Review of Anti-infective Therapy

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierz20

An update on COVID-19 pandemic: the

epidemiology, pathogenesis, prevention and
treatment strategies

Hin Fung Tsang, Lawrence Wing Chi Chan, William Chi Shing Cho, Allen Chi
Shing Yu, Aldrin Kay Yuen Yim, Amanda Kit Ching Chan, Lawrence Po Wah
Ng, Yin Kwan Evelyn Wong, Xiao Meng Pei, Marco Jing Woei Li & Sze-Chuen
Cesar Wong

To cite this article: Hin Fung Tsang, Lawrence Wing Chi Chan, William Chi Shing Cho, Allen
Chi Shing Yu, Aldrin Kay Yuen Yim, Amanda Kit Ching Chan, Lawrence Po Wah Ng, Yin Kwan
Evelyn Wong, Xiao Meng Pei, Marco Jing Woei Li & Sze-Chuen Cesar Wong (2020): An update on
COVID-19 pandemic: the epidemiology, pathogenesis, prevention and treatment strategies, Expert
Review of Anti-infective Therapy, DOI: 10.1080/14787210.2021.1863146

To link to this article: https://doi.org/10.1080/14787210.2021.1863146

Published online: 29 Dec 2020. Submit your article to this journal

Article views: 3505 View related articles

View Crossmark data Citing articles: 7 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ierz20
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY
https://doi.org/10.1080/14787210.2021.1863146

REVIEW

An update on COVID-19 pandemic: the epidemiology, pathogenesis, prevention

and treatment strategies
Hin Fung Tsanga, Lawrence Wing Chi Chana, William Chi Shing Cho b, Allen Chi Shing Yuc, Aldrin Kay Yuen Yimc,
Amanda Kit Ching Chand, Lawrence Po Wah Ngd, Yin Kwan Evelyn Wonga, Xiao Meng Peia, Marco Jing Woei Lic
and Sze-Chuen Cesar Wonga
a
Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong Special Administrative Region; bDepartment of
Clinical Oncology, Queen Elizabeth Hospital, Hong Kong Special Administrative Region; cDepartment of Research, Codex Genetics Limited, Hong
Kong Special Administrative Region; dDepartment of Pathology, Queen Elizabeth Hospital, Hong Kong Special Administrative Region

ABSTRACT ARTICLE HISTORY

Introduction: To date, the transmission of Coronavirus Disease-2019 (COVID-19) is still uncontrollable with Received 12 July 2020
the fact that the numbers of confirmed and death cases are still increasing. Up to 1st October 2020, 33,842,281 Accepted 4 December 2020
confirmed cases and 1,010,634 confirmed deaths have been reported to the World Health Organization from KEYWORDS
216 different countries, areas and territories. Despite the urgent demand for effective treatment strategies, COVID-19; SARS-CoV-2;
there is still no specific antiviral treatment for COVID-19 and the treatment guidelines for COVID-19 vary coronavirus Disease-2019;
between countries. severe acute respiratory
Area covered: In this article, we summarized the current knowledge on COVID-19 and the pandemic syndrome coronavirus 2;
worldwide. Moreover, the epidemiology, pathogenesis, prevention and different treatment options will novel coronavirus; COVID-19
be discussed so that we shall prepare ourselves better to fight with severe acute respiratory syndrome management; COVID-19
treatment
coronavirus 2 (SARS-CoV-2).
Expert opinion: The situation of the COVID-19 pandemic is still unpredictable. There is no effective
vaccine or specific anti-viral drug to treat serve COVID-19 patients. Combination therapies have shown
promising clinical improvement. Repurposing FDA-approved drugs might be one of possible treatment
options. Without specific treatment and vaccines for COVID-19, the most effective way to prevent from
being infected is to generate an ecosystem with effective protection, precautions and preventive
measures.

1. Introduction 2. Epidemiology

An outbreak of an atypical pneumonia caused by a novel corona­
virus was reported in Wuhan, in Hubei Province of China in
December, 2019 [1,2]. The International Committee on
Taxonomy of Viruses (ICTV) and World Health Organization
(WHO) later named this coronavirus and the disease caused by
this virus as severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) and Coronavirus Disease-2019 (COVID-19). Patients
suffering from SARS-CoV-2 infection usually presented with fever,
dry cough, upper airway congestion, sputum production, and
shortness of breath, but rarely headache, hemoptysis, and diarrhea
[3,4]. Loss of smell (anosmia) and loss of taste (ageusia) have also
been reported [5]. According to the statistics from WHO,
33,842,281 confirmed cases and 1,010,634 confirmed deaths
have been reported as of October 1, 2020 [6]. Despite the urgent
need of effective treatment strategies, still, there is no specific
antiviral treatment for COVID-19 currently and the treatment
guidelines for COVID-19 vary between countries. In this paper,
we summarized the currently available data on COVID-19. Our
goal is to discuss the epidemiology, pathogenesis, prevention,
and different possible treatment options of COVID-19 for better
acknowledgment of this newly found coronavirus – SARS-CoV-2.
In late December 2019, the first COVID-19 patient was identi­
fied in Wuhan, Hubei Province, China and the first cluster of
COVID-19 patients was epidemiologically related to the
Wuhan wet animal wholesale market [7]. COVID-19 was then
spreading rapidly to other provinces and countries including
Japan, Korea, and Thailand. As a result, Asia became the first
outbreak continent whereas China occupied the majority
COVID-19 confirmed cases and death around the world. After
variable transmission routes, including international convey­
ance transmission via cruise ship and airplane, local transmis­
sion and community transmission, other continents, such as
Europe and the United States of America (USA) have followed.
On March 19, 2020, the data of WHO showed that the total
number of confirmed deaths in Italy (3,407) exceeded those in
China (3,253) [8]. On March 28, 2020, the number of confirmed
cases of COVID-19 in the USA (85,228) exceeded China
(82,213) and the USA became the country with the largest
number of confirmed cases among the world [9]. On May 5,
2020, WHO data reported that 3,525,087 cases were confirmed
and 248,913 people died around the world. One month later,
on June 5, 2020, the numbers climbed to 6,535,354 COVID-19

CONTACT Sze-Chuen Cesar Wong cesar01@netvigator.com Department of Health Technology and Informatics, Hong Kong Polytechnic University,
Hong Kong Special Administrative Region
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 H. F. TSANG ET AL.
Article highlights
● Genetic sequence of SARS-CoV-2 showed 80% identical to SARS-CoV
and 50% to MERS-CoV.
● Angiotensin-converting enzyme (ACE) 2 has been identified as the
receptor molecule for the cellular entry of SARS-CoV-2. ACE2-positive
cells are the target cells and are susceptible to SARS-CoV-2 infection.
● Cytokine storm in COVID-19 patients initiates inflammatory-induced
lung injury with deadly complications. Deaths mainly result from
acute respiratory distress syndrome (ARDS), acute respiratory failure,
coagulopathy, septic shock, metabolic acidosis, and cardiovascular
complications.
● Despite the urgent need of effective treatment strategies, still, there
is no specific antiviral treatment for COVID-19 currently and the
treatment guidelines for COVID-19 vary among countries.
● Combination treatment has been encouraged as part of the manage­
ment of critical COVID-19 patients in this pandemic. Repurposing
FDA-approved drugs might be one of the possible treatment options.
confirmed cases and 387,155 confirmed deaths worldwide
[10]. Among those reported cases, 1,837,803 confirmed cases
and 106,876 deaths were reported in the USA and it has
become the country with the greatest number of infection
and deaths due to COVID-19. Concerning the global trend of
COVID-19, the numbers of confirmed case and death keep
growing significantly. On 10 July 2020, there were 12,102,328
confirmed cases and 551,046 confirmed deaths reported to
WHO. The numbers of confirmed cases and confirmed death
have increased by 1.85 and 1.42-fold, in one month, respec­
tively and 3.43 and 2.21-fold in 2 months, respectively. Till
now, as of October 1, 2020, the numbers of confirmed cases
and confirmed deaths reported to WHO were 33,842,281 and
1,010,634, respectively.
Wang et al. showed that the first outbreak spreading rapidly
from Wuhan to whole Mainland China may be related to the
conveyance transmission. As Wuhan is one of the transportation
hubs in China, it allowed millions of people to leave the city and
spread the virus during the Spring Festival travel rush [11].
International conveyance transmission via cruise ship and airplane
played an important role in the second outbreak from Mainland
China to the Asia and then other continents. Person-to-person
spread is the main mode of transmission [12] as respiratory droplets
with SARS-CoV-2 can be sneezed and coughed out by an infected
person. These droplets can enter the lungs via inhalation, and
infecting people nearby. Besides the person-to-person spreading,
environmental contamination is another way to spread the virus.
For instance, it is known that COVID-19 can be spread indirectly if
a non-infected person touches the objects contaminated with
infectious droplets and then his own eyes, mouth, and nose. SARS-
CoV-2 can remain stable and infectious in aerosols for hours. On the
surfaces made of plastic or stainless steel, they can remain stable up
to days [13,14]. Therefore, this is one of the possible reasons
associated with nosocomial spread and super-spreading events.
The median incubation period of COVID-19 was estimated to
be 5.1 days (95% CI: 4.5 to 5.8 days) among 181 confirmed cases,
and 97.5% people developed symptoms within 11.5 days (95% CI:
8.2 to 15.6 days) of infection in the study performed by Lauer et al.
Approximately 1% of infected people developed symptoms after
14 days quarantine [15]. The mean serial interval of COVID-19
which present the time duration between a primary case patient
(infector) having symptom onset and a secondary case patient
(infectee) having symptom onset was estimated to be 3.96 days
(95% CI: 3.53–4.39 days). Base on the fact that the estimated mean
serial interval of COVID-19 was found to be shorter than the mean
incubation period, pre-symptomatic transmission is likely to take
place [16,17]. The people with symptoms are a source of infection
whereas those asymptomatic people can act as the hidden sources
of COVID-19 [18]. The basic reproduction number (R0) is a central
concept in infectious disease epidemiology indicating the risk and
the transmissibility of an infectious agent. If R0 is greater than 1, the
infected number is likely to increase exponentially and could lead
to epidemic or pandemic. However, if R0 is less than 1, the trans­
missibility of the virus is minimized and no longer invasive. The
estimated R0 of SARS-CoV-2 obtained by different studies ranged
from 1.4 to 6.49, and the mean of the R0 is 3.28, which is slightly
higher than that of SARS-CoV (R0 at 2 to 5) and the WHO estimate
at 1.95 [19–22].
The worldwide case fatality rate of COVID-19 was found to be
3.4%, which is higher than that of seasonal influenza. The male to
female case fatality ratio was elevated through all age groups [23].
In a study conducted in Italy and China, the age-specific fatality
rate was found to be 0–9 years old (0%); 10–19 years old (0–0.2%);
20–29 years old (0–0.2%); 30–39 years old (0.2–0.3%); 40–49 years
old (0.4%); 50–59 years old (1.0–1.3%); 60–69 years old (3.5–3.6%);
70–79 years old (8.0–12.8%) and 80 years old or above (14.8%-
20.2%) [24]. Deaths mainly result from acute respiratory distress
syndrome (ARDS), acute respiratory failure, coagulopathy, septic
shock, metabolic acidosis, and cardiovascular complications [23].
To compare the mortality rate in different countries where exceed
50,000 confirmed cases, France shows the highest mortality rate,
13.38%, and Germany shows the lowest mortality rate, 1.94% [10].
The cumulative incidence varies in different countries depends on
many factors such as population density and demographics, and
timing of mitigation strategies. However, for the cumulative mor­
tality varies, it may relate to hygiene awareness and healthcare
system overload or personal health status.
Personal health status includes age and underlying diseases
which will also lead to variant mortality rate. Although a thorough
analysis of the underlying causes is lacking, studies from China and
European countries displayed sexual dimorphism with regard to
detected cases and case fatality rate of COVID-19 – 73% infected
people were male and the median age was 49 years old; comor­
bidity was also observed, as 32% of those people are suffering
underlying disease, such as diabetes, hypertension, and cardiovas­
cular diseases [25]. Reports from Italy also suggested that aged
≥60 years, particularly aged ≥80 years and the presence of under­
lying health conditions are risk factors for severe COVID-19 [26].
Potential causes leading to the sex differences in incidence
include differences in the regulation of hormone-regulated expres­
sion of genes encoding angiotensin-converting enzyme (ACE) 2
and the host type 2 transmembrane serine protease (TMPRSS2),
which are necessary for SARS-CoV-2 to enter target cells, differ­
ences in immune responses to viral infection and different beha­
viors. Reports indicated that circulating levels of ACE2 are higher in
males as compared to females. A higher tissue expression of ACE2
has also been observed in Asian males as compared to females
[23]. The difference in the levels of sex hormones between male
and female could explain the difference in ACE2 expression as

increasing evidence shows that sex hormones, such as estrogen,
are involved in the regulation of the renin angiotensin aldosterone
system (RAAS), including ACE2 [23]. Stelzig, et al. reported that
estrogen can regulate the expression of ACE2 in differentiated
airway epithelial cells [27,28]. In terms of the immune responses,
reports showed that females exhibit higher inflammatory immune
responses as well as adaptive immune responses as compared to
male during viral infections. Females generally exhibit greater
humoral and cell-mediated immune responses to antigenic stimu­
lation. The number and activity of innate immune cells such as
monocytes, macrophages, dendritic cells and cytotoxic T cells are
also higher in females than in males. Studies also reported that
estrogen has a protective anti-inflammatory effect against corona­
viruses by inhibiting most proinflammatory cytokines, such as IL-1
and IL-6. Differences in behaviors and activities such as higher
smoking and drinking rates, low rates of hand washing and
delayed healthcare seeking in males may also contribute to the
sex differences in the incidence of COVID-19 [23].
From February 12 to March 28, 2020, the U.S. states report
also showed the relationship between the underlying health
conditions and severe outcomes, people who required inten­
sive care unit (ICU) admission is 78% while patients suffering
from at least one underlying health condition and requiring
hospitalization without ICU admission is 71%. Both of them
are more than the people who were not hospitalized (27%).
The most commonly reported conditions were cardiovascular
diseases, chronic lung diseases and diabetes mellitus [29].
Common symptoms of COVID-19 include cough (76%),
fever (98%) and myalgia or fatigue (44%) [25]. Less common
symptoms were sputum production (28%), headache (8%),
hemoptysis (5%) and diarrhea (3%) [25]. More than 50%
patient will develop dyspnea and the median time from illness
onset to dyspnea is 8.0 days [25]. Regarding the laboratory
abnormalities of COVID-19 patients, from a systemic review of
19 studies which involved 2,874 patients, mainly from China,
the blood counts of patients showed lymphopenia (83%).
Prolonged prothrombin times (>5%), mild thrombocytopenia
(~30%) and elevated D-dimer values (43–60%) were also
observed. Serum alanine aminotransferase level (~25%), aspar­
tate aminotransferse level (~33%), lactate dehydrogenase (~­
50–60%) and C-reactive protein (>60%) were elevated [30].
However, serum procalcitonin levels were normal in most
patients in another study [25].
3. Pathogenesis
SARS-CoV-2 is a new strain of β-coronavirus from group 2B classi­
fied by phylogenetic analysis. SARS-CoV-2 is enveloped, positive-
sense, single-stranded RNA virus [7]. The genome of SARS-CoV-2
comprises 29,891 nucleotides that encode 9,860 amino acids. Non-
structural proteins (NSPS) are encoded by 5ʹ-untranslated region
(5ʹ-UTR) and open reading frame (orf1/ab) for replication-
transcription complex (RTC) formation in double membrane vesi­
cles (DMVs). Accessory proteins and 3ʹ-untranslated region (3ʹ-UTR)
are also involved. Structural proteins include spike (S), envelop (E),
membrane (M) and nucleocapsid (N) proteins [2,31]. Receptor-
binding domain (RBD) in S1 subunit of S protein showed important
role for direct host entry [2]. M protein helps to shape the virions
and bind nucleocapsid. E protein involves in viral pathogenesis
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 3
through virus assembly and release. N protein packs the encapsi­
dated genome into virions [31]. Orf3b, which is one of the
N proteins, shown as IFN-β activities antagonist in synthesis and
signaling, which is beneficial for viral replication [2,31].
The genetic sequence of SARS-CoV-2 showed 80% identical
to SARS-CoV and 50% to MERS-CoV [7]. Whether SARS-CoV-2 is
originated from bats or transmitted through pangolins as the
intermediate host to humans is still questionable. The evi­
dence from the phylogenetic study has indicated that SARS-
CoV and MERS-CoV are originated from bats and infect wild
animals as the intermediate host to infect humans [7].
Pangolin was suspected to be the intermediate host as the
coronavirus genetic sequences from animals showed 99%
similarity to those from infected humans during the outbreak.
Three viral nucleic acid sequence shared more than 80%
resemblance to SARS-CoV-2 in Rhinolophus genus have also
been observed [32–35]. However, hypothesis of intermediate
host involvement remains to be confirmed as the ACE2 can be
expressed in wild range of animal species [35].
ACE2 is a membrane-bound protein that plays important role in
the renin angiotensin aldosterone system (RAAS) and it expresses
in different organs in humans, including the cardiovascular system,
adipose tissues, gastrointestinal tract, kidneys, the central nervous
system, and the lungs. Inhibition of ACE2 could reduce the clear­
ance of harmful molecules such as angiotensin II as well as the
production of anti-inflammatory and pro-regenerative molecules
such as angiotensin 1–7 [34]. Previous studies showed the protec­
tive effect of ACE2 against ARDS in animal models. ACE2 has been
identified as the receptor molecule for the cellular entry of SARS-
CoV-2. Therefore, ACE2-positive cells are the target cells and are
susceptible to SARS-CoV-2 infection. In human tissues, ACE2 has
the highest expression in the small intestine, testis, kidneys, heart,
thyroid and adipose tissue, whereas it has the lowest expression in
the blood, spleen, bone marrow, brain, blood vessels and muscle.
Medium expression of ACE2 were found in the lungs, colon, liver,
bladder, and adrenal gland [36]. Thus, expression of ACE2 is con­
nected to the symptoms of COVID-19 patients. Patients with SARS-
CoV-2 infection showed primarily respiratory system abnormalities
such as cough, sore throat, shortness of breath, and pneumonia.
Some patients may also suffer from digestive system symptoms
such as diarrhea, nausea, poor appetite, vomiting, and abdominal
pain. SARS-CoV-2 RNA was detected in stool in 48.1% of patients
during the course of illness, indicating the possibility of fecal
aerosol transmission of SARS-CoV-2 [37,38]. In the lungs, ACE2
mainly expressed in bronchial transient secretory cells or type 2
alveolar cells [35].
COVID-19 progression can be divided into three phases: early
infection phase involving viral replication and mild symptoms;
pulmonary phase involving adaptive immunity stimulation and
predominance of respiratory symptoms; and hyperinflammation
phase involving hyperinflammatory conditions such as ARDS.
Recognition of each phase might be crucial in making appropriate
clinical decision in COVID-19 management.
3.1. First phase (early phase of infection)
During the early phase of infection, SARS-CoV-2 infiltrates the
lung parenchyma and starts proliferation. ACE2 and TMPRSS2
play crucial roles in cellular entry of SARS-CoV-2, similar to that
4 H. F. TSANG ET AL.
of SARS-CoV [1]. The S1 subunit of the spike protein attaches
to cellular ligand ACE2 on the host cell surface. Cellular pro­
tease priming by TMPRSS2 facilitates S1/S2 subunit cleavage
of spike protein and the S2ʹ subunit allows the fusion of the
virus through the host cell membranes [1]. Coronavirus gen­
ome replication and transcription take place at cytoplasmic
membranes after cell entry. The replicase complex mediates
the continuous and discontinuous synthesis of RNA, 16 viral
subunits and numbers of cellular proteins were then gener­
ated. Unlike other RNA viruses, the replicase complex only
presented in SARS-CoV-2 for numbers of RNA processing
enzymes employment, including putative sequence-specific
endoribonuclease, 3ʹ -to- 5ʹ exoribonuclease, 2ʹ-O-ribose
methyltransferase, ADP ribose 1ʹ- phosphatase etc [32].
Budding from the host cell is presented when replicated
RNA is incorporated into virions [32]. This phase is character­
ized by the presence of mild constitutional symptoms and
initial response by innate immune system.
The synthesis of type I interferons (IFN) is activated after
viral invasion, promoting downstream JAK-STAT signal path­
way for increased expression of IFN-stimulated genes (ISGs).
Spreading of the virus is restricted by antigen-presenting
macrophage and NK cells [39,40]. Blocking of IFN production
by the N protein of SARS-CoV is important for viral survival
directly [39,40]. The prolonged incubation period of viral infec­
tion effectively helps the virus escape from the innate immune
response at early stage of infection theoretically [35]. Innate
immune responses of type I IFN and monocyte-macrophages
need to be further investigated in COVID-19 patients, as the
dysregulated innate immune response caused lethal pneumo­
nia in young SARS-CoV-2-infected patients [35]. In adaptive
immunity, Th1 type immune response is important to virus
clearance. Helper T cells activate T-dependent B cells for viral-
specific antibodies promotion. Cytotoxic T cells kill virus-
infected cells directly. Particularly, helper T cells promotes NF-
kB signaling pathway for proinflammatory cytokines introduc­
tion [40]. Limited serology study showed the neutralization
effect in Vero E6 cells with 5 COVID-19 patient sera that
were IgG-positive. All patient sera were able to neutralize
100 TCID50 (50% tissue-culture-infective dose) of COVID-19
in titer 1:40 through 1:80 [33].
3.2. Second phase (pulmonary phase)
Pulmonary phase is characterized by the presence of inflam­
matory response, tissue damage, and respiratory failure. The
viral entry in human lung tissues induced mild upper respira­
tory tract dysfunction in most cases [35]. Scientists believed
that viral replication and budding triggers type 2 alveolar cells
to undergo apoptosis and epithelial regeneration of cells,
similar to that of SARS-CoV. Although matches the Berlin
definitions of serve state, COVID-19 induced respiratory failure
showed different features from that of typical ARDS. ARDS is
a complex clinical syndrome of acute respiratory failure devel­
oped from non-cardiogenic pulmonary edema. Bacterial and
viral pneumonia are the most common clinical disorders asso­
ciated with the development of ARDS. In brief, inflammatory
pathways are activated when the lung is injured by infection
or inflammatory conditions. Excessive levels of cytokines are
present. Development of oxidative stress as well as the pre­
sence of dysregulated and excessive inflammation cause
alveolar cell damage and necrosis [41]. Increased endothelial
and epithelial permeability results in the accumulation of
protein-rich alveolar edema fluid. Alveolar barrier function
and osmotic gradient that drives alveolar fluid clearance are
disrupted. Cell necrosis and edema fluid accumulation trigger
more pronounced inflammatory and immune response. The
accumulation of pulmonary edema fluid in the interstitium
and air space of the lung causes impaired gas exchange,
resulting in hypoxemia, impaired carbon dioxide excretion,
and acute respiratory failure [42]. Approximately 20% of the
infected patients developed hypoxia, ground glass infiltrate
and ARDS, leading to multiple organ failure. Severe scarring
and fibrosis of the lung cells are observed [39]. Diffuse alveolar
damage with fibrin rich hyaline membrane and a few multi­
nucleated giant cells are presented. Reduced ability of epithe­
lium repairing and mucociliary clearance in elderly deteriorate
the condition quickly, and eventually death [39].
3.3. Third phase (hyperinflammation phase)
Hyperinflammation phase is characterized by the presence of
systemic inflammation and damage of distant organs as
a result of the increased host inflammatory response and
hypercoagulable state, resulting in multiorgan failure (MOF).
High leukocyte number with lymphopenia and increased
levels of plasma pro-inflammatory cytokines were observed,
especially higher levels of IL-2, IL-6, IL-7, IL-10, C-reactive
protein (CRP), granulocyte-colony stimulating factor (G-CSF),
interferon-gamma inducible protein (IP) 10, monocyte che­
moattractant protein (MCP) 1, macrophage inflammatory pro­
tein (MIP) 1α, and tumor necrosis factor (TNF) α in COVID-19
patients with severe condition [7,35]. These ‘Cytokine storm’
initiates inflammatory-induced lung injury with life-
threatening complications such as MOF, ARDS, septic shock,
hemorrhage/coagulopathy, acute heart/liver/kidney injury,
and secondary bacterial infections. This phenomenon is similar
to the situation in SARS-CoV and MERS-CoV infections [35].
Studies showed that progesterone-based compounds can
affect immune responses and susceptibility to infections at
diverse mucosal sites such as genital, gastrointestinal, and
respiratory tract by altering cellular signaling and activity,
which in turn affect the outcome of infections. These com­
pounds can reduce inflammation by inhibiting the production
of proinflammatory cytokines and increasing the production
of anti-inflammatory cytokines during viral infection and pro­
mote repair of damaged respiratory epithelium. The difference
in the levels of sex steroids may affect different course and
outcome of COVID-19 in males and females [43].
4. Treatment Strategies
There are some potential treatments for COVID-19 such as
immunotherapy, cellular therapy, antiviral therapy and
Chinese herbal medicine. However, all of them are still under
development or investigation and the treatment guidelines for
COVID-19 vary between countries. As both MERS-CoV and
SARS-CoV are β-coronaviruses which are closely linked to
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 5

SARS-CoV-2, they present similar properties. Most of the treat­
ment ideas of COVID-19 are coming from previous therapy
researches of MERS and SARS. Figure 1 shows the summary of
the potential therapies of COVID-19.
4.1. General treatments
General treatments include supportive treatments and taking
rest. These actions make sure the sufficient daily energy intake
and monitor the vital signs such as oxygen saturation, respira­
tory rate, and heart rate [19]. As for patients with mild COVID-
19, symptomatic treatment such as antipyretics for fever and
pain, adequate nutrition, and rehydration are recommended
by the WHO. However, antibiotic therapy or prophylaxis is not
recommended, as widespread use of antibiotics may lead to
higher resistance rate and increase the burden of disease and
deaths during COVID-19 pandemic [44–46]. If patients are
suffering refractory hypoxemia, WHO recommends the extra­
corporeal membrane oxygenation (ECMO) for them [44–46].
4.2. Anti-inflammatory agents
progression to respiratory failure and death. In a controlled,
open-label trial that involved 9,355 patients hospitalized with
COVID-19, the use of dexamethasone reduced 28-day mortal­
ity in patients receiving respiratory support, either invasive
mechanical ventilation, or oxygen. However, there was no
evidence demonstrating that the use of dexamethasone
alone without respiratory support could provide benefit
among COVID-19 patients [45]. However, several systematic
reviews and meta-analysis of the impact of corticosteroids
therapy on SARS, MERS and COVID-19 patients revealed no
significant reduction of the risk of death as well as hospitaliza­
tion duration. Due to inadequate evidence of effectiveness
and the possible harm of corticosteroids therapy, WHO recom­
mended routine corticosteroid therapy should be avoided
unless indicated for other reasons such as the present of
chronic obstructive pulmonary disease (COPD), septic shock
or ARDS. Antenatal corticosteroid therapy is recommended for
women at risk of preterm birth from 24 to 34 weeks with no
clinical evidence of maternal infection as well as adequate
childbirth and newborn care. Clinicians should balance the
potential benefits and harm when considering corticosteroids
for patients with COVID-19 [46].

4.2.1. Glucocorticoids
COVID-19 is associated with dysregulated and excessive 4.2.2. Tocilizumab
inflammation, resulting in diffuse lung damage. SARS-CoV-2 infection induces excessive cytokine release, followed
Glucocorticoids have been used in syndromes similar to by lung injury and results in COVID-19. Elevated serum interleukin-
COVID-19, such as SARS, Middle East respiratory syndrome 6 (IL-6) level is associated with worse outcome in COVID-19
(MERS), severe influenza, and community-acquired pneumo­ patients. Tocilizumab is a recombinant-humanized monoclonal
nia. Systemic or locally administration of glucocorticoids may antibody targeting both soluble and membrane-bound forms of
modulate inflammation-mediated lung injury and reduce IL-6 receptor. Tocilizumab is recommended for the treatment of

Anti-virial therapy Anti-inflammatory agents

Lopinavir/ritonavir Interferons Glucocorticoids Tocilizumab

Chloroquine and
Remdesivir
hydroxychloroquine
Coronavirus
Disease 2019
(COVID-19)
Convalescent Natural compounds Mesenchymal stem
plasma therapy
(e.g. herbal medicine, hormones) cell treatment

Immuotherapy Adjunctive therapy

Figure 1. Summary of potential therapies of COVID-19. In adition to general treatment by extracorporeal membrane oxygenation (ECMO), different potential
treatments for serve COVID-19 patients, including anti-viral therapy, anti-inflammatory therapy, immunotherapy and adjunctive therapy have been proposed. The
effectiveness and clinical benefits of these therapies on COVID-19 are still under investigation.
6 H. F. TSANG ET AL.
severe rheumatoid arthritis, systemic juvenile idiopathic arthritis,
giant cell arthritis, and life-threatening cytokine release syndrome.
It is proposed that treatment with tocilizumab might have a clinical
benefit because of its anti-IL-6 nature. In a multicentre, retrospec­
tive study (n = 544), patients treated with tocilizumab, either
administered intravenously or subcutaneously, could reduce the
risk of invasive mechanical ventilation or death [47]. In another
study (n = 100), patients treated with tocilizumab (8 mg/kg intra­
venous infusions 12 h apart for 2 days) showed significant clinical
improvement in respiratory condition [48]. However, in a meta-
analysis that assessed the efficacy of tocilizumab for the treatment
of severe COVID-19, there is no conclusive evidence that treatment
with tocilizumab would provide additional benefit to patients
with severe COVID-19. Therefore, the effects on clinical out­
comes of tocilizumab in the treatment of COVID-19 remain to
be determined [49].
4.3. Antiviral therapy
4.3.1. Chloroquine and Hydroxychloroquine
Chloroquine is a drug that is commonly used in autoimmune and
antimalarial diseases. Wang et al. reported that chloroquine can be
a potential drug to suppress the COVID-19 effectively in vitro [11].
Chloroquine was found to be effective against many viruses
including coronaviruses and dengue virus. It can increase endoso­
mal pH that prevents virus or cell fusion to block the viral infection,
and induce phospholipidosis, leading to the accumulation of bis­
(monoacylglycero)phosphate (BMP). It is believed that the com­
bined effects of chloroquine on endosomal pH as well as the
accumulation of BMP may result in the impairment of SARS-CoV
-2 endosomal:lysosomal trafficking [50]. Moreover, chloroquine
can inhibit the acidic proteases involved in the maturation of
virus fusion protein and has been shown that chloroquine can
interfere the glycosylation of the cellular receptors in SARS-CoV.
Besides the antiviral ability, it also owns the immune-modulating
ability to enhance the antiviral effect synergistically [51]. Gao et al.
demonstrated that chloroquine treatment is superior in stopping
the exacerbation of pneumonia, improving lung imaging, and
shortening the disease course compared with the control treat­
ment [52]. However, in light of the cardiovascular toxicity and other
safety concerns of chloroquine, the usage of the chloroquine in
therapies is limited. As a result, an alternative compound called
hydroxychloroquine is proposed. Hydroxychloroquine is proposed
to control the cytokine storm in COVID-19 patients. It is slightly
different from chloroquine, but it shows better tolerability than
chloroquine and it is already a long-term usage in patients with
rheumatological disorders [53]. In a clinical trial, azithromycin was
reported to enhance the efficacy of hydroxychloroquine in the
treatment of serve COVID-19 patients [54]. However, the efficacy
of the regimen of hydroxychloroquine in combination with azi­
thromycin in COVID-19 treatment has been questioned by several
large clinical studies recently [55,56] and it is no longer recom­
mended as treatment or prophylaxis for COVID-19 by the
WHO [46].
4.3.2. Type 1 interferons (IFN–I)
Type 1 interferons (IFN–I) are a group of cytokines secreted by
various cell types, depending on the viral components recog­
nition via pattern recognition receptors (PRR). IFN-I are the
cytokines that first produced during viral infection. Interferon
Alpha/Beta receptors (IFNAR) on the plasma membrane recog­
nize IFN-I and induce the phosphorylation of transcriptional
factors such as STAT1. Interferon-stimulated genes (ISG) will be
activated if factors re-localize to nucleus. ISG play important
role in signaling, inflammation and immune-modulation pro­
cess. Therefore, they will interfere the replication of virus and
spread through several mechanisms. For instance, the cell
metabolism will be slow down or adaptive immunity will be
activated by cytokine secretion. ISGs encode PRRs which will
further sensitize the cell to pathogens and lead to membrane
fluidity minimization which can prevent the viral egress or
membrane fusion. IFN-I occupies the majority part of antiviral
immunity [57]. IFN-1 is effective in administration after infec­
tion shortly. However, it cannot inhibit replication of virus and
has some side effects when administered later.
4.3.3. Lopinavir/ritonavir (Kaletra)
Lopinavir/ritonavir (LPV/RTV) is a combination of protease inhibi­
tors used to interfere the replication and synthesis of human
immunodeficiency virus (HIV). Only immature and noninfectious
virus can be produced under the action of LPV/RTV. Thus, it was
proposed to be used to inhibit the viral protein synthesis of SARS-
CoV-2 in COVID-19 patients although coronaviruses encode
a different enzymatic class of protease. In a case reported by Lim
et al., after the usage of LPV/RTV, the viral load of SARS-CoV-2 was
significantly reduced and the clinical symptoms were improved
during the treatment [58]. However, from another randomized,
controlled, open-label trial in adults hospitalized with severe
COVID-19, Cao et al. found that there were no observable treat­
ment benefits beyond standard care when LPV/RTV was used
alone [59]. In another randomized, controlled, open-label, platform
trial that involved 7,825 patients hospitalized with COVID-19,
a randomized comparison between lopinavir-ritonavir (lopinavir
400 mg plus ritonavir 100 mg orally every 12 hours for 10 days) and
usual care was performed. Results showed that lopinavir-ritonavir
is not an effective treatment for COVID-19 patients. Allocation to
lopinavir-ritonavir did not reduce the duration of hospital stay or
28-day mortality. Lopinavir-ritonavir monotherapy does not
improve clinical outcomes for patients hospitalized with COVID-
19 [60].
4.3.4. Remdesivir
Remdesivir is a broad spectrum anti-viral drug that has been
shown to inhibit SARS-CoV-2, both in vitro and in vivo. It is one
of the possible direct anti-viral medication against SARS-CoV-2
that has been approved by several regulatory offices globally.
In a double-blind, randomized, placebo-controlled trial that
involved 1,062 patients hospitalized with COVID-19, patients
were randomly assigned to receive either remdesivir (200 mg
on day 1, followed by 100 mg daily for up to 9 additional days)
or placebo for up to 10 days. Remdesivir was shown to be
superior to placebo by shortening the time to recovery.
Patients who received remdesivir in the study had a median
recovery time of 10 days (95% CI: 9 to 11 days) whereas those
who received placebo had a median recovery time of 15 days
(95% CI: 13 to 18 days) [61]. However, several studies have
demonstrated that remdesivir is optimally suit for viral pro­
phylaxis or initiation before the peak viral replication. Initiation

of remdesivir following peak viral replication would be unable
to affect disease severity or mortality [62–64].
4.3.5. Combination treatment
Although the clinical efficacy of the above antiviral drugs against
SARS-CoV-2 is still under investigation, these antiviral drugs are
potential treatment for COVID-19. A multi-center randomized
phase 2 trial in patients with COVID-19 showed that early treat­
ment with a triple combination of interferon beta-1b (8 million
international units [IU]), lopinavir-ritonavir (lopinavir 400 mg and
ritonavir 100 mg), and ribavirin 400 mg can effectively suppress the
viral load of SARS-CoV-2 and shorten the hospital stay in patients
with mild to moderate COVID-19 [65]. However, further evaluation
for the drug efficacy in patient, potential interaction with different
therapeutic drugs and any adverse reactions for the antiviral drugs
are still in process [19].
4.4. Cellular therapy
4.4.1. Mesenchymal stem cells (MSCs)
Mesenchymal stem cells can be isolated from peripheral blood,
umbilical cord blood and placenta. It has strong anti-inflammatory
and immune-modulatory functions that can suppress the infiltra­
tion of immune cells into lung tissues and pro-inflammatory cyto­
kine secretion to improve the lung injury and ARDS. Moreover, it
also enhances tissue repair and reduces lung fibrosis.
COVID-19 can cause immune overreaction in the body as well
as cytokine storm syndromes that indicate the production of
a large number of inflammatory factors in immune system. Apart
from routine antiviral treatment, MSCs can also treat the cytokine
storm syndromes to prevent the COVID-19 progression in critical ill
patients and reduce the mortality [66]. Figure 2 shows the principle
of MSCs therapy for COVID-19 patients.
cytokine storm in lungs
TNFα MIP1A
IP10
GSCF
IL-6
IL-2
IL-7
Acute respiratory distress
syndrome (ARDS)
Figure 2. Principle of mesenchymal stem cells (MSCs) therapy for COVID-19 patients. In COVID-19 patients, immune overreaction results in the overproduction
of a large amount of immune cells and inflammatory factors, causing a cytokine storm in the lungs, followed by edema and may lead to acute respiratory distress
syndrome (ARDS). MSCs therapy prevents the storm release of cytokines as well as other inflammatory factors by the immune system and promote tissue repair by
the regenerative properties of the stem cells, in order to prevent long-term lung damage caused by COVID-19.
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 7
The advantages of MSCs therapy include easily accessible of
MSCs from different tissues such as bone marrow and adipose
tissues, reasonable expand time to expand to clinical volume and
no adverse reactions for allogeneic MSCs. However, this approach
is still investigational. The supply of the sources of clinical-grade
MSCs is one of the limitations for this technique [66].
4.5. Immunotherapy
4.5.1. Convalescent plasma therapy
Convalescent plasma (CP) collected from recovered patients con­
tains several antiviral antibodies. CP has been used widely in curing
infectious diseases such as Ebola [17]. CP therapy is a passive
immunotherapy that contains neutralizing antibody. CP-derived
antibodies can assist the complement activation and phagocytosis
process to prevent the virus replication [67]. Figure 3 shows the
principle of convalescent plasma therapy for COVID-19 patients.
From previous research in SARS, Wong et al. found that patients
reduced the viral load in plasma from ~105 copies/mL to unde­
tectable levels after receiving CP transfusion after 24 hours during
the early stage of the disease [68]. Convalescent plasma from
recovered patients should be collected within 2 weeks after recov­
ery, so that the neutralization antibody titer remains high enough
for treatment. However, one predicament is the difficulty to obtain
suitable plasma during convalescence. Therefore, further investi­
gation and design efficacy as well as safety CP are necessary [21].
4.6. Potentially effective natural compounds or
promising treatments
Hesperetin is a natural flavonoid found in citrus fruits. It can sup­
press 3 C-like protease cleavage activity of SARS. It is also reported
that hesperetin has the potential function to inhibit ACE2 and
MCP1
Attenuation of the cytokine
storm in lungs;
reduce inflammation and
oxidative stress;
stabilize endothelial fluid
leakage and maintain
Mesenchymal alveolar-capillary barrier
stem cell therapy function; promote tissue
repair
8 H. F. TSANG ET AL.

COVID-19 exposure
prophylactic

recovery blood draw

Blood plasma therapeutic

containing COVID-19 patients
antibodies
extracted from
recovered patients
COVID-19 patients

Figure 3. Principle of convalescent plasma therapy for COVID-19 patients. The blood from patients recovered from COVID-19 contains specific antibodies
against SARS-CoV-2. Plasma with specific antibodies is obtained and can be transferred to another COVID-19 patient for therapeutic purpose or to people who are at
high risk of exposure to SARS-CoV-2 for prophylactic purpose.

hence block SARS-CoV-2 infection [19]. The report from Ni et al.
showed that a traditional Chinese medicine call Shuang-huang-
lian oral liquid (SHL) contains three Chinese herbs extraction,
namely forsythia, honeysuckle, and Scutellaria baicalensis [69]. It
can resolve the symptoms without any adverse effects in COVID-19
patients who have received other treatment previously, such as
antibiotics or antiviral compounds but with no positive response
and symptoms became worse [69]. Other natural compounds such
as curcumin and quercetin might also be potential inhibitory
compounds against SARS-CoV-2 infection [70,71]. In addition to
natural compounds, treatment with hormones could also be one
of the potential options for adjuvant treatment. Melatonin is a well-
known anti-inflammatory and anti-oxidative molecule that might
be beneficial to COVID-19 patients by reducing vessel permeabil­
ity, anxiety, sedation used, and improving sleep quality [72].
Vitamin D supplementation is believed to be helpful in reducing
the risk of COVID-19 despite of a lack of direct evidence on the
association between vitamin D levels and COVID-19 severity and
mortality. A high-quality randomized controlled trials and large
population studies are necessary for further investigation [73–75].
4.7. Future perspective
Studying the interactions between SARS-CoV-2 proteins and
human proteins may give new insight on the development of
potential therapeutic regimen to treat COVID-19. In a study, 26
out of 29 SARS-CoV-2 proteins were cloned and express in
human cells to identify the human proteins that are physically
associated with those viral proteins. A total of 332 high-
confidence protein–protein interactions between SARS-CoV-2
and human proteins that are connected with processes such
as protein trafficking, translation, transcription, and regulation
of ubiquitination were identified. Of which, 66 druggable
targets targeted by 69 compounds, including 29 US FDA-
approved drugs, 12 drugs undergoing clinical trails and 28
preclinical compounds were identified [76]. In another study,
the nucleoside triphosphate hydrolase (NTPase) activity that
hydrolyze all types of NTPs as well as the RNA helicase activity
that unwinds RNA helices in the presence of NTP and Mg2+ of
the SARS-CoV-2 encoded nonstructural protein 13 (nsp13)
were demonstrated. Bismuth salts such as bismuth potassium
citrate (BPC), ranitidine bismuth citrate (RBC) and bismuth
citrate (BC) were reported to be able to inhibit the both
NTPase and helicase activities of SARS-CoV-2 nsp13 in a dose-
dependent manner [77]. The results from these studies identi­
fied valuable target for the development of antivirals or repur­
posing FDA-approved drugs against SARS-CoV-2 in the future.
5. Prevention
5.1. Vaccines
Although the development of vaccines to prevent COVID-19
has begun, the development is a long process that may not be
able to resolve this pandemic outbreak in short period [21,78].
With better understanding of the genome of SARS-CoV-2,
most of the strategies in vaccine development target the
S protein-coding sequence or antigens derived from the
S protein SARS-CoV-2. Currently, vaccine production platforms
for SARS-CoV-2 include live-attenuated vaccine, inactivated
virus vaccine, subunit vaccine, viral vector-based vaccine,
DNA vaccine, and RNA vaccine [79].
5.1.1. Live-attenuated vaccine (LAV)
LAV can stimulate the immune system by inducing the toll-like
receptors (TLRs) including TLR3, TLR7/8 and TLR9 [79].
However, extensive tests are required and necessary to ensure
the safety and efficacy of the vaccines [79]. Recently, several
LAVs including one co-developed by Codagenix and the
Serum Institute of India are in pre-clinical stage [80,81].
5.1.2. Inactivated virus vaccine
Inactivated virus vaccines are stable and safer as compared to
LAVs. It can be used along with other adjuvants to increase its
immunogenicity [79]. Moreover, preexisting technologies and
infrastructure required are available for development.
However, booster shots are required in most cases to maintain
the immunity [79]. Large amounts of viruses need to be
handled during preparation and the immunogenic particles
have to be preserved well to maintain the efficacy of the
vaccine [79]. Inactivated SARS-CoV-2 vaccine (Vero cell)

developed by Beijing Institute of Biological Products Co., Ltd
(ClinicalTrials.gov: NCT04560881) and adsorbed COVID-19
(inactivated) vaccine developed by Sinovac Life Sciences Co.,
Ltd (ClinicalTrials.gov: NCT04456595) have entered phase III
clinical trial.
5.1.3. Subunit vaccine
Subunit vaccines are made based on synthetic peptides or
recombinant antigenic proteins which can stimulate immune
response [79]. They do not contain any live viral components.
Therefore, subunit vaccines are safe for administration with
fewer side effects [79]. However, the immunogenicity of sub­
unit vaccine is low and immunological memory for future
response is doubtful [79]. NVX-CoV2373 developed by
Novavax, Inc (ClinicalTrials.gov: NCT04533399) and adjuvanted
recombinant protein developed by Anhui Zhifei Longcom
Biopharmaceutical and Institute of Microbiology, Chinese
Academy of Sciences (ClinicalTrials.gov: NCT04466085) have
entered phase II clinical trial.
5.1.4. Viral vector-based vaccine
Viral vector-based vaccines are based on viral vectors. They are
regarded as potential tools for gene therapy and vaccines. It
shows a highly specific gene delivery into the host cell to
trigger vigorous immune response by offering a long term
and high level of antigenic protein expression [79]. However,
integration of the viral genome into host genome can lead to
cancer [79]. Also, the presence of preexisting immunity against
the vector due to prior exposure might reduce the efficacy of
the vaccine [79]. ChAdOx1 nCoV-19 developed by The
University of Oxford is composed of a non-replicating adeno­
virus vector and the genetic sequence of the S protein of
SARS-CoV-2. This vaccine is relative safe in children and indi­
viduals with underlying disease due to the non-replicating
nature of adenovirus vector. It has entered phase III clinical
trial (ClinicalTrials.gov: NCT044516746). Other viral vector-
based vaccines including Ad5-nCoV developed by CanSino
Bioloics Inc and Beijing Institute of Biotechnology
(ClinicalTrials.gov: NCT04526990) and Ad26COVS1 developed
by Janssen Pharmaceutical Companies (ClinicalTrials.gov:
NCT04505722) have also entered phase III clinical trial.
5.1.5. DNA vaccine
DNA vaccines involve direct introduction of plasmid contain­
ing the DNA encoding for the antigen and an adjuvant which
induces the adaptive immune response into appropriate tis­
sues [79]. Transfected cells can express the transgene similar
to that from live virus. This approach can stimulate both B-cell
and T-cell responses and the synthetic DNA is temperature
stable [79]. Handling of infectious viral particles is not required
during the preparation of the vaccines [79]. However, integra­
tion of foreign DNA into host genome can lead to cancer. Also,
the titers of antibodies obtained are lower than those
obtained by other vaccination strategies [79]. Recently, INO-
4800 developed by Inovio Pharmaceuticals (ClinicalTrials.gov:
NCT04447781), AG0301-COVI19 co-developed by Osaka
University and AnGes, Inc (ClinicalTrials.gov: NCT04463472)
and GX-19 developed by Genexine, Inc. (ClinicalTrials.gov:
NCT04445389) have entered phase I/II clinical trial.
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 9
5.1.6. RNA vaccine
RNA vaccines involve the introduction of RNA sequence
encoding for the antigen to induce adaptive immune
response [79]. RNA does not integrate into host genome.
The risk of insertional mutagenesis and anti-vector immunity
can be avoided [79]. However, introduction of RNA strand in
the vaccine may elicit unintended immune response which
raises safety concern of the vaccine. Delivering RNA vaccine
effectively to the target tissue is challenging because RNA
vaccines are temperature sensitive and are broken down easily
[79]. An mRNA-based vaccine, mRNA-1273, co-developed
Moderna and the Vaccine Research Center at the National
Institutes of Health that expresses has entered phase III clinical
trial (ClinicalTrials.gov: NCT04470427). It targets antigen in vivo
and elicits antiviral response toward the spike proteins of
SARS-CoV-2 after intramuscular injection to human bodies.
5.2. Personal protection
At present, there is a lack of effective and definite treatment
for COVID-19. The most effective way for the public to reduce
the chance of being infected is to make effective protection
and precautions, such as maintaining good personal hygiene,
wearing medical mask, getting enough rest and avoiding
going to crowded places [11]. Maintaining an interpersonal
distance of 2 m can be considered as an effective measure to
minimize of the risk of transmission [82]. Recent study has
shown that community-wide face mask-wearing may control
COVID-19 in the community by reducing the emission of
infected saliva and respiratory droplets from individuals with
subclinical or mild COVID-19 to reduce the risk of transmis­
sion [83].
For Healthcare professionals, standard precautions with
proper usage of personal protective equipment (PPE) such as
gloves, gown, eye protection, face mask and N95 respirator
when performing aerosol-generating procedures can reduce
the risk of infection.
For governments, early detection, early isolation, and early
treatment are significant to cut off the spread of the virus and
the rebound of positive cases. The application of online geo­
graphical tracking system and mapping of COVID-19 cases
using big data analysis allows timely and effective tracing
and mapping super-spreader in the community for epidemic
monitoring and response [84].
6. Conclusion
To date, the transmission of COVID-19 is still uncontrollable
with the fact that numbers of confirmed and death cases keep
increasing. Although different potential treatment strategies
have been discussed in this paper, there is still no effective
vaccine or specific anti-viral drug to treat COVID-19. The treat­
ment approaches discussed has reflected the current knowl­
edge at the time of writing the manuscript, but the field is
rapidly evolving. Combination treatment has been encour­
aged as part of the management of critical COVID-19 patients
in this pandemic. Development and investigation of appropri­
ate anti-viral drugs and vaccines for the treatment and
10 H. F. TSANG ET AL.
prevention of COVID-19 have begun. In the future, more spe­
cifically designed randomized, controlled clinical trials are
necessary to determine the most effective evidence-based
treatment and management of COVID-19.
7. Expert opinion
The situation of the COVID-19 pandemic is still unpredictable.
There is no effective vaccine or specific anti-viral drug to treat
serve COVID-19 patients. Combination therapies such as triple
combination of interferon beta-1b, lopinavir-ritonavir, and
ribavirin or hydroxychloroquine plus azithromycin showed
promising clinical improvement in the treatment. However,
further studies on the combinations are needed. Adjunctive
treatments might play a role in COVID-19 treatment in the
future. However, current evidence is not sufficient to support
the routine use of adjunctive treatments over standard treat­
ments unless more evidence-based clinical trials have been
performed. Development and investigation of appropriate
anti-viral drugs and vaccines for the treatment and prevention
of COVID-19 have begun to treat critically ill patients and to
limit the transmission of SARS-CoV-2 to stop the spread of
COVID-19 in the world. Repurposing FDA-approved drugs
might be one of possible options.
Currently, there is still a lack of an effective and definite
treatment for COVID-19, the most feasible way for the public to
reduce the chance of being infected is to implement a reliable
protection and precaution strategy. Community-wide face mask-
wearing and maintain a social distance among individuals have
been proven as an effective mean to control COVID-19 in the
community by reducing the emission of infected saliva and
respiratory droplets with subclinical or mild COVID-19 to reduce
the risk of transmission. Further investigation on complete patho­
genesis and pathophysiology of COVID-19 is still necessary to
gain better disease management and prognosis for patient care.
As the world is still in the midst of a COVID-19 pandemic,
many scientists in the Universities and the companies are work­
ing for a novel COVID-19 vaccine. We hope that the vaccine can
be ready by 2020 so that at least 60% to 70% of the population
can develop antibodies, whether from a vaccine or infected and
recovering from COVID-19, to create herd immunity. Before the
COVID-19 vaccine arrives, we have to adapt to this new social
and economic culture. Governments must continue to invest in
public health, economic stimulus, and social safety nets to sup­
port countries to recover rapidly from the COVID-19 pandemic.
Besides, governments must work together so that tourism and
commercial activities can be resumed and facilitate the recovery
in a global manner.
Acknowledgments
We thank Dr. Liu Shao Haei for providing an updated information on the
pathogenesis and prevention of the COVID-19.
Funding
This paper was not funded.
Declaration of interest
The authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as
a potential conflict of interest.
Author contributions
Tsang HF and Wong SC wrote the first draft of the paper and were
responsible for the continuous revision of it; Chan LW, Cho WC, Yu AC,
Yim AK, Li MJ, Chan AK, Ng LP, Wong YK and Pei XM gave invaluable
comments and revised the paper; Chan LW, Cho WC, and Wong SC
conceived and designed the contents of the paper.
ORCID
William Chi Shing Cho http://orcid.org/0000-0003-4174-4586
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell
entry depends on ACE2 and TMPRSS2 and is blocked by a clinically
proven protease inhibitor. Cell. 2020;181(2):271–280.e8.
2. Chan JF, Kok KH, Zhu Z, et al. Genomic characterization of the 2019
novel human-pathogenic coronavirus isolated from a patient with
atypical pneumonia after visiting Wuhan. Emerg Microbes Infect.
2020;9:221–236.
3. Jin YF, Yang HY, Ji WQ, et al. Virology, epidemiology, pathogenesis,
and control of COVID-19. Viruses. 2020;12:372.
4. Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140
patients infected by SARS-CoV-2 in Wuhan, China. Allergy.
2020;75(7):1730–1741.
5. Spinato G, Fabbris C, Poiesel J, et al. Alterations in smell or taste in
mildly symptomatic outpatients with SARS-CoV-2 Infection. JAMA.
2020;323:2089–2091.
6. World Health Organization. Overview of coronavirus (COVID-19).
[cited 2020 Jul 10]. Available from: https://covid19.who.int/
7. Rothan H, Byrareddy SN. The epidemiology and pathogenesis of
coronavirus disease (COVID-19) outbreak. J Autoimmun.
2020;109:102433.
8. World Health Organization. Coronavirus disease 2019 (COVID-19):
situation report, 60. 2020.
9. World Health Organization. Coronavirus disease 2019 (COVID-19):
situation report, 68. 2020.
10. World Health Organization. Coronavirus disease 2019 (COVID-19):
situation report, 80. 2020.
11. Wang W, Tang J, Wei F. Updated understanding of the outbreak of
2019 novel coronavirus (2019-nCoV) in Wuhan, China. J Med Virol.
2020;92:441–447.
12. Centers for Disease Control and Prevention. Coronavirus disease
2019 – how it spreads. Available from: https://www.cdc.gov/corona
virus/2019-ncov/prevent-getting-sick/how-covid-spreads.html?CDC_
AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-
ncov%2Fprepare%2Ftransmission.html. Accessed 9 April 2020].
13. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and
surface stability of SARS-CoV-2 as compared with SARS-CoV-1.
N Engl J Med. 2020;382:1564–1567.
14. Centers for Disease Control and Prevention. Coronavirus disease
2019. laboratories. Available from: https://www.cdc.gov/corona
virus/2019-nCoV/lab/index.html Accessed 25 April 2020.
15. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of corona­
virus disease 2019 (COVID-19) from publicly reported confirmed
cases: estimation and application. Ann Intern Med.
2020;172:577–582.

16. Du Z, Xu X, Wang Y, et al. Serial interval of COVID-19 among
publicly reported confirmed cases. Emerg Infect Dis. 2020;26
(6):1341–1343. .
17. Nishiura H, Linton NM, Akhmetzhanov AR. Serial interval of novel
coronavirus (COVID-19) infections. Int J Infect Dis. 2020;93:284–286.
18. Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV
Infection from an Asymptomatic Contact in Germany. N Engl
J Med. 2020;382:970–971.
19. Li H, Liu SM, Yu XH, et al. Coronavirus disease 2019 (COVID-19):
current status and future perspectives. Int J of Antimicrob Agents.
2020;55:105951.
20. Liu Y, Gayle AA, Wilder-Smith A, et al. The reproductive number of
COVID-19 is higher compared to SARS coronavirus. J Travel Med.
2020;27:taaa021.
21. Zhai P, Ding Y, Wu X, et al. The epidemiology, diagnosis and
treatment of COVID-19. Int J Antimicrob Agents. 2020;55:105955.
22. Zhang S, Diao MY, Yu W, et al. Estimation of the reproductive
number of novel coronavirus (COVID-19) and the probable out­
break size on the Diamond Princess cruise ship: a data-driven
analysis. Int J Infect Dis. 2020;93:201–204.
23. Gebhard C, Regitz-Zagrosek V, Neuhauser HK, et al. Impact of sex
and gender on COVID-19 outcomes in Europe. Biol Sex Differ.
2020;11:29.
24. Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics
of patients dying in relation to COVID-19 in Italy. JAMA. 2020;323
(18):1775–1776.
25. Huang C, Wang Y, Li X, et al. Clinical features of patients infected
with 2019 novel coronavirus in Wuhan, China. Lancet.
2020;395:497–506.
26. Italian National Institute of Health. Characteristics of COVID-19
patients dying in Italy Report based on available data on
March 20th, 2020. 2020. [cited 2020 Jun 5]. Available from:
https://www.epicentro.iss.it/en/coronavirus/sars-cov-2-analysis-of-
deaths
27. Stelzig KE, Canepa-Escaro F, Schiliro M, et al. Estrogen regulates the
expression of SARS-CoV-2 receptor ACE2 in differentiated airway
epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2020;318(6):
L1280–L1281.
28. Al-Lami RA, Urban RJ, Volpi E, et al. Novel corona virus infectious
disease (COVID-19). Mayo Clin Proc. 2020;95(8):1559–1561.
29. Centers for Disease Control and Prevention. COVID-19 response
team. preliminary estimates of the prevalence of selected under­
lying health conditions among patients with coronavirus disease
2019 — United States, February 12–March 28, 2020. Morbidity
Mortality Weekly Rep. 2020;69:382–386.
30. Wiersinga WJ, Rhodes A, Cheng AC. Pathophysiology, transmission,
diagnosis, and treatment of coronavirus disease 2019 (COVID-19).
JAMA. 2020;324(8):782–793.
31. Chen Y, Liu QY, Guo D. Emerging coronaviruses: genome structure,
replication, and pathogenesis. J Med Virol. 2020;92:418–423.
32. Mousavizadeh L, Sorayya G. Genotype and phenotype of COVID-19:
their roles in pathogenesis. J Microbiol, Immun and Infection. 2020.
DOI:10.1016/j.jmii.2020.03.022
33. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated
with a new coronavirus of probable bat origin. Nature.
2020;579:270–273.
34. Luan J, Lu Y, Jin X, et al. Spike protein recognition of mammalian
ACE2 predicts the host range and an optimized ACE2 for
SARS-CoV-2 infection. Biochem Biophys Res Commun.
2020;526:165–169.
35. Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19
and potential vaccines: lessons learned from SARS and MERS
epidemic. Asian Pac J Allergy Immunol. 2020;38:1–9.
36. Li MY, Li L, Zhang Y, et al. Expression of the SARS-CoV-2 cell
receptor gene ACE2 in a wide variety of human tissues. Infect Dis
Poverty. 2020;9:45.
37. Kang MK, Wei J, Yuan J, et al. Probable evidence of fecal aerosol
transmission of SARS-CoV-2 in a high-rise building. Ann Intern Med.
2020;M20–0928.
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 11
38. Cheung KS, Hung IF, Chan PP, et al. Gastrointestinal manifestations
of SARS-CoV-2 infection and virus load in fecal samples from the
Hong Kong Cohort and systematic review and meta-analysis.
Gastroenterology. 2020.
39. Mason RJ. Pathogenesis of COVID-19 from a cell biology
perspective. Eur Respir J. 2020;55:2000607.
• Described the pathogenesis of COVID-19.
40. Li G, Fan YH, Lai Y, et al. Coronavirus infections and immune
responses. J Med Virol. 2020;92:424–432.
41. Imai Y, Kuba K, Neely GG, et al. Identification of oxidative stress and
Toll-like receptor 4 signaling as a key pathway of acute lung injury.
Cell. 2008;133:235–249.
42. Huppert LA, Matthay MA, Ware LB. Pathogenesis of acute respira­
tory distress syndrome. Semin Respir Crit Care Med. 2019;40
(1):31–39.
43. Hall OJ, Klein SL. Progesterone-based compounds affect immune
responses and susceptibility to infections at diverse mucosal sites.
Mucosal Immunol. 2017;10:1097–1107.
44. Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and
clinical therapies on coronavirus disease 2019 (COVID-19) outbreak
- an update on the status. Mil Med Res. 2020;7:11.
45. Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospita­
lized patients with covid-19 – preliminary report. N Engl J Med.
2020. 10.1056/NEJMoa2021436.
46. World Health Organization. Clinical management of COVID-19.
[cited 2020 Oct 10]. Available from: https://covid19.who.int/
47. Guaraldi G, Meschiari M, Cozzi-Lepri A, et al. Tocilizumab in patients
with severe COVID-10: a retrospective cohort study. Lancet. 2(3):
E474–E484
48. Toniati P, Piva S, Cattalini M, et al. Tocilizumab for the treatment of
severe COVID-19 pneumonia with hyperinflammatory syndrome
and acute respiratory failure: A single center study of 100 patients
in Brescia, Italy. Autoimmun Rev. 2020;19(7):102568.
49. Lan SH, Lai CC, Huang HT, et al. Tocilizumab for severe COVID-19:
a systematic review and meta-analysis. Int J Antimicrob Agents.
2020;56(3):106103.
50. Carrière F, Longhi S, Record M. The endosomal lipid bis­
(monoacylglycero) phosphate as a potential key player in the
mechanism of action of chloroquine against SARS-COV-2 and
other enveloped viruses hijacking the endocytic pathway.
Biochimie. 2020;179:237–246.
51. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effec­
tively inhibit the recently emerged novel coronavirus (2019-nCoV)
in vitro. Cell Res. 2020;30(3):269–271.
52. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has
shown apparent efficacy in treatment of COVID-19 associated
pneumonia in clinical studies. Biosci Trends. 2020;14:72–73.
53. McCreary EK, Pogue JM. Coronavirus disease 2019 treatment:
a review of early and emerging options. Open Forum Infect Dis.
2020;7(7):ofaa105.
54. Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and
azithromycin as a treatment of COVID-19: results of an open-label
non-randomized clinical trial. Int J Antimicrob Agents. 2020;56
(1):105949.
55. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of
hydroxychloroquine as postexposure prophylaxis for covid-19.
N Engl J Med. 2020;383(6):517–525. .
56. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of
chloroquine diphosphate as adjunctive therapy for patients hospita­
lized with sever acute respiratory syndrome coronavirus 2 (SARS-CoV-
2) infection: a randomized clinical trial. JAMA. 2020;3(4):e208857.
57. Sallard E, Lescure FX, Yazdanpanah Y, et al. Type 1 interferons as
a potential treatment against COVID-19. Antiviral Res.
2020;178:104791.
58. Lim J, Jeon S, Shin HY, et al. Case of the index patient who caused
tertiary transmission of COVID-19 infection in Korea: the applica­
tion of lopinavir/ritonavir for the treatment of COVID-19 infected
pneumonia monitored by quantitative RT-PCR. J Korean Med Sci.
2020;35:e79.
12 H. F. TSANG ET AL.
59. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults
hospitalized with servere covid-19. N Engl J Med. 2020;382
(19):1787–1799.
60. RECOVERY Collaborative Group. Lopinavir-ritonavir in patients
admitted to hospital with COVID-19 (RECOVERY): a randomized,
controlled, open-label, platform trial. Lancet. 2020. 10.1016/
S0140-6736(20)32013-4
61. Beigel JH, Tomashek KM, Dodd LE, et al. Redesivir for the treatment
of covid-19 – final report. N Engl J Med. 2020;383(19):1813–1826.
62. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe
COVID-19: a randomized, double-blind, placebo-controlled, multi­
centre trial. Lancet. 2020;395:1569–1578.
63. De Wit E, Feldmann F, Cronin J, et al. Prophylactic and thera­
peutic remdesivir (GS-5734) treatment in the rhesus macaque
model of MERS-CoV infection. Proc Natl Acad Sci USA.
2020;117:6771–6776.
64. Agostini ML, Andres EL, Sims AC, et al. Coronavirus susceptibility to
the antiviral remdesivir (GS-5734) is mediated by the viral polymer­
ase and the proofreading exoribonuclease. Mbio. 2018;9:1–15.
65. Hung IFN, Lung KC, Tso EYK, et al. Triple combination of interferon
beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of
patients admitted to hospital with COVID-19: an open-label, rando­
mized, phase 2 trial. Lancet. 2020;395:1695–1704.
•• Described the clinical performance of triple combination ther­
apy in COVID-19 treatment.
66. Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal Stem Cell
Therapy for COVID-19: present or Future. Stem Cell Rev and Rep.
2020;16:427–433.
• Described the potential of using mesenchymal stem cell ther­
apy in COVID-19 treatment.
67. Teixeira da Silva JA. Convalescent plasma: a possible treatment of
COVID-19 in India. Med J Armed Forces India. 2020;76:236–237.
• Described the potential of using convalescent plasma in
COVID-19 treatment.
68. Wong SS, Yuen KY. The management of coronavirus infections with
particular reference to SARS. J Antimicrob Chemother.
2008;62:437–441.
69. Ni L, Zhou L, Zhou M, et al. Combination of western medicine and
Chinese traditional patent medicine in treating a family case of
COVID-19 in Wuhan. Front Med. 2020;14:210–214.
70. Zahedipour F, Hosseini SA, Sathyapalan T, et al. Potential effects of
curcumin in the treatment of COVID-19 infection. Phyother Res.
2020;34(11):2911–2920.
71. Xiong X, Wang P, Su K, et al. Chinese herbal medicine for corona­
virus disease 2019: a systematic review and meta-analysis.
Pharmacol Res. 2020;160:105056.
72. Zhang R, Wang X, Ni L, et al. COVID-19: melatonin as a potential
adjuvant treatment. Life Sci. 2020;250:117583.
73. Zemb P, Bergman P, Camargo CA, et al. Vitamina D deficiency and
the COVID-19 pandemic. J Glob Antimicrob Resist.
2020;22:133–134.
74. Grant WB, Lahore H, McDonnell SL, et al. Evidence that Vitamin
D supplementation could reduce risk of influenza and COVID-19
infections and deaths. Nutrients. 2020;12(4):988.
75. Ali N. Role of vitamin D in preventing of COVID-19 infection,
progression and severity. J Infect Public Health. 2020;13
(1):1373–1380.
76. Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein
interaction map reveals targets for drug repurposing. Nature.
2020;583:459–468.
77. Shu T, Huang M, Wu D, et al. SARS-coronavirus-2 Nsp13 possesses
NTPase and RNA helicase activities that can be inhibited by bis­
muth salts. Virol Sin. 2020;35(3):321–329.
78. Ahmed SF, Quadeer AA, McKay MR. Preliminary identification of
potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-
2) based on SARS-CoV immunological studies. Viruses. 2020;12:254.
79. Kaur SP, Gupta V. COVID-19 Vaccine: a comprehensive status
report. Virus Res. 2020;288:198114.
80. Tu YF, Chien CS, Yarmishyn AA, et al. A review of SARS-CoV-2 and
the ongoing clinical trials. Int J Mol Sci. 2020;21:2657.
81. Amanat F, Krammer F. SARS-CoV-2 vaccines: status report.
Immunity. 2020;52:583–589.
82. Setti L, Passarini F, Gennaro GD, et al. Airborne transmission route
of COVID-19: why 2 meters/6 feet of inter-personal distance could
not be enough. Int J Environ Res Public Health. 2020;17(2932):2932.
83. Cheng VCC, Wong SC, Chuang VWM, et al. The role of
community-wide wearing of face mask for control of coronavirus
disease 2019 (COVID-19) epidemic due to SARS-CoV-2. J Infect.
2020;81:107–114.
• Described the effect of community-wide wearing of face mask
in controlling COVID-19.
84. Boulos MNK, Geraghty EM. Geographical tracking and mapping of
coronavirus disease COVID-19/severe acute respiratory syndrome cor­
onavirus 2 (SARS-CoV-2) epidemic and associated events around the
world: how 21st century GIS technologies are supporting the global
fight against outbreaks and epidemics. Int J Health Geogr. 2020;19:8.