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COVID‐19 under spotlight: A close look at the origin, transmission, diagnosis, and treatment of the 2019‐nCoV disease

September 2020
Journal of Cellular Physiology 235(12):8873-8924

September 2020
235(12):8873-8924

DOI:10.1002/jcp.29735

Authors:

Roghayeh Sheervalilou

Zahedan University of Medical Sciences

Milad Shirvaliloo

Iran University of Medical Sciences

Nahid Dadashzadeh

Iranian Legal Medicine Organization

Sakine Shirvaliloo

Iran University of Medical Sciences

Show all 9 authorsHide

Months after the outbreak of a new flu‐like disease in China, the entire world is now in a state of caution. The subsequent less‐anticipated propagation of the novel coronavirus disease, formally known as COVID‐19, not only made it to headlines by an overwhelmingly high transmission rate and fatality reports, but also raised an alarm for the medical community all around the globe. Since the causative agent, SARS‐CoV‐2, is a recently discovered species, there is no specific medicine for downright treatment of the infection. This has led to an unprecedented societal fear of the newly born disease, adding a psychological aspect to the physical manifestation of the virus. Herein, the COVID‐19 structure, epidemiology, pathogenesis, etiology, diagnosis, and therapy have been reviewed.

Presents a schematic of viral structure and the entry mechanism of SARS‐CoV‐2.

…

Figures - uploaded by Milad Shirvaliloo

Content may be subject to copyright.

Content uploaded by Milad Shirvaliloo

Content may be subject to copyright.

Received: 13 April 2020

Accepted: 17 April 2020

DOI: 10.1002/jcp.29735

MINI‐REVIEW

COVID‐19 under spotlight: A close look at the origin,

transmission, diagnosis, and treatment of the 2019‐nCoV

disease

Roghayeh Sheervalilou

|Milad Shirvaliloo

|Nahid Dadashzadeh

Sakine Shirvalilou

|Omolbanin Shahraki

|Younes Pilehvar‐Soltanahmadi

Habib Ghaznavi

|Samideh Khoei

|Ziba Nazarlou

Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran

Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran

Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran

Cellular and Molecular Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia, Iran

Zahedan University of Medical Sciences, Zahedan, Iran

Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

Material Engineering Department, College of Science Koç University, Istanbul, Turkey

Correspondence

Habib Ghaznavi, Zahedan University of

Medical Sciences, Zahedan 9816743463, Iran.

Email: ghaznavih@yahoo.com and

dr.ghaznavi@zaums.ac.ir

Samideh Khoei, Department of Medical

Physics, School of Medicine, Iran University

of Medical Sciences, Tehran, Iran.

Email: khoei.s@iums.ac.ir and

skhoei@gmail.com

Abstract

Months after the outbreak of a new flu‐like disease in China, the entire world is now

in a state of caution. The subsequent less‐anticipated propagation of the novel

coronavirus disease, formally known as COVID‐19, not only made it to headlines by

an overwhelmingly high transmission rate and fatality reports, but also raised an

alarm for the medical community all around the globe. Since the causative agent,

SARS‐CoV‐2, is a recently discovered species, there is no specific medicine for

downright treatment of the infection. This has led to an unprecedented societal fear

of the newly born disease, adding a psychological aspect to the physical manifes-

tation of the virus. Herein, the COVID‐19 structure, epidemiology, pathogenesis,

etiology, diagnosis, and therapy have been reviewed.

KEYWORDS

2019‐nCoV or COVID‐19 or SARS‐CoV‐2, diagnosis, epidemiology, etiology, pathogenesis,

therapy

1|INTRODUCTION

CoVs were recognized as “novel respiratory tract viruses”over

half a century ago. The title was conferred in 1962, following the

examination of samples collected from individuals who had

manifested symptoms of respiratory tract infection (Hamre &

Procknow, 1966). Initially, CoVs were not considered as highly

pathogenic for humans. That was until 2002, however, that CoVs

emerged in the form of Severe Acute Respiratory Syndrome

(SARS) in the Guangdong state of China (Sahin et al., 2020).

Almost a decade later, another highly pathogenic CoV appeared

in the Middle East countries, which similarly led to severe

respiratory symptoms of acute onset. The then‐novel species

was named Middle East Respiratory Syndrome Coronavirus

(MERS‐CoV; Zaki, Van Boheemen, Bestebroer, Osterhaus, &

Fouchier, 2012).

In December 2019, a cluster of insidious Coronavirus infec-

tions was reported in the Huanan Seafood Market, located in

Wuhan State of Hubei Province in China. Unlike the name, live-

stock animals were also traded in the market alongside their

marine relatives. Days later, the cluster turned into a local net-

work and set off the alarm for the Chinese government. It was

then that a pneumonia epidemic of unknown cause became the

focus of global attention (Sahin et al., 2020). Chinese authorities

announced on January 7, 2020 that a new type of CoV (novel CoV,

nCoV) was isolated (Imperial College London, 2020;WorldHealth

Organization, 2020). On December 12, 2019, a pneumonia case of

unknown origin was reported in Wuhan, China. Initial laboratory

tests ruled out Influenza and infection with recognized CoVs.

Following the incident, 27 new cases of pneumonia of viral origin

were officially reported on December 31, 2019. A week later on

January 7, 2020, the Chinese authorities announced that a new

species of CoV was isolated in the country (Zumla, Hui, Azhar,

Memish, & Maeurer, 2020).

Given the whereabouts of the first case ever reported, the in-

fection was speculated to have been contracted from a zoonotic

agent. Etiologic investigations on patients who had been hospitalized

with a similar medical history supported the likelihood of a viral

infection transmitted from animals to humans (Sahin et al., 2020;

World Health Organization, 2020; Yin & Wunderink, 2018). nCoV

was duly reported to have been originated from wild bats. Falling in

the category of group 2 β‐CoVs, the novel Coronavirus only shares a

70% similarity in genetic sequence with its predecessor, SARS‐CoV,

which also belongs to the exact same family (Gralinski &

Menachery, 2020).

The tantalizing surge in the number of cases infected with SARS‐

CoV‐2 in China, despite the closure of markets and evacuation of the

vicinity, fulfilled the burden of proof that the virus can also be

transmitted from human to human. Soon thereafter, peculiar cases of

acute respiratory syndrome started appearing in other Asian coun-

tries, ultimately spreading to North America and Europe. (Sahin

et al., 2020; World Health Organization, 2020; Yin & Wunderink,

2018). Following an emergent briefing on January 30, 2020,

The World Health Organization (WHO) declared the outbreak of

COVID‐19 as a Public Health Emergency of International Concern

(Organization, 2020).

The epidemic began to emerge with the advent of the Chinese

New Year, a traditionally important festival that is heavily celebrated

across the country. The coincidence paved the way for SARS‐CoV‐2

to turn into an unprecedented massive Coronavirus outbreak, which

required extensive measurements to be contained. With a population

of 10 million, Wuhan City also served as an important pathway for

millions of people traveling in celebration of the Spring Festival.

Accordingly, the number of cases to be diagnosed with COVID‐19

showed an overwhelming increase between January 10–22, 2020

(Chen, Zhang et al., 2020).

Despite the arbitrary speculations, not only did the recent

outbreak of COVID‐19 egress the country of origin, it also pro-

ceeded to become a global concern in the form of a pandemic

(Yang et al., 2020). COVID‐19 is an acute self‐resolving respiratory

disease in most of the cases, however, it can also be fatal in some

cases. The disease was initially reported to have a mortality rate of

2%. If severe, COVID‐19 might result in death as a result of the

preceding extensive alveolar damage, and failure of the lungs (Xu

et al., 2020). As of February 15, 2020, a total of 66,580 cases had

been confirmed, with over 1,524 deaths. However, there have no

specific reports on pathology, as performing an autopsy or biopsy

was not possible in most of the cases (Chan et al., 2020; Huang

et al., 2020). Table 1. Represents the WHO situation reports on

March 24, 2020 (www.WHO.int).

A total of 8,096 SARS cases and 774 deaths across 29 countries

were reported for an overall case‐fatality rate (CFR) of 9.6%. MERS is

still not contained and is thus far responsible for 2,494 confirmed

cases and 858 deaths across 27 countries for a CFR of 34.4%. De-

spite the much higher CFR of 9.6% and 34.4% for SARS and MERS,

the novel Coronavirus epidemic has led to a larger death toll. The

Chinese government had reported 72,528 confirmed cases, with

1,870 deaths, as of February 18, 2020. These statistics yield a

crude CFR of 2.6%. However, one should not haste to generalize

this number, as most possibly the total number of patients with

COVID‐19 is much higher. That is, because the cases are not readily

identifiable, as many asymptomatic patients are missed during the

process (Wu et al., 2020; Yan et al., 2020). Despite the higher

transmissibility than SARS and MERS, COVID‐19 is still a relatively

unknown disease and requires further investigations to be fully

understood (Yan et al., 2020).

TABLE 1 The number of cases and death

of Covid‐19 outbreak according to World

Health Organization statistics (April

13, 2020)

Region

Total (new) cases in

last 24 hr

Total (new) death in

last 24 hr

Globally 1,773,084 confirmed (76,498) 111,652 deaths (5,702)

Western Pacific Region 121,426 confirmed (1,310) 4,125 deaths (67)

European Region 913,349 confirmed (33,243) 77,419 deaths (3,183)

South‐East Asia Region 16,883 confirmed (842) 766 deaths (38)

Eastern Mediterranean Region 99,713 confirmed (3,768) 5,107 deaths (164)

American Region 610,742 confirmed (36,804) 23,759 deaths (2,228)

African Region 10,259 confirmed (531) 464 deaths (21)

SHEERVALILOU ET AL.

2|PATHOGENESIS

Initially, the virus interacts with sensitive human cells that exhibit

distinct receptors for the viral Spike protein. After making a suc-

cessful entry, the RNA‐based genome starts replicating itself, and

expressing specific sequences that results in production of useful

accessory proteins; facilitating the adaptation of CoV to its human

host (ViralZone., 2019). Alterations in genetic make‐up that result

from recombination, exchange, insertion, or deletion of genes, are

frequently reported among CoVs; a phenomenon that might have

played a part in the past epidemics (Sahin et al., 2020). Therefore,

the classification of CoVs is continuously being changed. Based on

the most recent classification provided by The International Com-

mittee on Taxonomy of Viruses, there are four genera of CoVs, that

comprise a total of 38 unique species (Subissi et al., 2014). Thus,

variable mechanisms could be involved in the process of pathogen-

esis. For instance, SARS‐CoV binds to angiotensin I converting en-

zyme 2 (ACE2). On the other hand, MERS‐CoV is more inclined to

attach the cellular receptor of dipeptidyl peptidase 4 (Lambeir,

Durinx, Scharpé, & De Meester, 2003). Following a cascade of signals

after binding, the viral genome is successfully injected into the target

cell. The genomic RNA that regulates the expression of structural and

nonstructural polyproteins, is polyadenylated and encapsulated.

These proteins are then cleaved by certain proteases that exhibit

chymotrypsin‐like activity (Lambeir et al., 2003; ViralZone, 2019).

Through replication and transcription, the resulting protein complex

drives the production of negative‐sense RNA or (−) RNA. Full‐length

(−)RNAs produced by replication are ultimately used as templates for

generation of positive‐sense RNA or (+) RNA (Luk, Li, Fung, Lau, &

Woo, 2019; ViralZone, 2019). All of the structural proteins are then

translated from a subset of 7–9 subgenomic RNAs, which are pro-

ducts of discontinuous transcription. The resulting protein complex is

the assembled together to envelope the viral genome, making a nu-

cleocapsid in the process, that will bud into the lumen of the en-

doplasmic reticulum to finally complete the intracellular cycle. Newly

formed virions are then expelled from the infected cell through

exocytosis. The CoVs released thereafter are now capable to infect

a wide spectrum of human cells, including lung, renal, hepatic, in-

testinal, and lower respiratory tract cells, as well as T lymphocytes

(Chhikara, Rathi, Singh, & Poonam, 2020; Lambeir et al., 2003).

Figure 1presents a schematic of viral structure and the entry

mechanism of SARS‐CoV‐2.

2.1 |Respiratory system

SARS‐CoV‐2 tends to infect the respiratory tract, thus, pneumonia

is a primary clinical finding in patients with COVID‐19 (Huang

et al., 2020; Li, Guan, et al., 2020;Zhuetal.,2020). However,

pneumonia is only a component of the SARS that might develop in

some cases. The resulting SARS may then be aggravated and lead

to serious conditions that are extremely difficult to control, for

example, septic shock, metabolic acidosis, and coagulation

dysfunction (Kofi Ayittey, Dzuvor, Kormla Ayittey, Bennita

Chiwero, & Habib, 2020).

Investigation on the radiological findings of COVID‐19‐

associated pneumonia have yielded little, if any, information that are

mostly unspecific. Progressive lung lesions are usually detected in

patients with COVID‐19, about 1 week after the onset of signs and

symptoms (Ooi et al., 2004). The lesions then become aggravated

during the 2nd week, and lead to formation of irregular reticular

opacities mixed with ground glass opacities (GGOs), which can be

detected by CT at the fourth week. In a recent cohort study, 85.7%

(54/63) of subjects with COVID‐19‐associated pneumonia showed

disease progression, defined by an increased extent of GGO, on early

follow‐up CT (Pan et al., 2020). Pulmonary fibrous cords was re-

ported in one particular patient that displayed signs of improvement,

as the inflammatory secretions had been absorbed (Pan &

Guan, 2020). Long‐term complications of COVID‐19 in patients

with severe pneumonia might include an array of fibrotic changes

often observed in the late stages of lung injury, for example, re-

ticulation, interlobular septal thickening, and traction bronchiectasis

(Kim, 2020).

2.2 |Immune system

There have been several reports that indicated meager Cytolethal

Distending Toxin‐induced lymphocytes, with a density as low as

200 cells/mm

in three patients with SARS‐CoV infection (Chu

et al., 2014; Zhou et al., 2014). As in the case of SARS‐CoV‐2, it has

been suspected that infection with this type of CoV might lead to

FIGURE 1 Presents a schematic of viral structure and the entry

mechanism of SARS‐CoV‐2

SHEERVALILOU ET AL.

inflammatory cytokine storm (Chen, Liu, et al., 2020; Zumla

et al., 2020); a life‐threatening condition characterized by elevated

levels of interleukin 6 (IL‐6) in plasma. A number of investigations

recently conducted on COVID‐19 have reported that IL‐6 levels was

actually higher in the patients with severe disease (Cai, 2020; Chen,

Liu, et al., 2020; Xiang et al., 2020). This could highlight the im-

portance of IL‐6 as a biomarker for evaluation of disease severity

(Chen, Zhao, et al., 2020).

2.3 |Liver damage

Impaired liver function tests have been reported for a number of

patients with SARS‐CoV‐2 infection, suggesting hepatic damage as an

extrapulmonary complication of COVID‐19 in almost one half of the

patients (Chen, Zhou, et al., 2020; Wang, Hu, et al., 2020). A recent

study has concluded that liver function abnormality might stem from

infection of bile duct cells with SARS‐CoV‐2. Nonetheless, the alka-

line phosphatase value, which is an index of bile duct damage, were

not specific in patients with COVID‐19 (Chen, Zhou, et al., 2020;

Wang, Hu, et al., 2020). Investigation of liver biopsy specimens was

accompanied by new pathological findings. Scientists have reported

moderate microvascular steatosis, and mild lobular and portal ac-

tivity in these patients, that suggests liver damage may have

arisen from either SARS‐CoV‐2 infection or drug‐induced liver

(Xu et al., 2020).

2.4 |Myocardial, gastrointestinal, and renal

symptoms: homeostasis of electrolytes

An essential player in maintenance of electrolyte balance and blood

pressure, ACE2 is regarded by many as the principal counter‐

regulatory arm in the axis of renin–angiotensin‐aldosterone system

(RAAS; Santos, Ferreira, & Simões e Silva, 2008). Upon infection,

SARS‐CoV‐2 binds ACE2. This results in degradation of ACE2,

which subsequently dampens the counter‐effect of ACE2 on RAAS.

The final effect of ACE2 in an otherwise healthy adult is to increase

reabsorption of sodium and the reciprocal excretion of potassium

ions (K

). The concomitant re‐uptake of water with sodium

reabsorption prompts an increase in blood pressure (Weir &

Rolfe, 2010). Potassium is the predominant intracellular ion, that is

majorly involved in regulation of cell membrane polarity. Too low

levels of K+ in blood, known as hypokalemia, can result in cellular

hyper‐polarity. A hyper‐polarized cell membrane tends to be depo-

larized faster than normal, causing aberrancy in the function of

cardiac cells (Bielecka‐Dabrowa et al., 2012).

In a recent cohort study, patients diagnosed with COVID‐19

were categorized into three groups: severe hypokalemia, hypokale-

mia, and normokalemia. The study reported that 93% of patients with

a severe clinical condition had hypokalemia. Scientists did not find a

direct link between gastrointestinal symptoms and hypokalemia

among 108 patients with both severe or moderate hypokalemia.

Further investigations established an association between para-

meters such as body temperature, creatine kinase (CK), creatine ki-

nase myocardial band (CK‐MB), lactate dehydrogenase (LDH), and

C‐reactive protein (CRP) with the severity of hypokalemia. Reportedly,

hypokalemia was most often observed with patients who had elevated

levels of serum CK, CK‐MB, LDH, and CRP. Potassium (K

) loss in the

urine was determined to be the primary cause of hypokalemia.

Hypokalemia requires strenuous efforts to be corrected. This is

chiefly due to the incessant loss of K

in the urine, as a result of ACE2

degradation. In the case of COVID‐19‐associated hypokalemia,

however, the patients seemed to respond well to potassium supple-

ments when the critical phase had passed [49]. Therefore, one should

consider the impact of hypokalemia in COVID‐19 morbidity, and its

effect on the outcomes of treatment. This is a condition that must

be carefully addressed for, as patients with COVID‐19 are more in-

clined to develop dysfunctions in heart, lungs, and other vital organs

(Li, Hu, Su, & Dai, 2020).

3|POSSIBLE FACTORS CORRELATED

WITH COVID‐19

3.1 |Sex

Several studies have sought to compare the sex differences in the

clinical findings of severe COVID‐19. In one study, scientists in-

vestigated 47 patients with COVID‐19, 28 (59.6%) of whom were

men. Procalcitonin (PCT) level was reported to be higher in men than

in women. The results also showed higher amounts of serum

N‐terminal‐pro brain natriuretic peptide, as increased levels of the

molecule were detected in men 57.1% than women 26.3%. Further-

more, 17.9% of male patients were reported test‐positive for influ-

enza A antibody, whereas no such records were registered for female

patients. During a 2‐week stay at the hospital, 17.9% of male, and

5.3% of female patients deteriorated, and hence were reassigned to

the critical‐type group. There was no mortality reports among wo-

men, whereas 3.6% of male patients had deceased due to COVID‐19

complications. A total of 21.1% and 3.6% of female and male patients

successfully recovered, and were discharged from the hospital. Based

on the current evidence, men are more likely to develop complica-

tions, and experience worse in‐hospital outcomes compared with

women (Li, Zhang, et al., 2020).

3.2 |Pregnancy

A group of researchers led by Chen investigated the clinical char-

acteristics of SARS‐CoV‐2 infection in nine pregnant women. Their

aim was to evaluate the likelihood of intrauterine/vertical transmis-

sion of SARS‐CoV‐2 from mother to baby. All of the women who

were being investigated had cesarean section in the third trimester

of their previous pregnancies. Seven patients were febrile, and vari-

ably presented other symptoms such as cough, sore throat, myalgia,

SHEERVALILOU ET AL.

and malaise. Fetal distress was reported in two cases. Lymphopenia

and increased aminotransferase activity were observed in five and

three patients, respectively. There was no mortality cases, as none of

the patients in the study developed severe COVID‐19‐associated

pneumonia. Nine livebirths were recorded. The newborns displayed

no signs of asphyxia. A 1‐min Apgar score of 8–9, and a 5‐min Apgar

score of 9–10 were calculated for all nine newborns. Samples col-

lected from six patients, including amniotic fluid, cord blood, neonatal

throat swab, and breastmilk proved test‐negative for SARS‐CoV‐2.

The clinical features of COVID‐19‐associated pneumonia observed in

these pregnant women shared a great similarity to characteristics

reported for COVID‐19‐associated pneumonia in nonpregnant adult

patients (Chen, Guo, et al., 2020).

3.3 |Blood type

In a recent investigation, scientists in China looked into the pattern

of blood type distribution in 2,173 patients in three hospitals, who

had been confirmed to have SARS‐CoV‐2 infection. Accordingly, they

compared their findings regarding the blood type of patients with

that of the healthy population who lived in the same area as the

patients in the study. Apparently, there was a higher prevalence of

blood type A among the patients with COVID‐19 than in the normal

population. On the contrary, it seemed that individuals with O blood

type were spared somehow, as there were fewer patients with this

blood type in this study (both p< .001). A series of meta‐analyses on

the available data indicated a significantly higher risk for COVID‐19

in people with blood type A, relative to individuals with non‐A blood

types. However, an opposite scenario seemed to be true for the

blood type O community, since, according to the literature, are less

susceptible for contracting infectious diseases such as COVID‐19

(Zhao et al., 2020).

4|ETIOLOGY: SOURCES AND MODES

OF TRANSMISSION

According to the literature, the pathogen and area of origin were

similar in both SARS and COVID‐19 outbreaks. However, despite this

similarity, the raised public awareness and extensive interventional

procedures that might have once proved effective for SARS con-

tainment, have been rendered ineffective against the 2019 novel

Coronavirus; as the disease is already more widespread than SARS

(Liu, Gayle, Wilder‐Smith, & Rocklöv, 2020). A large family of viruses,

CoVs are common among many different animal species, including

cattle, civets, camels, and bats. However, these CoVs are not solely

restricted to animal populations, as they can occasionally infect hu-

mans, bringing epidemics such as SARS, MERS, and in recent memory,

COVID‐19 (Sahin et al., 2020). Recent investigations conducted on

the origins of CoVs responsible for the past epidemics have reported

bats as the primary reservoir for both SARS‐CoV and MERS‐CoV;

suggesting that other animal species were involved in the process

merely as intermediate hosts. Accordingly, the majority of bat‐

associated CoVs belong to α‐CoV and β‐CoV genera, while almost all

of the avian CoVs fall in the other two genera; γ‐CoVs and δ‐CoVs

(Yin & Wunderink, 2018). It has been suggested that species re-

sponsible for the recent epidemic is reminiscent of the CoV isolated

in bats. Trafficking of wild animals in Huanan Seafood Market, lo-

cated in Wuhan State of Hubei Province in China, where the first

cases were reported, further supports this finding. Only 10 days

following the first outbreak, secondary cases started emerging. Al-

though the new cases had no contact with the marketplace, they did

have a history of social contact with the salesmen and people

who had previously been there. The growing pile of confirmed cases from

healthcare workers in Wuhan City is an strong indicator of human‐to‐

human transmission in the case of SARS‐CoV‐2(Sahinetal.,2020).

Transmission of the virus from human to human occurs mostly

with close contact. The short distance between individuals in close

social contacts makes it possible for respiratory droplets of the in-

fected person, released by coughing and sneezing, to reach other

people in the proximity. This is similar to the transmission of Influ-

enza and other respiratory infection. It still remains unclear if the

virus can be contracted by touching surfaces, and then touching

mouth, nose, or even eyes (WHO, 2020). Apparently, COVID‐19 is

considered most contagious when individuals infected with the virus

is symptomatic. However, there have been cases who reportedly had

contracted the disease from asymptomatic patients in the prodrome

period of COVID‐19. Transmission of the novel Coronavirus has yet

to be clarified by more investigations. (Rothe et al., 2020).

4.1 |Presumed asymptomatic carrier‐based

transmission of COVID‐19

Investigation on a familial cluster of five patients concluded that

SARS‐CoV‐2 might have actually been transmitted by an asympto-

matic carrier in the family (Bai et al., 2020). Surprisingly, the first

reverse transcription polymerase chain reaction (RT‐PCR) test of the

asymptomatic family member was reported negative; a noteworthy

example of a false‐negative result. Unwanted false‐negative results

are inevitably reported due to a number of factors, for example,

quality of the test kit, sufficiency of the collected sample, or per-

formance of the test by clinicians. To this date, RT‐PCR has widely

been used as a reliable diagnostic method (Corman et al., 2020).

Thus, her second RT‐PCR result, reported positive, was unlikely to

have been a false‐positive result; hence, it was accepted as the de-

finite evidence that the suspected person had indeed been infected

with SARS‐CoV‐2 (Bai et al., 2020).

There was also another study that reported an asymptomatic

young boy with COVID‐19 infection. However, CT scans obtained

from the subject exhibited abnormalities, indicative of an on‐going

pulmonary pathology (Chan et al., 2020). If we presume that the

findings regarding asymptomatic carrier‐based transmission of

COVID‐19 can be replicated, this would prove COVID‐19 an over-

whelmingly challenging issue to be controlled (Bai et al., 2020).

SHEERVALILOU ET AL.

The incubation period for the asymptomatic patient in the case of

familial cluster was 19 days. Despite being a long period, it still

perfectly falls in the suggested incubation period of 0–24 days (Bai

et al., 2020; Guan et al., 2020).

5|DIAGNOSIS

A proper diagnosis of COVID‐19 is made based on the following criteria,

which have been recently suggested based on the initial investigations:

(a) clinical signs and symptoms, (b) history of traveling or close contact

with people suspected to be infected, (c) positive test result for the

pathogen, and (d) pathologic findings on CT images. The key clinical

features of COVID‐19, though nonspecific, include fever, dry cough,

dyspnea, and pneumonia (Chen, Zhou, et al., 2020; Huang et al., 2020;

Li, Guan, et al., 2020; Wang, Hu, et al., 2020). Rapid screening of patients

with acute respiratory symptoms, initiation of an appropriate quar-

antine program, and development of therapeutic measures have been

suggested as a top‐priority strategy to control the spread of COVID‐19

(Tian et al., 2020;Wang,Kang,etal.,2020). According to the data

gathered by individual‐level surveillance, it is strongly recommended

that the elderly and male patients should be diagnosed in a timely

manner, as progression of the respiratory pathology to pneumonia

might result in catastrophic outcomes (Jian‐ya, 2020).

5.1 |Clinical symptom spectrum

Understanding the otherwise nonspecific clinical signs and symptoms

of COVID‐19 is a crucial step toward appropriate management of the

disease. Patients mostly complain of fever, non‐productive cough,

and body ache or extreme tiredness. In some cases, diarrhea and

nausea precede fever by a few days, suggesting that fever might not

be the initial manifestation of infection. A small number of patients

reportedly had headache, or even developed hemoptysis (Guan

et al., 2020; Wang, Hu, et al., 2020). Some patients remained

asymptomatic, despite being tested positive for the disease (Chan

et al., 2020). According to several studies, infection with SARS‐CoV‐2

in the elderly, especially the male community, is more likely to result

in severe alveolar damage and respiratory failure (Chen, Zhou,

et al., 2020). Occasionally, the disease may be demonstrated with a

fulminant natural history, rapidly progressing to organ dysfunction,

and even death in critical cases. Organ dysfunction includes condi-

tions such as shock, ARDS, acute cardiac injury, and acute kidney

injury (Huang et al., 2020; Wang, Hu, et al., 2020). From a laboratory

point of view, lymphopenia, thrombocytopenia, impaired pro-

thrombin time (PT), and elevated serum levels of CRP stand among

the findings that can be reported for patients with COVID‐19 (Chen,

Zhou, et al., 2020; Guan et al., 2020; Huang et al., 2020; Wang, Hu,

et al., 2020). Overall, any patient with fever and acute respiratory

symptoms, who is reported to have lymphopenia or leukopenia on lab

examination, should be suspected. A history of travel to Wuhan or

having close contact with local residents is a strong indicator for

careful management of the patient (Zu et al., 2020). Table 2re-

presents the criteria for diagnosis of COVID‐19 infected patients

(Committee, 2020b; Zu et al., 2020;WWW.ClinicalTrials.gov).

5.2 |Epidemiological history

Shortly after the onset of the epidemic, The National Health Com-

mission of China (Committee, 2020a; Organization, 2020a) initiated

the Diagnosis and Treatment Program of COVID‐19‐associated

pneumonia, following the guidelines provided by WHO on SARS

and MERS (Azhar & EI‐Kafrawy, 2014; Organization, 2017,2020b).

According to the newly formulated criteria, a “suspected case”is

defined as a patient with epidemiological history, that is traveling and

contact, and two clinical findings pertinent to the disease. If, how-

ever, an epidemiological history is not confirmed, then the patient

must present at least three clinical findings to be considered as a

suspected case. Based on the Trial, Fifth Edition (Committee, 2020b),

pathologic findings indicative of viral pneumonia on chest CT scans

provide enough evidence for clinical diagnosis of COVID‐19. None-

theless, as of February 17, 2020, WHO does not approve of any

diagnosis based solely on radiologic findings, without obtaining an

RT‐PCR test from the patient (Organization, 2020c). In the more

recent revision of the Chinese Diagnosis and Treatment Program, 6th

Edition, the term “clinical diagnosis”was removed and replaced with

“etiological diagnosis”(Organization, 2020a). According to the

recent revision, it is imperative that an etiological diagnosis of

COVID‐19 is made at first, which can then be complemented by a

positive real‐time RT‐PCR assay for SARS‐CoV‐2, which is duly per-

formed on the sputum or blood sample of the patient. After the final

diagnosis is made, confirmed patients are categorized into mild,

moderate, severe, and critical types, based on the severity of disease

(Zu et al., 2020).

5.3 |COVID‐19 detection tests: Pathogenic

laboratory testing, real‐time RT‐PCR, and sequencing

of nucleic acid

Table 3(Ai et al., 2020; Bai et al., 2020; Chen, Zhao, et al., 2020; Shi

et al., 2020; Tian et al., 2020; Wang, Kang, et al., 2020;Wu&

McGoogan, 2020; Yan et al., 2020; Yang et al., 2020) and Table 4

represent 2020 studies on diagnosis of COVID‐19 infected patients

and related clinical trials, respectively.

5.3.1 |Reverse transcriptase polymerase chain

reaction

Despite being the diagnostic gold standard, pathogenic lab testing is

a rather time‐consuming procedure, with unavoidable false‐positive

results (Wang, Kang, et al., 2020). It is recommended that lab testing

should be performed, as soon as the patient is identified as a “person

SHEERVALILOU ET AL.

under investigation”(PUI). Viral nucleic acid required for an RT‐PCR

test is usually extracted from secretions of the lower respiratory

tract, for example, bronchoalveolar lavage; however, tracheal aspi-

rate or sputum can also be used (Chu et al., 2020; Corman

et al., 2020). Since the onset of the epidemic, several factors have

been found to affect the final efficiency of nucleic acid testing, that is,

availability, quality, stability, and reproducibility of detection kits. In

most of the cases, the tests need to be repeated for several times

(Wang, Kang, et al., 2020), as the estimated detection rate of the test

falls in an underwhelming range of 30–50% (Chu et al., 2020; Corman

et al., 2020; Zhang et al., 2020). In spite of being a valuable asset, the

undesirable false‐negative results of RT‐PCR have prompted careful

clinical and etiological evaluation of COVID‐19 in suspected cases

as the first‐line diagnostic method (Zu et al., 2020).

5.3.2 |Computed tomography (CT)

CT has proved to be of great value in diagnosis of the COVID‐19‐

associated pneumonia, as it provides major evidence, that cannot

readily be obtained with alternative methods. It is true that CT is a

reliable imaging modality in subtle detection of viral pneumonia and

screening of suspected cases; however, it should be noted that many

pulmonary diseases of inflammatory nature share similar radio-

graphic findings (Wang, Kang, et al., 2020). The majority of patients

with COVID‐19 present with GGO in their chest CT, which later

progress into multilobar consolidations. There have been several

reports of rounded opacities, which are sometimes peripherally

distributed in the lung (Chung et al., 2020; Huang et al., 2020).

In contrast to CT, plain chest radiography (CXR) has not been re-

commended as a first‐line imaging method, because this modality

does not provide the clarity viewed on CT scans, especially in the

early stages of pulmonary infection (Ng et al., 2020). Nevertheless,

CXR is capable of recording pathologic changes in patients with se-

verely progressed COVID‐19, as the bilateral multifocal consolida-

tions present in these patients are too dense to be missed. The

notorious “white lung”appearance can be optimally viewed on

CXRs of critically ill patients (Zu et al., 2020). CT resulted in diagnosis

of 14,840 new cases as of February 13, 2020 (Zu et al., 2020).

Therefore, slice chest CT is an adequately sensitive and reliable

method in early detection of pneumonia in patients with COVID‐19

(Chan et al., 2020; Ng et al., 2020).

5.3.3 |Novel approaches: Artificial intelligence‐

based technologies

Depp learning, as a novel AI‐based modality might be able to analyze

radiographic features of COVID‐19, and help clinicians provide an

accurate clinical diagnosis based on a precedented pattern (Wang,

Kang, et al., 2020). As part of recent advancements, Convolutional

Neural Network (CNN), a class of deep neural networks, has been

shown to be capable of medical image analysis. To this date, CNN has

been successfully employed in investigations on the nature of pul-

monary nodules reported in CT images, diagnosis of pneumonia in

children based on CXR, and image recognition in cystoscopy videos

(Choe et al., 2019; Kermany et al., 2018; Negassi, Suarez‐Ibarrola,

Hein, Miernik, & Reiterer, 2020; Wang et al., 2018).

TABLE 2 Criteria for clinical severity of confirmed COVID‐19 pneumonia

Patient Clinical findings CT (imaging findings of pneumonia) Organ damage

Mild Negative None None

No dyspnea, with or without cough, fever

<38°C (quelled without treatment)

No history of chronic respiratory disease

Moderate dyspnea, with or without cough Multifocal patchy GGOs with subpleural distribution None

SpO2 >93% without oxygen inhalation

Severe Fever Diffuse heterogeneous consolidation with GGO, None

Muscle ache Rapid progression (>50%) on CT imaging within 24–48 hr

Headache

Confusion

Respiratory distress:

RR ≥30 times/min

SpO2 < 93% at rest

PaO2/FiO2 ≤300 mmHg

Critical Shock “Extra pulmonary”organ

failure or MODS

Respiratory failure

need mechanical assistance

Intensive care unit is needed

Abbreviations: FiO2, fraction of inspired oxygen; GGO, ground‐glass opacity; MODS, multiple organ dysfunction syndrome; PaO2, partial pressure of

oxygen; RR, respiratory rate, SpO2, oxygen saturation.

SHEERVALILOU ET AL.

TABLE 3 Studies for diagnosis, prognosis and therapy of COVID‐19 patients

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

Wu et al. (2020),

China

Retrospective study/

Chinese Center

for Disease

Control and

Prevention

72,314; subjects:

confirmed cases

44,672 (62%),

suspected cases

16,186 (22%),

diagnosed cases

10,567 (15%),

asymptomatic

cases 889 (1%)/

age N= 44,672:

80: 3% (1,408),

30–79: 87%

(38,680), 20–29:

8% (3,619),

10–19: 1% (549),

<10: 1% (416)

PCR Throat swab

samples

Confirmed cases

based on positive

PCR, suspected

cases based on

symptoms and

exposures only,

clinically cases

based on

symptoms,

exposures, and

CT, asymptomatic

cases diagnosis

by positive PCR

Spectrum of disease:

(N= 44,415);

mild: 81%

(36,160), severe:

14% (6,168),

critical:

5% (2,087)

Cardiovascular

disease: 10.5%,

diabetes: 7.3%,

chronic

respiratory

disease: 6.3%,

hypertension:

6.0%,

cancer: 5.6%

About a week 2.3% (1,023 of

44,672

confirmed

cases), 14.8%

aged >80 years

(208 of 1,408),

8.0% aged

70–79 years

(312 of 3,918)

49.0% in

critical cases

(1,023

of 2,087)

Next step: to help “buy

time”for more

diagnostic and

therapeutic

research before

COVID‐19

becomes too

widespread

Tian et al. (2020),

China

Retrospective study/

Beijing

Emergency

Medical Service

262/47.5/48.5% male Real‐time RT‐PCR Respiratory

specimens

COVID‐19 infected

patients/

residents of

Beijing: 92

(73.3%), patients

had been to

Wuhan: 50

(26.0%), close

contact with

confirmed cases:

116 (60.4%), no

contact history:

21 (10.9%)

Spectrum of disease:

sever: 46 (17.6%);

common: 216;

(82.4%); mild:

192 (73.3%);

nonpneumonia:

11 (4.2%);

asymptomatic:13

(5.0%)

Fever (82.1%), cough

(45.8%), fatigue

(26.3%), dyspnea

(6.9%), headache

(6.5%)/pulmonary

infection, chronic

cardiovascular

disease and heart

failure: 1,

pulmonary

infection and

multiple chronic

diseases: 1

Incubation: 6.7 days,

illness onset to

visit hospital:

4.5 days

3 (0.9%) Results: As of

February 10, 45

(17.2%) patients

have discharged

For COVID‐19

control: first step

is prevent

transmission at

early stage, next

steps is early

isolation and

quarantine of

suspected

subjects

Wang et al. (2020),

China

Retrospective cohort/

Xi'an Jiaotong

University First

Affiliated

Hospital,

Nanchang

University First

Hospital and

Xi'an No.8

Hospital of Xi'an

Medical College

99 CT, artificial

intelligence,

inception

migration‐

learning

model

–Pathogen‐confirmed

COVID‐19

patients

Spectrum of disease:

typical viral

pneumonia or

negative group:

55, confirmed

nucleic acid

testing or positive

group: 44. CT

(453 CT images):

negative: 258,

positive: 195

Viral pneumonia

symptoms

––

Screening:

The internal

validation;

accuracy: 82·9%,

specificity: 80·5%,

sensitivity: 84%

The external testing;

accuracy: 73·1%,

specificity: 67%,

sensitivity: 74%

Algorithm prediction:

a rate of 2 s per

case on the

graphic

processing unit

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

Interpretation: the

early diagnosis

through fast,

accurate, safe and

noninvasive

methods is crucial

for control of

virus

Yan et al. (2020),

China

Retrospective study/

Tongji Hospital

375, 58.83, 58.7%

males

CT, machine

learning

model (a

supervised

XGBoost

classifier)

–Validated or

suspected

COVID‐19

patient/Wuhan

residents (37.9%),

familial cluster

(6.4%), health

workers (1.9%)

Spectrum of disease:

critical patients:

46.1%, severe

cases:

RR ≥30bpm or

SPO2 ≤93%

on rest

Fever: 49.9%, cough:

13.9%, fatigue

3.7%, dyspnea

2.1%, shock: 2

174

16 + 1

Interpretation: the

three indices‐

based prognostic

prediction model

might predict

themortality risk,

recognition of

critical cases, help

to early

identification, on

time intervention,

reducing

mortality rate

Shi et al. (2020),

China

Retrospective/

hospitals in

Wuhan

81, 49–5, 42 (52%)

men and 39 (48%)

women

Next‐generation

sequencing or

RT‐PCR, serial

chest CT

Throat swab

specimens

Confirmed COVID‐19

pneumonia

patients/direct

exposure to

Huanan seafood

market: 31 (38%),

health‐care

workers: 15

(19%), familial

clusters: 7 (9%),

any obvious

history of

exposure:

28 (35%)

Spectrum of disease:

mean number of

involved lung

segments: 10.5

(SD 6.4): group 1:

subclinical

patients (CT

before symptom

onset): 2.8 (3.3),

group 2: ≤1 week

after symptom

onset/11.1 (5.4),

group 3: >1–2

weeks/13.0 (5.7),

group 4: >2–3

weeks/12.1 (5.9).

CT:

ALL:

bilateral abnormality:

64 [79%],

peripheral 44

[54%], Ill‐defined

66 [81%], GGO:

53 [65%], mainly

Fever: 59 [73%], dry

cough: 48 [59%]

nonspecific

symptoms:

dizziness:

2 [2%], diarrhea:

3 [4%], vomiting:

4 [5%], headache:

5 [6%], generalised

weakness:

7 [9%]/chronic

pulmonary

disease

(tuberculosis): 1,

T2D: 1,

hypertension/

cardiovascular/

erebrovascular

disease: 1

Symptom onset and

discharge of

23–2 days

3 (4%) By February 8, 2020,

62 (77%) patients

discharged

Interpretation:

COVID‐19

pneumonia

include CT

abnormalities that

rapidly progress

from focal

unilateral to

diffuse bilateral

GGO coexisted

with

consolidations

within 1–3 weeks

(even in

asymptomatic

patients).

Early diagnosis

through combined

CT with clinical

and laboratory

findings

(Continues)

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

involving the

right lower lobes:

225 [27%] of 849.

Group 1 (n=15):

unilateral: 9

[60%]/multifocal

8 [53%]/GGO: 14

[93%]; Group 2

(n= 21): bilateral

19 [90%]/diffuse

11 [52%]/GGO

predominance 17

[81%]; Group 3

(n= 30): GGO 17

[57%],

consolidation/

mixed patterns:

12 [40%]; Group

4(n=15):

consolidation/

mixed patterns:

8 [53%].

Blood:

Group1: Lower CRP

and AST

Bai et al. (2020),

China

Case study/The Fifth

People's Hospital

of Anyang

6, Patient 1: 20‐year‐

old woman,

patients 2–6: four

women 42–57

years old

CT, RT‐PCR Nasopharyn-

geal swabs

Patient 1: met with

Patients 2 and 3,

and accompanied

five relatives

(Patients 2–6),

Patients 2–6: no

visited Wuhan or

been in contact

with any other

people traveled

to Wuhan

Spectrum of disease:

severe

pneumonia: 2,

moderate: others.

A familial cluster

of five patients

with respiratory

symptoms, 1

asymptomatic

family member.

Blood:

all symptomatic

patients:

increased CRP,

reduced

lymphocyte.

CT: multifocal GGO:

in all

symptomatic

patients,

Fever: patients 2–6 19 days for patient 1 –Transmission:

COVID‐19

transmission

could transmit by

an asymptomatic

carrier S

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

subsegmental

consolidation/

fibrosis: 1.

Patient 1: normal CT,

CRP and

lymphocyte

count, RT‐PCR:

negative, positive,

negative.

Patients 2–6:

COVID‐19 confirmed.

PCR: positive for

patients 2–6

within 1day

Ai et al. (2020),

China

Cohort/Tangji hospital

of Tongji Medical

College

Huazhong

University of

Science and

Technology,

Wuhan, Hubei

1,014/51 ± 15/

46% man

Laboratory test,

chest CT

(7 day

interval), RT‐

PCR (Taq man

one step):

multiple

assays (3day

interval)

Throat swab Suspected of nCoV/

China

Positive CT: 88%

(888/1,014),

positive RT‐PCR:

59% (601/1,014).

Sensitivity of CT

based on positive

RT‐PCR: 97%

(95%CI, 95–98%,

580/601).

Negative RT‐PCR/

positive CT: 75%

(308/413).

Initial positive CT

consistent with

COVID‐19 before

the initial positive

RT‐PCR: 60–93%.

Improvement in

follow‐up CT

before the RT‐

PCR turning

negative: 42%

(24/57), CT:

GGO: 46% [409/

888],

consolidations:

50% [447/888],

bilateral findings:

90% [801/888]

Fever, dry cough Initial + to −PCR:

5.1 ± 1.5 days,

Initial −to + PCR:

6.9 ± 2.3 days

–Diagnosis: chest CT, as

a highly sensitive

method, could be

considered as a

primary tool for

infection

diagnosis in

epidemic areas

(Continues)

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

Chen et al. (2020),

China

General Hospital of

Central Theater

Command, PLA

48/age; critically ill:

79.6 ± 12, sever:

63.9 ± 15, mild:

45.8 ± 14/31

males (77.1%)

and 17

females (22.9%)

Real‐time RT‐PCR,

CT, GLMs

analysis

Serum, throat‐

swab

specimens

Laboratory confirmed

cases

Spectrum of disease:

mild: 21 (43.7%),

severe 10

(20.8%), critically

ill 17 (35.4%).

Blood: low/lower

lymphocytes:

severe and

critically ill,

higher

neutrophils:

critically ill,

higher PCT:

critically ill.

Parameters stand for

the organ

dysfunction; TnT,

AST, ALT, CRE,

and BUN: higher

in critically ill

patients.

PCR:

positive RNAaemia:

(a) serum: 5

(10.4%) of

critically ill, (b)

throat‐swab: 48

positive.

IL‐6: value ≥100:

35.3% in critically

ill, 10‐folds higher

IL‐6 (cytokine

storm): critically

ill, RNAaemia

positive: IL‐6

≥100 (R= 0.902)

Mild: fever,

respiratory

symptoms

Severe: shortness of

breath,

RR ≥30 times/

min, oxygen

saturation

(resting state)

≤93%, PaO2/

FiO2 ≤300 mmHg

Critically ill:

respiratory

failure, shock,

multiple organ

failure/diabetes:

12 [25%],

hypertension: 23

[49.7%], heart

disease: 8

[16.7%], mixed

fungal infection:

27.1%, bacterial

infection: (2.1%)

–3Diagnosis; RNAaemia

positive test

confirmed

critically ill

patients

Prognosis: strong

association

between

RNAaemia with

cytokine storm

can be applied to

predict the poor

prognosis

Therapeutic approach:

in critically

patients, IL‐6

should be

considered as a

therapeutic target

Fan et al. (2020),

China

Retrospective cohort

study/three

tertiary hospitals

of Wenzhou

149/45.11 ± 13.35/81

(54.4%) males

Laboratory test,

PCR, CT

Blood RT‐PCR confirmed

patients: Hubei

travel/residence

history: N=85,

contact with people of

Hubei: N=49, no

traceable

exposure

history: N=15

Blood:

decreased oxygen

saturation:

14(9.4%),

leukopenia: 33

(24.2%),

lymphopenia: 53

(35.6%), low

platelets: 20

Fever:

114/149, 76.5%,

Cough: 87/

149, 58.4%,

Expectoration:

4 8/149, 32.2%, mild

infection/

cerebrovascular

Negative CT: 10

days, 6.8

(5.0) days

0 (0.0%) Diagnosis: a normal CT

cannot exclude

the diagnosis of

COVID‐19

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

(13.4%), elevated

CRP: 82 (55.0%),

ALT/AST/CK and

D‐dimer: less

common.

CT: most involved

lung segments: 6

and, GGO: 287

segments, mixed

opacity: 637

segments,

consolidation:

170 segments,

lesions: more in

the peripheral

lung with a

patchy form,

normal CT on

admission: N=17,

negative CT:

N=12, no

significant

difference

between patients

with or without

exposure history

or digestive

diseases:

52 (34.9%)

Fan et al. (2020),

China

Retrospective, case

series/Chongqing

University Three

Gorges Hospital

51/45/32 (62.7%) men Laboratory

test, CT

Blood Confirmed COVID‐19:

patients had been

to Wuhan:

43 (84.3%), contact

history of

COVID‐19

patients: 4 (7.7%),

no clear contact

history:4 (7.7%)

Spectrum of disease:

nonsevere patients:

n= 44, severe

patients:

7 (13.7%)

Blood: lymphopenia:

26 (51.0%),

elevated CRP:

32 (62.7%).

CT:

GGO: 41 [80.4%],

local

consolidation of

pneumonia:

17 [33.3%], pleural

thickening: 20

(39.2%), small

amount of pleural

effusion:

Fever:

43 [84.3%], cough:

38 [74.5%], dry cough

with

expectoration:

16 (31.4%), fatigue: 22

[43.1%], asthenia:

22 (43.1%),

dyspnea: 11/DM:

4 [57.1%]

2–5 days 1 Therapy:

TCM decoction: 28

[54.9%], aerosol

inhalation of

recombinant

human

Interferon a‐1b: 51

(100%), Lopinavir/

Ritonavir: 51

[100%], Bacillus

licheniformis

capsules: 44

[86.3%],

glucocorticoid

treatment:

10 (19.6%)

Older patients with

server COVID‐

19 (N=7)

(Continues)

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

7 (13.7%), streak

shadow of lung: 8

(15.7%), multiple

solid nodular

shadow: 4 (7.8%),

air bronchogram:

2 (3.9%), single

lobe lesions: 2

(3.9%), multiple

lobe lesions:

49 (96.1%)

Antibiotic treatment: 7

[100%],

nutritional diet: 6

[85.7%), human

albumin infusion:

4 (57.1%),

immunoglobulin

treatment: 4

(57.1%),

mechanical

ventilation:

6 [85.7%]

Results and

interpretation:

discharged 50

patients after 12

days, without the

common clinical

symptoms, with

the significant

increased

lymphocyte

(p= .008) and

significant

decreased CRP

significantly

(p< .001)

Fan et al. (2020),

China

Retrospective/

Shanghai Public

Health Clinical

Center

148/50.5/49.3%

females and

50.7% males

Laboratory test,

RT‐PCR and

CT scanning

Sera Confirmed SARS‐CoV‐

2‐infected

patients/a history

of related

epidemiology

Blood:

elevated LDH, AST,

ALT, GGT,

TB, ALP:

35.1%, 21.6%, 18.2%,

17.6%, 6.1%,

4.1% in all

patients; lower

CD4+ and CD8+

T cells: (62.67%)/

(56.1%) patients

with abnormal

liver function

received more

treatment

compared with

normal liver

Fever: (70.1%), cough:

(45.3%),

expectoration at

admission:

(26.7%),

Abnormal liver

functions at

admission: 75

patients (50.7%)

with moderate‐

high degree fever

(44%) in males,/

chronic hepatitis

BorC:N=8

5 days (3–7) 1 Therapy:

Antibiotics

(Levofloxacin,

Meropenem,

Moxifloxacin,

Cephalosporin),

interferon,

antiviral drugs

(Arbidol,

Lopinavir/

ritonavir,

Dnrunavir)

Results and

interpretation:

all patients discharged

from the hospital.

Lopinavir/Ritonavir

treatment can

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

function

(25%) (p= .009)

significantly

alleviate the

SARS‐CoV‐2‐

induced liver

function damage

Chen et al. (2020)

China

Retrospective/

Zhongnan

Hospital of

Wuhan

University,

Wuhan

9/26–34/female Clinical records,

laboratory

results, CT

scans

Amniotic fluid,

cord

blood, and

neonatal

throat

swab,

breastmilk

samples

Pregnant women with

laboratory‐

confirmed

COVID‐19

pneumonia and

caesarean section

in their third

trimester/a

history of

epidemiological

exposure to

COVID‐19

Blood:

lymphopenia: N=5,

elevated CRP:

N= 6, increased

ALT and AST:

N= 3, normal

WBC count:

N= 7, lower

WBC: N=1.

Nine mothers: none

developed severe

COVID‐19

pneumonia or

dying as of Feb4.

Six mothers:

amniotic fluid, cord

blood, neonatal

throat swab, and

breastmilk:

negative for

COVID‐19.

Nine livebirths:

with 1‐min Apgar

score of 8–9 and

a5‐min Apgar

score of 9–10, No

neonatal

asphyxia.

CT:

multiple patchy

ground‐glass

shadows: N=8

Fever: N= 7, cough

N= 4, myalgia

N= 3, sore throat:

N= 2, malaise:

N= 2, fetal

distress:

N= 2/gestational

hypertension:

N= 1, pre‐eclampsia:

N= 1, influenza

virus

infection: N=1

Short None Therapy: oxygen

support (nasal

cannula) and

empirical

antibiotic

treatment: N=9,

antiviral

therapy: N=6

Interpretation: no

evidence for

intrauterine

infection caused

by vertical

transmission in

late pregnancy

Lim et al. (2020),

Korea

Public health center,

Myongji Hospital

1/54/male PCR, CT Throat swab,

sputum

A Korean man living in

Wuhan China/

Virus

transmission;

from index patient

Patient A to

Spectrum of disease:

mild respiratory

symptoms.

CT:

small consolidation in

right upper lobe,

Chills, muscle pain 5–7 days –Therapy:

Lopinavir/Ritonavir

Results and

interpretation:

significant decrease in

β‐coronavirus

viral loads due to

(Continues)

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

Patients B,

C, D@@

GGO in both

lower lobes

the natural course

of the healing

process rather

than

administration of

Lopinavir/

Ritonavir, or both

Wu et al. (2020),

China

Retrospective/three

Grade IIIA

hospitals of

Jiangsu

80/46.1/41

female (51.25%)

Laboratory testing,

real time RT‐

PCR, CT

Throat swab

and/or

nose

swab,

blood

Confirmed COVID‐19

patients/with a

history of

epidemic in

Wuhan and

without contact

with the seafood

market

Spectrum of disease:

mild: 28 (35.00%),

moderate: 49

(61.25%), severe:

3 (3.75%),

critically ill: none

Laboratory:

lower WBC: 36

(45.00%),

lymphocytopenia:

26 (32.50%),

lower platelets:

11 (13.75%), high

CRP: 62

(77.50%), high

ESR: 59 (73.75%),

elevated PCT:

1 (1.25%).

Liver function:

increased ALT/AST: 3

(3.75%), lower

albumin:

2 (2.50%).

Abnormal myocardial

enzyme spectrum

and increase of

CK: 18 (22.50%).

Increased LDH:

17 (21.25%).

Renal function

damage:

2 (2.50%).

Serious renal function

damage: 1.

Hyperglycemia:

19 (23.17%).

Increased D‐dimer:

3 (3.75%).

Fever:

63 (78.75%), cough:

51 (63.75%),

shortness of

breath: 30

(37.50%), muscle

ache: 18

(22.50%),

headache: 13

(16.25%) liver

dysfunction: 3

(3.75%)/

cardiovascular/

cerebrovascular,

endocrine,

digestive,

respiratory,

malignancies and

nervous system

diseases:

38 (47.50%)

8.0 Not now Therapy:

all patients:

single antibiotic mainly

Moxifloxacin and

Ribavirin antiviral

therapy, 12

(14.63%) patients:

methylprednisolone

sodium succinate

methylpredniso-

lone, 35 (43.75%)

patients:

noninvasive ventilator,

1 patient:

hemodialysis, 3

patients: TCM

Interpretation: 21

cases discharged

from the hospital:

With no obvious

gender

susceptivity,

lower proportion

of liver

dysfunction,

abnormal CT and

higher frequency

nucleic acid

detection

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

9 kinds of respiratory

pathogens and

influenza A/B

nucleic acids: all

patients.

CT: abnormal: 55

(68.75%),

bilateral

pneumonia: 36

(45.00%),

unilateral

pneumonia: 19

(23.75%), normal:

25 (31.25%).

Organ damage: acute

respiratory

injury: 10

(12.50%), renal

injury: 2 (2.50%)

Li et al. (2020),

China

Retrospective study/

hospital in

Wenzhou

175/46/92 women,

83/men

Real‐time PCR, CT Respiratory

tract

samples or

blood

samples

Confirmed COVID‐

19/a history of

exposure to the

epidemic area: 57

(33%) patients

Spectrum of disease:

COVID‐19:

mild: mild clinical

manifestations,

no pneumonia;

moderate:

respiratory

symptoms, mild

pneumonia,

severe (37):

pneumonia,

ARDS with RR

>30 times/min,

oxygen saturation

<93%; critical (3):

pneumonia,

shock, respiratory

failure, and

failures in other

organs, nearly all

patients: GGO

severe hypokalemia:

39 (higher body

temperature,

higher heart rate

Cough, fever,

pneumonia/

hypertension: 28,

diabetes: 12,

other

conditions:31

6–Therapy:

1 severe hypokalemia

patients;

3 g/day K

,34(SD =4)

g potassium

during

hospital stay

Good response of

patients to K+

supplements

when they

inclined to

recovery

Interpretation:

hypokalemia is

prevailing in

COVID‐19

patients

(Continues)

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

and RR, higher

prevalence of

dyspnea or

tachypnea

(p< .05)),

hypokalemia 69,

normokalemia

patients 67.

Correlations: severity

of hypokalemia

with body

temperature, CK,

CK‐MB, LDH, and

CRP (p< .01),

93% of severe/

critically ill

patients showed

hypokalemia

Lan et al. (2020),

China

Case study/Zhongnan

Hospital of

Wuhan

University,

Wuhan

4, 30–36 years, 2 male RT‐PCR, thin‐

section CT

Throat swabs Medical personnel

quarantined at

home with

COVID‐19

Spectrum of disease:

mild to moderate

Results: (at

admission); PCR

positive: for all

CT positive: for

all GGO, or mixed

GGO/

consolidation

(after therapy); 2

consecutive

negative RT‐PCR:

all (after

discharge);

repeated RT‐PCR

5–13 days later:

all positive

Fever:3, cough: 3,

both: 3

Symptom onset to

recovery:

12–32 days

–Therapy: antiviral

treatment (75mg

of oseltamivir

every 12hr)

Resolved clinical

symptoms and CT

abnormalities: 3

Delicate patches of

GGO: 1

Interpretation:

possibility of at

least a proportion

of recovered

patients act as

virus carriers

Li et al. (2020),

China

Retrospective study/

Sino‐French New

Town area Tongji

Hospital

47, 62, 28

(59.6%) men

Real‐time RT‐PCR Throat‐swab

specimens,

sputum or

endotra-

cheal

aspirates

Patients with severe

COVID‐19

Spectrum of disease:

severe: 41

critical: 5(17.9%)

men and 1 (5.3%)

women

Common: oxygen

saturation <93%

after routine

Fever: 34 [72.3%],

cough: 36

[76.6%], myalgia:

5 [10.6%], fatigue:

7 [14.9%]/

comorbidities:

30 (63.8%):

–3.6% in men and 0

in women

Therapy:

antibiotics applied

more in the men

than the women

Results and

interpretation: 4

(21.1%) women/1

man (3.6%)

discharged.

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

Nasal oxygen supply:

3 men/1 woman

Blood: PCT: higher in

men, N‐terminal‐

pro brain

natriuretic

peptide: Higher in

16(57.1%) men/5

(26.3%) women,

Positive influenza A

antibody: 5

men (17.9%)

COPD, hypertension/

CVD lower

in men

Possibility of sex

differences in

severe COVID‐19

patients, Men

with more

complicated

clinical condition

and worse

outcomes

Han et al. (2020) Case study/People's

Hospital in

Wuwei

A47‐year‐old man/

smoking for 20

years/no alcohol

abuse

RT‐PCR, CT Nasopharyn-

geal swab

specimens

Confirmed SARS‐CoV‐

2/returned to

Wuwei city on

January 18 from

Wuhan city

by car

Blood:

decreased

lymphocytes,

increased CRP,

slightly elevated

fibrinogen,

neutrophil, LDH,

and fibrinogen

PCR: positive for

expression of

RdRPN, N and E

genes

CT: multiple patchy

high‐density

shadows

scattered mainly

in the border

regions of lungs,

solid changes,

GGO changes,

slightly thickened

pleura

Fever, cough

productive of

white phlegm,

bosom frowsty,

stuffy/runny

noses, vertigo,

fatigue, chest

tightness, nausea,

expiratory

dyspnea, poor

diet, lethargy/

hypertension

grade 2 and T2D

––

Therapy:

combination therapy

including:

Lopinavir/Ritonavir

(800/200 mg

daily),

methylpredniso-

lone (40 mg daily),

recombinant

human interferon

α‐2b (10 million

IU daily),

ambroxol

hydrochloride

(60 mg daily)

moxifloxacin

hydrochloride

(0.4 g daily), high

flow

humidification

oxygen inhalation

therapy,

treatment of

blood glucose,

blood pressure,

and rehydration

therapy

Results interpretation:

the persistent

negative results of

SARS‐CoV‐2on

days 6 and 7,

normal TLC, lung

(Continues)

SHEERVALILOU ET AL.

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

lesions partially

absorbed, The

patient

discharged.

Laboratory tests

like TLC are

necessary, CT

combined with

RT‐PCR is helpful,

Lopinavir/

Ritonavir are

effective after

failure of

methylpredniso-

lone/interferon

alfa‐2b

Liu et al. (2020),

China

Retrospective cohort

and case study/

Zhongnan

Hospital of

Wuhan

University Dawu

County People's

Hospital

124 patients, 22

patients:

12 therapy (mean age

53), 10 control

(mean age 58)

CT, PCR Serum 124 confirmed

COVID‐19 cases,

12 HCOV

infected patients

Blood: (Study 1)

decreased

platelet: 25

(20.2%),

prolonged PT: 77

(62.1%),

increased FIB: 27

(21.8%), and

increased D‐

dimer: 26 (21.0%)

Spectrum of disease:

(study 2) severe

cases: 6 mild

cases: 4 critically

ill: 2

CT: (study 2) Bilateral

pneumonia: all

Study 1:

hypercoagul-

ability

Study 2: cough: all

shortness of

breath: most of

them, nausea and

vomiting: 60.0%/

DM,

cardiovascular

and

cerebrovascular

diseases: 4

patients from the

DIP, 5 patients

control group

–1Therapy: Dipyridamole

(150 mg in three

separate doses for

7 consecutive

days), antiviral

(ribavirin, 0.5g,

Q12hr), corticoid

(methylpredniso-

lone sodium

succinate, 40mg,

qd), oxygen

therapy,

nutritional

support

Results and

interpretation:

significant

increase in

platelet/

lymphocyte,

significant

decrease in D‐

dimer levels

Discharged patients:

50% of severe

cases and all 4

mild cases.

Dipyridamole

adjunctive

SHEERVALILOU ET AL.

The 21st century has seen many AI‐based models to be in-

corporated in several scientific fields, particularly imaging studies.

Diagnostic AI‐based models might actually be a forward leap in tasks

that simply cannot be handled by manpower, especially risk prior-

itization, that can greatly help improve patient turnaround time.

Given the shortage of human resources and inadequate number of

hospital beds in a country like China, AI‐based models for analysis of

CXR and CT scans can be useful in ruling out irrelevant cases, and

resource‐wise admission of patients to the hospitals (Kim, 2020).

6|PREDICTION

Recent studies focused on prognosis of COVID‐19 concluded that

the load of SARS‐CoV‐2 RNA in blood (RNAemia) is correlated with

Cytokine Release Storm (CRS) and poor prognosis of the disease. In

one particular study, scientists used Generalized Linear Models to

generate a prediction model for natural history of disease based on

the C

value of real‐time RT‐PCR results. They reported that trace-

able amounts of SARS‐CoV‐2 RNA was detected in blood plasma of

15% of COVID‐19 positive patients enrolled at the study. Their

findings drew a direct link between serum markers and disease se-

verity, as RNAemia and high levels of IL‐6 (nearly 10‐fold) were ex-

clusively reported in critically ill patients. Interestingly, there was

also an association between the extremely high levels of IL‐6 with the

incidence of RNAemia (R= 0.902) in patients. Findings also suggested

that vital signs of patients were also affected by high levels of both

serum markers (R= 0.682). According to this study, IL‐6 might be of

clinical value in identification and treatment of patients with an ex-

cessive inflammatory response (Chen, Zhao, et al., 2020). Table 3

(Chen, Zhao, et al., 2020; Yan et al., 2020) and Table 4represent

2020 studies on prognosis of COVID‐19 infected patients and

related clinical trials, respectively.

7|THERAPY

Scientists have made strenuous efforts to come up with an effective

regimen for successful treatment of COVID‐19 (Gao, Tian, &

Yang, 2020). Table 3(Chen, Guo, et al., 2020; Fan et al., 2020; Han

et al., 2020; Lan et al., 2020; Li, Zhang, et al., 2020; Li, Hu, et al., 2020;

Lim et al., 2020; Liu et al., 2020; Liu et al., 2020; Wu et al., 2020;

Wu & McGoogan, 2020), Tables 4and 5(Zhang & Liu, 2020) re-

present 2020 studies on treatment of COVID‐19 infected patients,

related clinical trials and available therapeutic options, respectively.

7.1 |Chloroquine phosphate

Chloroquine phosphate is an old medicine, that has been widely

used for treatment of malaria in endemic regions. It is also a salutary

treatment of choice for certain progressive anti‐inflammatory

diseases, for example, rheumatoid arthritis, and systemic lupus

TABLE 3 (Continued)

Study/region

Study type/

medical team

Patient/median

age/sex Diagnostic test Sample

Inclusion criteria/

residency Test results

Most common

symptoms/chronic

disease

Incubation

period (day) Case fatality rate

Diagnosis/prognosis/

therapy

therapy could

significantly

reduce viral

replication,

inhibits

hypercoagulability

and improves

immune recovery

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; CK‐MB,

creatine kinase myocardial band; COPD, chronic obstructive pulmonary disease; CRE, serum creatinine; CRP, C‐reactive protein; CT, computed tomography; CVD, cardiovascular disease; DM, diabetes

mellitus; DM, diabetes mellitus; ESR, erythrocyte sedimentation rate; FIB, fibrinogen; FiO2, fraction of inspired oxygen; GGO, ground‐glass opacity; GGT, γ‐glutamyltransferase; GLM, Generalized Linear

Model; LDH, lactate dehydrogenase; nCoV, novel coronavirus; PaO2, partial pressure of oxygen; PCT, procalcitonin; PT, prothrombin time; RNAaemia, SARS‐CoV‐2 nucleic acid; RR, respiratory rate; RT‐PCR,

reverse transcriptase polymerase chain reaction; SpO2, oxygen saturation; T2D, type 2 diabetes; TB, total bilirubin; TCM, traditional Chinese medicine; TCM, traditional Chinese medicine; TLC, total

lymphocyte count; TnT, troponin T; WBC, white blood cell.

SHEERVALILOU ET AL.

TABLE 4 Clinical trials for COVID‐19 or SARS‐nCoV2

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

The efficacy and safety of

huaier in the adjuvant

treatment of COVID‐19

Drug: Huaier Granule COVID‐19 550, all, 18–75 Treatment Experimental group: standard

therapy + Huaier granule 20 g,

po, tid for 2 weeks (or until

discharge)

Control group: standard therapy

II, III Primary (up to 28 days): all cause

mortality

Secondary (up to 28 days): clinical status,

differences in oxygen intake

methods, supplemental oxygenation,

mechanical ventilation, mean PaO2/

FiO2, length of hospital stay, Length

of ICU stay (days), pulmonary

function (up to 3 months after

discharge)

NCT04291053/Not

yet recruiting,

Apr1‐Sep1 2020

Clinical trial on regularity of

TCM syndrome and

differentiation treatment

of COVID‐19

Drug: TCM prescriptions China/COVID‐19 340, all, 18–75 Treatment Exposure group: integrated TCM

and western medicine cohort

(routine treatment+ one or

two of the following antiviral

drugs + the following TCM

regimens: take decocted or

granule, one dose a day)

Control group: western medicine

cohort (routine

treatment + one or both of the

following antiviral drugs)

Not applicable Primary (9 days): The relief/

disappearance rate of main

symptoms, chest CT absorption

Secondary (9 days): virus antigen

negative conversion rate, Clinical

effective time: the average effective

time. The number of severe and

critical conversion cases, Incidence

of complications, Traditional

Chinese Medicine Syndrome Score

Other outcome measures (9 days): CRP

changes, ESR changes, PCTchanges,

The index of T cell subsets changed

NCT04306497/

Recruiting,

Mar2‐May 2020

Recombinant human

angiotensin‐converting

enzyme 2 (rhACE2) as a

treatment for patients

with COVID‐19

Drug: Recombinant human

angiotensin‐converting

enzyme 2 (rhACE2)

China/COVID‐19 24, all, 18–80 Treatment Experimental group: 0.4 mg/kg

rhACE2 IV BID for 7 days and

standard of care

Control group: standard of care

Not applicable Primary (14 days): time course of body

temperature, viral load over time

Secondary (14 days): P/F ratio over time,

sequential organ failure assessment

score over time, Pulmonary Severity

Index, image examination of chest

over time, proportion of subjects

who progressed to critical illness or

death, Time from first dose to

conversion to normal or mild

pneumonia, T‐lymphocyte counts

over time, C‐reactive protein levels

over time, angiotensin II (Ang II)

changes over time, angiotensin 1–7

(Ang 1–7) changes over time,

angiotensin 1–5 (Ang 1–5) changes

over time, renin changes over time,

aldosterone changes over time,

angiotensin‐converting enzyme

changes over time, angiotensin‐

converting enzyme 2 (ACE2)

changes over time, IL‐6 changes

over time, IL‐8 changes over time,

NCT04287686/

Withdraw, Feb‐

Apr 2020

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

soluble tumor necrosis factor

receptor type II (sTNFrII) changes

over time, Plasminogen activator

inhibitor type‐1 changes over time,

Von willebrand factor changes over

time, tumor necrosis factor‐α

changes over time, soluble receptor

for advanced glycation end products

(sRAGE) changes over time,

surfactant protein‐D changes over

time, angiopoietin‐2 changes over

time, frequency of adverse events

and severe adverse events

The COVID‐19 mobile health

study (CMHS)

nCapp, a cell phone‐based

autodiagnosis system

China/COVID‐19 450, all, 18–90 Diagnosis Training: nCapp, a cell phone‐based

autodiagnosis system,

combined with 15 questions

online, and a predicated

formula to autodiagnosis of the

risk of COVID‐19

Validation: nCapp, a cell phone‐

based autodiagnosis system,

combined with 15 questions

online, and a predicated

formula to auto‐diagnosis of

the risk of COVID‐19

–Primary (1day): accuracy of nCapp

COVID‐19 risk diagnostic model

NCT04275947/

Recruiting, Feb

14‐May 31 2020

A Pilot Study of Sildenafil in

COVID‐19

Drug: Sildenafil citrate

tablets (G1)

China/COVID‐19 10, all, 18 years

and older

Treatment Experimental group: sildenafil

citrate tablet 0.1 g/day for

14 days

Not applicable Primary (14 days): rate of disease

remission, rate of entering the

critical stage, time of entering the

critical stage

Secondary (14 days): rate of no fever,

rate of respiratory symptom

remission, rate of lung imaging

recovery, rate of C‐reactive protein

(CRP) recovery, rate of Biochemical

criterion (CK, ALT, Mb) recovery,

rate of undetectable viral RNA

(continuous twice), time for

hospitalization, rate of adverse

event

NCT04304313/

Recruiting, Feb

9‐Nov 9 2020

Critically Ill patients with

COVID‐19 in Hong Kong:

a multicentre

observational cohort study

–Hong Kong/

COVID‐19

8 descriptive A case series of 41 hospitalized

patients with confirmed

infection

30% required critical care

admission: developed severe

respiratory failure, 10%

−Primary (28 days): 28 day mortality

Secondary (28 days): vasopressor days,

days on mechanical ventilation,

sequential organ function

assessment score, ECMO use,

percentage nitric oxide use,

NCT04285801/

Completed, Feb

14‐Feb 25 2020

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

required mechanical

ventilation, 5% needed

extracorporeal membrane

oxygenation support mortality

rate: 15%

percentage free from oxygen

supplement

Treatment of mild cases and

chemoprophylaxis of

contacts as prevention of

the COVID‐19 epidemic

Drug: antiviral treatment and

prophylaxis, Standard

Public Health measures

COVID‐19 3,040, All, 18

Years and

older

Treatment Experimental: antiviral treatment

and prophylaxis: darunavir

800 mg/cobicistat 150mg

tablets (oral, 1 tablet q24h,

taking for 7 days) and

hydroxychloroquine (200mg

tablets) 800mg on Day 1, and

400 mg on days 2, 3, 4.

Contacts: a prophylactic

regimen of hydroxychloroquine

(200 mg tablets) 800 mg on

Day 1, and 400 mg on days

2,3,4. Other: standard public

health measures

Active comparator: standard public

health measures

III Primary (up to 14 days after start of

treatment): effectiveness of

chemoprophylaxis assessed by

incidence of secondary COVID‐19

cases

Secondary: the virological clearance rate

of throat swabs, sputum, or lower

respiratory tract secretions at days

3, the mortality rate of subjects at

weeks 2, proportion of participants

that drop out of study (up to 14 days

after start of treatment), proportion

of participants that show

noncompliance with study drug (up

to 14 days after start of treatment)

NCT04304053/Not

yet recruiting,

Mar15‐

Jul15 2020

Comparison of lopinavir/

ritonavir or

hydroxychloroquine in

patients with mild

coronavirus disease

(COVID‐19)

Drug: lopinavir/ritonavir,

Drug:

hydroxychloroquine

sulfate

Korea/COVID‐19 150, all, 16 years

to 99 years

Treatment Experimental: lopinavir/ritonavir

200 mg/100 mg 2 tablets by

mouth, every 12 hr for

7–10 days

Active comparator:

hydroxychloroquine 200mg 2

tablets by mouth, every 12 hr

for 7–10 days

No intervention: control, no

lopinavir/ritonavir and

hydroxychloroquine

II Primary: viral load (hospital Day 3, 5, 7,

10, 14, 18)

Secondary viral load change (hospital

Day 3, 5, 7, 10, 14, 18), time to

clinical improvement (time frame: up

to 28 days), percentage of

progression to supplemental oxygen

requirement by Day 7, Time to

NEWS2 (National Early Warning

Score 2) of 3 or more maintained for

24 hr by Day 7, time to clinical

failure, defined as the time to death,

mechanical ventilation, or ICU

admission (up to 28 days), rate of

switch to lopinavir/ritonavir or

hydroxychloroquine by Day 7,

adverse effects (up to 28 days),

concentration of lopinavir/ritonavir

and hydroxychloroquine (1, 2, 4, 5,

12 hr after taking intervention

medicine)

NCT04307693/

Recruiting,

Mar11‐

May 2020

Study to evaluate the safety

and antiviral activity of

remdesivir (GS‐5734™)in

Drug: remdesivir, standard

of care

United States, Hong

Kong/

COVID‐19

400, all, 18 years

and older

Treatment Experimental: demdesivir (RDV), 5

days participants will receive

continued standard of care

III Primary: proportion of participants with

normalization of fever and oxygen

saturation through day 14

NCT04292899/

Recruiting,

Mar6‐May 2020

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

participants with severe

coronavirus disease

(COVID‐19)

therapy together with RDV

200 mg on Day 1 followed by

RDV 100 mg on Days 2, 3, 4,

and 5

Experimental: remdesivir, 10 days

participants will receive

continued standard of care

therapy together with RDV

200 mg on Day 1 followed by

RDV 100 mg on Days 2, 3, 4, 5,

6, 7, 8, 9, and 10

Secondary: proportion of participants

with treatment emergent adverse

events leading to study drug

discontinuation (first dose date up

to 10 days)

Study to evaluate the safety

and antiviral activity of

remdesivir (GS‐5734™)in

participants with

moderate coronavirus

disease (COVID‐19)

compared to standard of

care treatment

Drug: remdesivir, standard

of care

United States,

Hong Kong,

600, all, 18 years

and older

Treatment Experimental: remdesivir, 5 days

participants will receive

continued standard of care

therapy together with RDV

200 mg on Day 1 followed by

RDV 100 mg on Days 2, 3, 4,

and 5.

Experimental: remdesivir, 10 days

participants will receive

continued standard of care

therapy together with RDV

200 mg on Day 1 followed by

RDV 100 mg on Days 2, 3, 4, 5,

6, 7, 8, 9, and 10.

Active comparator: continued

standard of care therapy

III Primary (up to 14 days): proportion of

participants discharged by day 14‐

secondary (up to 10 days):

proportion of participants with

treatment emergent adverse events

leading to study drug

discontinuation

NCT04292730/

Recruiting, Mar‐

May 2020

Bevacizumab in severe or

critical patients with

COVID‐19

pneumonia‐RCT

Drug: bevacizumab China/COVID‐19

Pneumonia

118, all, 18–80 Treatment Experimental; bevacizumab, group:

bevacizumab 500mg + 0.9% NaCl

100 ml, intravenous drip

No intervention: control group

Not applicable Primary: proportion of patients whose

oxygenation index increased by

100 mmHg on the 7th day after

admission

NCT04305106/Not

yet recruiting,

Mar12‐

May31 2020

The efficacy and safety of

thalidomide in the

adjuvant treatment of

moderate new coronavirus

(COVID‐19) pneumonia

Drug: thalidomide, placebo COVID‐19

thalidomide

100, all, 18 years

and older

Treatment Placebo comparator: control group:

placebo 100mg, po, qn, for

14 days

Experimental: thalidomide group

100 mg, po, qn, for 14 days.

Other name: fanyingting

II Primary (up to 28 days): time to clinical

recovery time to clinical recovery

(up to 28 days)

Secondary (up to 28 days): all cause

mortality (up to 28 days), frequency

of respiratory progression, Time to

defervescence

Others(up to 28 days): time to cough

reported as mild or absent,

respiratory improvement time,

frequency of requirement for

supplemental oxygen or noninvasive

ventilation, Time to 2019‐nCoV

RT‐PCR negative in upper

NCT04273529/Not

yet recruiting,

Feb20‐

Jun30 2020

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

respiratory tract specimen, change

(reduction) in 2019‐nCoV viral load

in upper respiratory tract specimen

as assessed by area under viral load

curve, frequency of requirement for

mechanical ventilation, frequency of

serious adverse events, Serum TNF‐

α,IL‐1β,IL‐2, IL‐6, IL‐7, IL‐10, GSCF,

IP10, MCP1, MIP1αand other

cytokine expression levels before

and after treatment

The efficacy and safety of

thalidomide combined

with low‐dose hormones

in the treatment of Severe

COVID‐19

Placebo, drug: thalidomide COVID‐19

thalidomide

40, all, 18 years

and older

Treatment Placebo comparator: control group

α‐interferon: nebulized

inhalation, 5 million U or

equivalent dose added 2 ml of

sterile water for injection, 2

times a day, for 7 days; abidol,

200 mg/time, 3 times a day, for

7 days; methylprednisolone:

40 mg, q12h, for 5 days.

placebo: 100 mg/d, qn, for

14 days

Experimental: thalidomide group α‐

interferon: nebulized

inhalation, 5 million U or

equivalent dose added 2 ml of

sterile water for injection, 2

times a day, for 7 days; abidol,

200 mg/time, 3 times a day, for

7 days; methylprednisolone:

40 mg, q12h, for 5 days.

thalidomide: 100 mg/d qn for

14 days

II Primary (up to 28 days): time to clinical

improvement

Secondary (up to 28 days): clinical status

(days 7, 14, 21, and 28), time to

hospital discharge or NEWS2

(National Early Warning Score 2) of

≤2 maintained for 24 hr, all cause

mortality, duration (days) of

mechanical ventilation, duration

(days) of extracorporeal membrane

oxygenation, duration (days) of

supplemental oxygenation, length of

hospital stay (days), time to 2019‐

nCoV RT‐PCR, change (reduction) in

2019‐nCoV viral load in upper and

lower respiratory tract specimens as

assessed by area under viral load

curve, frequency of serious adverse

drug events, Serum TNF‐α,IL‐1β,IL‐

2, IL‐6, IL‐7, IL‐10, GSCF,

IP10#MCP1, MIP1α, and other

cytokine expression levels before

and after treatment

NCT04273581/Not

yet recruiting,

Feb18‐

May30 2020

Tetrandrine tablets used in the

treatment of COVID‐19

Drug: tetrandrine China/COVID‐19 60, all, 18–75 Treatment Experimental: tetrandrine cohort

after the subjects were

enrolled, they were given

“Tetrandrine 60mg QD”for a

course of 1 week (take 6 days,

stop using for 1 day)

No intervention: control cohort

treatment according to

standard protocols without

intervention

IV Primary (12 weeks): survival rate

secondary (2 weeks): body

temperature

NCT04308317/

Enrolling by

invitation, Mar5‐

May1 2020

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

Fingolimod in COVID‐19 Biological: UC‐MSCs, other:

placebo

China/COVID‐19 30, all, 18–80 Treatment Experimental: treatment group:

each patient in the fingolimod

treatment group was given

0.5 mg of fingolimod orally

once daily, for three

consecutive days

No Intervention: control group

II Primary (5 day after treatment): the

change of pneumonia severity on X‐

ray images

NCT04280588/

Recruiting,

Feb22‐Jul1 2020

Therapy for pneumonia

patients infected by 2019

novel coronavirus

Biological: UC‐MSCs, other:

placebo

China/COVID‐19 48, all, 18–75 Treatment Experimental: UC ‐MSCs treatment

group, participants will receive

conventional treatment plus

four times of 0.5*10E6 UC‐

MSCs/kg body weight

intravenously at Day1, Day3,

Day5, Day7)

Placebo comparator: control group,

participants will receive

conventional treatment plus 4

times of placebo intravenously

at Day1, Day3, Day5, Day7

Not applicable Primary (at baseline, Day 1, Weeks 1, 2,

4, 8): size of lesion area by chest

imaging, blood oxygen saturation

Secondary (at baseline, Day 1, Weeks 1,

2, 4, 8): rate of mortality within 28‐

days, sequential organ failure

assessment, side effects in the UC‐

MSCs treatment group,

Electrocardiogram, the changes of

ST‐T interval mostly, Concentration

of C‐reactive protein C‐reactive

protein, immunoglobulin, CD4 + and

CD8 + T cells count, Concentration

of the blood cytokine (IL‐1β,IL‐6, IL‐

8,IL‐10,TNF‐α), Concentration of the

myocardial enzymes

NCT04293692/

Recruiting,

Feb24‐Feb1

2020–2021

The Use PUL‐042 inhalation

solution to prevent

COVID‐19 in adults

exposed to SARS‐CoV‐2

Drug: PUL‐042 inhalation

solution, drug: placebo

COVID‐19 200, all, 18 years

and older

Treatment Experimental: PUL‐042 inhalation

solution, PUL‐042 inhalation

solution (20.3µg Pam2:

29.8 µg ODN/mL) given by

nebulization on study days 1,3,

6, and 10

Placebo comparator: sterile normal

saline for inhalation, sterile

normal saline for inhalation

given by nebulization on study

days 1, 3, 6, and 10

II Primary (14 days): Prevention of

COVID‐19

NCT04313023/Not

yet recruiting,

Apr‐Oct 2020

Treatment of COVID‐19

patients using Wharton's

jelly‐mesenchymal stem

cells

Biological: WJ‐MSCs Arabia Amman,

Jordan/use of

stem cells for

COVID‐19

treatment

5, all, 18 years

and older

Treatment Experimental: WJ‐MSCs WJ‐MSCs

will be derived from cord tissue

of newborns, screened for

HIV1/2, HBV, HCV, CMV,

mycoplasma, and cultured to

enrich for MSCs.

WJ‐MSCs will be counted and

suspended in 25 ml of saline

solution containing 0.5%

human serum albumin, and will

IPrimary (3 weeks): Clinical outcome, CT

Scan, RT‐PCR results

Secondary (8 weeks): RT‐PCR results

NCT04313322/

Recruiting,

Mar16‐

Sep30 2020

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

be given to patient

intravenously

Myocardial damage in

COVID‐19

Non China/COVID‐19

cardiovascular

diseases

500, all, 18 years

and older

Prognostic Discharged group (no intervention)

the individual which is defined

as patient discharged from

hospital

Dead group (no intervention) The

individual which is defined as

patient with all‐cause death

–Primary (75 days): the myocardial injury

incidence, the risk factors analysis

for the death

Secondary (75 days): clinical

characteristics, clinical course,

cardiovascular comorbidity, Analysis

of causes of death

NCT04312464/

Enrolling by

invitation, Jun1‐

Mar18 2020

Treatment with mesenchymal

stem cells for severe

corona virus disease

2019(COVID‐19)

Biological: MSCs, biological:

saline containing 1%,

human serum albumin

(solution of MSC

China/COVID‐19 60, all, 18–70 Treatment Experimental: mesenchymal stem

cells (MSCs), conventional

treatment plus MSCs

participants will receive

conventional treatment plus 3

times of MSCs ((4.0*10E7 cells

per time) intravenously at Day

0, Day 3, Day 6)

Placebo comparator: placebo

conventional treatment plus

placebo participants will

receive conventional treatment

plus 3 times of placebo (saline

containing 1% human serum

albumin (solution of MSC) 3

times of placebo (intravenously

at Day 0, Day 3, Day 6)

I, II Primary (28 days): improvement time of

clinical critical treatment index, side

effects in the MSCs treatment group

Secondary: proportion of patients in

each classification of clinical critical

treatment index (baseline, Days 7,

14, 28), all cause mortality on Day

28, invasive mechanical ventilation

rate (Day 28), duration of oxygen

therapy (Day 28), duration of

hospitalization (Day 28), incidence

of nosocomial infection (Day 28),

CD4+ T cell count by flow

cytometry in two groups (baseline,

Day, 3, 6, 10, 14, 21, 28)

NCT04288102/

Recruiting,

May5‐Dec31

2020–2021

The clinical study of carrimycin

on treatment patients with

COVID‐19

Drug: carrimycin, drug:

lopinavir/ritonavir tablets

or arbidol or chloroquine

phosphate, Drug: basic

treatment

–520, all, 18–75 Treatment Experimental: carrimycin basic

treatment + carrimycin

Active comparator: lopinavir/

ritonavir or arbidol or

chloroquine phosphate any of

basic treatment+ lopinavir/

ritonavir tablets or arbidol or

chloroquine phosphate

IV Primary (30 days): fever to normal time

(day), pulmonary inflammation

resolution time (HRCT) (day),

negative conversion (%) of 2019‐

nCOVRNA in gargle (throat swabs)

at the end of treatment

NCT04286503/Not

yet recruiting,

Feb23‐Feb28

2020–2021

Efficacy and safety of

corticosteroids in

COVID‐19

Drug: methylprednisolone China/COVID‐19 400, all, 18 years

and older

Treatment Experimental; Pred group:

methylprednisolone 1mg/kg/

day ivgtt for 7 days

No intervention: con group

Not applicable Primary (14 days): the incidence of

treatment failure in 14 days

Secondary: clinical cure incidence (14

days), the duration of virus change

to negative (14 days), mortality at

Day 30, ICU admission rate in

30 days

NCT04273321/

Recruiting,

Feb14‐

May30 2020

Evaluation of the efficacy and

safety of sarilumab in

Drug: sarilumab, drug: placebo United States/

COVID‐19

400, all, 18 years

and older

Treatment Experimental: sarilumab high dose:

single intravenous (IV) dose of

sarilumab, other names:

II, III Primary: time to resolution of fever for

at least 48 hr without antipyretics

for 48 hr (Up to Day 29), percentage

NCT04315298/

Recruiting,

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

hospitalized patients with

COVID‐19

Kevzara®, REGN88,

SAR153191

Experimental: sarilumab low dose:

single intravenous (IV) dose of

sarilumab Other Names:

Kevzara®, REGN88,

SAR153191

Placebo comparator: single

intravenous (IV) dose of

placebo to match sarilumab

administration

of patients reporting each severity

rating on a 6‐point ordinal scale

(Day 15)

Secondary (up to Day 29): time to

improvement in oxygenation for at

least 48hr, mean change in the 6‐

point ordinal scale, clinical status

using the 6‐point ordinal scale, time

to improvement in one category

from admission using the 6‐point

ordinal scale, time to resolution of

fever for at least 48 hr without

antipyretics by clinical severity, time

to resolution of fever for at least

48 hr without antipyretics by

baseline IL‐6 levels, time to

improvement in oxygenation for at

least 48hr by clinical severity, time

to improvement in oxygenation for

at least 48 hr by baseline IL‐6 levels,

time to resolution of fever and

improvement in oxygenation for at

least 48hr, time to change in

National Early Warning Score 2

(NEWS2) scoring system, time to

score of <2 maintained for 24 hr in

NEWS2 scoring system, mean

change in NEWS2 scoring system,

number of days with fever, number

of patients alive off oxygen, number

of days of resting respiratory rate

>24 breaths/min, number of days

with hypoxemia, number of days of

supplemental oxygen use, time to

saturation ≥94% on room air,

number of ventilator free days in

the first 28 days, number of patients

requiring initiation of mechanical

ventilation, number of patients

requiring noninvasive ventilation,

number of patients requiring the use

of high flow nasal cannula, number

of patients admitted into an

intensive care unit, number of days

of hospitalization among survivors,

number of deaths due to any cause

(up to Day 60), incidence of serious

Mar16‐Mar16

2020–2021

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

adverse events (Up to Day 60),

incidence of severe or life‐

threatening bacterial, invasive

fungal, or opportunistic infection,

Incidence of severe or life‐

threatening bacterial, invasive

fungal, or opportunistic infection in

patients with grade 4 neutropenia,

Incidence of hypersensitivity

reactions, incidence of infusion

reactions, incidence of

gastrointestinal perforation, white

blood cell count, hemoglobin levels,

platelet count, creatinine levels,

total bilirubin level, alanine

aminotransferase level, aspartate

aminotransferase level

Washed microbiota

transplantation for

patients with 2019‐nCoV

infection

Other: washed microbiota

transplantation, other:

placebo

China/COVID‐19

complicated

with refractory

intestinal

infections

0, all, 14–70

complicated

with

refractory

intestinal

infections

Treatment Experimental: observational group

5 u washed microbiota

suspension administered via

nasogastric tube, nasojejunal

tube or oral, combining with

standard therapy

Placebo comparator: control group

5 u placebo (edible suspension

of the same color as the

washed microbiota suspension)

administered via nasogastric

tube, nasojejunal tube or oral,

combining with standard

therapy

Not applicable Primary (2 weeks): number of

participants with improvement from

severe type to common type

NCT04251767/

Withdrawn,

Feb5‐

Apr30 2020

Safety and immunity of Covid‐

19 aAPC vaccine

Biological: pathogen‐

specific aAPC

China/Covid‐19

infection

100, all, 6 months

to 80 years

Treat and Prevent

Covid‐19

Infection

Experimental: the subjects will

receive three injections of

5×10^6 each Covid‐19/aAPC

vaccine via subcutaneous

injections

IPrimary (0–28 day): frequency of vaccine

events, frequency of serious vaccine

events, proportion of subjects with

positive T cell response

Secondary (0–28 day): mortality,

duration of mechanical ventilation if

applicable, proportion of patients in

each category of the 7‐point scale

(7, 14, and 28 days after

randomization), proportion of

patients with normalized

inflammation factors (7 and 14 days

after randomization), clinical

improvement based on the 7‐point

scale if applicable, lower Murray

NCT04299724/

Recruiting,

Feb15‐Dec31

2020–2024

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

lung injury score if applicable (7

days after randomization)

Safety related factors of

endotracheal intubation in

patients with severe

Covid‐19 pneumonia

Severe covid‐19 pneumonia

with ET

COVID‐19

endotracheal

intubation

120, all, 18–90 Observational Intervention details: other: severe

covid‐19 pneumonia with ET,

severe covid‐19 pneumonia

undergoing endotracheal

intubation

–Primary:

Success rate of intubation (the time span

between 1hr before intubation and

24 hr after intubation), infection

rate of anesthesiologist (the time

span between 1 hr before intubation

and 14 days after intubation)

Secondary:

Extubation time (the time span between

1 hr before intubation and 30 days

after intubation)

NCT04298814/Not

yet recruiting,

Mar7‐

Jul30 2020

Immunity and safety of Covid‐

19 synthetic minigene

vaccine

Biological: injection and

infusion of LV‐SMENP‐

DC vaccine and antigen‐

specific CTLs

China/COVID‐19 100, all, 6 months

to 80 years

Treatment Experimental: pathogen‐specific DC

and CTLs patients will receive

approximately 5× 10

LV‐DC

vaccine and 1 × 10

CTLs via

subcutaneous injections and iv

infusions, respectively

Primary:

Clinical improvement based on the

7‐point scale (28 days after

randomization), lower Murray lung

injury score (7 days after

randomization)

Secondary (0–28 day): 28‐day mortality,

duration of mechanical ventilation,

duration of hospitalization,

proportion of patients with negative

RT‐PCR results (7 and 14 days after

randomization), proportion of

patients in each category of the

7‐point scale (7, 14, and 28 days

after randomization), proportion of

patients with normalized

inflammation factors (7 and 14 days

after randomization), frequency of

vaccine/CTL events, frequency of

serious vaccine/CTL events

NCT04276896/

Recruiting,

Mar24‐Dec31

2020–2024

Phase I clinical trial in healthy

adult

Biological: recombinant novel

coronavirus vaccine

(adenovirus type 5

vector)

–108, all, 18–60 Prevention Experimental: low‐dose group

subjects received one dose of

5E10 vp Ad5‐nCoV at 18–60

years old

Experimental: middle‐dose group

Subjects received one dose of 1E11

vp Ad5‐nCoV at 18–60

years old

Experimental: high‐dose group

Subjects received one dose of

1.5E11vp Ad5‐nCoV at 18–60

years old

IPrimary (0–7 days postvaccination):

safety indexes of adverse reactions

Secondary (Day 14, 28, Month 3, 6

postvaccination):

Safety indexes of adverse events (0–28

days postvaccination), safety

indexes of SAE (0–28 days, within 6

mouths postvaccination), safety

indexes of lab measures (pre‐

vaccination, Day 7 postvaccination),

immunogencity indexes of GMT

(ELISA) (Day 14, 28, Month 3, 6

NCT04313127/Not

yet recruiting,

Mar1Dec20

2020–2022

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

postvaccination), immunogencity

indexes of GMT (pseudoviral

neutralization test method),

immunogencity indexes of

seropositivity rates, immunogencity

indexes of seropositivity rates

(pseudoviral neutralization test

method, immunogencity indexes of

GMI (ELISA), immunogencity

indexes of GMI (pseudoviral

neutralization test method),

immunogencity indexes of GMC

(Ad5 vector), immunogencity

indexes of GMI (Ad5 vector),

immunogencity indexes of cellular

immune

Other (day、14,28, Month3,6

postvaccination):

Consistency analysis(ELISA and

pseudoviral neutralization test

method), Dose‐response

relationship (Humoral immunity),

Persistence analysis of anti‐S

protein antibodies, Time‐dose‐

response relationship (Humoral

immunity), Dose‐response

relationship (cellular immunity),

Persistence analysis of cellular

immuse, Time‐dose‐response

relationship (cellular immunity)

Development and verification

of a new coronavirus

multiplex nucleic acid

detection system

Diagnostic test: new QIAstat‐

Dx fully automatic

multiple PCR detection

platform

China/COVID‐19 100, all, 16 years

to 100 years

Diagnostic Diagnostic test: new QIAstat‐Dx

fully automatic multiple PCR

detection platform

We use the new QIAstat‐Dx fully

automatic multiple PCR

detection platform to test the

enrolled patients

–Primary:

Sensitivity, spectivity turnaround time of

the New QIAstat‐Dx fully automatic

multiple PCR detection platform (3

months)

NCT04311398/Not

yet recruiting,

Mar14‐

Dec1, 2020

Hydroxychloroquine treatment

for severe COVID‐19

pulmonary infection

(HYDRA Trial)

Drug: hydroxychloroquine,

drug: placebo oral tablet

COVID‐19 severe

acute

respiratory

syndrome

500, all, 18–0 Treatment Active comparator: treatment

Hydroxychloroquine tablet 200 mg

every 12hr for 10 days

Placebo comparator: placebo

identical placebo, one tablet every

12 hr for 10 days

III Primary (up to120 days):

All‐cause hospital mortality

Secondary (up to120 days):

Length of hospital stay, Need of

mechanical ventilation, ventilator

free days, Grade 3–4 adverse

reaction

NCT04315896/Not

yet recruiting,

Mar23‐Mar22

2020–2012

Drug: tocilizumab Injection Treatment Experimental: Tocilizumab Injection II Primary (up to 1 month):

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

Tocilizumab in COVID‐19

pneumonia (TOCIVID‐19)

Italy/COVID‐19

pneumonia

330, child, adult,

older adult,

child, adult,

older adult

Tocilizumab 8mg/kg (up to a

maximum of 800 mg per dose),

with an interval of 12 hr

One‐month mortality rate

Secondary (up to 1 month):

interleukin‐6 level, lymphocyte count,

C‐reactive protein level (cycle 1 and

2 every 12 hr), PaO2 (partial

pressure of oxygen)/FiO2 (fraction

of inspired oxygen, FiO2) ratio (or P/

F ratio) (baseline, during treatment

(cycle 1 and 2 every 12 hr), change

of the SOFA (sequential organ

failure assessment) (baseline, during

treatment (cycle 1 and 2 every

12 hr), number of participants with

treatment‐related side effects as

assessed by Common Terminology

Criteria for Adverse Event version

5.0, Radiological response, Time

Frame: at baseline (optional), after 7

days and if clinically indicated,

duration of hospitalization. Time

Frame: from baseline up to patient's

discharge, Remission of respiratory

symptoms

NCT04317092/

Recruiting,

Mar19‐Dec19

2020–2022

Mesenchymal stem cell

NestCell® to treat

patients with severe

COVID‐19 pneumonia

Biological: NestCell® COVID‐19

pneumonia

6, all, 18 years

and older

Treatment Experimental: NestCell®:

All patients will receive

conventional treatment plus 3

times of 1 × 106 cells/kg body

weight intravenously on Day1,

Day3, and Day7

IPrimary (28 days):

Disappear time of ground‐glass shadow

in the lungs

Secondary:

Rate of mortality within 28‐days,

Improvement of clinical symptoms

including duration of fever and

respiratory (At Baseline, Day 3, 7,

10, 14, 21, 28), Time of nucleic acid

turning negative (28 days), CD4+

and CD8+ T cell count (At Baseline,

Day 3, 6, 10, 14, 21, and 28),

changes of blood oxygen (At

Baseline, Day 3, 6, 10, 14, 21, and

Day 28), side effects in the

treatment group (28 days)

NCT04315987/Not

yet recruiting,

Apr‐Jun 2020

CD24Fc as a non‐antiviral

immunomodulator in

COVID‐19 treatment

Drug: CD24Fc, drug: placebo United States/severe

coronavirus

disease

(COVID‐19)

230, all, 18 years

and older

Treatment Experimental: CD24Fc treatment

Single dose at Day 1, CD24Fc,

480 mg, diluted to 100 ml with

normal saline, IV infusion in

60 min

Placebo comparator: placebo

III Primary (14 days):

Improvement of COVID‐19 disease

status secondary (14 days):

Conversion rate of clinical status at Day

8 (7 days), conversion rate of clinical

status at Day 15, hospital discharge

time, all cause of death, duration of

NCT04317040/Not

yet

recruiting,May‐

May 2020–2022

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

Single dose at Day 1, normal saline

solution 100ml, IV infusion in

60 min

mechanical ventilation, duration of

pressors, duration of ECMO,

duration of oxygen therapy, length

of hospital stay, absolute

lymphocyte count

Acute kidney injury in patients

hospitalized with

COVID‐19

–China/COVID‐19

acute kidney

injury‐kidney

function

287, all, 18 years

and older

Observational Acute kidney injury:

COVID‐19 patients with acute

kidney injury

nonacute kidney injury:

COVID‐19 patients without acute

kidney injury

–

Rate of death,

the length of

hospital stay

Primary (up to 60 days):

Rate of acute kidney injury

Secondary (up to 60 days):

NCT04316299/

Completed, Feb

26‐Mar8 2020

Phase I clinical trial in healthy

adult

Logical: recombinant novel

coronavirus vaccine

(adenovirus type 5

vector)

COVID‐19 108, all, 18–60 Treatment (Adenovirus Type 5 Vector)

Experimental: low‐dose group

Subjects received one dose of 5E10

vp Ad5‐nCoV at 18–60

years old

Experimental: middle‐dose group

Subjects received one dose of 1E11

vp Ad5‐nCoV at 18–60

years old

Experimental: high‐dose group

subjects received one dose of

1.5E11vp Ad5‐nCoV at 18–60

years old

IPrimary (0–7 days postvaccination):

Safety indexes of adverse reactions

Secondary (0–28 days postvaccination,

within 6 mouths postvaccination):

Safety indexes of adverse events, Safety

indexes of SAE, Safety indexes of lab

measures, Immunogencity indexes

of GMT (ELISA), Immunogencity

indexes of GMT (pseudoviral

neutralization test method) (Day 14,

28, Month 6 postvaccination),

Immunogencity indexes of

seropositivity rates (ELISA) (Day 14,

28, Month 3, 6 postvaccination),

Immunogencity indexes of

seropositivity rates(pseudoviral

neutralization test method) (Day 14,

28, Month 6 postvaccination),

Immunogencity indexes of GMI

(ELISA) (Day 14, 28, Month 3, 6

postvaccination), Immunogencity

indexes of GMI (pseudoviral

neutralization test method) (Day 14,

28, Month 6 postvaccination),

Immunogencity indexes of GMC

(Ad5 vector) (Day 14, 28, Month 3, 6

postvaccination), Immunogencity

indexes of GMI(Ad5 vector) (Day 14,

28, Month 3, 6 postvaccination),

Immunogencity indexes of cellular

immune (Day 14, 28, Month 6

postvaccination)

Other (Day 14,28, Month 6

postvaccination):

NCT04313127/Not

yet recruiting,

Mar19‐Dec20

2020–2021

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

Consistency analysis (ELISA and

pseudoviral neutralization test

method), dose‐response relationship

(humoral immunity) (Day 14, 28,

Month 3, 6 postvaccination),

Persistence analysis of anti‐S

protein antibodies (Day 14, 28,

Month 3, 6 postvaccination), Time‐

dose‐response relationship

(Humoral immunity) (Day 14, 28,

Month 3, 6 postvaccination), Dose‐

response relationship (cellular

immunity) (Day 14, 28, Month 6

postvaccination), Persistence

analysis of cellular immuse (Day 14,

28, Month 6 postvaccination), Time‐

dose‐response relationship (cellular

immunity) (Day 14, 28, Month 6

postvaccination)

Favipiravir combined with

tocilizumab in the

treatment of corona virus

disease 2019

Drug: favipiravir combined

with tocilizumab, drug:

favipiravir, drug:

tocilizumab

China, COVID‐19 150, all, 18–65 Treatment Experimental: favipiravir combined

with tocilizumab group

Favipiravir: On the 1st day,

1,600 mg each time, twice a

day; from the 2nd to the 7th

day, 600 mg each time, twice a

day. Oral administration, the

maximum number of days

taken is not more than 7 days.

Tocilizumab: the first dose is

4–8 mg/kg and the

recommended dose is 400 mg.

For fever patients, an

additional application (the

same dose as before) is given if

there is still fever within 24 hr

after the first dose and the

interval between two

medications ≥12 hr.

Intravenous infusion. The

maximum of cumulative

number is two, and the

maximum single dose does not

exceed 800mg

Active comparator: favipiravir

group

Not applicable Primary (3 months):

Clinical cure rate

Secondary (14 days after taking

medicine):

Viral nucleic acid test negative

conversion rate and days from

positive to negative, duration of

fever, lung imaging improvement

time, mortality rate because of

corona virus disease 2019 (3

months), rate of noninvasive or

invasive mechanical ventilation

when respiratory failure occurs (3

months), mean in‐hospital time (3

months)

NCT04310228/

Recruiting,

Mar8‐May 2020

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

On the 1st day, 1,600 mg each time,

twice a day; from the 2nd to

the 7th day, 600 mg each time,

twice a day. Oral

administration, the maximum

number of days taken is not

more than 7 days

Active comparator: tocilizumab

group

The first dose is 4–8 mg/kg and the

recommended dose is 400 mg.

For fever patients, an

additional application (the

same dose as before) is given if

there is still fever within 24 hr

after the first dose and the

interval between two

medications ≥12 hr.

Intravenous infusion, The

maximum of cumulative

number is two, and the

maximum single dose does not

exceed 800mg

Novel coronavirus induced

severe pneumonia treated

by dental pulp

mesenchymal stem cells

Biological: dental pulp

mesenchymal stem cells

‐COVID‐19 24, all, 18–75 Treatment Experimental: pulp mesenchymal

stem cells 1. 3, 7 days to

increase the injection of

mesenchymal stem cells

Early Phase I Primary (14 days):

Disppear time of ground‐glass shadow in

the lungs

Secondary:

Absorption of lung shadow absorption by

CT Scan‐Chest (7, 14, 28, and 360

days), Changes of blood oxygen (3,

7, and 14 days)

NCT04302519/Not

yet Recruiting,

Mar5‐Jul30

2020–2021

Multicenter clinical study on

the efficacy and safety of

Xiyanping injection in the

treatment of new

coronavirus infection

pneumonia (general and

severe)

Drug: lopinavir/ritonavir

tablets combined with

Xiyanping injection drug:

lopinavir/ritonavir

treatment

COVID‐19 80, all, 18–100 Treatment Experimental: experimental group

of ordinary COVID‐19:

Xiyanping injection, 10–20 ml daily,

Qd, the maximum daily does

not exceed 500 mg

(20 ml) + lopinavir tablet or

ritonavir tablet+ alpha‐

interferon nebulization, for

7–14 days,

Active comparator: control group of

ordinary COVID‐19:

Lopinavir/ritonavir tablets, two

times a day, two tablets at a

time; alpha‐interferon

nebulization

Not applicable Primary:

Clinical recovery time (up to Day 28)

NCT04295551/Not

yet Recruiting,

Mar14‐Apr14

2020–2021

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

Experimental: experimental group

of severe COVID‐19:

Xiyanping injection, 10–20 ml daily,

Qd, the maximum daily does

not exceed 500 mg

(20 ml) + lopinavir tablet or

ritonavir tablet+ alpha‐

interferon nebulization, for

7–14 days

Prognostic factors of patients

with COVID‐19

–China/SARS‐CoV‐2

outcome, fatal

201, all, 18 years

and older

Prognostic SARS‐CoV‐2Outcome, fatal –Primary (30 days):

all‐cause mortality

Secondary (15 days):

all‐cause mortality,

Severe state

NCT04292964/

Completed

Mar1‐

Mar13 2020

Chloroquine prevention of

coronavirus disease

(COVID‐19) in the

healthcare setting

Drug: chloroquine, drug:

placebo

COVID19

coronavirus

acute

respiratory

illnesses

10,000, all, 16

years and

older

Prevention Experimental: chloroquine:

a loading dose of 10 mg base/kg

followed by 150 mg daily

(250 mg chloroquine

phosphate salt) will be taken

for 3 months

Placebo comparator: placebo

Not applicable Primary (approximately 100 days):

Number of symptomatic COVID‐19

infections

Secondary (approximately 100 days):

Symptoms severity of COVID‐19,

duration of COVID‐19, number of

asymptomatic cases of COVID‐19,

number of symptomatic acute

respiratory illnesses, genetic loci

and levels of biochemical

components will be correlated with

frequency of COVID‐19, ARI, and

disease severity

Other (approximately 100 days):

Drug exposure‐protection relationship

NCT04303507/Not

yet recruiting,

May‐May

2020–2022

Yinhu Qingwen decoction for

the treatment of mild/

common CoVID‐19

Drug: YinHu QingWen

decoction, drug: YinHu

QingWen decoction(low

dose), other: Chinese

medicine treatment,

other: standard western

medicine treatment

China/CoVID‐19

Chinese

medicine

300, all, 18 years

and older

Treatment Experimental: Yin Hu Qing Wen

decoction group

Based on the standard western

medicine treatment, the

patients will be given Yinhu

Qingwen decoction (granula)

for 10 days.

Drug: YinHu QingWen decoction

YinHu QingWen decoction

(granula) consits of 11 Chinese

herbal medicine as

honeysuckle, Polygonum

cuspidatum, Schizonepeta,

Longspur epimedium, and so

forth. The decoction granula

will be dissolved into 600 ml

III

Primary (up to 28 days):

Mean clinical recovery time

Secondary (up to 28 days):

Time to CoVID‐19 RT‐PCR negative in

upper respiratory tract specimen,

change (reduction) in CoVID‐19

viral load in upper respiratory tract

specimen as assessed by area under

viral load curve, time to

defervescence (in those with fever

at enrollment), time to cough

reported as mild or absent (in those

with cough at enrollment rated

severe or moderate), time to

dyspnea reported as mild or absent

(on a scale of severe, moderate, mild

NCT04278963/

Active, Not

Recruiting,

Feb27‐Jan 2020

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

decoction and divided to three

times (once with 200 ml). It will

be given a 200 ml per time,

three times a day, for 10 days

Other: standard western medicine

treatment treatment is

according to the protocol of

treatment of CoVID‐19

infection according to guideline

appoved by National Health

Commission of China

Placebo comparator: Yinhu

Qingwen decoction low‐dose

group

Based on the standard western

medicine treatment, the

patients will be given 10% dose

of Yinhu Qingwen decoction

(granula) for 10 days

Drug: YinHu QingWen decoction

(low dose) this intervention is

given as 10% dose of YinHu

QingWen decoction (granula).

The granula will be dissolved

into 600ml decoction and

divided to three times (once

with 200ml). It will be given a

200 ml per time, three times a

day, for 10 days

Other: standard western medicine

treatment standard western

medicine treatment is

according to the protocol of

treatment of CoVID‐19

infection according to guideline

appoved by National Health

Commission of China

Active comparator: integrated

Chinese and western medicine

group

Based on the standard western

medicine treatment, the

patients will be given Chinese

medicine decotion granula

according to their symptoms.

The daily dose of Chinese

medicine decoction granula will

absent, in those with dyspnea at

enrollment rated as severe or

moderate)

Frequency of requirement for

supplemental oxygen or noninvasive

ventilation, frequency of respiratory

progression, severe case incidence,

proportion of rehospitalization or

admission to ICU, all‐cause

mortality, frequency of serious

adverse events

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

also be dissolved to 600 ml

decoction and divided into

three times (once with 200 ml).

The Chinese medicine

decoction will be given 200 ml

per time, three times a day for

10 days

Other: Chinese medicine treatment

This intervention will be given with

Chinese medicine decoction

granula based on the symptoms

differentiation of the patients

for 10 days

Other: standard western medicine

treatment

Standard western medicine

treatment is according to the

protocol of treatment of

CoVID‐19 infection according

to guideline appoved by

National Health Commission of

China

Prognositc factors in COVID‐

19 patients complicated

with hypertension

–China, COVID‐19 0, all, 18–100 Prognostic ACEI treatment

hypertension patients with ACEI

treatment when suffered with

novel coronavirus infection in

China

Control

hypertension patients without ACEI

treatment when suffered with

novel coronavirus infection in

China

–Primary (up to 28 days):

Occupancy rate in the intensive care

unit, mechanical ventilation, death

Secondary (up to 28 days):

All cause mortality, time from onset of

symptoms to main outcome and its

components, time to clinical

recovery

NCT04272710/

Withdrawn,

Jan25‐

Apr30 2020

Evaluating the efficacy and

safety of bromhexine

hydrochloride tablets

combined with standard

treatment/standard

treatment in patients with

suspected and mild novel

coronavirus pneumonia

(COVID‐19)

Drug: bromhexine

hydrochloride tablets,

drug: arbidol

hydrochloride granules,

drug: recombinant human

interferon α2b spray,

drug: favipiravir tablets

China, novel

coronavirus

pneumonia

2019‐nCoV

60, all, 18–80 Treatment Experimental: group A treatment

group:

Bromhexine hydrochloride tablets,

arbidol hydrochloride granules:

Standard treatment refers to the

latest edition of pneumonia

diagnosis and treatment

scheme for novel coronavirus

infection. Arbidol

hydrochloride granules is

recommended but not

enforced to use

Recombinant human interferon α2b

spray:

Not applicable Primary (within 14 days from the start of

medication):

Time to clinical recovery after treatment

Secondary (within 14 days from the start

of medication):

Rate of aggravation, clinical remission

rate, dynamic changes of

oxygenation index, time to cure, rate

to cure, time to defervescence, time

to cough remission,days of

supplemental oxygenation, rate of

patients with requring supplemental

oxygen, rate of patients with

mechanical ventilation, time of

NCT04273763/

Enrolling by

invitation,

Feb16‐

Apr30 2020

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

Standard treatment refers to the

latest edition of pneumonia

diagnosis and treatment

scheme for novel coronavirus

infection

Favipiravir tablets

Active comparator; group B control

group:

Drug: arbidol hydrochloride

granules

Standard treatment refers to the

latest edition of pneumonia

diagnosis and treatment

scheme for novel coronavirus

infection. arbidol hydrochloride

granules is recommended but

not enforced to use

Drug: recombinant human

interferon α2b spray

Standard treatment refers to the

latest edition of pneumonia

diagnosis and treatment

scheme for novel coronavirus

infection

negative COVID‐19 nucleic acid

results, rate of negative COVID‐19

nucleic acid results, rate of ICU

admission, 28‐day mortality (From

the first day of screening to the day

of follow‐up (28 days))

Various combination of

protease inhibitors,

oseltamivir, favipiravir,

and chloroquin for

treatment of covid19: a

randomized control trial

Drug: oral Thailand,

coronavirus

infections

COVID19

80, all, 16–100 Treatment Experimental: oseltamivir plus

chloroquin in mild COVID19

Oseltamivir 300 mg per day plus

chloroquin 1,000 mg per Day In

mild COVID19

Experimental: lopinavir and

ritonavir plus favipiravir

Lopinavir 10mg/kg and ritonavir

2.5 mg/kg plus favipiravir

2,400 mg, 2,400mg, and

1,200 mg every 8 hr on Day 1,

and a maintenance dose of

1,200 mg twice a day in Mild

COVID19

Experimental: lopinavir and

ritonavir plus oseltamivir in

mild COVID19

Lopipinavir 10mg/kg and ritonavir

2.5 mg/kg plus oseltamivir

4–6 mg/kg In mild COVID19

III Primary (Up to 24 weeks):

SARS‐CoV‐2 eradication time

Secondary (up to 24 weeks):

Number of patient with death, number of

patient with recovery adjusted by

initial severity in each arm, number

of day with ventilator dependent

adjusted by initial severity in each

arm,number of patient developed

acute respiratory distress syndrome

after treatment

Other (up to 24 weeks):

Number of patient with acute

respiratory distress syndrome

recovery

NCT04303299/Not

yet recruiting,

Mar15‐

Nov30 2020

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

Experimental: lopinavir and

ritonavir oseltamivir moderate

to severe COVID19

Lopipinavir 10mg/kg and ritonavir

2.5 mg/kg plus oseltamivir

4–6 mg/kg in moderate to

critically ill COVID19

Experimental: favipiravir lopinavir/

ritonavir for mod. To severe

favipiravir 2,400mg, 2,400 mg, and

1,200 mg every 8 hr on Day 1,

and a maintenance dose of

1,200 mg twice a day plus

lopipinavir 10mg/kg and

ritonavir 2.5mg/kg in

moderate to critically ill

COVID19

Experimental: darunavir/ritonavir

oseltamivir chloroquine mod‐

severe

Combination of Darunavir 400 mg

every 8hr ritonavir Ritonavir

2.5 mg/kg plus Oseltamivir

4–6 mg/kg plus Chloroquine

500 mg per Day In moderate to

critically ill COVID19

Experimental: darunavir/ritonavir

favipiravir chloroquine mod‐

severe

Favipiravir 2,400mg, 2,400 mg, and

1,200 mg every 8 hr on Day 1,

and a maintenance dose of

1,200 mg twice a day plus

darunavir 400mg every 8hr

ritonavir ritonavir 2.5 mg/kg

plus chloroquine 500 mg per

Day In moderate to critically ill

COVID19

No intervention: conventional

qurantine

Patient who unwilling to treatment

and willing to quarantine in

mild COVID19

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

Yinhu Qingwen Granula for the

treatment of severe

CoVID‐19

Drug: Yinhu Qingwen granula,

drug: Yin Hu Qing Wen

granula (low does), other:

standard medical

treatment

China, COVID‐19

severe

pneumonia

Chinese

medicine

116, all, 18 years

and older

Treatment Experimental:

Yinhu Qingwen granula group:

Drug: Yinhu Qingwen Granula

Yinhu Qingwen granula is a kind of

herbal granula made from

“Yinhu Qingwen Decoction,”

which consits of 11 Chinese

herbal medicine as

honeysuckle, Polygonum

cuspidatum, schizonepeta,

Longspur epimedium, etc. The

granula will be dissolved into

600 ml decoction and divided

to three times (once with

200 ml). It will be given a

200 ml per time, three times a

day, for 10 days.

Other: standard medical treatment

Standard medical treatment is

adhered to the protocol of the

treatment for the severe

CoVID‐19 according to the

guideline approved by National

Health Commission of China.

Placebo comparator: Yinhu

Qingwen granula low‐dose

group:

Drug: Yin Hu Qing Wen granula

(low does). This intervention is

given as 10% dose of YinHu

QingWen Granula.The granula

will be dissolved into 600 ml

decoction and divided to three

times (once with 200 ml).

Other: standard medical treatment

Standard medical treatment is

adhered to the protocol of the

treatment for the severe

CoVID‐19 according to the

guideline approved by National

Health Commission of China.

II Primary (Day 10):

changes in the ratio of PaO2 to FiO2

from baseline

Secondary (up to 30 days):

PaO2, blood oxygen saturation (SpO2),

clinical status rating on the 7‐point

ordinal scale, time to clinical

improvement, duration (hours) of

noninvasive mechanical ventilation

or high‐flow nasal catheter oxygen

inhalation use, duration (hours) of

invasive mechanical ventilation use,

duration (hours) of extracorporeal

membrane oxygenation (ECMO)

use, duration (days) of oxygen use,

The proportion of the patients

reporting 2019‐nCoV RT‐PCR

negativity at Day 10 after

treatment, the counts/percentage of

lymphocyte, time to hospital

discharge with clinical recovery

from the randomization, the

incidence of critical status

conversion in 30 days, all‐cause

mortality within 30 days, frequency

of severe adverse drug events

NCT04310865/Not

yet recruiting,

Mar20‐Jun30

2020–2021

Clinical characteristics and

long‐term prognosis of

2019‐nCoV infection in

children

–China, 2019‐nCoV 500, all, up to 18

years

Prognosis 2019‐nCoV infection group

Children hospitalized with direct

laboratory confirmed of novel

coronavirus with or without

–Primary (6 months):

The cure rate of 2019‐nCoV, the

improvement rate of 2019‐nCoV,

the incidence of long‐term adverse

outcomes

NCT04270383/Not

yet recruiting,

Feb15‐

Dec30 2020

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

pneumonia are classified as the

2019‐nCoV infection group

Control group Children hospitalized

with pneumonia other than the

novel coronavirus pneumonia

during the same hospitalization

period as 2019‐nCoV infection

group are classified as the

control group

Secondary (2 weeks):

Duration of fever, duration of

respiratory symptoms, duration of

hospitalization, number of

participant(s) need intensive care,

number of participant(s) with acute

respiratory distress syndrome,

number of participant(s) with extra‐

pulmonary complications, including

shock, renal failure, multiple organ

failure, hemophagocytosis

syndrome, et al., number of

participant(s) who died during the

trial (10 months)

The effect of T89 on improving

oxygen saturation and

clinical symptoms in

patients with COVID‐19

Drug: T89 Coronavirus disease

2019 novel

coronavirus

pneumonia

120, all, 18–85 Treatment Experimental: The T89 treatment

group Besides a standard

background treatment

(antiviral

drug + antibacterial + oxygen

therapy + Traditional Chinese

Medicine decoction), all

subjects in the T89 treatment

group will receive 30 pills of

T89 each time, orally, BID

(every morning and evening),

for 10 days (depending on

clinical need and practicability,

the use can be extended for up

to 14 days)

No intervention: the blank control

group

All subjects in the blank control

group will only receive a

standard background

treatment (antiviral

drug + antibacterial + oxygen

therapy + Traditional Chinese

Medicine decoction), for

10 days.

Not applicable Primary (Day −1 to 10): the time to

oxygen saturation recovery to

normal level (≥97%), the proportion

of patients with normal level of

oxygen saturation(≥97%)

Secondary (Day −1 to 10):

The degree of remission of symptoms of

patients, including: fatigue, nausea,

vomiting, chest tightness, shortness

of breath, and so forth, the time to

the myocardial enzyme spectrum

recovery to normal after treatment,

the proportion of the patients with

normal myocardial enzyme

spectrum after treatment, the time

to the electrocardiogram recovery

to normal level after treatment, the

proportion of the patients with

normal electrocardiogram after

treatment, the time to the

hemodynamics recovery to normal

after treatment, the proportion of

the patients with normal

hemodynamics after treatment, the

time to exacerbation or remission of

the disease after treatment, the

proportion of the patients with

exacerbation or remission of disease

after treatment, the proportion of

patients who need other treatment

(e.g., heparin, anticoagulants) due to

microcirculation disorders, the all‐

NCT04285190/Not

yet recruiting,

Feb26‐

Sep15 2020

(Continues)

SHEERVALILOU ET AL.

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

cause mortality rate, the proportion

of patients with acidosis, the total

duration of the patients in‐hospital,

the total duration of oxygen

inhalation during treatment, the

oxygen flow rate during treatment,

the oxygen concentration during

treatment

Immunoregulatory therapy for

2019‐nCoV

Drug: PD‐1 blocking

antibody + standard

treatment, drug:

Thymosin + standard

treatment, other:

standard treatment

‐2019 nCoV, PD‐1 120, all, 18 years

and older

Treatment Experimental: PD‐1 group

Anti‐PD‐1 antibody, 200 mg, IV,

one time

Experimental: thymosin group

Thymosin, 1.6mg sc qd, last for

5 days

Placebo comparator: control group

stand treatment

II Primary (7 days):

lung injury score

Secondary:

Absolute lymphocyte counts (7, 14 and

28 days), serum level of CRP, PCT

and IL‐6 (3, 7 and 14 days), SOFA

score (7 days), all cause mortality

rate (28 days), ventilation free days

(28 days), ICU free days (up to

28 days)

NCT04268537/Not

yet recruiting,

Feb10‐

Oct31 2020

Tocilizumab vs CRRT in

management of cytokine

release syndrome (CRS) in

COVID‐19

Drug: tocilizumab, other:

standard of care,

procedure: continuous

renal replacement

therapy

China, Covid‐19

SARS cytokine

storm (and

2 more…)

120, all, 18–80 Observational Tocilizumab

Subjects received 8 mg/kg (body

weight) Tocilizumab once in

100 ml 0.9% saline solution and

administered intravenously

within no <60 min. Tocilizumab

was administered according—

continuous renal replacement

therapy

Femoral vein catheterization was

performed to complete

continuous renal replacement

therapy for consecutive three

times or more. to the local label

Standard care

Standard of care therapy per local

written policies or guidelines

–Primary (up to 14 days):

Proportion of participants with

normalization of fever and oxygen

saturation

Secondary:

Duration of hospitalization (Up to 28

days), proportion of participants

with normalization of fever (up to

14 days), change from baseline in

white blood cell and differential

count (up to 28 days), time to first

negative in 2019 novel corona virus

RT‐PCR test (Up to 28 days), all‐

cause mortality (up to 12 weeks),

change from baseline in hsCRP (Up

to 28 days), change from baseline in

cytokines IL‐1β,IL‐10, sIL‐2R, IL‐6,

IL‐8 and TNF‐α(Up to 28 days),

change from baseline in proportion

of CD4+ CD3/CD8 + CD3 T cells

(Up to 28 days)

NCT04306705/

Recruiting,

Feb20‐

Jun20 2020

Sars‐CoV2 seroconversion

among front line medical

and paramedical staff in

emergency, intensive care

units and infectious

disease departments

during the 2020 Epidemic

Other: blood sample France, Sars‐CoV2 1,000, all, child,

adult, older

adult

Other Caregiver

caregivers from emergency, ICU,

virology and infectious disease

services:

Two blood samples at T0 and 3

months

Not applicable Primary (3 months):

Quantify the proportion of patients with

documented Sars‐CoV2 infection

among medical and paramedical

staff

Secondary (3 months):

NCT04304690/

Recruiting,

Mar16‐

Oct16 2020

SHEERVALILOU ET AL.

erythematosus. Recently, an investigation in China reported that

remdesivir and chloroquine phosphate were effective experimental

agents for controlling SARS‐CoV‐2 infection in the lab (Chen

et al., 2013). Initial findings reported by a recent study on effec-

tiveness of therapeutic agents in management of SARS‐CoV‐2 in-

fection, and suggested successful application of chloroquine

phosphate in treatment of patients with COVID‐19‐associated

pneumonia. Following the promising results, scientists re-

commended chloroquine phosphate to be included in treatment

regimen of COVID‐19 patients with severe involvement of the

lungs (Yu et al., 2013). On February 15, 2020, participants from

different organizations, including medical experts and authorities,

made an agreement on potency of Chloroquine phosphate against

SARS‐CoV‐2 infection (https://www.clinicaltrialsarena.com/analysis/

coronavirus-mers-cov-drugs/).

So far, close monitoring of over 100 patients, who were under

treatment of chloroquine phosphate, has provided further evidence

regarding the effectiveness of this long‐known medicine. Investiga-

tions indicated that chloroquine phosphate prevented exacerbation

of pneumonia in these patients, improved their chest CT findings, and

shortened the otherwise long natural course of the disease. Im-

portantly, there have been no records of severe reaction or hy-

persensitivity to this therapeutic agent. It has been suggested that

the broad‐spectrum antiviral activity of chloroquine phosphate lies

within the complicated pharmacodynamics of the drug that results in

a basic shift in the endosomal pH required for successful fusion of

virus onto the host cell. chloroquine phosphate also seems to have

disruptive effects on glycosylation of cellular receptors of SARS‐CoV

(Yin & Wunderink, 2018; Zumla et al., 2020), rendering them

nonfunctional. It also interferes with activation of p38 mitogen‐

activated protein kinase, a signaling event involved in replication of

HCoV‐229E (Kono et al., 2008).

7.2 |Lopinavir/ritonavir, leronlimab, galidesivir

Lopinavir/Ritonavir, commonly used for treatment of HIV infection,

has been indicated for treatment of COVID‐19 in a number of re-

ports (Kim et al., 2020). Previous studies suggested that when com-

bined together, Lopinavir and Ritonavir act in concert to hinder

further replication of SARS‐CoV, and improve the clinical status of

patients with SARS (Chu et al., 2004). This might also mean that the

well‐known antiretroviral duo can also prove beneficial in treatment

of COVID‐19.

Other candidates for possible management of SARS‐CoV‐2 in-

clude Leronlimab and Galidesivir, both of which have been of clinical

value in treatment of several fatal viral infections, and were shown to

improve the survival of patients. Leronlimab is a humanized mono-

clonal antibody (CCR5 antagonist). Galidesivir, on the other hand,

belongs to the family of nucleoside RNA polymerase inhibitors

(https://www.clinicaltrialsarena.com/analysis/coronavirus-mers-cov-

drugs/). In the absence of any specific therapeutic agents to quell

SARs‐CoV‐2, it might be a salutary strategy to repurpose the already

TABLE 4 (Continued)

Study title Interventions Location/condition Subjects, sex, age Primary purpose Arms Phase Measure outcome/time frame Code/status/date

Identification of risk factors for

seroconversion, quantify the

proportion of asymptomatic

infections among staff who have

seroconverted, describe

symptomatic infections for

personnel developing acute clinical

(respiratory or digestive) viral

syndrome

SHEERVALILOU ET AL.

TABLE 5 Therapeutic options that are available for the treatment of novel coronaviruses (cell line, animal, and human studies)

General treatment Nutritional interventions,

targets or function

Vit A Measles virus, measles‐related

pneumonia, HIV, avian CoV, IBV

Upregulating the elements of the innate immune, Making the cells refractory to

infection

B vit MERS‐CoV Enhancing immune system, Inhibiting the of neutrophil infiltration into the lungs,

Anti‐inflammatory effects during ventilator‐induced lung injury

Vit C Avian CoV Supporting immune functions, protecting against CoV infection, preventing of the

lower respiratory tract infections

Vit D Bovine CoV Triggering the maturation of immune cells

Vit E Coxsackievirus, bovine CoV Antioxidant function

Omega‐3 PUFA Influenza virus, HIV Attenuating the replication of influenza virus

Selenium Influenza virus, avian CoV Antioxidant function, inducing immune response

Zinc Influenza virus, avian CoV, SARS‐CoV Maintenance/development of innate and adaptive immune systems simultaneously

Iron Viral mutations Enhancing the immune system

Immunoenhancers IFNs SARS‐CoV, MERS‐CoV Acting as apart of the innate immune response, Inhibiting the replication of CoVs in

animal and human

IVIg SARS‐CoV Increasing the viscosity in hypercoagulable states

Ta1 SARS‐CoV Restoring the homeostasis of the immune system, Increasint the resistance

glucocorticoid‐induced death of thymocyte

TP5, munox Restore antibody production Restoring antibody production, Enhancing the antibody response, As adjuvant

treatment

Levamisole Immunostimulant/

immunosuppressive agent

Increasing the functions of cellular immunity, Act as immunostimulant agent or

immunosuppressive agent through dose‐and time‐dependent manner, reversing

the depressed helper/inducer lymphocytes

Cyclosporine A SARS‐CoV, avian infectious bronchitis

virus

Both facilitating or inhibiting virus replication, blocking the all genera replication

of CoV

CTM Glycyrrhizin, Baicalin, Ginseng SARS‐CoV, avian infectious

bronchitis virus

Enhancing host immunity, Inhibiting the replication of SARS‐associated virus and

SARS‐CoV, Enhancing the specific‐antibody responses

Specific treatments Protease inhibitors 3C‐like inhibitors Cinanserin, SARS‐CoV Act as serotonin receptor antagonist, Inhibiting the replication

Flavonoids MERS‐CoV Act as antioxidant and antiviral compound, blocking the enzymatic activity of MERS‐

CoV/3CLpro

PLP inhibitors SARS‐CoV Inhibit PLP of SARS‐CoV

S protein‐ACE2 blockers Human mAb SARS‐CoV Neutralizing SARS‐CoV, inhibiting syncytia formation between cells expressing the S

protein and the SARS‐CoV receptor ACE2

Chloroquine SARS‐CoV Possess antiviral effect, inhibiting of SARS‐CoV infection via interfering with ACE2

Emodin SARS‐CoV Blocking the interaction between the S protein of virus and ACE2

Promazine SARS‐CoV Inhibiting the replication of virus, inhibiting the binding of S protein to ACE2

Nicotianamine Inhibiting the ACE2

SHEERVALILOU ET AL.

available medicine, and include them in treatment of COVID‐19

(Tian et al., 2020).

Several clinical trials can be viewed at ClinicalTrials.gov,

that are currently in progress. These trials have specially focused

on potency of Remdesivir, immunoglobulins, and combinational

therapies, for example, Arbidol hydrochloride with interferon

atomization, ASC09F and oseltamivir, ritonavir and oseltamivir, and

lopinavir combined with ritonavir (https://clinicaltrials.gov/ct2/

results?cond=&2019nCoV&term=&cntry=&state=&city=&dist=).

7.3 |RAAS inhibitors

ACE2 is a prominent regulatory arm in the RAAS axis, thus, a dis-

ruption in ACE‐Angiotensin II‐Angiotensin Type 1 Receptor (AT1R),

and ACE2/Angiotensin‐(1‐7)/Mas Receptor axes can result in multi-

system inflammation. Increased levels of ACE and Angiotensin II in

plasma are considered poor prognostic factors in severe pneumonia.

Several studies on animal models have reported effectiveness of

RAAS inhibitors in alleviation of severe pneumonia and acute re-

spiratory failure. In the aftermath of SARS‐CoV‐2 and ACE2 binding,

the enzyme is eventually degraded, hence, the inhibition of ACE2/

Angiotensin‐(1‐7)/Mas Receptor pathway. Accordingly, it is assumed

that ACE and AT1R inhibitors might be game‐changing agents that

can especially be administered for COVID‐19 patients who have

serious impairments in their homeostasis. Maintenance of home-

ostasis may ultimately result in suppression of the inflammatory re-

sponse, mostly in the pulmonary tissue (Sun, Yang, Sun, & Su, 2020).

7.4 |Combination therapy

Combination therapy is a more extensive and rigorous approach

mainly aimed at correction of life‐threatening events such as

shock, hypoxemia, secondary or super infection, and maintenance of

homeostasis, that is, electrolyte, acid and base balance. As a palliative

practice, antiviral treatment in the early stages of COVID‐19 might

lessen the severity and prevent further progression of the disease.

Trials on combination therapy with lopinavir/ritonavir and arbidol

(umifenovir) have reported satisfactory results in treatment of

COVID‐19. Alongside a proper antiviral treatment, patients may also

benefit from an artificial liver blood purification system, which is

capable of rapidly removing the inflammatory factors from blood,

thus, halting the disastrous cytokine release syndrome. This system

can also facilitate the sustenance of critically ill patients by preser-

ving the balance of bodily fluid. Administration of glucocorticoids in

moderate doses is another intervention that has recently been in-

dicated for patients with severe COVID‐19‐associated pneumonia.

However, secondary fungal infection should be considered. Patients

with an oxygenation index of less than 200 mmHg might benefit

more from oxygen therapy than noninvasive ventilation. A rational

prescription of antimicrobial medicines has been cautioned only for

patients with remittent fever and elevated antimicrobial prophylaxis

Antiviral treatments Ribavirin SARS‐CoV Inhibiting the the replication of SARS‐associated CoV

LPV/RTV (Kaletra) HIV, SARS‐CoV, MERS‐CoV protease inhibitor

RDV SARS‐CoV, MERS‐CoV Improving the pulmonary function, reducing the lung viral loads and severe lung

pathology

Nelfinavir HIV, SARS‐CoV Act as selective inhibitor of HIV protease, Inhibiting the replication virus

ARB influenza A/B, hepatitis C virus Blocking viral fusion, entry and replication

Nitric oxide SARS Antiviral effects

Other compounds ALA human CoV‐229E, HIV Act as antioxidant, inhibiting the replication of HIV‐1

Estradiol and

phytoestrogen

SARS‐CoV, MERS, influenza A Reducing virus replication in primary human nasal epithelial cells

Mucroporin‐M1 influenza H5N1 viruses, and

SARS‐CoV

Virucidal activity against viruses

Abbreviations: 3 CLpro, 3C‐like protease; Ab, antibody; ACE2, angiotensin converting enzyme 2; ALA, α‐lipoic acid; ARB, arbidol; CoV, coronavirus; CTM, Chinese traditional medicine; HIV, human

immunodeficiency virus; IBV, bronchitis virus; IFN, interferons; IVIg, intravenous gammaglobulin; LPV/RTV, lopinavir/ritonavir; mAb, monoclonal antibody; PLpro, papain‐like protease; PUFA, polyunsaturated

fatty acids; RDV, remdesivir; S, spike; Ta1, thymosin α‐1; TP5, thymopentin; Vit, vitamin.

SHEERVALILOU ET AL.

should be prescribed rationally and was not recommended except for

patients with long course of disease, repeated fever, and elevated

PCT levels. Ultimately, to maintain the balance of intestinal micro-

biota, oral intake of prebiotics or probiotics has been suggested. This

can reduce the risk of secondary infections as a result of microbial

translocation; however, effectiveness of such interventions on post-

infection clearance pattern of SARS‐CoV‐2 has not been studied

(Xu et al., 2020).

7.5 |Other future possible options

7.5.1 |Convalescent blood therapy

A conspicuously conventional method, transfusion of human con-

valescent plasma, might be viewed as a beneficial strategy for pre-

vention and even treatment of COVID‐19. The method is as facile as

its age since it only requires an adequate number of recovered pa-

tients who are willing to donate their immunoglobulin‐containing

serum. Although one still might argue the possibility of SARS‐CoV‐2

infection via convalescent blood transfusion, no such incident with

SARS‐CoV was reported by WHO amidst the outbreak of the disease

in 2003. The heft of past experience should come to mind once it is

noted that the majority of approaches and therapeutic strategies that

are currently being tested for COVID‐19 are derived from clinical

experience in treatment of SARS, MERS, and other correspondents

viral epidemics (Casadevall & Pirofski, 2020; Cunningham, Goh, &

Koh, 2020).

7.5.2 |Mesenchymal stem cell (MSC) therapy

A new therapeutic for treating immune‐mediated diseases, MSC

therapy might have the capability to terminate the inappropriate

release of cytokines in COVID‐19. Through its anti‐inflammatory

effects, MSC therapy has been reported to improve respiratory

function in murine models with acute lung injury. Evidence suggests

that MSCs might be doing so by repressing the aberrant release of

inflammatory factors (Hu & Li, 2018; Wang, Yao, Lv, Ling, & Li, 2017;

Xiang et al., 2017). In particular, a study by Chinese scientists con-

cluded that transplantation of MSCs could be considered as a novel

approach in treatment of viral pneumonia, noting promissory im-

plications of this method in management of H7N9‐induced ARDS.

Since H7N9 and SARS‐CoV‐2 can result in similar complications, for

example, ARDS and respiratory failure, MSC‐based therapy might

lead to a new path in treatment of COVID‐19‐associated pneumonia

(Chen, Hu, et al., 2020).

7.5.3 |Nano drug delivery systems

It has long been known that the traditional circulation‐based delivery

of therapeutic agents is not as effect, prompting pharmaceutical

industries to develop novel platforms for delivery of molecules to

hard‐to‐reach tissues in human body. Conjugation of antiviral agents,

particularly nucleoside analogs, with specific nanoparticles has

proved to be effectual in treatment of resistant HIV infection

(Agarwal, Chhikara, Doncel, & Parang, 2017; Agarwal, Chhikara,

Quiterio, Doncel, & Parang, 2012). Today, an appreciable number of

drug delivery platforms based on nanotechnology are available that

can be experimentally used with custom therapeutic formulations

for treatment of COVID‐19 (Chhikara & Varma, 2019) in hopes of

shortening the course of the disease (Chhikara et al., 2020).

7.5.4 |Psychological interventions

Progression of COVID‐19, similar to any other disease, can result in

suffering of the patients, prompting psychological symptoms, which

will require special interventions. It has been well‐established today

that individuals who fall victim to public health emergencies, for

example, disease outbreaks, develop variable degrees of stress dis-

orders. The problem persists even after the individual has recovered

and discharged from the hospital (Cheng, Wong, Tsang, &

Wong, 2004; Fan, Long, Zhou, Zheng, & Liu, 2015). With that in mind,

one should consider several factors for classification of patients who

will most probably benefit from psychological interventions; that is

overall course of the disease, severity, and quality of hospitalization

(e.g., home, ordinary wards, ICU, etc.) (Duan & Zhu, 2020).

In large‐scale outbreaks such as COVID‐19 epidemic, health-

care workers become the frontline at providing psychological

cares for patients who battle against the disease. Primary medical

and mental care should be provided for those individuals who are

recognized as “suspected case”and duly quarantined at home.

(Duan & Zhu, 2020).

Interventions should be discreetly formulated following a thor-

ough evaluation of risk factors involved in emerging of these psy-

chological issues, including a history of impaired mental health,

bereavement after a deceased family member, panic, separation from

loved ones, and a low income (Kun, Han, Chen, Yao, & Anxiety, 2009).

8|PATIENTS RECOVERED FROM

COVID‐19

The following criteria must be met in order for a patient to be dis-

charged from hospital or released from quarantine: (a) having been

afebrile for at least 3 consecutive days, (b) remission of respiratory

distress, (c) regression of infiltrations/consolidations on chest CT

images, and two consecutive negative reports of RT‐PCR test per-

formed at least 1 day apart (d). Despite these thoroughly formulated

criteria, one study reported positive RT‐PCR test results 5–13 days

after hospital discharge for four patients with COVID‐19, who met all

of the criteria above before they were discharged. These findings are

important in that they imply the slight possibility that even a fully

recovered patient might still be a silent carrier of the virus. In this

SHEERVALILOU ET AL.

scenario, however, no family members were reported to be infected,

since all of the four patients with bizarrely late positive tests were

medical professional, and followed all of the guidelines while they

were at home quarantine. With due attention to this incident, the

current criteria for hospital discharge may need to be reconsidered

(Lan et al., 2020).

9|CONCLUSIONS AND FUTURE

PERSPECTIVES

Deemed a global health emergency, COVID‐19 outbreak has

continued to be the headline of the news. The number of con-

firmed cases is on the rise, and the seamless spread of the virus

has become a plight for general population, and the entire medical

community. In spite of the extreme preventive measures while

near a patient, clinicians are still at great risk for contracting

the disease from the visitors. Else, it is vividly known that quar-

antine alone is not the optimal choice for containing of the virus.

On the other hand, the devastating potential impact of the out-

break is a much feared topic around the world. Science has always

been the ultimate arsenal of weaponry when it comes to battling

obstinate pathogens; however, time is needed for conduction of

proper investigations on human‐to‐human and animal‐to‐human

transmission of SARS‐CoV‐2.

With no access to requisite information on the structure and life

cycle of the novel Coronavirus, research and development programs

on therapeutic agents become a far‐fetched milestone, rendering the

tried‐and‐true primary prevention measures the only proper means

to confront SARS‐CoV‐2. As of today, few existing drugs have been

considered for treatment of COVID‐19, with scant reports on ben-

evolence of the results. As our meager knowledge of SARS‐CoV‐2is

advancing, one may speculate the advent of an effectual vaccine,

alongside treatment options that might include antiviral agents, and

even monoclonal antibodies. At the time of writing this manuscript,

no definitive treatment option has been known for COVID‐19;

however, the unabating flow of investigations and clinical trials may

soon lead us to the optimal therapy for COVID‐19‐associated

pneumonia.

Needless to say, the fascinatingly high transmissibility of

COVID‐19 demands meticulous monitoring of the transmission

routes and patterns to a reach a firm theory on adaptive mechanisms

wielded by SARs‐CoV‐2, thus, making an accurate prediction about

the future outcomes regarding pathogenicity, transmissibility, and

evolution of the virus. These efforts will hopefully result in better

prognosis and fewer mortalities.

ACKNOWLEDGMENTS

This review was conducted under supervision of Zahedan University

of Medical Sciences and Iran University of Medical Sciences.

CONFLICT OF INTERESTS

The authors declare that they have no conflict of interest.

AUTHOR CONTRIBUTIONS

All authors contributed to different parts of the study.

ORCID

Roghayeh Sheervalilou http://orcid.org/0000-0001-7996-845X

Milad Shirvaliloo https://orcid.org/0000-0001-5122-1274

Habib Ghaznavi http://orcid.org/0000-0002-4629-1697

Samideh Khoei http://orcid.org/0000-0001-9357-0229

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SHEERVALILOU ET AL.

Investigating the Association between COVID-19 Prognosis and Demographic and Clinical Features, Underlying Diseases, and Drug and Supplement Use in Patients Hospitalized in Zabol, Iran: A Single-Center Retrospective Study

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Liver Iron Overload Drives COVID-19 Mortality: a Two-Sample Mendelian Randomization Study

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Oct 2023
BIOL TRACE ELEM RES

Iron overload has been associated with an increased risk of COVID-19 severity and mortality in observational studies, but it remains unclear whether these associations represent causal effects. We performed a two-sample Mendelian randomization (MR) to determine associations between genetic liability to iron overload and the risk of COVID-19 severity and mortality. From genome-wide association studies of European ancestry, single-nucleotide polymorphisms associated with liver iron (n = 32,858) and ferritin (n = 23,986) were selected as exposure instruments, and summary statistics of the hospitalization (n = 16,551) and mortality (n = 15,815) of COVID-19 were utilized as the outcome. We used the inverse-variance weighted (IVW) method as the primary analysis to estimate causal effects, and other alternative approaches as well as comprehensive sensitivity analysis were conducted for estimating the robustness of identified associations. Genetically predicted high liver iron levels were associated with an increased risk of COVID-19 mortality based on the results of IVW analysis (OR = 1.38, 95% CI: 1.05–1.82, P = 0.02). Likewise, sensitivity analyses showed consistent and robust results in general (all P > 0.05). A higher risk of COVID-19 hospitalization trend was also observed in patients with high liver iron levels without statistical significance. This study suggests that COVID-19 mortality might be partially driven by the iron accumulation in the liver, supporting the classification of iron overload as one of the independent death risk factors. Therefore, avoiding iron overload and maintaining normal iron levels may be a powerful measure to reduce COVID-19 mortality.

Status and Developing Strategies for Neutralizing Monoclonal Antibody Therapy in the Omicron Era of COVID-19

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May 2023

The monoclonal antibody (mAb)-based treatment is a highly valued therapy against COVID-19, especially for individuals who may not have strong immune responses to the vaccine. However, with the arrival of the Omicron variant and its evolving subvariants, along with the occurrence of remarkable resistance of these SARS-CoV-2 variants to the neutralizing antibodies, mAbs are facing tough challenges. Future strategies for developing mAbs with improved resistance to viral evasion will involve optimizing the targeting epitopes on SARS-CoV-2, enhancing the affinity and potency of mAbs, exploring the use of non-neutralizing antibodies that bind to conserved epitopes on the S protein, as well as optimizing immunization regimens. These approaches can improve the viability of mAb therapy in the fight against the evolving threat of the coronavirus.

Association between leukocyte telomere length and COVID-19 severity

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Full-text available

May 2023

Background Inter-individual variations in the clinical manifestations of SARS-CoV-2 infection are among the challenging features of COVID-19. The known role of telomeres in cell proliferation and immune competency highlights their possible function in infectious diseases. Variability in telomere length is an invaluable parameter in the heterogeneity of the clinical presentation of diseases. Result In this study, our aim was to investigate the possible association between leukocyte telomere length (LTL) and COVID-19 severity. LTL was measured in 100 patients with moderate and severe forms of COVID-19 using the quantitative PCR (q-PCR) method. Statistical analysis confirmed a strong inverse correlation between relative LTL and COVID-19 severity. Conclusions These findings suggest that LTL can be a useful parameter for predicting disease severity in patients, as individuals with short telomeres may have a higher risk of developing severe COVID-19.

Lipids and lipid derivatives for delivery of the CRISPR/Cas9 system

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Full-text available

Dec 2022
J DRUG DELIV SCI TEC

The discovery of genome editing technology based on the bacterially derived CRISPR system (clustered regularly interspaced short palindromic repeats) has led to tremendous progress in biotechnology and gene therapy. The CRISPR/Cas9 system has many advantages over other genome editing technologies, including multiplexing, high accuracy, cost-effectiveness, and simplicity. However, the safe and effective delivery of the genome editing system's components into the target cells, is one of the major challenges in genome editing. This has a direct effect on the success and therapeutic applications of this system. A variety of different delivery methods including physical delivery methods, viral and non-viral vectors are used to deliver CRISPR/Cas9 system components. However, employing physical delivery techniques and viral vectors has limitations, including cellular damage, immune system response induction, low specificity, need for expertise and expensive equipment, etc. Recently, the development and use of nanoparticle-based delivery systems for efficient delivery of the CRISPR/Cas9 system has attracted significant attention. The application of nanoparticles for the delivery of CRISPR/Cas9 system components has been highlighted by benefits including simple synthesis, cost-effectiveness, size tunability, high loading capacity, high efficiency, non-mutagenicity, non-immunogenicity, etc. Here, we will review developments in the delivery of CRISPR/Cas9 system components employing lipid-based nanoparticles and highlight forthcoming challenges. Graphical abstract a b c d e f g h Share Cite ‫ص‬ 10:24 2023/ 11/ 2 Lipids and lipid derivatives for delivery of the CRISPR/Cas9 system-ScienceDirect

Clinical Trials of Mesenchymal Stem Cells for the Treatment of COVID 19

Article

Oct 2023
Curr Stem Cell Res Ther

Shiva Asadpour

Mesenchymal Stem Cells (MSCs) are being investigated as a treatment for a novel viral disease owing to their immunomodulatory, anti-inflammatory, tissue repair and regeneration characteristics, however, the exact processes are unknown. MSC therapy was found to be effective in lowering immune system overactivation and increasing endogenous healing after SARS-CoV-2 infection by improving the pulmonary microenvironment. Many studies on mesenchymal stem cells have been undertaken concurrently, and we may help speed up the effectiveness of these studies by collecting and statistically analyzing data from them. Based on clinical trial information found on clinicaltrials. gov and on 16 November 2020, which includes 63 clinical trials in the field of patient treatment with COVID-19 using MSCs, according to the trend of increasing studies in this field, and with the help of meta-analysis studies, it is possible to hope that the promise of MSCs will one day be realized. The potential therapeutic applications of MSCs for COVID-19 are investigated in this study.

Orthopedic surgical scoring in asymptomatic COVID-19 patients

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Bioscreening specific peptide-expressing phage and its application in sensitive dual-mode immunoassay of SARS-CoV-2 spike antigen

Article

Aug 2023
TALANTA

Biorecognition components with high affinity and selectivity are vital in bioassay to diagnose and treat epidemic disease. Herein a phage display strategy of combining single-amplification-panning with non-amplification-panning was developed, by which a phage displaying cyclic heptapeptide ACLDWLFNSC (peptide J4) with good affinity and specificity to SARS-CoV-2 spike protein (SP) was identified. Molecular docking suggests that peptide J4 binds to S2 subunit by hydrogen bonding and hydrophobic interaction. Then the J4-phage was used as the capture antibody to establish phage-based chemiluminescence immunoassay (CLIA) and electrochemical impedance spectroscopy (EIS) analytical systems. The as-proposed dual-modal immunoassay platform exhibited good sensitivity and reliability in SARS-CoV-2 SP and pseudovirus assay. The limit of detection for SARS-CoV-2 SP by EIS immunoassay is 0.152 pg/mL, which is dramatically lower than that of 42 pg/mL for J4-phage based CLIA. Further, low to 40 transducing units (TU)/mL, 10 TU/mL SARS-CoV-2 pseudoviruses can be detected by the proposed J4-phage based CLIA and electrochemical immunosensor, respectively. Therefore, the as-developed dual mode immunoassays are potential methods to detect SARS-CoV-2. It is also expected to explore various phages with specific peptides to different targets for bioanalysis.

COVID-19 and immunity

Chapter

Jan 2023

Diabetes mellitus in relation to COVID-19

Chapter

Apr 2023

The recent ongoing COVID-19 pandemic caused by the SARS-CoV-2 virus saw many hospitalizations and deaths among elderly patients. It has been reported that the most common underlying conditions in these patients were obesity and diabetes. While both type 1 and type 2 diabetes pose a higher risk of severe or fatal COVID-19 infections, patients with type 2 diabetes required ICU treatment at a greater frequency than those with type 1 diabetes. However, whether diabetes affects susceptibility for COVID-19 has yet to be explored. This chapter focuses on both type 1 and type 2 diabetes, with the main goal of understanding this chronic condition during the pandemic, based on currently available case studies.

A deep learning algorithm using CT images to screen for Corona virus disease (COVID-19)

Article

Full-text available

Feb 2021

Objective The outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) has caused more than 26 million cases of Corona virus disease (COVID-19) in the world so far. To control the spread of the disease, screening large numbers of suspected cases for appropriate quarantine and treatment are a priority. Pathogenic laboratory testing is typically the gold standard, but it bears the burden of significant false negativity, adding to the urgent need of alternative diagnostic methods to combat the disease. Based on COVID-19 radiographic changes in CT images, this study hypothesized that artificial intelligence methods might be able to extract specific graphical features of COVID-19 and provide a clinical diagnosis ahead of the pathogenic test, thus saving critical time for disease control. Methods We collected 1065 CT images of pathogen-confirmed COVID-19 cases along with those previously diagnosed with typical viral pneumonia. We modified the inception transfer-learning model to establish the algorithm, followed by internal and external validation. Results The internal validation achieved a total accuracy of 89.5% with a specificity of 0.88 and sensitivity of 0.87. The external testing dataset showed a total accuracy of 79.3% with a specificity of 0.83 and sensitivity of 0.67. In addition, in 54 COVID-19 images, the first two nucleic acid test results were negative, and 46 were predicted as COVID-19 positive by the algorithm, with an accuracy of 85.2%. Conclusion These results demonstrate the proof-of-principle for using artificial intelligence to extract radiological features for timely and accurate COVID-19 diagnosis. Key Points • The study evaluated the diagnostic performance of a deep learning algorithm using CT images to screen for COVID-19 during the influenza season. • As a screening method, our model achieved a relatively high sensitivity on internal and external CT image datasets. • The model was used to distinguish between COVID-19 and other typical viral pneumonia, both of which have quite similar radiologic characteristics.

Relationship between the ABO Blood Group and the COVID-19 Susceptibility

Article

Full-text available

Aug 2020
CLIN INFECT DIS

To explore any relationship between the ABO blood group and the COVID-19 susceptibility, we compared ABO blood group distributions in 2,173 COVID-19 patients with local control populations, and found that blood group A was associated with an increased risk of infection, whereas group O was associated with a decreased risk.

Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients

Article

Full-text available

Apr 2020
CLIN INFECT DIS

Background: Although the detection of SARS-CoV-2 viral load in respiratory specimens has been widely used to diagnose coronavirus disease-19 (COVID-19), it is undeniable that serum SARS-CoV-2 nucleic acid (RNAaemia) could be detected in a fraction of COVID-19 patients. However, it is not clear whether testing for RNAaemia is correlated with the occurrence of cytokine storms or with the specific class of patients. Methods: This study enrolled 48 patients with COVID-19 admitted to the General Hospital of Central Theater Command, PLA, a designated hospital in Wuhan, China. The patients were divided into three groups according to the "Diagnosis and Treatment of New Coronavirus Pneumonia (6th edition)" issued by the National Health Commission of China. The clinical and laboratory data were collected. The serum viral load and IL-6 levels were determined. . Results: Clinical characteristics analysis of 48 cases of COVID-19 showed that RNAaemia was diagnosed only in the critically ill group and seemed to reflect the severity of the disease. Furthermore, the level of inflammatory cytokine IL-6 in critically ill patients increased significantly, almost 10 times that in other patients. More importantly, the extremely high IL-6 level was closely correlated with the detection of RNAaemia (R = 0.902). Conclusions: Detectable serum SARS-Cov-2 RNA(RNAaemia) in COVID-19 patients was associated with elevated IL-6 concentration and poor prognosis. Because the elevated IL-6 may be part of a larger cytokine storm which could worsen outcome, IL-6 could be a potential therapeutic target for critically ill patients with an excessive inflammatory response.

Treatment of COVID-19: Old tricks for new challenges

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Dec 2020

The Author's Response: Case of the Index Patient Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Pneumonia Monitored by Quantitative RT-PCR

Article

Full-text available

Feb 2020

Corona virus SARS-CoV-2 disease COVID-19: Infection, prevention and clinical advances of the prospective chemical drug therapeutics

Article

Full-text available

Mar 2020

The recent outbreak of Corona virus SARS-CoV-2 disease COVID-19 in the China and subsequent intermittent spread of infection to other countries has alarmed the medical and scientific community mainly because of lethal nature of this infection. Being a new virus in the category, the immediate emergency therapy is not available for the treatment of this disease, leading to widespread fear of infection and has created social issues for infected peoples. Herein, the epidemiology of COVID-19 infection, transmission characteristics of SARS-CoV-2 virus spread, effectiveness of preventive measures, coronavirus family, structural characteristics of virus, current literature advances for the diagnostics development (RT-PCR, CT-Scan, Elisa) and possible drug development based virus life cycle (Entry inhibitors, replication inhibitors, nucleoside, nucleotide, protease inhibitors, heterocyclic drugs, including biological therapeutics (monoclonal antibodies therapy, vaccine development) and herbal formulations have been reviewed. The chemical drug molecules with prospective application in the treatment of COVID-19 have been included in the discussion. Full text: http://thesciencein.org/journal/index.php/cbl/article/view/103

Prediction of survival for severe Covid-19 patients with three clinical features: development of a machine learning-based prognostic model with clinical data in Wuhan

Preprint

Full-text available

Mar 2020

The sudden increase of COVID-19 cases is putting a high pressure on healthcare services worldwide. At the current stage, fast, accurate and early clinical assessment of the disease severity is vital. To support decision making and logistical planning in healthcare systems, this study leverages a database of blood samples from 404 infected patients in the region of Wuhan, China to identify crucial predictive biomarkers of disease severity. For this purpose, machine learning tools selected three biomarkers that predict the survival of individual patients with more than 90% accuracy: lactic dehydrogenase (LDH), lymphocyte and high-sensitivity C-reactive protein (hs-CRP). In particular, relatively high levels of LDH alone seem to play a crucial role in distinguishing the vast majority of cases that require immediate medical attention. This finding is consistent with current medical knowledge that high LDH levels are associated with tissue breakdown occurring in various diseases, including pulmonary disorders such as pneumonia. Overall, this paper suggests a simple and operable formula to quickly predict patients at the highest risk, allowing them to be prioritised and potentially reducing the mortality rate. Funding None.

Clinical Features of COVID-19-Related Liver Damage

Article

Apr 2020
CLIN GASTROENTEROL H

Background & Aims Some patients with SARS-CoV-2 infection have abnormal liver function. We aimed to clarify the features of COVID-19-related liver damage to provide references for clinical treatment. Methods We performed a retrospective, single-center study of 148 consecutive patients with confirmed COVID-19 (73 female, 75 male; mean age, 50 years) at the Shanghai Public Health Clinical Center from January 20 through January 31, 2020. Patient outcomes were followed until February 19, 2020. Patients were analyzed for clinical features, laboratory parameters (including liver function tests), medications, and length of hospital stay. Abnormal liver function was defined as increased levels of alanine and aspartate aminotransferase, gamma glutamyltransferase, alkaline phosphatase, and total bilirubin. Results Fifty-five patients (37.2%) had abnormal liver function at hospital admission; 14.5% of these patients had high fever (14.5%), compared with 4.3% of patients with normal liver function (P=.027). Patients with abnormal liver function were more likely to be male, and had higher levels of procalcitonin and C-reactive protein. There was no statistical difference between groups in medications taken before hospitalization; a significantly higher proportion of patients with abnormal liver function (57.8%) had received lopinavir/ritonavir after admission compared to patients with normal liver function (31.3%). Patients with abnormal liver function had longer mean hospital stays (15.09±4.79 days) than patients with normal liver function (12.76±4.14 days) (P=.021). Conclusions More than one third of patients admitted to the hospital with SARS-CoV-2 infection have abnormal liver function, and this is associated with longer hospital stay. A significantly higher proportion of patients with abnormal liver function had received lopinavir/ritonavir after admission; these drugs should be given with caution.

Clinical Features of COVID-19-Related Liver Damage

Article

Jan 2020

The convalescent sera option for containing COVID-19

Article

Mar 2020

COVID‐19 under spotlight: A close look at the origin, transmission, diagnosis, and treatment of the 2019‐nCoV disease

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