ArticlePDF AvailableLiterature Review

COVID-19: Between Past and Present

October 2020
Viral Immunology 34(3):13

October 2020
34(3):13

DOI:10.1089/vim.2020.0102

Authors:

Areej M Assaf

University of Jordan

Randa Nayef Haddadin

University of Jordan

Amal Akour

University of Jordan

Since the WHO declared coronavirus disease 2019 (COVID-19) as a pandemic, huge efforts were made to understand the disease, its pathogenesis, and treatment. COVID-19 is caused by severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV2), which is closely related to SARS-associated coronavirus (SARS-CoV). This article attempts to provide a timely and comprehensive review of the coronaviruses over the years, and the epidemics they caused in this century with a focus on the current pandemic COVID-19. It also covers the basics about the disease immunopathogenesis, diagnosis, prognosis, and treatment options. Although almost every single week new clinical findings are published, which change our understanding of COVID-19, this review explores and explains the disease and the treatment options available so far. In summary, many therapeutic options are being investigated to treat and/or ameliorate the symptoms of COVID-19, but none is registered and no sufficient data to support immune-based therapy beyond the context of clinical trials. For that, strengthening our immune system is the best defense at this time.

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COVID-19: Between Past and Present

Areej M. Assaf, Randa N. Haddadin, and Amal A. Akour

Abstract

Since the WHO declared coronavirus disease 2019 (COVID-19) as a pandemic, huge efforts were made to

understand the disease, its pathogenesis, and treatment. COVID-19 is caused by severe acute respiratory

syndrome (SARS) coronavirus-2 (SARS-CoV2), which is closely related to SARS-associated coronavirus

(SARS-CoV). This article attempts to provide a timely and comprehensive review of the coronaviruses over the

years, and the epidemics they caused in this century with a focus on the current pandemic COVID-19. It also

covers the basics about the disease immunopathogenesis, diagnosis, prognosis, and treatment options. Although

almost every single week new clinical ﬁndings are published, which change our understanding of COVID-19,

this review explores and explains the disease and the treatment options available so far. In summary, many

therapeutic options are being investigated to treat and/or ameliorate the symptoms of COVID-19, but none is

registered and no sufﬁcient data to support immune-based therapy beyond the context of clinical trials. For that,

strengthening our immune system is the best defense at this time.

Keywords: COVID-19, SARS-CoV2, immunopathology, therapy, cytokine storm, coronavirus

Introduction

On the last day of the 2019 year, December 31, China

reported a cluster of pneumonia cases of unknown eti-

ology to the WHO ofﬁce in China. The cases were reported

from the city of Wuhan in Hubei province, China. With time,

the disease spread in China and other countries affecting

thousands of people (117). In January, the Chinese authorities

identiﬁed the virus as a novel coronavirus (2019-nCoV) and

sequenced its genome. Later, the virus was ofﬁcially named

SARS-CoV2.

On January 30, 2020, the WHO considered the outbreak as

‘‘Public Health Emergency of International Concern’’ (117)

and on February 11, the disease caused by the virus was

named COVID-19, short for ‘‘coronavirus disease 2019’’

(119). Within 3 months, the disease spread to 117 countries

and territories, affecting more than 125,000 patients and

claimed the lives of more than 4,600 persons. This had urged

the WHO on March 12 to declare the disease a pandemic

(118). By the mid of August 2020, more than 21 million

people were affected by the disease and the deaths surpassed

760,000 (World Health Organization. COVID-19 Dashboard.

https://covid19.who.int/. Accessed August 17, 2020).

The aim of this review is to provide a timely and com-

prehensive review of human coronaviruses over years, and

the epidemics they caused in this century with a focus on the

current pandemic, COVID-19. Also, to cover the basics

about the disease immunopathogenesis, diagnosis, progno-

sis, and treatment options. Due to the variable clinical

ﬁndings in the clinical data of infected patients, we hope, in

this review, to help in exploring and explaining the disease

and the treatment options available so far.

Coronaviruses Background, Origin, and Reservoirs

Coronaviruses are a group of viruses that belong to Cor-

onaviridae family. The name corona comes from the resem-

blance to solar corona or the crown. This halo appearance is

given by the S protein spikes projecting from the envelope

when visualized by electron microscope (42). Members of

this family are enveloped nonsegmented positive-sense

single-strand RNA viruses, with large RNA genome. Ac-

cording to the International Committee on Taxonomy of

Viruses (ICTV), this family has two subfamilies, Orthocor-

onavirinae and Letovirinae (57). The Orthocoronavirinae

previously known as Coronavirinae has four genera, Alpha-

coronavirus, Betacoronavirus, Gammacoronavirus,and

Deltacoronavirus. Orthocoronavirinae has the largest iden-

tiﬁed RNA genome containing about 32 kb (42,89).

Viruses in the genera Alphacoronaviruses and Betacor-

onaviruses infect mainly mammals, Gammacoronavirus in-

fects avians, and viruses belonging to the Deltacoronavirus

were found in both mammals and avian species (89). In the

past it was thought that coronaviruses of animals cannot be

Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman, Jordan.

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transmitted to humans. But the outbreaks and pandemics in the

last two decades by these viruses showed that they are po-

tential zoonotic pathogens, where a spillover occurs from

animals to humans. This made the animals as reservoir hosts.

Numerous animal species can harbor these viruses such as

bats, rodents, lagomorphs, and other vertebrates (8).

Human coronaviruses

Human coronaviruses (HCoV) were ﬁrst identiﬁed in

1962 (59). HCoV-229E and HCoV-OC43 were the ﬁrst to

be identiﬁed. Later, in the early years of the 21st century,

another two HCoV were identiﬁed, HCoV-NL63 and

HCoV-HKU1 (42,57). 229E and NL63 are alphacor-

onaviruses, whereas OC43 and HKU1 are betacoronaviruses

(42,57,76). These viruses were found to be globally dis-

tributed and circulating worldwide, that is, they are endemic

to human population (42). They cause mild-to-moderate

upper respiratory tract infections and considered the second

most common cause of coryza or common cold, where 15–

30% of respiratory tract infections are linked to them (42).

In some cases, lower respiratory tract infections such as

bronchitis or pneumonia may occur but these are linked to

immunocompromised patients and elderly (60). The preva-

lence of these human species varies depending on the time

of the year and the geographic region.

In the last two decades three new HCoV emerged: SARS-

CoV (the beta coronavirus that causes severe acute respi-

ratory syndrome), MERS-CoV (the beta coronavirus that

causes Middle East Respiratory Syndrome), and the most

recent SARS-CoV2 (the novel beta coronavirus that causes

coronavirus disease 2019, or COVID-19). Unlike the pre-

vious viruses, these three species caused severe respiratory

illnesses that affected the lower respiratory tract and resulted

in fatalities. They spread worldwide causing epidemics and

the current pandemic. Since the emergence of these epi-

demics, attention has been paid to coronavirus ability to

transfer from wildlife animals to domestic animals or to

humans (79).

SARS outbreak, symptoms, and epidemiology

In the mid November 2002, severe cases of respiratory

illnesses appeared in Guangdong Province, China. In

February 2003, an ofﬁcial report was received by WHO

about atypical pneumonia affecting 305 persons and resulted

in 5 deaths (122). WHO named the outbreak as SARS and

issued emergency travel recommendations to alert health

authorities and the public to a worldwide threat to health

(122). Within a few months, the illness spread to more than

25 countries in North America, South America, Europe, and

Asia, including Canada, which was considered a hotspot of

the illness outside Asia (76). The outbreak affected 8,098

patients worldwide and claimed the lives of 774 with a

mortality rate of 9% (19).

SARS is presented with high fever (more than 38C),

headache, body aches, and general feeling of discomfort.

Some patients show mild respiratory symptoms. Within a

week, patients develop dry cough then the severe disease

progresses rapidly to respiratory distress, which requires

intensive care. Most of these patients develop severe

pneumonia and 10–20% develop diarrhea (19,121).

In March 2003, one laboratory each in Hong Kong, Ger-

many, and the Centers for Disease Control and Prevention

(CDC), USA, almost simultaneously were able to isolate the

virus that caused the SARS (65). The virus genome was

sequenced and revealed that it is a new HCoV (35,65). The

virus was named SARS-associated coronavirus (SARS-

CoV), which is a betacoronavirus.

Members of betacoronaviruses are clustered into four lin-

eages, A, B, C, and D. SARS-CoV belongs to B lineage. It is

thought to be originated from bat coronaviruses, which spilled

over to humans (55,121). Bats were found to host several

strains of coronaviruses and many of these are genetically

related to SARS-CoV. Their spike proteins are similar to those

of SARS-CoV and they use the same receptors to enter host

cells (121). However, it is thought that there are intermediate

hosts between bats and humans. Civet cats were suspected as

an intermediate host and transmission host. When the outbreak

started from a wet market in Guangdong Province, SARS-

CoV was isolated from civet cats. Chinese health ofﬁcials

ordered massive culling of these cats and other mammals to

contain the spread of the outbreak (87).

MERS outbreak, symptoms, and epidemiology

Ten years after the emergence of SARS, in June 2012, a

man in Saudi Arabia died from severe pneumonia and renal

failure (31). A novel coronavirus was isolated from his

sputum. In the meantime, several other cases were retro-

spectively identiﬁed from patients in Jordan, which had

occurred in April 2012. The virus was called MERS cor-

onavirus (MERS-CoV) (31,123). Within one year, the virus

affected eight countries, the majority in the Middle East and

some European countries. During that year, 64 laboratory

conﬁrmed cases were reported, with 60% mortality (123).

All the cases were linked to people traveling or residing in

the Arabian Peninsula or countries near it. In 2015, the

largest outbreak outside the Arabian Peninsula occurred in

the Republic of Korea.

Until now, the disease is still under surveillance. By

November 2019, 27 countries have reported cases of this

disease and the total number of cases reached 2,494, with

858 deaths (34.3%) (124). Although some of the infected

people are asymptomatic, most of the patients presented

with fever, cough, and shortness of breath. Some also had

diarrhea and nausea or vomiting. The symptoms take 2–14

days to appear. Many patients develop severe complications,

such as pneumonia and kidney failure (18,56). Patients with

severe illness require support in intensive care and those

who had respiratory failure require mechanical ventilation.

More than 30% of the patients died. The majority of those

who died had pre-existing medical conditions, such as dia-

betes, cancer, chronic lung disease, chronic heart disease,

and chronic kidney disease (18,56).

Several studies suggested that the disease is transmitted

through animal–human contact and less frequently through

human–human contact (8). The later was mostly seen in

hospitals. In general, the infected people had close contact

with ill people (124).

After reporting cases and isolating the virus, the search for

the virus reservoirs commenced. Bats were suspected and

surveyed with many other animals. MERS-CoV was geno-

typically linked to the betacoronavirus lineage C viruses

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identiﬁed in bats (8). But, no decisive evidence was found to

prove that bats are the natural reservoirs of the virus. How-

ever, serological screening showed that dromedary camels

have high MERS-CoV antibodies. In addition, MERS CoV

and other coronaviruses related to MERS-CoV lineage were

detected in many cases in dromedary camels in the Middle

East and many parts in Africa (18,26).

Coronavirus disease-2019

Until this date (August, 2020), COVID-19 is still spreading

in the globe at different rates. In some countries the number of

new cases is declining, in others it is ascending. The disease

presents with variable signs and symptoms and the symptoms

range from no symptoms or mild ﬂu-like symptoms to acute

respiratory distress and multiple organ dysfunction. This will

be discussed in more details in immunopathogenesis and

clinical presentation of SARS-CoV2 section.

The origin of the of SARS-CoV2 is still under investi-

gation. Two scenarios were proposed for its origin, (i)

Natural selection in an animal host followed by zoonotic

transfer or (ii) Zoonotic transfer followed by natural selec-

tion in humans (4). Full-length genome sequencing of the

viruses isolated from ﬁve patients in China showed that the

viruses are identical and share 80% nucleotide sequence to

SARS-CoV. Phylogenetic analysis of the virus showed that

it is a lineage B betacoronavirus closely related to a SARS-

like coronavirus in bats. The resemblance was 96% in nu-

cleotide sequence, which suggests that SARS-COV2 could

have been emerged from bats, which makes bats as a likely

reservoir host for the virus, however, it is not known yet if

there is an intermediate host for this virus (132).

To date, it is known that the virus can be transmitted mainly

through small respiratory droplets (sneezing or coughing) or

through close contact (nearly 6 feet) (17). The respiratory

droplets are either inhaled or landed on surfaces that are con-

tacted by people who touch their eyes, nose, or mouth (17,36).

The virus seems to be transmitted easily and sustainably from

human to human (community spread) through the respiratory

routes. Recently, growing evidence suggests the possible

transmission of the virus through aerosols, which was seen in

crowded and closed settings with inadequate ventilation

(80,81). This has driven the WHO to urgently request more

investigational studies about this route of transmission (120).

Role of Angiotensin-Converting Enzyme 2

in COVID-19 Pathogenesis

Angiotensin-Converting Enzyme 2 (ACE2) is a type I

transmembrane zinc metalloenzyme and carboxypeptidase

with homology to ACE that is an essential regulator of heart

function (30). It was found to be highly expressed in many

cells like alveolar epithelial type II cells of lung, esophagus

upper and stratiﬁed epithelial cells, nasal epithelial cells,

colon, myocardial cells, kidney proximal tubule cells, epi-

thelia of the small intestine, testes, and bladder urothelial

cells (127,131,135).

The ACE2 gene is located on chromosome Xp22, spans

39.98 kb of genomic DNA, encoding a protein of 805 amino

acids, and contains 20 introns and 18 exons (107). Its ex-

pression was found to be associated with age, but not sex or

race. Its expression was positively correlated with age

among middle-aged and older adults, whereas no signiﬁcant

difference was found among individuals of East Asian,

African or European ancestry (24).

The ACE2 gene exhibits a high degree of genetic poly-

morphism (15,74). A very recent study by Cao et al., in-

vestigated the allele frequency (AF) differences between

East Asian, European, African, South Asian, and admixed

American (15). Their ﬁndings suggested that the genotypes

of ACE2 gene polymorphism among East Asian population

may be associated with higher expression levels of ACE2.

Also, moderate difference was shown in AFs of genetic

analysis of expression quantitative trait loci (eQTLs) be-

tween South Asians and East Asians, which suggests the

potential difference of ACE2 expression in different popu-

lations and ethnicities in Asia and the diversity of ACE2

expression pattern in populations (15).

ACE2 has been found to be a receptor for the entry of the

novel human pathogenic coronaviruses SARS-CoV and

SARS-CoV2 with an increasing evidence of its role in its

pathogenesis (88,132). The suggested mechanism for the viral

entrance involves binding of its spike proteins, S-protein,

which are located on the coat of the virus, with ACE2 re-

ceptors, which are normally found on the epithelial cells of

different organs (66). This binding is proteolytically processed

by type 2 transmembrane protease, TMPRSS2, which would

lead to the cleavage of ACE2 and the activation of the spike

protein, thus, facilitating virus entry and replication (53).

Many similarities were found between the original SARS-

CoV and the new virus (SARS-CoV2). Both share 76.5%

identity in amino acid sequences with a high degree of ho-

mology (66,125). Although studies showed that SARS-CoV

spike protein has a strong binding afﬁnity to human ACE2,

recent studies suggested that SARS-CoV2 recognizes human

ACE2 more efﬁciently, increasing the ability of SARS-CoV2

to transmit from one person to another (85,125).

Lung appears to be the most vulnerable target organ for

SARS-CoV2 and according to Zhang and his team, they re-

cently indicated that it could be due to the vast surface area of

the lung making the lung highly susceptible to inhaled viruses

in addition to other biological factors (128). Zhao et al. (131)

demonstrated that 83% of ACE2-expressing cells in adults

were in alveolar epithelial type II cells (AECII), which can

serve as a reservoir for viral invasion. Their gene ontology

enrichment analysis showed that the ACE2-expressing AECII

have high levels of multiple viral process-related genes, in-

cluding regulatory genes for viral processes, viral life cycle,

virion assembly, and regulation of viral genome replication,

suggesting that the ACE2-expressing AECII facilitate cor-

onaviral replication in the lung (131).

In a previous study on SARS-CoV infection, ACE2 ex-

pression was found to be positively correlated with the dif-

ferentiation state of human airway epithelia. Undifferentiated

cell expression ACE2 was poorly infected with SARS-CoV,

whereas the well-differentiated cells expressed more ACE2

and were readily infected (135).

Studies suggested that the susceptibility, symptoms, and

outcome of COVID-19/SARS-CoV2 infection might be

correlated with the state of cell differentiation of human

airway epithelia, expression level, and expression pattern of

human ACE2 in different tissues (15,135,128). The ex-

pression level of ACE2 receptors was found to be increased

in hypertension and diabetic patients treated with ACE in-

hibitors and angiotensin II type-I receptor blockers (44,66,110).

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Several hypotheses were published regarding the rela-

tionship between diabetes and hypertension treatment with

ACE2-stimulating drugs, and the increase in ACE2 ex-

pression, and their role in increasing the risk of developing

severe and fatal COVID-19. However, limited evidence

showed changes in ACE2 levels expressed in serum or

pulmonary samples (88). These hypotheses were recently

refuted by the European Society of cardiology indicating

that there is no scientiﬁc base or evidence to support (91).

Other very recent studies found an ACE2 genetic predis-

position for the increased risk of SARS-CoV2 infection.

ACE2 genetic polymorphisms have been linked to diabetes

mellitus, cerebral stroke, and hypertension (39). A previous

study found a high degree of genetic heterogeneity among

ACE2 polymorphisms that are linked to type 2 Diabetes (70).

Smoking, which in the developed world is the primary

etiological factor behind chronic obstructive pulmonary

disease (COPD), is considered as a factor to increase vul-

nerability to respiratory viruses like SARS-CoV2 (10).

Smoking was found to upregulate ACE2 receptors on the

airway epithelium. Guoshuai Cai (2020) recently reported

signiﬁcantly a higher ACE2 gene expression in smoker

samples compared with nonsmoker (11). Consequently, the

increased number of ACE2 is expected to facilitate infection

with SARS-CoV2 (10,15).

Differences in ACE2 coding variants among different

populations suggest that the diverse genetic basis might

affect ACE2 functions among populations which could af-

fect the association between ACE2 and S-protein in SARS-

CoV2. Therefore, the state of cell differentiation and ACE2

expression levels are both important determinants of the

susceptibility of human airway epithelia to infection. The

expression level and expression pattern of human ACE2 in

different tissues and populations might be critical for the

susceptibility, symptoms, and outcome of SARS-CoV2 in-

fection. In summary, differences in immunity, ACE2 gene

expression, age, or even genetic background may contribute

to the different susceptibility to and severity of SARS-CoV2

infection.

Immunopathogenesis and Clinical Presentation

of SARS-CoV2

The immunopathology of the novel SARS-CoV2 is still

under investigation. Although, it can activate both innate and

adaptive immunity, an uncontrolled and impaired immune

response might occur leading to harmful tissue damages lo-

cally and systemically. Since the start of the pandemic, sev-

eral hypotheses have been suggested describing the

interaction of the immune system with the virus in the de-

velopment of the disease and its most severe forms, where

cytokine storm had the most important role (6,86). While

trying to restore hemostasis after infection, inﬂammation

happens, which can be very harmful if not controlled (6,86).

As the virus name indicate, SARS-CoV2 affects the lungs

leading in some cases to SARS. On the other hand, it had a

probable asymptomatic incubation period between 2 days

and 2 weeks, where the virus can be transmitted (23,44,111).

In some cases a period of 2–3 weeks was observed between

developing symptoms and the ﬁnal clinical outcome (108).

According to the clinical studies of hospitalized COVID-19

patients, most frequently they show symptoms associated

with viral pneumonia, fever, sore throat, cough, myalgia,

and fatigue (23,51). In addition to that, a few cases showed

severe-to-critical complications, where most of them did not

develop severe clinical manifestations in the early stages of

the disease, but at the later stage. They showed respiratory

failure requiring mechanical ventilation, septic shock, or

other organ dysfunction or failure requiring intensive care at

the hospital (108).

By the end of the third month of the pandemic, a group

of European physicians submitted a letter to the American

Journal of Respiratory and Critical Care Medicine, show-

ing discrepancies in patients with COVID-19 presenting

an atypical form of Acute Respiratory Distress Syndrome

(ARDS) recommending to avoid jumping to unnecessary

mechanical ventilation (46).

Recent clinical reports described destructive damages in

the cardiovascular system, kidneys, gut, and brain (109).

Signiﬁcant observations were also reported showing the

tendency of the patients to form clots in blood leading to

vessel obstruction, which might result in pulmonary embo-

lism or large vessel ischemic stroke, in addition to forming

ischemic ﬁngers and toes (109).

A recent study indicated that the chance of survival fol-

lowing SARS-CoV2 infection in people 60 years of age and

older is *95% in the absence of comorbid conditions. But the

chance considerably decreased in patients with health condi-

tions and continues to decrease with age beyond 60 years

(94,96,103). From the experience of scientist and clinicians in

COVID-19, not all people exposed to SARS-CoV2 are in-

fected and relatively a small proportion of infected patients

develop severe respiratory syndrome (51).

According to Wang et al. SARS-CoV2 infection can be

divided into three stages: an asymptomatic stage with or

without viral detection, where the patients might spread the

virus unknowingly, a nonsevere symptomatic stage with

viral presence and a severe respiratory symptomatic stage

with high viral load, which occurs in about 15% of the

conﬁrmed cases (45,111). However, transmission of the

virus might occur from presymptomatic patients, where they

are infected but did not develop symptoms yet (114). This

variation in response to the viral infection is one of the main

concerns to scientists and clinicians where the overall im-

munity of the infected patients cannot explain the differ-

ences in disease presentation.

Innate and adaptive immunity

in COVID-19-infected patients

Limited information is available regarding the immuno-

logical response to SARS-CoV2 in infected patients. Thus,

to understand its immunological response, we have returned

to previous studies on SARS-CoV in addition to the current

ﬁndings about SARS-CoV2 patients. Generally, the innate

immune system is the ﬁrst to respond after viral infection. It

recognizes the virus through pattern recognition receptors

(PRRs) like Toll-like receptor (TLR) (2,73). This leads to

the activation of different pathways where the virus induces

the expression of inﬂammatory factors and the synthesis of

type I interferons (IFNs) limiting its spread and accelerating

macrophage phagocytosis of viral antigens (2). However,

the nucleocapsid protein (N) of SARS-CoV can help the

virus to escape immune responses (73).

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Recently lots of efforts and studies were done trying to

understand the immune response to SARS-CoV2. Innate

immunity was linked with the development of the cytokine

storm and found to be responsible for boosting more severe

forms of the disease (6). When the virus infects the upper and

lower respiratory tract it either causes a mild or a highly acute

respiratory syndrome. This critical and fatal outcome is due to

the release of interleukin (IL)-1band IL-6 proinﬂammatory

cytokines after SARS-CoV2 binds to TLRs leading to the

activation of the immune response (6,86). Those stimulated

proinﬂammatory cytokines in addition to tumor necrosis

factor (TNF) mediates lung inﬂammation, fever, and ﬁbrosis

(86). Therefore, harmful tissue damage both at the site of

virus entry and at systemic level might occur.

The adaptive immune response activates CD4

and CD8

T lymphocytes, which play a critical role in clearing the

virus by eliminating virus-infected cells. CD4

helper T

cells can direct the cytotoxic T cells and B cells and enhance

their function to eliminate the virus (78,133). Activated

CD8

cytotoxic T cells will directly kill infected cells by

secreting molecules like granzymes, perforin, and IFN-cto

eradicate the virus, whereas CD4

T cells will stimulate B

cells to produce antibodies speciﬁc to the virus (105).

The early stage defense antibodies produced after almost 1

week of SARS-CoV2 viral infection are the neutralizing IgM

antibodies. They are relatively efﬁcient in fully blocking viral

entrance into the host cells, limiting the infection, and are

considered as a critical immune player for protection against

viral diseases. Then, the class switch, where high-afﬁnity IgG

antibodies are developed for the long-term immunity and im-

munological memory (67). Subsequently, cellular immunity

will be mediated by T lymphocytes. This adaptive immune

response is directed by T helper cells, where cytotoxic T cells

will then play a vital role in the destruction and clearance of the

viral infected cells (67). However, T cell exhaustion might be

induced due to viral persistent stimulation that leads to the loss

of the cytokine production ability and reduced functions (43,83).

On the other hand, in patients with severe SARS-CoV

infection, a delayed adaptive immune response development

and prolonged viral clearance were noticed (14). Also, in a

previous study measuring the T cell responses in patients

with MERS-CoV infection, all tested MERS survivors de-

veloped both CD4

and CD8

T cell responses, and patients

with mild or subclinical illness developed prominent virus-

speciﬁc CD8

T cell response (129).

In this rapidly evolving ﬁeld, researchers reported that indi-

viduals with positive SARS-CoV2 polymerase chain reaction

(PCR) results were able to develop IgM, IgA, and IgG anti-

bodies against SARS-CoV2 surface spike and nucleocapsid

proteins within 1–2 weeks after havingsymptoms and continue

elevation after initial viral clearance (97). According to Seow

et al., patients with severe COVID-19 symptoms showed higher

levels of antibodies compared with those with mild disease (97).

They also showed that their levels began to decline 20–30 days

post onset of symptoms and sometimes nearly to undetectable

levels in less than 2 months after symptoms appeared.

The length of the antibody-speciﬁc response to SARS-

CoV2 is still unknown. On the other hand, the antibodies

produced in patients infected with SARS-CoV or MERS-

CoV coronaviruses were found to wane over time ranging

between 12 and 52 weeks from the onset of the disease,

while homologous reinfections were detected (58).

As the antibody levels declined with time, it was impor-

tant to identify antigen-speciﬁc T cell responses in COVID-

19 patients. Recently, physicians and scientists were able to

detect and characterize some of SARS-CoV2 T cell re-

sponses in humans (98). Nevertheless, they are still uncer-

tain about the role of the adaptive immunity in the disease,

whether it is protective or pathogenic or both depending on

the time, composition, or magnitude of the adaptive re-

sponse. According to Blanco-Melo et al. an early CD4

and

CD8

T cell response against SARS-CoV2 can be protec-

tive, but it is difﬁcult to have an early response due to the

efﬁcient innate immune evasion mechanisms of SARS-

CoV2 in humans (7). On the other hand, in the presence of

sustained high viral load in lungs, late T cell response may

increase the pathogenic inﬂammatory outcomes (52).

Cytokine storm mechanism in COVID-19

Although cytokines are known to play an important role

in immunopathogenesis during viral infection, overreactive

and dysregulated immune responses were observed in

SARS-CoV2 patients leading to organ damages (6,86). This

was also observed in the previous human coronaviruses,

SARS and MERS, where they might enhance an over-

reactive immune response leading to the production of cy-

tokine storm that can cause severe damages to the lungs

causing ARDS and to other organs, which might lead to

multiorgan failure and even death (20).

Previous in vitro studies at the early stage of SARS-CoV

infection showed a delay in the release of cytokines and che-

mokines at the respiratory epithelial cells, dendritic cells, and

macrophages (25,64). Whereas at later stages, cells secrete low

levels of the antiviral factors, interferons (IFNs), and high

levels of proinﬂammatory cytokines [IL-1b, IL-6, and TNF and

chemokines (C-C motif chemokine ligand (CCL)-2, CCL-3,

and CCL-5)] (28,67), where they contribute to the occurrence

of ARDS in SARS-CoV patients (14). These ﬁndings sup-

ported the view that high viral load and cytokine/chemokine

dysregulation can cause the cytokine storm, which is accom-

panied with immunopathological changes in the lungs.

The severe systemic elevation of the proinﬂammatory

cytokines leading to cytokine storm in COVID-19 infections

was mostly noticed in elderly critical adults (77). Meftahi

et al. reported that balance between proinﬂammatory and

anti-inﬂammatory immune responses is needed to limit the

progression of COVID-19 infection. Healthy adults showed

this balance in the cytokine network and were able to shut

down immune activity at the right time. Whereas, elderly

patients did not show the same balanced immune response

as a young adult (77).

Laboratory ﬁndings in COVID 19

In the previous studies for the acute phase of SARS-CoV

infection, lymphocytopenia, mainly T lymphocytes, was

observed, and both CD4

and CD8

T lymphocytes were

decreased (68). In SARS-CoV2-infected patients, studies

showed a normal leukocyte, platelet count, and lymphocy-

topenia at the early stage of the disease. Upon admission,

lymphocytopenia, thrombocytopenia, and leukopenia were

observed (51,111). Diao et al., showed that CD4

and CD8

T cells were dramatically reduced in COVID-19 patients,

especially among elderly patients and those needed the

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intensive care unit (33). According to Zhou et al., age,

lymphopenia, leucocytosis, and elevated ALT, lactate de-

hydrogenase, high-sensitivity cardiac troponin I, creatine

kinase, d-dimer, serum ferritin, IL-6, prothrombin time,

creatinine, and procalcitonin were associated with death in

severe cases of COVID-19 patients (128).

Selected Potential Pharmacotherapeutic Options

for Treating COVID-19

To this date, there are no drugs that have proven effective

for the management of COVID-19 (38,126). So, there is a

crucial need to look for therapeutic options to control virus

entry, replication and/or spread. Developing new drugs that

target various steps of the viral infection would be the op-

timum choice, however, the later would not be practical in

lieu of urgency to ﬁnd a treatment for this pandemic in-

fection. Therefore, screening of the existing drugs with

potential antiviral effect can hopefully create new thera-

peutic options, while bypassing much of the costs and time

involved with having a new drug available in the market.

We have done an online search on PubMed and Web of

Science with the keywords of SARS, MERS, and cor-

onaviruses, treatment, and prevention. The followings sum-

marize some of the proposed therapeutic options available

for the treatment of this novel coronaviruses.

Small molecules

Chloroquine/hydroxychloroquine and other antimalarial

agents. As mentioned in the Role of Angiotensin-

Converting Enzyme 2 in COVID-19 Pathogenesis section,

ACE2 receptor is the site of binding of SARS-CoV, which

mediates its entry into the cell through binding with spike

(S) protein (66). Thus, blocking the binding of S protein to

ACE2 would be a key for the treatment of SARS-CoV2

infection.

Chloroquine interferes with the glycosylation of cellular

receptor of SARS-CoV2, ACE2, and thus prevents viral entry

(72). It also works by increasing the pH in mammalian cell

lysosomes, which will subdue viral replication (72). Recently,

it was shown that chloroquine and hydroxychloroquine can

reduce the production of various proinﬂammatory cytokines,

such as IL-1, IL-6, interferon-a, and tumor necrosis factor,

which are involved in the cytokine storm. These immuno-

modulatory effects potentiate the antiviral effects of these

agents in the treatment of COVID-19 (130).

It was anecdotally reported that this antimalarial drug has

antiviral effect probably due to its ability to inhibit viral

entry and/or replication. Chloroquine showed in vitro ac-

tivity against SARS-CoV and MERS-CoV (112), in addi-

tion, its less toxic derivative, hydroxychloroquine (HCQ),

showed an in vitro activity against the novel SARS-CoV2

(72). Clinically, however, there is still a controversy about

the clinical efﬁcacy and safety of chloroquine or HCQ.

Cortegiani et al. summarized 23 clinical trials in China that

have pending approval or already recruiting patients (27),

which are using chloroquine with or without other agents.

Awaiting the efﬁcacy and safety results from these trials,

scrutiny should be exercised upon clinically utilizing this

drug (27). Two debatable French studies by Gautret et al.

(47,48) showed a reduction of viral load when HCQ used in

combination of hydroxychloroquine with azithromycin in

patients with COVID-19 25% (74) at day 6 of treatment, and

93% of patients had negative PCR test after 8 days. In spite

of promising results, those studies suffered from small

sample size (48) and the lack of a control group (47).

Conversely, a recent study from China in 30 individuals

with COVID-19 found no difference in the rate of virologic

clearance nor clinical improvement after 5 days of using

HCQ compared with placebo (22).

Even more, a phase 2b randomized controlled trial (RCT)

in 81 patients with severe COVID-19 infection showed that

lethality rate was signiﬁcantly higher in the high-dose group

when compared with low-dose group (39% vs. 15%, re-

spectively), which warranted the cessation of the high dose

immediately (CloroCovid-19) (9). Due to inconsistencies in

the abovementioned results, timely results from studies with

larger sample size, and in patients with severe COVID-19

are pivotal to dictate the drug’s utilization worldwide.

A total of 1,542 patients were randomized to hydroxy-

chloroquine and compared with 3,132 patients randomized

to usual care alone. Interestingly, preliminary (unpublished)

results showed that there was no signiﬁcant difference in the

28-day mortality (25.7% hydroxychloroquine vs. 23.5%

standard care), as well as the lack of beneﬁcial effects on

hospital stay duration or other outcomes (63,104). In addi-

tion, the interim results from solidarity trial, which was

established by the WHO, showed that hydroxychloroquine

and lopinavir/ritonavir did not provide a signiﬁcant reduc-

tion in the mortality of hospitalized COVID-19 patients

when compared with standard care. Therefore, WHO dis-

counted both treatment arms immediately (116). These

preliminary results dampened the initial enthusiasm toward

hydroxychloroquine.

Another antimalarial drug, arbidol, was also tested against

other antiviral agents (32,69,115,134). One study retrospec-

tively analyzed data from ﬁfty patients who were randomized

to receive arbidol (n=17) versus the antiviral lopinavir/rito-

navir (LPV/r) (n=34) (134). In the arbidol arm, no viral load

could be detected in pharyngeal swab after 2 weeks of treat-

ment, whereas it was found in 44.1% of patient in the LPV/r

group. Furthermore, a cohort study showed that LPV/r com-

bined with arbidol versus LPV/r alone showed more favorable

outcomes in terms of absence of viral load after weeks, as well

as improvement of chest CT scan (32).

Despite these promising results, the latest observational

cohort study (32) showed that there was no evidence to prove

that LPV/r and arbidol could shorten the negative conversion

time of novel coronavirus nucleic acid in pharyngeal swab nor

improve the symptoms of patients. Furthermore, the combi-

nation usage of LPV/r and arbidol has no beneﬁt of improving

the disease, while posing more adverse effects when com-

pared with conventional therapy (115).

Remdesivir. This drug was originally developed for

Ebola, as well as other single-strand RNA viruses, including

coronavirus-related viruses, SARS (112) and MERS (49).

Remdesivir (RDV) gets incorporated into viral RNA, and

targets RNA polymerase thereafter, and thus inhibits viral

replication. RDV has shown to inhibit coronavirus replica-

tion in cell culture and animal models (16,112). Accord-

ingly, it is very plausible that this drug would work in

clinical settings (3,16). There are still pending multiple

clinical trials with larger sample size, with a target of

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thousands patients. Until data from such trials are published,

we need to interpret results about RDV efﬁcacy and safety

very cautiously (37,84,102).

Presently, there have been published results about the

compassionate use of RDV in treating patients hospitalized

for COVID-19 (50). Clinical improvement in oxygen-

support class was observed in 68% (36/61) of patients, 47%

(25/61) of patients were discharged, and mortality was 13%

(7/61). While results from this study is promising, this study

lacked a control arm and is underpowered (49). Therefore,

the efﬁcacy and safety of RDV should be further evaluated

with randomized, placebo-controlled trials.

On a larger scale, a multicenter, placebo-controlled RCT,

which recruited 237 patients with severe COVID-19 symp-

toms, recently evaluated the efﬁcacy and safety of RDV

(113). Patients were randomized in a 2:1 ratio either to re-

ceive IV RDV (200mg on Day 1 followed by 100mg for

days 2–10) versus placebo. There was no statistical difference

in time to clinical improvement in both groups, as well as

adverse events and mortality rate. However, more patients in

the RDV group discontinued the drug due to adverse events

(12%) compared with placebo (5%), and the trial was

therefore stopped before the intended sample size is reached

(113). While the later study was a well-designed RCT to

evaluate efﬁcacy and safety of RDV, it is still too early to

judge the success or failure of RDV from this study. First, the

intended sample size was 453 and since the trial was stopped

early, this lead to underpowered results. Second, there is no

consensus on what is minimally accepted clinical improve-

ment difference, since this was the ﬁrst RCT evaluating RDV.

Favipiravir. Favipiravir, another RNA polymerase in-

hibitor, marketed as Avigan, developed by Fujiﬁlm, Toya-

ma, in Japan is being tested for efﬁcacy and safety in China.

Previous studies showed that favipiravir, the anti-inﬂuenza

drug, inhibits SARS-CoV2 in some cultured cells and pro-

tects mice against Ebola (101). So far, favipiravir was

compared with the anti-HIV combination lopinavir in 80

patients in a nonrandomized trial. On day 1, the intervention

arm took 1,600 mg of favipiravir twice (in two separate

doses), in addition to inhaled interferon. On day 2 until the

end, the dose was reduced to 600 mg twice daily, and they

kept taking inhaled interferon. The control group received

lopinavir/ritonavir for 14 days at a dosage of 400 mg, then

100 mg, twice daily, with inhaled interferon (12).

The preliminary results showed that favipiravir may po-

tentially be superior to lopinavir/ritonavir, as evidenced by

better chest X-ray images and thus lung improvement in the

intervention group, an effect that was interestingly inde-

pendent of viral load reduction effect. No signiﬁcant adverse

reactions were noted in the favipiravir treatment group, and

it had signiﬁcantly fewer adverse effects than the lopina-

vir/ritonavir group. In addition, a recent preprint showed

that this drug is superior to arbidol in terms of latency to

relief fever and cough, but did not signiﬁcantly improve

clinical recovery rate after 1 week of treatment (21).

Prodrug EIDD-2801. Base-modiﬁed nucleoside analog,

beta-D-N(4)-hydroxycytidine (NHC), has shown potent an-

tiviral activity against wide spectrum of viruses, such as

Venezuelan equine encephalitis virus (VEEV), respiratory

syncytial virus (RSV), inﬂuenza A virus (IAV), inﬂuenza B

virus (IBV), chikungunya virus (CHIKV), and CoVs, plau-

sible through inducing mutagenesis in the viral RNA (92).

The novel broad-spectrum antiviral drug was tested in

mouse pathogenesis models of SARS-CoV2 and MERS-

CoV for both prophylactic as well as therapeutic use (100).

This drug was shown to reduce viral load in the lungs and to

improve the pulmonary function, provided its use within 24–

48 h of the symptoms’ initiation. Very recently, this drug

passed phase 1 trial and was found to be safe, and therefore

Ridgeback biotherapeutics, a majority-women-owned bio-

technology company, announced the commencement of two

phase 2 trials to test the efﬁcacy of EIDD-2801 as an anti-

viral medication for COVID-19 in newly diagnosed and

hospitalized patients, respectively (95).

Biologics

It was found that patients who had higher concentrations

of proinﬂammatory cytokines and chemokines, were more

likely to be admitted to an intensive care unit, namely,

G-CSF, IP-10/CXCL10, monocyte chemoattractant protein

1 (MCP1), and TNFa, as well as elevated cytokines from T

helper 2 cells such as Interleukin (IL)-4 and reduced IL-10

(34,71). Therefore, it is tempting to assume that interfering

with these inﬂammatory pathways can potentially amelio-

rate symptoms of COVID-19.

IL-6 inhibitors. Genentech



, with collaboration with the

Food and Drug Administration (FDA), commenced a ran-

domized, double-blind, placebo-controlled phase 3 clinical

trial to examine the safety and efﬁcacy of tocilizumab in

addition to standard care in hospitalized adult patients with

severe COVID-19 pneumonia compared with placebo plus

standard care. The primary and secondary endpoints of the

study include clinical status, mortality, mechanical ventila-

tion, and ICU variables (41). Two trials are held to test the

efﬁcacy and safety of tocilizumab in the management of

COVID-19. A 150-patient unblinded RCT is assessing to-

cilizumab in combination with favipiravir, compared against

each drug alone, with time clinical cure rate as the major

outcome (NCT04310228) (40).

Another Chinese multicenter RCT trial with 188 patients

is assessing tocilizumab alone versus standard care in pa-

tients with severe COVID-19 and elevated IL-6 levels

(ChiCTR2000029765) (1). An open-label, noncontrolled,

nonpeer-reviewed study was conducted in China in 21 pa-

tients with severe respiratory symptoms related to COVID-

19. In addition to standard care (including lopinavir and

methylprednisolone), patients received a single dose of in-

travenous infusion with 400 mg tocilizumab. There was a

clinical improvement as patients had less oxygen require-

ments, normalized lymphocyte counts, and 19 patients were

discharged after about 2 weeks of tocilizumab treatment

(82). It is noteworthy that this study had a small sample size

and no control arm, therefore, results should be interpreted

with extreme caution.

Sarilumab, and leronlimab are other IL-6 inhibitors,

which are being evaluated in critically and severely ill

COVID-19 patients. Sarilumab is tested in a phase 2/3 trial,

which is multicenter, double-blind, trial with an adaptive

design, which is anticipated to enrol around 400 patients.

The evaluation of outcomes will occur on two stages. In the

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ﬁrst one, the effect of sarilumab on fever and the need for

supplemental oxygen will be examined. The second, will

assess longer-term outcomes, such as mortality and the need

for mechanical ventilation, supplemental oxygen, and/or

hospitalization (93).

Leronlimab, a chemokine receptor type 5 antagonist, will

also be evaluated in a phase 2b/3 trial (106). As of mid-April,

one severely ill COVID-19 patient and 15 mild/moderate pa-

tients were enrolled. The mortality rate will be assessed at 2

and 4-week intervals. An interim analysis will be performed

on the ﬁrst 50 patients. This agent has been granted a Fast

Track designation from the FDA for two potential indications

of COVID-19. The drug was chosen based on preliminary

results, in eight severely ill COVID-19 patients who demon-

strated a signiﬁcant improvement in several important im-

munologic biomarkers after a 3-day course of Leronlimab.

Patient test data reveal reduction in cytokines, IL-6, and a

pattern of normalization of the CD4/CD8 ratio (106).

Interferon-beta. Interferon-beta (INF-b) is an endoge-

nous protein, which coordinates the antiviral response.

Studies showed that deﬁciency in IFN-bproduction in-

creases the odds of a more severe lower respiratory tract

disease during respiratory viral infections, especially in

those at risk. Interestingly, viruses, including coronaviruses

such as SARS-CoV (5) and MERS-CoV, (99) have devel-

oped mechanisms, which suppress endogenous INF-bpro-

duction that augments the virus’s ability to escape the innate

immune system. It is therefore expected that the addition of

exogenous INF-bbefore or during viral infection of the

lower respiratory system would either prevent or greatly

diminish cell damage and viral replication, respectively.

Synairgen



, a respiratory drug development company,

developed IFN-b-1a for direct delivery to the lungs through

nebulization. It is pH neutral, and is free of mannitol, argi-

nine, and human serum albumin, making it suitable for in-

haled delivery direct to the site of action. With collaboration

of the National Institute of Health (NIH), Synairgen have

shown that INF-bcould protect against SARS-COV2 infec-

tion of lung cells in vitro (75). Very recently, a double-blind,

placebo-controlled Phase 2 trial in COVID-19 patients is

taking place. It is anticipated to recruit 100 COVID-19 pa-

tients, will take place across a number of NHS trusts, and has

been adopted by the NIH Research (NIHR) Respiratory

Translational Research Collaboration, which consists of

leading centers in respiratory medicine in the UK (2).

Granulocyte/macrophage colony-stimulating factor alpha

monoclonal antibody (Mavrilimumab). Granulocyte/macro-

phage colony-stimulating factor alpha (GM-CSFRa)works

upstream of interleukin-6 in the pathophysiology of the hy-

perinﬂammation associated with severe pneumonia of

COVID-19 (71). Mavrilimumab, an investigational fully hu-

man monoclonal antibody that inhibits GM-CSFRa,isnow

being tested in uncontrolled, single-center pilot study (61).

Patients with severe pneumonia from COVID-19, deﬁned as

acute respiratory distress, fever, and clinical and biological

markers of systemic hyperinﬂammation status were treated

with a single intravenous dose of mavrilimumab.

To date, six patients have been treated with this drug.

While being well tolerated, all patients showed an early

resolution of fever and improvement in oxygenation within

1–3 days. Interestingly, none of these patients has pro-

gressed to require mechanical ventilation and half of them

were discharged within 5 days (61).

Dexamethasone. Dexamethasone is a synthetic sys-

temic glucocorticoid, which is known for its potent anti-

inﬂammatory effect (62). Dexamethasone acts by suppressing

proinﬂammatory cytokines IL-1, IL-2, IL-6, IL-8, TNF, and

IFN-c, all of which are linked to COVID-19 severity. In vitro

studies showed that dexamethasone protected alveolar cells

from destruction by proinﬂammatory cytokines (62).

Preliminary results from the RCOVERY Trial showed

that dexamethasone reduced the mortality rate in hospital-

ized COVID-19 patients when compared with those given

usual care (54). Indeed, 454/2,104 (21.6%) patients allo-

cated dexamethasone and 1,065/4,321 (24.6%) patients

allocated usual care died within 28 days (age-adjusted

rate ratio =0.83; and 95% conﬁdence interval 0.74–0.92;

p<0.001), which was dependent on the level of respiratory

support at randomization. Thus, the signiﬁcant reduction in

mortality in the dexamethasone group was mostly signiﬁ-

cant among those receiving invasive mechanical ventilation

or oxygen at randomization, but not among patients not

receiving respiratory support (54).

Plasma of recovered COVID-19 patients

Plasma from patients who recovered from COVID-19

contains the SARS-CoV2-speciﬁc neutralizing antibodies,

which could infer a passive immunity to the recipients. The

later can be utilized to produce two potential therapeutic

modalities: convalescent plasma and hyperimmune immu-

noglobulins. A recent Cochrane living review summarized

20 studies, including one RCT, 3 nonrandomized controlled

trials, and 16 non-randomized noncontrolled trials. Collec-

tively, the controlled trials showed that there was a low-

certainty evidence about the effectiveness of these therapies

in reducing all-cause mortality, time to death, or even im-

provement of clinical symptoms, as assessed by the need of

respiratory support.

For the safety, the majority of evidence comes from the

uncontrolled trials. These studies reported side effects, in-

cluding death, anaphylaxis, dyspnea, and lung injury, but

most of them were found to be transfusion related. So until

more properly designed studies are available plasma-derived

therapies cannot be reliably recommended for the manage-

ment (90).

Conclusions and Future Insights

In this review we tried to explore and explain the disease

in a timely and comprehensive manner over the years.

During those years, lots of challenges faced the scientists

and researchers. Complete understanding of the viral

mechanism of action and the process and mechanism of the

immune system in the presence of the virus is needed to

determine the potential therapeutic options for SARS-CoV2

and all were and are still being investigated globally.

Future studies should focus on targeting more sites of

viral entry and replication, which was the basis for inves-

tigating drugs like hydroxychloroquine and RDV, respec-

tively. For instance, it was found that the spike glycoprotein

of the new coronavirus SARS-CoV2 contains a multibasic

8 ASSAF ET AL.

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furin-like cleavage site, which was lacking in other related

SARS-like coronaviruses (28). These viral fusion proteins are

activated by proteases in the host cell, therefore, any modi-

ﬁcations in the cleavage site/s with proteolytic activity will

alter the spike glycoprotein, which will ultimately dictate

viral membrane fusion, entry, and hence the tropism of the

host cell (28).

Furin is a convertase enzyme that is highly expressed in

lungs, so the novel SARS-CoV2 may successfully exploit

this convertase to activate its surface glycoprotein. Thus, the

inhibition of this enzyme might represent a novel target for

antiviral therapy. Inhibition of furin had shown to inhibit

proinﬂammatory and matrix protein production, such as

TGF-b, platelet-derived growth factor, TNF-a-Converting

Enzyme, and MMP2 in in vitro models (29) and conse-

quently reducing proinﬂammatory cytokines (TNF-a, IL-

1b), while increasing the anti-inﬂammatory IL-10 and IL-4,

in vivo (29).

Many furin inhibitors have been previously suggested in

literature to treat various diseases such as cancer as well as

bacterial and viral infections. Nevertheless, while furin can

have a role in controlling inﬂammation through its im-

munomodulation function, which can be very beneﬁcial

when treating immune-related diseases like COVID19, it

might also cause long-term adverse effects if used long

term. Therefore, more studies should be done to evaluate

their safety and efﬁcacy (29).

Furthermore, phenotypic screening strategy could be

used, which includes the identiﬁcation of molecules with

particular biological effects in cell-based assays or animal

models. This might entail screening large libraries of

chemical compounds in automated high-throughput cel-

lular assays that measure the levels of various proteins

or effects on characteristics, such as cell proliferation.

For example, just recently, the antiparasite ivermectin

was found to inhibit SARS-CoV2, when added to Vero-

hSLAM cells 2 h postinfection with SARS-CoV2 and

cause around *5,000-fold reduction in viral RNA at 48 h.

These interesting results merit further evaluation of this

medication (13).

Thereafter, ﬁnding the right animal model would be

crucial, which might be a challenge for this virus, which

exhibited various responses in different species. For exam-

ple, dogs and cats seem to handle this virus very well. But

either way, this process will take years, so the best we can

do is to repurpose existing medications for treatment of

COVID-19, while waiting for the vaccines.

In conclusion, according to results from the most recent

studies, antiviral and antimicrobial agents have limited use

in the management of coronavirus. RDV is only re-

commended by CDC in severe cases of COVID-19, and the

use of high-dose chloroquine is discouraged. Likewise, there

are still no sufﬁcient data to support immune-based therapy

beyond the context of clinical trials.

Author Disclosure Statement

The authors declare no conﬂict of interest.

Funding Information

No funding was received for this article.

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Address correspondence to:

Prof. Areej M. Assaf

Department of Biopharmaceutics and Clinical Pharmacy

School of Pharmacy

The University of Jordan

Amman 11942

Jordan

E-mail: areej_assaf@ju.edu.jo;

areej_assaf@hotmail.com

THE STORY OF SARS-COV-2 13

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The Polish COVID Stress Scales: Considerations of psychometric functioning, measurement invariance, and validity

Article

Full-text available

Dec 2021
PLOS ONE

The COVID Stress Scales (CSS) were developed to measure stress in response to the COVID-19 pandemic. To further investigate the psychometric properties of the CSS, we used data collected in Poland across two waves of assessment (N = 556 at T1 and N = 264 at T2) to evaluate the factor structure, reliability (at the item and scale level), measurement invariance (across the Polish and Dutch translations of the CSS, and time), over time stability, and external associations of the Polish-language version of the CSS (CSS-PL). Overall, results suggest that the CSS-PL is psychometrically robust, largely invariant across the countries and time-lags considered. The CSS-PL was also positively related to other measures of COVID-19 fear, health anxiety, obsessive compulsive symptoms, anxiety, depression, and intent to receive a COVID-19 vaccine. This study thus provides considerable information about the CSS’s items and scales, and lays the foundation for future investigations into COVID stress across time and different populations.

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Article

Full-text available

Sep 2023

Nosebleed or epistaxis is one of the most common forms of presenting an emergency in the ENT field. Since March 11, 2020, the World Health Organisation has proclaimed COVID-19 a global pandemic, and the world has been closed down. The main objective of the study is to analyse and compare the dynamics of epistaxis aetiology among the cases that required hospitalisation in the pre-pandemic period and the period of the COVID 19 pandemic. The study is multicenter retrospective from October 2018 to May 2022, including 380 cases of hospitalised epistaxis, with the mention that March 2020 is considered the beginning of the pandemic period. 60.8% of the patients enrolled in the study in the pre-pandemic period (60.8%) and 39.2% in the pandemic period. Differences between groups were not statistically significant between study entries (pre-pandemic vs. pandemic) and age (p=0.331), gender (p=0.916) or existence of local causes for epistaxis (p=0.895). Patients with general causes for epistaxis were more frequently enrolled in the pandemic period, while patients without general causes for epistaxis were more frequently enrolled in the pre-pandemic period. Patients with a hospitalisation period of more than 5 days were more frequently enrolled in the pre-pandemic period while patients with a hospitalisation period of 3 to 5 days were more frequently enrolled in the pandemic period. Also, patients with idiopathic epistaxis were more frequently enrolled in the pre-pandemic period. Based on the results presented in our study, the period of the Covid 19 pandemic directly influenced both the number of patients and the period of hospitalisation.

Red Blood Cell Malfunction in COVID-19: Molecular Mechanisms and Therapeutic Targets

Article

Nov 2022
VIRAL IMMUNOL

The world has been facing a pandemic for the past 2 years. COVID-19 still leads to millions of deaths worldwide , while deteriorating the global economy. The need for therapeutic targets, thus, remains. Interestingly, red blood cells, apart from gas exchange, also serve as modulators of innate and adaptive immunity. This function is accommodated mainly by surface molecules (proteins, lipids, and carbohydrates) and increased antioxidant capacity. However, under the circumstances of a disease state, red blood cells can become proinflammatory cells. Recent evidence has shown that, in the context of COVID-19, erythrocytes present protein oxidation, decreased antioxidant capacity, increased glycolysis, altered membrane lipidome, increased binding of Cytosine-Guanine (CpG) DNA and complement proteins, and low CD47 levels. These changes lead to an erythrocyte-dependent inflammation, which possibly participates in the hyperinflammation status of COVID-19. The current knowledge for the dysfunction of red blood cells during COVID-19 implies that the BAND3 protein and toll-like receptor 9 are potential therapeutic targets for COVID-19.

Prevalence and predictors of self‐medication drugs to prevent or treat COVID‐19: Experience from a Middle Eastern country

Article

Sep 2021

Background Lack of definitive cure for COVID-19 and the late introduction of a vaccine were responsible to push the general public to look for a remedy to treat or prevent COVID-19. The objective of this study was to evaluate patterns and factors that affect self-medication practices in Jordan during the pandemic. Methods This was a cross-sectional study using an online questionnaire that was developed, piloted and distributed to the general public via various social media platforms. The questionnaire assessed the type of drugs and treatments used to self -medicate, the reasons behind their self- medication, and the factors affecting their practices. Results A total of 1179 participants (females 46.4%) with a mean age of 32 (SD=12.5) completed the questionnaire. The overall prevalence of the use of at least one product to treat or prevent COVID-19 was 80.4 %. The most commonly used products to self-medicate were vitamin C (57.6%), followed by paracetamol (51.9%), zinc (44.8%) and vitamin D (32.5%). Female gender (odds ratio [OR]) = 1.603, working in the medical field (OR =1.697), and history of COVID-19 infection (OR =2.026) were variables associated with self-medication. The most common sources of participants’ information about drugs to prevent or treat COVID-19 were newspapers (n=519, 44.0%), followed by pharmacists (43.4%), friends (33.8%) and internet searching such as Google (30.7%). Conclusion This study identified the main drugs and supplements used during COVID-19 and the motives behind their use. It also identified the most influential source of information on the public during the pandemic. Self-medication can lead to worsening of the patient’s health and delay seeking medical advice from healthcare professionals. Efforts should be done to help mitigate risks of self-medications by active involvement of pharmacists and other members of healthcare team to refute false claims about drug, especially in the media.

Prevalence and predictors of self-medication drugs to prevent or treat COVID-19: experience from a Middle Eastern country

Preprint

Jul 2021

Across the Vast Land—Some Aspects on Libya’s Geography

Chapter

Full-text available

Aug 2020

In a historical context, the term Libya has a really long tradition. Herodotus, for example, used it to describe an area that covers the Northern part of Africa between the Atlantic Ocean in the west and the Red Sea in the east. At that time, Libya was known to be a separate continent, the third one besides Europe and Asia.

On Major Trans-Saharan Trails

Chapter

Full-text available

Aug 2020

The map “Important Caravan Tracks and Oases” offers an overview of the progression of the most significant caravan and pilgrim routes and local trading routes. It reveals the location of the most important oases in present-day Libya.

Across the Sahara - Tracks, Trade and Cross-Cultural Exchange in Libya

Book

Full-text available

Aug 2020

This open access book provides a multi-perspective approach to the caravan trade in the Sahara during the 19th century. Based on travelogues from European travelers, recently found Arab sources, historical maps and results from several expeditions, the book gives an overview of the historical periods of the caravan trade as well as detailed information about the infrastructure which was necessary to establish those trade networks. Included are a variety of unique historical and recent maps as well as remote sensing images of the important trade routes and the corresponding historic oases. To give a deeper understanding of how those trading networks work, aspects such as culturally influenced concepts of spatial orientation are discussed. The book aims to be a useful reference for the caravan trade in the Sahara, that can be recommended both to students and to specialists and researchers in the field of Geography, History and African Studies. Link: https://link.springer.com/book/10.1007/978-3-030-00145-2

Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection

Preprint

Full-text available

Jul 2020

Antibody (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re-infection. Using sequential serum samples collected up to 94 days post onset of symptoms (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody (nAb) responses when sampled beyond 8 days POS. We demonstrate that the magnitude of the nAb response is dependent upon the disease severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow up period. Whilst some individuals with high peak ID 50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID 50 had titres approaching baseline within the follow up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy′s and St Thomas′ Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection that causes low disease severity and the circulating seasonal coronaviruses that are associated with common colds. This study has important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection.

The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging”

Article

Full-text available

Sep 2020
INFLAMM RES

Purpose: Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely, ample evidences have been shown that the severity of COVID-19 infections varies widely from children (asymptomatic), adults (mild infection), as well as elderly adults (deadly critical). It has proven that COVID-19 infection in some elderly critical adults leads to a cytokine storm, which is characterized by severe systemic elevation of several pro-inflammatory cytokines. Then, a cytokine storm can induce edematous, ARDS, pneumonia, as well as multiple organ failure in aged patients. It is far from clear till now why cytokine storm induces in only COVID-19 elderly patients, and not in young patients. However, it seems that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, which is characterized by "inflamm-aging". It is highly likely that "inflamm-aging" is correlated to increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection. Methods: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for COVID-19, Coronavirus, SARS-CoV-2, senescent cell, cytokine storm, inflame-aging, ACE2 receptor, autophagy, and Vitamin D. Electronic database searches combined and duplicates were removed. Results: The aim of the present review was to summarize experimental data and clinical observations that linked the pathophysiology mechanisms of "inflamm-aging", mild-grade inflammation, and cytokine storm in some elderly adults with severe COVID-19 infection.

COVID 19: A Clue From Innate Immunity

Article

Full-text available

Jun 2020
IMMUNOL RES

The recent COVID-19 pandemic has had a significant impact on our lives and has rapidly expanded to reach more than 4 million cases worldwide by May 2020. These cases are characterized by extreme variability, from a mild or asymptomatic form lasting for a few days up to severe forms of interstitial pneumonia that may require ventilatory therapy and can lead to patient death.Several hypotheses have been drawn up to understand the role of the interaction between the infectious agent and the immune system in the development of the disease and the most severe forms; the role of the cytokine storm seems important.Innate immunity, as one of the first elements of guest interaction with different infectious agents, could play an important role in the development of the cytokine storm and be responsible for boosting more severe forms. Therefore, it seems important to study also this important arm of the immune system to adequately understand the pathogenesis of the disease. Research on this topic is also needed to develop therapeutic strategies for treatment of this disease.

COVID 19: a clue from innate immunity

Article

Full-text available

Jun 2020

The recent COVID-19 pandemic has had a significant impact on our lives and has rapidly expanded to reach more than 4 million cases worldwide by May 2020. These cases are characterized by extreme variability, from a mild or asymptomatic form lasting for a few days up to severe forms of interstitial pneumonia that may require ventilatory therapy and can lead to patient death. Several hypotheses have been drawn up to understand the role of the interaction between the infectious agent and the immune system in the development of the disease and the most severe forms; the role of the cytokine storm seems important. Innate immunity, as one of the first elements of guest interaction with different infectious agents, could play an important role in the development of the cytokine storm and be responsible for boosting more severe forms. Therefore, it seems important to study also this important arm of the immune system to adequately understand the pathogenesis of the disease. Research on this topic is also needed to develop therapeutic strategies for treatment of this disease.

A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19

Article

Full-text available

May 2020

Objective: To evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the treatment of patients with moderate coronavirus disease 2019 (COVID-19). Methods: We prospectively enrolled 30 treatment-naïve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Center. The patients were randomized 1：1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only. The primary endpoint was negative conversion rate of SARS-CoV-2 nucleic acid in respiratory pharyngeal swab on days 7 after randomization. This study has been approved by the Ethics Committee of Shanghai Public Health Clinical Center and registered online (NCT04261517). Results: One patient in HCQ group developed to severe during the treatment. On day 7, nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). The median duration from hospitalization to virus nucleic acid negative conservation was 4 (1,9) days in HCQ group, which is comparable to that in the control group [2 (1,4) days, Z=1.27, P>0.05]. The median time for body temperature normalization in HCQ group was 1 (0,2) day after hospitalization, which was also comparable to that in the control group [1 (0,3) day]. Radiological progression was shown on CT images in 5 cases (33.3%) of the HCQ group and 7 cases (46.7%) of the control group, and all patients showed improvement in follow-up examinations. Four cases (26.7%) of the HCQ group and 3 cases (20%) of the control group had transient diarrhea and abnormal liver function (P>0.05). Conclusions: The prognosis of COVID-19 moderate patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.

The dynamics of humoral immune responses following SARS-CoV-2 infection and the potential for reinfection

Article

Full-text available

May 2020

SARS-CoV-2 is a novel coronavirus that is the causative agent of coronavirus infectious disease 2019 (COVID-19). As of 17 April 2020, it has infected 2 114 269 people, resulting in 145 144 deaths. The timing, magnitude and longevity of humoral immunity is not yet understood for SARS-CoV-2. Nevertheless, understanding this is urgently required to inform the likely future dynamics of the pandemic, to guide strategies to allow relaxation of social distancing measures and to understand how to deploy limiting vaccine doses when they become available to achieve maximum impact. SARS-CoV-2 is the seventh human coronavirus to be described. Four human coronaviruses circulate seasonally and cause common colds. Two other coronaviruses, SARS and MERS, have crossed from animal sources into humans but have not become endemic. Here we review what is known about the human humoral immune response to epidemic SARS CoV and MERS CoV and to the seasonal, endemic coronaviruses. Then we summarize recent, mostly non-peer reviewed, studies into SARS-CoV-2 serology and reinfection in humans and non-human primates and summarize current pressing research needs.

The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) — China, 2020

Article

Jan 2020

Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review

Article

Oct 2020

Background: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required. OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. Search methods: We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 19 August 2020. Selection criteria: We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. Data collection and analysis: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' 2.0 tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, mortality (time to event), improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events (AEs), and serious adverse events (SAEs). Main results: This is the second living update of our review. We included 19 studies (2 RCTs, 8 controlled NRSIs, 9 non-controlled NRSIs) with 38,160 participants, of whom 36,081 received convalescent plasma. Two completed RCTs are awaiting assessment (published after 19 August 2020). We identified a further 138 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 73 are randomised (3 reported in a study registry as already being completed, but without results). We did not identify any completed studies evaluating hyperimmune immunoglobulin. We did not include data from controlled NRSIs in data synthesis because of critical risk of bias. The overall certainty of evidence was low to very low, due to study limitations and results including both potential benefits and harms. Effectiveness of convalescent plasma for people with COVID-19 We included results from two RCTs (both stopped early) with 189 participants, of whom 95 received convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. We are uncertain whether convalescent plasma decreases all-cause mortality at hospital discharge (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.22 to 1.34; 1 RCT, 86 participants; low-certainty evidence). We are uncertain whether convalescent plasma decreases mortality (time to event) (hazard ratio (HR) 0.64, 95% CI 0.33 to 1.25; 2 RCTs, 189 participants; low-certainty evidence). Convalescent plasma may result in little to no difference in improvement of clinical symptoms (i.e. need for respiratory support) at seven days (RR 0.98, 95% CI 0.30 to 3.19; 1 RCT, 103 participants; low-certainty evidence). Convalescent plasma may increase improvement of clinical symptoms at up to 15 days (RR 1.34, 95% CI 0.85 to 2.11; 2 RCTs, 189 participants; low-certainty evidence), and at up to 30 days (RR 1.13, 95% CI 0.88 to 1.43; 2 studies, 188 participants; low-certainty evidence). No studies reported on quality of life. Safety of convalescent plasma for people with COVID-19 We included results from two RCTs, eight controlled NRSIs and nine non-controlled NRSIs assessing safety of convalescent plasma. Reporting of safety data and duration of follow-up was variable. The controlled studies reported on AEs and SAEs only in participants receiving convalescent plasma. Some, but not all, studies included death as a SAE. The studies did not report the grade of AEs. Fourteen studies (566 participants) reported on AEs of possible grade 3 or 4 severity. The majority of these AEs were allergic or respiratory events. We are very uncertain whether convalescent plasma therapy affects the risk of moderate to severe AEs (very low-certainty evidence). 17 studies (35,944 participants) assessed SAEs for 20,622 of its participants. The majority of participants were from one non-controlled NRSI (20,000 participants), which reported on SAEs within the first four hours and within an additional seven days after transfusion. There were 63 deaths, 12 were possibly and one was probably related to transfusion. There were 146 SAEs within four hours and 1136 SAEs within seven days post-transfusion. These were predominantly allergic or respiratory, thrombotic or thromboembolic and cardiac events. We are uncertain whether convalescent plasma therapy results in a clinically relevant increased risk of SAEs (low-certainty evidence). Authors' conclusions: We are uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. There was limited information regarding grade 3 and 4 AEs to determine the effect of convalescent plasma therapy on clinically relevant SAEs. In the absence of a control group, we are unable to assess the relative safety of convalescent plasma therapy. While major efforts to conduct research on COVID-19 are being made, recruiting the anticipated number of participants into these studies is problematic. The early termination of the first two RCTs investigating convalescent plasma, and the lack of data from 20 studies that have completed or were due to complete at the time of this update illustrate these challenges. Well-designed studies should be prioritised. Moreover, studies should report outcomes in the same way, and should consider the importance of maintaining comparability in terms of co-interventions administered in all study arms. There are 138 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 73 are RCTs (three already completed). This is the second living update of the review, and we will continue to update this review periodically. Future updates may show different results to those reported here.

Pre-existing immunity to SARS-CoV-2: the knowns and unknowns

Article

Jul 2020
NAT REV IMMUNOL

T cell reactivity against SARS-CoV-2 was observed in unexposed people; however, the source and clinical relevance of the reactivity remains unknown. It is speculated that this reflects T cell memory to circulating ‘common cold’ coronaviruses. It will be important to define specificities of these T cells and assess their association with COVID-19 disease severity and vaccine responses. Recent studies have shown T cell reactivity to SARS-CoV-2 in 20–50% of unexposed individuals; it is speculated that this is due to T cell memory to common cold coronaviruses. Here, Crotty and Sette discuss the potential implications of these findings for disease severity, herd immunity and vaccine development.

It is Time to Address Airborne Transmission of COVID-19

Article

Jul 2020
CLIN INFECT DIS

COVID-19: Between Past and Present

Abstract

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