Received: 24 July 2020 Revised: 18 September 2020 Accepted: 18 October 2020

DOI: 10.1002/ptr.6936

REVIEW

A pharmacology-based comprehensive review on medicinal

plants and phytoactive constituents possibly effective
in the management of COVID-19

Atefeh Jalali1,2 | Farid Dabaghian3 | Hossein Akbrialiabad1,4 |

5 1,2,6
Farzaneh Foroughinia | Mohammad M. Zarshenas

1
Medicinal Plants Processing Research Center,
Shiraz University of Medical Sciences, Arisen in China, COVID-19 (SARS-CoV-II) is a novel coronavirus that has been expan-
Shiraz, Iran
ding fast worldwide. Till now, no definite remedial drug or vaccine has been identified
2
Department of Phytopharmaceuticals
(Traditional Pharmacy), School of Pharmacy, for COVID-19 treatment. Still, for a majority of infected patients, supportive therapy
Shiraz University of Medical Sciences, is the cornerstone of the management plan. To the importance of managing the
Shiraz, Iran
3
COVID-19 pandemic, this article proposed to collecting capable medicinal plants and
Department of Pharmacognosy, School of
Pharmacy, Tehran University of Medical bioactive components in both treat and supportive therapy of this novel viral infec-
Sciences, Tehran, Iran
tion. Clinical points in the pathogenesis, symptoms, and complications of COVID-19
4
Student Research Committee, School of
Medicine, Shiraz University of Medical
were considered. The effective plants and bioactives that may play a role in support-
Sciences, Shiraz, Iran ive therapy/management of COVID-19 were searched, collected through the
5
Department of Clinical Pharmacy, Shiraz “Scopus” database and listed in three sections. Numerous medicinal plants such as
University of Medical Sciences, Shiraz, Iran
6 Citrus Spp., Camellia sinensis, and Glycyrrhiza glabra can interference with COVID-19
Epilepsy Research Center, Shiraz University
of Medical Sciences, Shiraz, Iran pathogenesis via inhibition of virus replication and entry to its host cells. Also, some
anti-inflammatory herbal medicine such as Andrographis paniculata, Citrus spp.,
Correspondence
Mohammad M. Zarshenas, Department of and Cuminum cyminum can relieve fever and cough in COVID-19 patients. Medicinal
Phytopharmaceuticals (Traditional Pharmacy),
plants such as G. glabra, Thymus vulgaris, Allium sativum, Althea officinalis, and Panax
School of Pharmacy, Shiraz University of
Medical Sciences, Shiraz, Iran. ginseng may modulate the immune system and possess prevention and supportive
Email: zarm@sums.ac.ir
therapy. However, more clinical data are required to confirm these hypotheses.
Funding information
Shiraz University of Medical Sciences, Grant/ KEYWORDS
Award Number: 99-01-106-22309 bioactive compounds, COVID-19, plant, supportive therapy, symptom therapy, treatment

1 | I N T RO DU CT I O N Epidemiologic studies revealed that possibly the disease is originated

COVID-19 is the third novel coronavirus that has emerged in the past
two decades. The previous epidemics of coronaviruses were severe
acute respiratory syndrome (SARS)-CoV and the Middle East respira-
tory syndrome (MERS)-CoV have been described as severe public
health issues (Rothan & Byrareddy, 2020). From mid-December to
29 December of 2019, 5 patients were admitted to the hospital with
an initial diagnosis of pneumonia with undefined etiology. One of
them died in the next consecutive days (Ren et al., 2020). In late
December 2019 and early January 2020, the flood of these patients
was admitted to the Chinese hospital in Hubei province, China.
from a local seafood market (Lu, Stratton, & Tang, 2020). Until now,
based on phylogenetic studies, the bats were considered as a possible
reservoir of disease; however, after that, pangolins raised suspicious
to be the real host that finally transmitted the disease to humans (Lam
et al., 2020). The further global spread of the virus occurred via drop-
let transmission in a human-human mode after coughing the sneezing
of inflicted patients (Rothan & Byrareddy, 2020). On 11th March
2020, the World health organization (WHO) declared the pandemic
state concerning COVID-19 (Jalali et al., 2013).
The primary pathogenesis of the virus is attaching the Angiotensin-
converting enzyme 2 (ACE 2) receptor on respiratory epithelial cells via

Phytotherapy Research. 2020;1–14. wileyonlinelibrary.com/journal/ptr © 2020 John Wiley & Sons Ltd 1
2 JALALI ET AL.
spike proteins of SARS-CoV-2 (H. Zhang, Penninger, Li, Zhong, &
Slutsky, 2020). Following the attachment and cell invasion, lung disease
(pneumonia and ARDS), blood infection (RNAemia), and damage to the
heart (acute cardiac injury), and damage to the kidney (acute renal injury)
may occur (Huang et al., 2020; Li, Geng, Peng, Meng, & Lu, 2020). The
high blood level of multiple cytokines and chemokines such as pro-
inflammatory cytokines TNF-α, IL-6, and IL-10 is noticed in these
patients (Diao et al., 2020). Acute Respiratory Distress Syndrome, as the
leading cause of mortality, is thought to occur due to cytokine storm
events in these patients (Mehta et al., 2020).
The symptoms of the COVID appear following the incubation
period of roughly five days (N. Chen et al., 2020). The range of the
time between commencements of the symptoms to the death time
is between 6 to 41 days with a median of 2 weeks (Wu et al., 2020). In
adults, the most common symptoms are cough, fever, and fatigue. Other
symptoms are headache, hemoptysis, and dyspnea (Lam et al., 2020). In
pediatrics, the common symptoms are similar, while rhinorrhea, abdomi-
nal pain, and diarrhea are more common in comparison to adults (Xia
et al., 2020). To date, older patients or cases with various comorbidities
(cardiovascular, respiratory, cerebrovascular, immunodeficiency, diges-
tive, and endocrine disease) are more prone to experience a severe form
of the ailment (Lam et al., 2020; Wang et al., 2020). The radiologic
aspect of diagnosis is mainly based on the pneumonia features, such as
multilocus ground glass appearance with patchy consolidation, in CT
scans, which is the primary imaging modality (Zu et al., 2020).
Currently, based on the molecular mechanisms of coronavirus
infection, some virally targeted inhibitor drugs such as chloroquine and
nucleoside analogs (such as Favipiravir, Ribavirin, and Galidesivir) is
under investigation (Zhang et al., 2020). Recently, the FDA approved
Remdesivir to use merely for critically ill patients (remdesivir EUA Letter
of Authorization - FDA, 2020). Still, for a majority of inflicted patients,
supportive therapy is the cornerstone of the management plan. For
thousands of years, herbal medicines have been prescribed for various
diseases by humankind. According to numerous papers, some medicinal
plants possess antiviral activity and have shown positive effects to treat
plenty of viral infections in practice. Medicinal plants have been applied
to treat viral infections act as antiviral agents, or they have been pre-
scribed as supportive therapy (Mukhtar et al., 2008).
To the importance of controlling the COVID-19 pandemic,
this research intended to collect capable medicinal plants and bioac-
tive components in both treatment and supportive therapy of this
emerged viral infection.
2 | MATERIALS AND METHODS
In this review, critical points in the treat and supportive therapy of
COVID-19 are presented in two sections as follows:
A. Effective medicinal plant/components with the potential to inter-
fering with COVID-19 pathogenesis
B. Effective medicinal plant/components for the sign and symptom
therapy
C. Effective medicinal plant/bioactive components for prevention
and support therapy of COVID-19
2.1 | Section A
In the first step, critical points in the pathogenesis were identified
through seeking the “Scopus” and “Google scholar” databases.
Based on the primary search, “ACE”, “SARS-3CLpro,” and “PLpro”
are considered as critical points in COVID-19 pathogenesis. Then,
these keywords with “plant” or “herb” or “natural” were searched
through the “Scopus” database. The subject area is limited to
medicine, pharmacology, toxicology, and pharmaceutics. No specific
restriction has been considered, and all clinical trials, in-vivo, in-vitro,
and in-silico studies were included and investigated. The papers
show that negative or poor results or have very toxic outcomes are
excluded. Finally, from out of 100 papers, 30 medicinal plants or
bioactive components with possible anti-SARS-CoV activity were
included in this review.
2.2 | Section B and C
Follow primary search in “Scopus” and “Google scholar” databases,
the underlying mechanisms may play a critical role in sign and symp-
tom management, and prevention and supportive therapy were clari-
fied. Then, 18 medicinal plants or bioactive components possessed
positive outcomes in the clinical trial, in-vitro, in-vivo, in-silico, and
traditional studies with considering their mechanism were mentioned
in section B. Also, in section C, 17 medicinal plants or bioactive com-
ponents with immunostimulant activity with considering SARS-CoV
activity in human bodies, are gathered through searching “Scopus”.
All literature research and data gathering have been performed
from first January 1990 up to first May 2020.
3 | RESULTS AND DISCUSSION
3.1 | Effective medicinal plant/components
with the potential to interfering with COVID-19
pathogenesis
In this part, two critical targets in SARS-CoV pathogenesis have been
recognized as follows (Arya, Das, Prashar, & Kumar, 2020; C.-N. Chen
et al., 2005; Wu et al., 2020; H. Zhang et al., 2020):
1. Inhibition of SARS-CoV entry to its host cells [Angiotensin-
Converting Enzyme (ACE) inhibition]
2. Inhibition of virus SARS-CoV replication [Chymotrypsin-like (3CLPro)
inhibition, protease Papain-like protease (PLpro) inhibition]
The first stage of SARS-CoV' pathogenesis is its entry to host cells
for evolving and replication. Then, the virus propagation can block in
JALALI ET AL.
early-stage via virus entry inhibition (Yi et al., 2004). Based on the
virus pathogenesis, the ACE 2 receptor is one of the more important
targets in COVID-19 entry into host cells (Dabaghian, Khanavi, &
Zarshenas, 2020; Zhang et al., 2020). ACE 2 is a metallopeptidase that
is remarkably expressed on lung alveolar epithelial cells and small
intestine enterocytes. Besides, the large number of ACE 2 receptors
are presented on arterial and venous endothelial cells and arterial
smooth muscle. Therefore, these critical organs can be most damaged
through COVID-19 infection (Hamming et al., 2004). Also, the SARS-
CoV-2, similar to other coronaviruses, requires proteolytic activity
for processing of replicas polyproteins during its maturation. Conse-
quently, SARS-CoV-2 encodes 3CLPro and PLpro, and they have
been regarded as a major molecular target for drug development
(Chen et al., 2005; ul Qamar, Alqahtani, Alamri, & Chen, 2020; Wu
et al., 2020).
Hence, the medicinal plants and bioactive components that
targeted these mechanisms can prevent corona viral infection and
introduce as COVID-19 inhibitory agents. For this purpose, the most
important plants or bioactive components hitting the ACE, SARS-
3CLpro, PLpro, and some other critical points in inhibition of SARS-
CoV replication and entry to its host cells were identified, then based
on further investigations, bioactive components, or medicinal plants
containing them were known, and all of them are compiled and
manifested in Table 1.
According to Table 1, some medicinal plants and bioactive
components can interference with COVID-19 pathogenesis via both
mentioned mechanisms and can introduce as effective adjutant com-
ponents in COVID-19 treat. The Andrographolide of Andrographis
paniculata and its Andrographiside ingredient can inhibit ACE and
SARS-3CLpro, respectively (Wu et al., 2020; Yan et al., 2020). The
polyphenol contents of Camellia sinensis, particularly Rutin, greatly
inhibit ACE and can block the entry virus to its host cells (Dong
et al., 2011; Liang et al., 1990; Yan et al., 2020). Besides, the phenolic
contents of C. sinensis such as theaflavin-3,30 -digallate, tannic acid,
and (−)-Epigallocatechin gallate via inhibiting SARS-3CLpro can hold
positive anti-COVID-19 activity (Chen et al., 2005; Wu et al., 2020).
The methanol extract of Equisetum hyemale inhibits ACE with
IC50 > 40% and its Herbacetin bioactive component inhibits SARS-
3CLpro (Choi et al., 2002; Jo et al., 2020; Park & Tomohiko, 2011; Qiu
et al., 1999). Also, the Secoisolariciresionol diglucoside and herbacetin
of Linum usitatissimum can inhibit COVID-19 pathogenesis via ACE
and SARS-3CLpro inhibition, respectively (Jo et al., 2020; Park &
Tomohiko, 2011; Prasad, 2013; Qiu et al., 1999).
The Citrus Spp. possess numerous amount of flavonoids such
as hesperetin, hesperidin, neohesperidin, and rhoifolin. These bioac-
tive components can interference with SARS-3CLpro in a dose-
dependent manner (Adem et al., 2020; Racchi, 2013; Yan et al., 2020)
(Jo et al., 2020; Refaat et al., 2015; Wu et al., 2020). Also, glycyrrhizin
is the bioactive component of Glycyrrhiza glabra can inhibit ACE with
IC50 > 40% (Choi et al., 2002; Yan et al., 2020). Then, some desirable
herbal drinks and fruits such as Citrus Spp., C. sinensis, and G. glabra
can block the COVID-19 pathogenesis.
3
3.2 | Effective medicinal plant/components
for the sign and symptom therapy
The COVID-19 as a viral infection leads to various complications and
symptoms in patients such as cough, fever, headache, hemoptysis,
dyspnea, and fatigue (Lam et al., 2020). Fever is the most common
symptom in patients suffering from COVID-19 (Chen et al., 2020).
The hypothalamus, as the main center of thermoregulation, sets the
body temperature according to physiological conditions. Among the
several influenced factors on thermoregulation, pro-inflammatory
cytokines such as interleukin-1β (IL-1β), tumor necrosis factor (TNF),
and interleukin-6 (IL-6), directly act on the hypothalamus and rise
the body temperature set point. However, fever seeks to boost the
healing process via enhancing leukocytes' function, but it induces
overproduction of pro-inflammatory and antipyretic cytokines such as
interleukin-10 (IL-10) (Aronoff & Neilson, 2001; Mehta et al., 2020;
Zetterstrom, Sundgren-Andersson, Ostlund, & Bartfai, 1998). Since
the cytokine storm is triggered and exacerbated by the high blood
levels of TNF-α, IL-6, and IL-10, then the prevention of these condi-
tions is considerable in COVID-19 patients (Diao et al., 2020; Mehta
et al., 2020).
As mentioned, fever management and modulating cytokine
levels play a critical role in the management of COVID-19. Regarded
as numerous antipyretics reduce body temperature via indirectly
targeted cytokines (inhibiting the enzyme cyclooxygenase), it seems
that selective antipyretic with cytokines modulating effect can be
more effective in manage of COVID-19.
Another severe complication in patients with COVID-19 is a dry
cough triggered by inflammatory or mechanical changes in the airways
(Chen et al., 2020). Although cough is a major protection reflex of the
lungs, excessive cough can lead to harmful complications such as
headache, pulmonary interstitial emphysema, laryngeal trauma, brady/
tachyarrhythmias, and overall decrease the patient quality of life
(Huliraj, 2014).
Numerous patients with COVID-19 suffer from bronchitis, and
their airways are irritated by excessive cough, then it seems to pre-
scribe antitussive drugs with anti-inflammatory and emollient effects
that can be serviceable in relieving and prevention of their coughs.
Since no research has been conducted on symptom therapy of
COVID-19 with this view, several effective plants or their bioactive
components on dry cough and fever with the possible mechanism of
actions are amassed and presented in Table 2.
According to Table 2, various herbal medicine and bioactive com-
ponents have the potential to alleviating cough and fever via anti-
inflammation activity. The andrographolide of A. paniculata is an
antipyretic agent via inhibiting the expression of IL-1β and IL-1α and
reducing the IL-6 level (Madav et al., 1995; Salim et al., 2014). Also,
based on an in-vivo study the antitussive activity of arabinogalactan
could have a synergistic effect with andrographolide of A. paniculata
(Gabriela Nosáľová et al., 2014). The Citrus spp. can relieve fever with
anti-inflammatory effect and relax tracheal muscle via opening the
conductance Ca2+-activated K+ channel by naringin and Naringenin
4 JALALI ET AL.

TABLE 1 Possible medicinal plants/components with the potential to interfering with COVID-19 pathogenesis

Scientific Antiviral Part/

No. name/family type Extract Main component Mechanism/outcome Study Ref.
1 Alnus japonica B - Diarylheptanoid PLpro inhibition/ - (J. Y. Park et al., 2012)
(Thunb.) Steud./ (Hirsutenone) IC50 = 4.1 μM
Betulaceae
2 Andrographis A - Andrographolide ACE inhibition 3 (Yan et al., 2020)
paniculata (Burm.f.) B - Andrographiside SARS-3CLpro inhibition 3 (Wu et al., 2020)
Nees/Acanthaceae
3 Artemisia annua L./ C Wp/et. - -/inhibition of infection 1 (Li et al., 2005)
Compositae [EC50 = 34.5 ± 2.6 μg/mL]
4 Asparagus racemosus A Rt/Aq - ACE inhibition/ 1 (Khan & Kumar, 2019)
Willd./Liliaceae C50 = 82.88%
5 Camellia sinensis (L.) A - Polyphenol (Rutin) ACE inhibition: Green 1,3 (Dong, Xu, Liang, Head,
Kuntze/Theaceae <oolong <white <black & Bennett, 2011;
<dark teas Liang, Liu, Xu, &
Hu, 1990; Yan
et al., 2020)
B - Phenol (theaflavin-3,30 - SARS-3CLpro inhibition 3 (C.-N. Chen et al., 2005;
digallate, tannic acid, Wu et al., 2020)
[−]-epigallocatechin
gallate)
6 Cibotium barometz B Rz - SARS-3CLpro inhibition/ 1 (Wen et al., 2011)
(L.) J.sm./ IC50 = 39 μg/mL
Cibotiaceae
7 Citrus Spp./Rutaceae B - Hesperetin, hesperidin SARS-3CLpro inhibition in 1,3 (Adem, Eyupoglu,
Rhoifolin, Neohesperidin dose-dependent manner Sarfraz, Rasul, &
Ali, 2020;
Racchi, 2013; Yan
et al., 2020)
(Jo, Kim, Shin, &
Kim, 2020; Refaat,
Desoukey, Ramadan,
& Kamel, 2015; Wu
et al., 2020)
8 Cynara scolymus L./ A - Cynaroside ACE inhibition/ 1,3 (Hammouda, El-Nasr, &
Compositae IC50 = 49.7% Shahat, 1993; Khan &
Kumar, 2019; Yan
et al., 2020)
9 Dioscorea batatas/ B Rz - SARS-3CLpro inhibition/ 1 (Wen et al., 2011)
Dioscoreaceae IC50 = 44 μg/mL
10 Erigeron abajoensis A - Flavone (Scutellarin) ACE inhibition 1 (Utomo &
Cronquist/ Meiyanto, 2020; W.
Compositae Wang et al., 2016;
G.-H. Zhang
et al., 2005)
11 Equisetum hyemale A -/met - ACE inhibition/IC50 > 40% - (Choi et al., 2002)
L./Equisetaceae B - Herbacetin Positive 3CL pro inhibitory 3 (Jo et al., 2020; B.-J.
activity Park &
Tomohiko, 2011; Qiu
et al., 1999)
12 Glycyrrhiza glabra L./ A - Glycyrrhizin ACE inhibition/IC50 > 40% - (Choi et al., 2002; Yan
Leguminosae et al., 2020)
JALALI ET AL. 5

TABLE 1 (Continued)

Scientific Antiviral Part/

No. name/family type Extract Main component Mechanism/outcome Study Ref.
13 Hibiscus sabdariffa L./ A - Anthocyanins ACE inhibition/#serum 4 (Nwachukwu, Aneke,
Malvaceae angiotensin-converting Obika, &
enzyme, #plasma Nwachukwu, 2015;
aldosterone Riaz & Chopra, 2018)
Delphinidin-3-O- ACE inhibition 1 (Ojeda et al., 2010)
sambubioside (1) IC50 = 84.5 μg/mL
Cyanidin-3-O- IC50 = 68.4 μg/mL
sambubioside (2)
14 Lindera aggregata C Rt/eth - -/antiviral 1 (Li et al., 2005)
(Sims) Kosterm./ [EC50 = 88.2 μg/mL]
Lauraceae
15 Linum usitatissimum A - Secoisolariciresionol ACE inhibition 2 (Prasad, 2013)
L./Linaceae diglucoside
B - Herbacetin SARS-3CLpro inhibition (Jo et al., 2020; B.-J.
Park &
Tomohiko, 2011; Qiu
et al., 1999)
16 1306 52 C St/eth Lycorine -/inhibition of viral 1 (S.-y. Li et al., 2005)
—fjfujg-Lycoris infection
radiate [EC50 = 15.7 ± 1.2 nM]
—Amaryllis
-
17 Hancornia speciosa A - Chlorogenic acid ACE inhibition 2,3 (Santos et al., 2016;
Gomes/ Silva et al., 2011; Yan
Apocynaceae et al., 2020)
18 Houttuynia cordata B -/Aq - SARS-3CLpro inhibition 1 (Lau et al., 2008)
Thunb./
Saururaceae
19 Isatis indigotica/ B - Phenol (indigo, sinigrin, SARS-3CLpro inhibition/ - (Lin et al., 2005; Wu
Brassicaceae aloe emodin, IC50 = 53.8 ± 4.2 μg/mL et al., 2020)
hesperetin, Sinigrin),
2,2-Di(3-indolyl)-
3-indolone,
Phaitanthrin D
20 Psoralea corylifolia L./ B Sd/eth Bavachinin, PLpro inhibition/dose 1 (D. W. Kim et al., 2014)
Fabaceae neobavaisoflavone, dependent manner (IC50
isobavachalcone, between 4.2 and
40 -O- 38.4 μM)
methylbavachalcone,
psoralidin, corylifol A
21 Rheum officinale A - Anthraquinone (Emodin) Positive ACE inhibitor in 4 (Chu et al., 2012; Yan
Baill./ combination with ACEI/ et al., 2020; Yang
Polygonaceae ARB agents et al., 2018)
22 Scutellaria baicalensis A - Baicalin ACE inhibition 3 (Yan et al., 2020)
Georgi/Lamiaceae B - Cosmosiin SARS-3CLpro inhibition 3 (Wu et al., 2020)
23 Paulownia tomentosa B Ft, met Geranylated flavonoids PLpro inhibition/ 1,3 (Cho et al., 2013)
Steud./ IC50 = 5.0–14.4 μM
Paulowniaceae
24 Pyrrosia lingua C Lf/Chf - -/inhibition of viral 1 (S.-y. Li et al., 2005)
(Thunb.) Farw./ infection[EC50 = 43.2
Polypodiaceae (±14.1) μg/ml]

(Continues)
6 JALALI ET AL.

TABLE 1 (Continued)

Scientific Antiviral Part/

No. name/family type Extract Main component Mechanism/outcome Study Ref.
25 Toona sinensis (Juss.) C Lf - -/anti SARS-CoV activity 1 (C. J. Chen et al., 2008)
M.Roem./ (selectivity index
Meliaceae 12  17)
26 Torreya nucifera (L.) B Lf/eth Biflavone SARS-3CLpro inhibition/ - (Ryu et al., 2010)
Siebold & Zucc./ [Amentoflavone (9)], 62% at 100 μg/mL
Taxaceae Authentic flavones
(Apigenin)
27 Tribulus terrestris L./ B Ft, met Cinnamic amides PLpro inhibition/ 1,3 (Song et al., 2014)
Zygophyllaceae IC50 = 15.8–70.1 μM
38 Tripterygium wilfordii B - Celastrol Interferon I up-regulation, 1 (Yu et al., 2017)
Hook. f./ downstream interferon
Celastraceae stimulation
29 - A - Tetra-O-galloyl-β-D- Bind to SARS-CoV S2 1 (Yi et al., 2004)
glucose, luteolin protein
30 - A,B - Lectin Viral attachment to host 1 (Keyaerts et al., 2007)
cells inhibition, SARS-
CoV replication cycle
inhibition/antiviral

Note: Antiviral activity type: (A) Virus entry inhibition to its host cells, (B) Inhibition of virus replication, (C) Non-specific anti-SARS-COV activity. Study
type: 1: In-vitro, 2: In-vivo, 3: In-silico, 4: Clinical trial.
Abbreviations: Ap, aerial part, Aq, aqueous; Chf, chloroform; Eth, Ethanol; Fl, flower, Lf, leaf, Met, methanol; Rt, root, Rz, rhizome, Sd, seed, St, stem, Wp,
whole plant.

TABLE 2 Possible medicinal plants/components for sign and symptom therapy of COVID-19

Plant
Scientific part/
No. name/family Sign extraction Main component Mechanism/outcome Study Ref.
1 Aloe barbadensis mill./ B Lf/- HF1Z (polysaccharide) Emollient/potent 2 (Nosalova et al., 2005)
Asphodelaceae antitussive activity
2 Althaea officinalis L./ A Flower - -/#fever (marshmallow 4 (Ebadinejad, Dashtgard,
Malvaceae rinse) & Mohseni
Zade, 2017)
B Rt Mucilage Emollient/potent 2 (Al-Snafi, 2013)
(polysaccharides) antitussive activity
3 Andrographis paniculata A - Andrographolide Inhibit the expression of 2 (Madav, Tripathi, &
(Burm.f.) Nees/ IL-1β and IL-1α, #IL-6 Mishra, 1995; Salim,
Acanthaceae release/antipyretic Kumolosasi, &
Jantan, 2014)
B Lf/Aq, Arabinogalactan, -/potent antitussive 2 (Gabriela Nosáľová
Aq-eth Andrographolide et al., 2014)
4 Angelica decursiva (Miq.) B Rt/Aq, Columbianadin #IL-1β,NO/#airway 1 (Lim et al., 2014)
Franch. & Sav./ eth inflammation
Apiaceae
5 Artemisia capillaris A - Capillarisin (flavone) #TNF-α, IL-1β, IL-1α, and 5 (Han et al., 2013)
Thunb./Compositae IL-6/antipyretic
6 Cinnamomum cassia (L.) A - 7-Hydroxycoumarin, #IL-1/antipyretic 2 (Kurokawa, Kumeda,
J.Presl/Lauraceae 4-allylanisole, Cinnamic Yamamura,
acid Ethylester, acetic Kamiyama, &
acid cinnamylester, 20 - Shiraki, 1998)
Hydroxyacetophenone,
2-Hydroxycinnamic
acid
7 Cissampelos pareira L./ A - - #TNF-α /antipyretic 2 (Sood et al., 2015)
Menispermaceae
JALALI ET AL. 7

TABLE 2 (Continued)

Plant
Scientific part/
No. name/family Sign extraction Main component Mechanism/outcome Study Ref.
8 Citrus spp. A - - Inhibit the expression of 2 (Al-Snafi, 2016a)
COX-2, iNOS, IL-1β
and IL-6/antipyretic
B - Naringin, Naringenin Opening conductance 1 (Shi et al., 2019)
Ca2+-activated K+
channel/relax tracheal
smooth muscle
9 Eriobotrya japonica B Lf/- - #iNOS and COX-2/ 1 (T. M. Kim, Paudel, &
(Thunb.) Lindl./ Kim, 2020)
Rosaceae
10 Euphorbia hirta L./ A - - #TNF-α/antipyretic 5 (Ahmad et al., 2013)
Euphorbiaceae
11 Cuminum cyminum L./ A - - Inhibit the expression of 5 (Al-Snafi, 2016b)
Apiaceae COX-2, iNOS, IL-1β
and IL-6/antipyretic
B -/Aq - #inflammation/significant 2 (Nosalova et al., 2005)
antitussive activity
12 Glycyrrhiza glabra L./ B -/Aq/ Arabinogalactan protein Spasmolytic activity, 2 (Saha et al., 2011)
Leguminosae protective effects on
mucous /# citric acid-
induced cough Guinea
pigs
13 Salvia officinalis L./ B Ap/- Polysaccharide Emollient/potent 2 (Nosalova et al., 2005)
Lamiaceae antitussive activity
14 Malva sylvestris L./ B -/St Polysaccharides Emollient/potent 2 (Nosalova et al., 2005)
Malvaceae antitussive activity
15 Paederia foetida L./ B Wp/eth - #inflammation/similar 2 (G Nosáľová, Mokrý,
Rubiaceae antitussive activity to Ather, & Khan, 2007)
the non-narcotic
antitussive
16 Radix Puerariae/ A - Puerarin (Isoflavonoid) #TNF-α, IL-1β, and IL-6, 2 (Yao et al., 2012)
PGE2 /antipyretic
17 Tetrastigma A Ap/- Galacturonic acid, Regulation of cytokine 2 (Zhu et al., 2020)
hemsleyanum Diels & glucose, mannose, secretion (IL-6, IL-10,
Gilg/Vitaceae arabinose, galactose, and IFN-γ)/positive
and rhamnose antipyretic activity
(polysaccharides) (200 and 400 mg/kg.
P.O.)
18 Ziziphus abyssinica A - - Antipyretic 2 (Sultana, Asif, Akhtar, &
Hochst. Ex A.Rich./ Ahmad, 2015)
Rhamnaceae

Note: Sign (Type of complication) A: fever, B: Cough. Study type: 1: In-vitro, 2: In-vivo, 3: In-silico, 4: Clinical trial, 5: Traditional medicine.
Abbreviations: Ap: Aerial part, Aq: Aqueous, Bk: Bark, Chf: chloroform, Eth: Ethanol, Ft: fruit, Fl: Flower, Lf: leaf, Met: Methanol; Rt: Root, Rz: Rhizome, Sd:
Seed, St: Stem, Wp: Whole plant.

(Al-Snafi, 2016a; Shi et al., 2019). The Cuminum cyminum holds
desirable antitussive and antipyretic activity with its anti-inflammatory
effect (Al-Snafi, 2016b; Nosalova et al., 2005).
The polysaccharides from the aerial part of Tetrastigma
hemsleyanum can regulate the cytokine secretion via interact with
TLR4 and reduce fever (Zhu et al., 2020). The reduction in the level of
TNF-α, IL-1β, and IL-6 is the potential antipyretic mechanism of Radix
Puerariae (Yao et al., 2012). Also, the Cissampelos pareira and Euphor-
bia hirta can reduce the level of TNF-α and exhibit antipyretic activity
(Ahmad et al., 2013; Sood et al., 2015).
Based on Table 2, the polysaccharides from various herbal medi-
cines such as Aloe barbadensis, Althaea officinalis, Salvia officinalis,
Malva sylvestris can relive cough with emollient effect (Al-Snafi, 2013;
Nosalova et al., 2005). Also, the arabinogalactan protein from aqueous
8 JALALI ET AL.
extract of G. glabra shows antitussive activity by its spasmolytic and
protective effects on mucous (Saha et al., 2011).
3.3 | Effective medicinal plant/bioactive
components for prevention and support therapy
of COVID-19
The damaging human immune system via SARS-CoV-2 is the most
important cause of death from COVID-19. The new coronavirus can
impair lymphocyte, particularly the level of CD4+ T cells is decreased,
and the immune system is damaged through the duration of the
disease (Nile et al., 2020; Qin et al., 2020). Cytokine storm that leads
to acute respiratory distress syndrome is triggered and exacerbated
by the high blood levels of TNF-α, IL-6, and IL-10 (Diao et al., 2020).
Consequently, the immune system is greatly affected during COVID-
19 disease and possesses a crucial role in its prognosis.
Till now, no vaccine has been identified to COVID-19 treat. Then,
the special growing attention has been created in desirable non-
specific approaches such as hand washing, wearing masks, gloves, and
gowns to protect the global population via diminishing the spread of
viruses. Besides, the consumption of vitamin, mineral supplementa-
tion, and other agents that augment and modulate the immune system
is suggested for improving the individual potential to overcoming
against COVID-19 (Del-Rio-Navarro, Espinosa-Rosales, Flenady, &
Sienra-Monge, 2012).
According to papers, someone who received vaccine BCG
in childhood has more immunity against the SARS-CoV-2 virus.It
suggested that innate immune cells such as monocyte, macrophage,
and natural killers play a more important role to induce immunological
memory rather than adaptive immune response (T-cell and B-cell)
(Votava & Beran, n.d.). Immunostimulant agents, also called biological
response modifiers, are various compounds that can induce activation
and upregulation of the immune system. These compounds can be
prescribed in the clinical to modulate the immune system (Puggioni
et al., 2019).
Altogether it seems that immunostimulant agents with the poten-
tial to improve and modulate the innate immune system may have
positive effects in prevention and support therapy of COVID-19 dis-
ease. Hence, the rational selection of immunomodulators and immu-
nostimulant agents according to their mechanism is necessary. In the
current study, various medicinal plants or bioactive components with
their possible stimulant mechanism are collected and exhibited in
Table 3.
According to the collected data in Table 3, the licorice infusion
from the roots of G. glabra can improve the innate immune system via
activation of granulocyte and natural killer (Cheel et al., 2010). Thymus
vulgaris and Urtica dioica improve the innate immune system, specifi-
cally (Adel et al., 2017; Hoseini & Yousefi, 2019). Also, neutrophils'
adherence and hematocrit values can increase via Allium sativum
(Aly & Mohamed, 2010). The Acemannan from Aloe vera leaves, the
aqueous extract of Althea officinalis, polysaccharides of Astragalus
membranaseus, and the chlorogenic acid 25% of Lonicera japonica have
positive effects on phagocytosis as the main component of the innate
immune system (Ardó et al., 2008; Shah et al., 2011; Stuart et al.,
1997). Besides, the polysaccharide Form the roots of Panax ginseng
can induce macrophage activity (Shin et al., 2002). On the other
hand, the increment in total leukocyte count may trigger via Curcuma
longa powder, Echinacea purpurea, Nelumbo nucifera, and Zingiber
officinal powder, and the leaves ethanol extract of Andrographis
paniculata in low dose can induce lymphocyte proliferation (Aly &
Mohamed, 2010; Pongtuluran & Rofaani, 2015; Sivagurunathan
et al., 2011; Sivagurunathan et al., 2012). All of these changes may
help the patients' immune system to compensate for the damage
induced from SARS-CoV-2 to it.
4 | CLINICAL TRIALS
Till now, no reliable plant-based clinical trial has been done on
COVID-19. As the importance of clinical data in plant selection for
design further studies, several mentioned plants in this article, evalu-
ated in clinical trials on the common cold and respiratory disorders,
were gathered in this section.
The safety and efficacy of a specific C. sinensis formulation con-
firmed via a randomized, double-blind, placebo-controlled study on
healthy adults (18–70 years old). The symptoms, illnesses duration,
and symptoms day were fewer in subjects receiving C. sinensis formu-
lation twice a day for three months in compression with participation
in the placebo group. Also, this study showed the C. sinensis enhances
gamma-interferon T cell function (Rowe, Nantz, Percival, Bukowski, &
Bukowski, 2007).
The positive effect of A. paniculata on symptomatic treatment
of uncomplicated upper respiratory tract infection confirmed via a
systematic review of randomized controlled trials. Based on this
review, A. paniculata extract can reduce symptom severity and intro-
duce as a suitable alternative for uncomplicated acute respiratory
tract infection (Poolsup, Suthisisang, Prathanturarug, Asawamekin, &
Chanchareon, 2004).
A double-blind, randomized clinical trial was conducted on forty-six
patients (7–12 years old) who have intermittent asthma. The subjects
were daily receiving the herbal mixture (50 g of M. chamomilla, 100 g of
A. officinalis flower, 100 g of M. sylvestris flower, 100 g of Hyssopus
officinalis floral branches, 50 g of Adiantum capillus-veneris aerial parts,
50 g of G. glabra roots, and 50 g of Ziziphus jujube fruit) or placebo ran-
domly for 5 days. The result showed a significant reduction in cough
severity and nighttime awakening in patients taking herbal mixture com-
pared to those receiving placebo (Javid et al., 2019).
The efficacy and safety of cough (EMA) granules (1 g of
A.officinalis, 100 mg of Sisymbrium irio, and 70 mg of Hedera helix
powdered extract) were evaluated in the clinical trial on 150 patients
(3 to above 15 years old) for upper respiratory disorders. The sub-
jects took cough (EMA) granules or placebo three times a day for one
week. This study showed cough (EMA) granules possess positive
effects in cough, cold, and flu symptoms and it was safe (Khan
et al., 2018).
JALALI ET AL. 9

TABLE 3 Possible medicinal plants/bioactive components for prevention and support therapy of COVID-19

Scientific Part/
No. name/family extraction Main component Mechanism/outcome Study Reference
1 Aloe vera (L.) Burm.f./ Lf/- Acemannan "phagocytosis/positive 1 (Stuart et al., 1997)
Xanthorrhoeaceae immunostimulant activity
2 Allium sativum L./ - - "neutrophils adherence, " 2 (Aly & Mohamed, 2010)
Amaryllidaceae hematocrit values/"survival
rates, resistance to cold
stress and infection in
Oreochromis niloticus
3 Andrographis paniculata Lf/eth - "lymphocyte cell 1 (Pongtuluran &
(Burm.f.) Nees/ proliferation/ Rofaani, 2015)
Acanthaceae Positive immunostimulant at
low dose (1 μg/mL)
4 Astragalus aaronii (Eig) - Polysaccharide (90%) /"phagocytic, "respiratory 2 (Ardó et al., 2008)
Zohary/Leguminosae burst activity/positive
immune stimulant activity,
#mortality (in Oreochromis
niloticus after Aeromonas
hydrophila infection)
5 Althea officinalis/ Rt/Aq - "phagocytosis, oxygen radicals 2 (Shah et al., 2011)
Malvaceae and leukotrienes release
from human neutrophils/
Immunostimulant
6 Cinnamomum zeylanicum/ Bk/- - "serum immunoglobulin levels 2 (Niphade, Asad,
Lauraceae and antibody titer values/ Chandrakala, Toppo, &
Immunostimulant activity in Deshmukh, 2009)
rat (100 mg/kg p.o.)
7 Curcuma longa L./ Powder - "neutrophils, " lymphocyte, 2 (Sivagurunathan, Meera, &
Zingiberaceae "the total leucocyte count Innocent, 2011)
numbers/positive
immunostimulant activity (in
fish Cirrhinus mrigala
infected with Pseudomonas
aeruginosa
/"immune response against 2 (Madpouly, Saif, &
infection or vaccination in Hussein, 2011)
Hubbard chicks
8 Echinacea purpurea (L.) Chicoric acid 0.5% Haematogenesis ("neutrophils 2 (Aly & Mohamed, 2010)
Moench/Compositae (organic compound of adherence, "hematocrit
the phenylpropanoid values, significant
class) "lymphocytic counts, "the
total leucocytic numbers)/
"survival rates, resistance to
cold stress and infection in
Oreochromis niloticus
9 Echinacea spp./ Lf, St, Rt - Immunostimulatory activity 1 (Pillai, Pillai, Mitscher, &
Compositae (based on the flow Cooper, 2007)
cytometry techniques)
10 Glycyrrhiza glabra L./ Rt/licorice Activation of granulocyte and 2 (Cheel et al., 2010)
Leguminosae infusion natural killer/non-specific
immune stimulator
11 Lonicera japonica Thunb./ Powder/- Chlorogenic acid (25%) "phagocytic, "respiratory 2 (Ardó et al., 2008)
Caprifoliaceae burst activity/#mortality (in
Oreochromis niloticus after
Aeromonas hydrophila
infection)

(Continues)
10 JALALI ET AL.

TABLE 3 (Continued)

Scientific Part/
No. name/family extraction Main component Mechanism/outcome Study Reference
12 Nelumbo nucifera -/eth (2%) - " Total erythrocyte count, 2 (Sivagurunathan, Innocent,
Gaertn./ "Haemoglobin, "Total & Lakshmi, 2012)
Nelumbonaceae leucocyte count/
Immunostimulant activity
(in Cirrhinus mrigala infected
with Pseudomonas
aeruginosa)
13 Panax ginseng C.A.Mey./ Rt/acid Polysaccharide "macrophage function, CD14 - (Shin et al., 2002)
Araliaceae and MHC class II
modulation/
immunomodulation
14 Rheum officinale Baill./ - Anthraquinones (0.1%– " increase the gene expression 2 (Liu et al., 2010)
Polygonaceae 0.2%) of HSP70/Immunostimulant
activity (in Macrobrachium
rosenbergii)
15 Thymus vulgaris L./ - - " innate immune 2 (Hoseini & Yousefi, 2019)
Lamiaceae (in Oncorhynchus mykiss)
16 Urtica dioica L./ Ap/eth - "innate immune response, 2 (Adel, Caipang, &
Urticaceae " immune responses/ Dawood, 2017)
Immunostimulant
(in Oncorhynchus mykiss)
17 Zingiber acuminatum Powder - "lymphocyte, "the total 2 (Sivagurunathan
Valeton/Zingiberaceae leucocyte count numbers/ et al., 2011)
positive immunostimulant
activity (in fish Cirrhinus
mrigala infected with
Pseudomonas aeruginosa)

Note: Study type: 1: In-vitro, 2: In-vivo.

Abbreviations: Ap, aerial part; Aqu, aqueous; Bk, bark; Chl, chloroform; Eth, ethanol; Fl, flower; Lf, leaf; Met, methanol; Rt, root; Rz, rhizome; Sd, seed; St,
stem; Wp, whole plant.

5 | C O N CL U S I O N S ACKNOWLEDG MENT
The authors of this manuscript wish to express their thanks and
The novel coronavirus disease has appeared in China and so far just appreciation to Shiraz University of Medical Sciences, Shiraz, Iran
Remdesivir approved for emergency COVID-19 treatment. To the aim (Project no: 99-01-106-22309).
of the study, the medicinal plants and bioactive components may be
effective in the treatment and supportive therapy of COVID-19 is CONFLIC T OF INT ER E ST
presented in three sections. Various valuable medicinal plants with The authors of this manuscript have no conflict of interest.
their bioactive components can interference with COVID-19 patho-
genesis via inhibition of SARS-CoV replication and entry to its host
OR CID
cells. Among those, Citrus Spp., C. sinensis, and G. glabra are the most
Atefeh Jalali https://orcid.org/0000-0001-6026-5447
desirable herbal drink or fruit that can introduce as effective adjutant
Hossein Akbrialiabad https://orcid.org/0000-0003-2018-6378
components in COVID-19 treat.
Farzaneh Foroughinia https://orcid.org/0000-0003-3993-2043
Also, some herbal medicines such as A. paniculata, Citrus spp., and
Mohammad M. Zarshenas https://orcid.org/0000-0002-8185-4993
Cuminum cyminum can alleviate fever and cough as the most common
complication of COVID-19 via their anti-inflammatory effect. On the
RE FE RE NCE
other hand, numerous medicinal plants such as G. glabra, Thymus
Adel, M., Caipang, C. M. A., & Dawood, M. A. (2017). Immunological
vulgaris, Allium sativum, Althea officinalis, and Panax ginseng may become responses and disease resistance of rainbow trout (Oncorhynchus
effective in the prevention and supportive therapy of COVID-19 via mykiss) juveniles following dietary administration of stinging nettle
modulating the immune system. (Urtica dioica). Fish & Shellfish Immunology, 71, 230–238.
Adem, S., Eyupoglu, V., Sarfraz, I., Rasul, A., & Ali, M. (2020).
In this review, we gathered possible useful medicinal plants and
Identification of potent COVID-19 main protease (Mpro) inhibitors
bioactive components in COVID-19 prevention and treatment to light from natural polyphenols: An in silico strategy unveils a hope against
a new scope for design further in-vivo and clinical studies. CORONA.
JALALI ET AL.
Ahmad, S. F., Bani, S., Sultan, P., Ali, S. A., Bakheet, S. A., Attia, S. M., &
Abd-Allah, A. R. A. (2013). TNF-α inhibitory effect of Euphorbia hirta
in rats. Pharmaceutical Biology, 51(4), 411–417. https://doi.org/10.
3109/13880209.2012.734315
Al-Snafi, A. E. (2013). The pharmaceutical importance of Althaea officinalis
and Althaea rosea: A review. International Journal of PharmTech
Research, 5(3), 1378–1385.
Al-Snafi, A. E. (2016a). Medicinal plants possessed anti-inflammatory anti-
pyretic and analgesic activities (part 2)-plant based review. Scholars
Academic Journal of Pharmacy, 5(5), 142–158.
Al-Snafi, A. E. (2016b). The pharmacological activities of Cuminum
cyminum-a review. IOSR Journal of Pharmacy, 6(6), 46–65.
Aly, S. a., & Mohamed, M. (2010). Echinacea purpurea and Allium sativum
as immunostimulants in fish culture using Nile tilapia (Oreochromis
niloticus). Journal of Animal Physiology and Animal Nutrition, 94(5),
e31–e39.
Ardó, L., Yin, G., Xu, P., Váradi, L., Szigeti, G., Jeney, Z., & Jeney, G. (2008).
Chinese herbs (Astragalus membranaceus and Lonicera japonica) and
boron enhance the non-specific immune response of Nile tilapia
(Oreochromis niloticus) and resistance against Aeromonas hydrophila.
Aquaculture, 275(1–4), 26–33.
Aronoff, D. M., & Neilson, E. G. (2001). Antipyretics: Mechanisms of action
and clinical use in fever suppression. The American Journal of Medicine,
111(4), 304–315. https://doi.org/10.1016/S0002-9343(01)00834-8
Arya, R., Das, A., Prashar, V., & Kumar, M. (2020). Potential inhibitors
against papain-like protease of novel coronavirus (SARS-CoV-2) from
FDA approved drugs. https://doi.org/10.26434/chemrxiv.11860011
Cheel, J., Van Antwerpen, P., Tůmová, L., Onofre, G., Vokurková, D.,
Zouaoui-Boudjeltia, K., … Nève, J. (2010). Free radical-scavenging,
antioxidant and immunostimulating effects of a licorice infusion
(Glycyrrhiza glabra L.). Food Chemistry, 122(3), 508–517.
Chen, C. J., Michaelis, M., Hsu, H. K., Tsai, C. C., Yang, K. D., Wu, Y. C., …
Doerr, H. W. (2008). Toona sinensis Roem tender leaf extract inhibits
SARS coronavirus replication. Journal of Ethnopharmacology, 120(1),
108–111. https://doi.org/10.1016/j.jep.2008.07.048
Chen, C.-N., Lin, C. P., Huang, K.-K., Chen, W.-C., Hsieh, H.-P., Liang, P.-
H., & Hsu, J. T.-A. (2005). Inhibition of SARS-CoV 3C-like protease
activity by theaflavin-3, 30 -digallate (TF3). Evidence-Based Complemen-
tary and Alternative Medicine, 2(2), 209–215.
Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., … Wei, Y. (2020).
Epidemiological and clinical characteristics of 99 cases of 2019 novel
coronavirus pneumonia in Wuhan, China: A descriptive study. The Lan-
cet, 395(10223), 507–513.
Cho, J. K., Curtis-Long, M. J., Lee, K. H., Kim, D. W., Ryu, H. W.,
Yuk, H. J., & Park, K. H. (2013). Geranylated flavonoids displaying
SARS-CoV papain-like protease inhibition from the fruits of Paulownia
tomentosa. Bioorganic and Medicinal Chemistry, 21(11), 3051–3057.
https://doi.org/10.1016/j.bmc.2013.03.027
Choi, G.-P., Chung, B.-H., Lee, D.-I., Lee, H.-Y., Lee, J.-H., & Kim, J.-D.
(2002). Screening of inhibitory activities on angiotensin converting
enzyme from medicinal plants. Korean Journal of Medicinal Crop Sci-
ence, 10(5), 399–402.
Chu, X., Wei, M., Yang, X., Cao, Q., Xie, X., Guan, M., … Deng, X. (2012).
Effects of an anthraquinone derivative from Rheum officinale Baill,
emodin, on airway responses in a murine model of asthma. Food and
Chemical Toxicology, 50(7), 2368–2375.
Dabaghian, F., Khanavi, M., & Zarshenas, M. M. (2020). Bioactive com-
pounds with possible inhibitory activity of angiotensin-converting
enzyme-II; a gate to manage and prevent COVID-19. Medical Hypothe-
ses, 143, 109841–109841. https://doi.org/10.1016/j.mehy.2020.
109841
Del-Rio-Navarro, B. E., Espinosa-Rosales, F. J., Flenady, V., & Sienra-
Monge, J. J. (2012). Cochrane review: Immunostimulants for
preventing respiratory tract infection in children. Evidence-Based Child
Health: A Cochrane Review Journal, 7(2), 629–717.
11
Diao, B., Wang, C., Tan, Y., Chen, X., Liu, Y., Ning, L., … Chen, Y. (2020).
Reduction and functional exhaustion of t cells in patients with corona-
virus disease 2019 (COVID-19). Frontiers in Immunology, 11. http://dx.
doi.org/10.3389/fimmu.2020.00827
Dong, J., Xu, X., Liang, Y., Head, R., & Bennett, L. (2011). Inhibition of
angiotensin converting enzyme (ACE) activity by polyphenols from
tea (Camellia sinensis) and links to processing method. Food & Func-
tion, 2(6), 310–319.
Ebadinejad, Z., Dashtgard, A., & Mohseni Zade, M. (2017). The effect of
wet spong with Luke warm water and marshmallow on reducing body
temperature of children admitted to the teaching hospital-Shohada
Qaen. Iranian Journal of Pediatric Nursing, 4(2), 9–16.
Hamming, I., Timens, W., Bulthuis, M., Lely, A., Navis, G., & van Goor, H.
(2004). Tissue distribution of ACE2 protein, the functional receptor for
SARS coronavirus. A first step in understanding SARS pathogenesis.
The Journal of Pathology: A Journal of the Pathological Society of Great
Britain and Ireland, 203(2), 631–637.
Hammouda, F., El-Nasr, M. S., & Shahat, A. (1993). Flavonoids ofCynara
scolymus L. cultivated in Egypt. Plant Foods for Human Nutrition, 44(2),
163–169.
Han, S., Lee, J. H., Kim, C., Nam, D., Chung, W. S., Lee, S. G., … Ahn, K. S.
(2013). Capillarisin inhibits iNOS, COX-2 expression, and
proinflammatory cytokines in LPS-induced RAW 264.7 macrophages
via the suppression of ERK, JNK, and NF-κB activation. Immuno-
pharmacology and Immunotoxicology, 35(1), 34–42.
Hoseini, S. M., & Yousefi, M. (2019). Beneficial effects of thyme (Thymus
vulgaris) extract on oxytetracycline-induced stress response, immuno-
suppression, oxidative stress and enzymatic changes in rainbow trout
(Oncorhynchus mykiss). Aquaculture Nutrition, 25(2), 298–309.
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., & Gu, X. (2020). Clinical
features of patients infected with 2019 novel coronavirus in Wuhan,
China. The Lancet, 395(10223), 497–506.
Huliraj, N. (2014). Diagnosis and management of dry cough: Focus on
upper airway cough syndrome and postinfectious cough. Indian Journal
of Clinical Practice, 24(9), 879–882.
Jalali, H. T., Petronilho, S., Villaverde, J. J., Coimbra, M. A.,
Domingues, M. R. M., Ebrahimian, Z. J., … Rocha, S. M. (2013). Assess-
ment of the sesquiterpenic profile of Ferula gummosa oleo-gum-resin
(galbanum) from Iran. Contributes to its Valuation as a Potential
Source of Sesquiterpenic Compounds. Industrial crops and products,
44, 185–191.
Javid, A., Motevalli Haghi, N., Emami, S. A., Ansari, A., Zojaji, S. A.,
Khoshkhui, M., & Ahanchian, H. (2019). Short-course administration of
a traditional herbal mixture ameliorates asthma symptoms of the com-
mon cold in children. Avicenna Journal of Phytomedicine, 9(2),
126–133.
Jo, S., Kim, S., Shin, D. H., & Kim, M.-S. (2020). Inhibition of SARS-CoV
3CL protease by flavonoids. Journal of Enzyme Inhibition and Medicinal
Chemistry, 35(1), 145–151.
Keyaerts, E., Vijgen, L., Pannecouque, C., Van Damme, E., Peumans, W.,
Egberink, H., … Van Ranst, M. (2007). Plant lectins are potent inhibi-
tors of coronaviruses by interfering with two targets in the viral repli-
cation cycle. Antiviral Research, 75(3), 179–187.
Khan, M. F., Akram, M., Akhter, N., Mukhtiar, M., Zahid, R., Khan, F. S., …
Sharif, A. (2018). The evaluation of efficacy and safety of cough (EMA)
granules used for upper respiratory disorders. Pakistan Journal of Phar-
maceutical Sciences, 31(6), 2617–2622.
Khan, M. Y., & Kumar, V. (2019). Mechanism & inhibition kinetics of
bioassay-guided fractions of Indian medicinal plants and foods as ACE
inhibitors. Journal of Traditional and Complementary Medicine, 9(1),
73–84.
Kim, D. W., Seo, K. H., Curtis-Long, M. J., Oh, K. Y., Oh, J. W., Cho, J. K., &
Park, K. H. (2014). Phenolic phytochemical displaying SARS-CoV
papain-like protease inhibition from the seeds of Psoralea corylifolia.
Journal of Enzyme Inhibition and Medicinal Chemistry, 29(1), 59–63.
12
Kim, T. M., Paudel, K. R., & Kim, D. W. (2020). Eriobotrya japonica leaf
extract attenuates airway inflammation in ovalbumin-induced mice
model of asthma. Journal of Ethnopharmacology, 253, 112082. http://
dx.doi.org/10.1016/j.jep.2019.112082
Kurokawa, M., Kumeda, C. A., Yamamura, J. I., Kamiyama, T., & Shiraki, K.
(1998). Antipyretic activity of cinnamyl derivatives and related com-
pounds in influenza virus-infected mice. European Journal of Pharma-
cology, 348(1), 45–51.
Lam, T. T.-Y., Shum, M. H.-H., Zhu, H.-C., Tong, Y.-G., Ni, X.-B., Liao, Y.-S.,
& Li, L.-F. (2020). Identifying SARS-CoV-2-related coronaviruses in
Malayan pangolins. Nature, 583(7815), 282–285. http://dx.doi.org/10.
1038/s41586-020-2169-0
Lau, K.-M., Lee, K.-M., Koon, C.-M., Cheung, C. S.-F., Lau, C.-P., Ho, H.-
M., & Fung, K.-P. (2008). Immunomodulatory and anti-SARS activities
of Houttuynia cordata. Journal of Ethnopharmacology, 118(1), 79–85.
Li, S.-y., Chen, C., Zhang, H.-q., Guo, H.-y., Wang, H., Wang, L., & Tan, X.
(2005). Identification of natural compounds with antiviral activities
against SARS-associated coronavirus. Antiviral Research, 67(1), 18–23.
Li, X., Geng, M., Peng, Y., Meng, L., & Lu, S. (2020). Molecular immune
pathogenesis and diagnosis of COVID-19. Journal of Pharmaceutical
Analysis, 10(2), 102–108.
Liang, Y., Liu, Z., Xu, Y., & Hu, Y. (1990). A study on chemical composition
of two special green teas (Camellia sinensis). Journal of the Science of
Food and Agriculture, 53(4), 541–548.
Lim, H. J., Lee, J. H., Choi, J. S., Lee, S. K., Kim, Y. S., & Kim, H. P. (2014).
Inhibition of airway inflammation by the roots of Angelica decursiva
and its constituent, columbianadin. Journal of Ethnopharmacology,
155(2), 1353–1361.
Lin, C.-W., Tsai, F.-J., Tsai, C.-H., Lai, C.-C., Wan, L., Ho, T.-Y., &
Chao, P.-D. L. (2005). Anti-SARS coronavirus 3C-like protease effects
of Isatis indigotica root and plant-derived phenolic compounds. Ant-
iviral Research, 68(1), 36–42.
Liu, B., Ge, X., He, Y., Xie, J., Xu, P., He, Y., … Chen, R. (2010). Effects of
anthraquinones extracted from Rheum officinale bail on the growth,
non-specific immune response of Macrobrachium rosenbergii. Aqua-
culture, 310(1–2), 13–19.
Lu, H., Stratton, C. W., & Tang, Y.-W. (2020). Outbreak of pneumonia of
unknown etiology in Wuhan, China: The mystery and the miracle. Jour-
nal of Medical Virology, 92(4), 401–402. http://dx.doi.org/10.1002/
jmv.25678
Madav, S., Tripathi, H., & Mishra, S. (1995). Analgesic, antipyretic and anti-
ulcerogenic effects of andrographolide. Indian Journal of Pharmaceuti-
cal Sciences, 57(3), 121.
Madpouly, H., Saif, M., & Hussein, A. (2011). Curcuma longa for protecting
chicks against Newcastle disease virus infection and immunosuppres-
sive effect of Marek's disease viral vaccine. International Journal of
Virology, 7(4), 176–183.
Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., &
Manson, J. J. (2020). COVID-19: Consider cytokine storm syndromes
and immunosuppression. The Lancet., 395, 1033–1034.
Mukhtar, M., Arshad, M., Ahmad, M., Pomerantz, R. J., Wigdahl, B., &
Parveen, Z. (2008). Antiviral potentials of medicinal plants. Virus Research,
131(2), 111–120. https://doi.org/10.1016/j.virusres.2007.09.008
Nile, S. H., Nile, A., Qiu, J., Li, L., Jia, X., & Kai, G. (2020). COVID-19: Patho-
genesis, cytokine storm and therapeutic potential of interferons. Cyto-
kine & Growth Factor Reviews., 53, 66–70. https://doi.org/10.1016/j.
cytogfr.2020.05.002
Niphade, S. R., Asad, M., Chandrakala, G. K., Toppo, E., & Deshmukh, P.
(2009). Immunomodulatory activity of Cinnamomum zeylanicum bark.
Pharmaceutical Biology, 47(12), 1168–1173.
Nosáľová, G., Majee, S. K., Ghosh, K., Raja, W., Chatterjee, U. R.,
Jureček, Ľ., & Ray, B. (2014). Antitussive arabinogalactan of
Andrographis paniculata demonstrates synergistic effect with
andrographolide. International Journal of Biological Macromolecules, 69,
151–157.
JALALI ET AL.
Nosáľová, G., Mokrý, J., Ather, A., & Khan, M. (2007). Antitussive activity
of the ethanolic extract of Paederia foetida (Rubiaceae family) in non-
anaesthetized cats. Acta Veterinaria Brno, 76(1), 27–33.
Nosalova, G., Sutovska, M., Mokry, J., Kardosova, A., Capek, P., & Khan, M.
(2005). Efficacy of herbal substances according to cough reflex.
Minerva Biotecnologica, 17(3), 141.
Nwachukwu, D. C., Aneke, E. I., Obika, L. F., & Nwachukwu, N. Z. (2015).
Effects of aqueous extract of Hibiscus sabdariffa on the renin-angio-
tensin-aldosterone system of Nigerians with mild to moderate essen-
tial hypertension: A comparative study with lisinopril. Indian Journal of
Pharmacology, 47(5), 540–545.
Ojeda, D., Jiménez-Ferrer, E., Zamilpa, A., Herrera-Arellano, A.,
Tortoriello, J., & Alvarez, L. (2010). Inhibition of angiotensin
convertin enzyme (ACE) activity by the anthocyanins delphinidin-
and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa. Journal of
Ethnopharmacology, 127(1), 7–10.
Park, B.-J., & Tomohiko, M. (2011). Feruloyl, caffeoyl, and flavonol gluco-
sides from Equisetum hyemale. Chemistry of Natural Compounds, 47(3),
363–365.
Park, J. Y., Jeong, H. J., Kim, J. H., Kim, Y. M., Park, S. J., Kim, D., &
Ryu, Y. B. (2012). Diarylheptanoids from Alnus japonica inhibit papain-
like protease of severe acute respiratory syndrome coronavirus. Bio-
logical and Pharmaceutical Bulletin, 35(11), 2036–2042.
Pillai, S., Pillai, C., Mitscher, L. A., & Cooper, R. (2007). Use of quantitative
flow cytometry to measure ex vivo immunostimulant activity of Echi-
nacea: The case for polysaccharides. The Journal of Alternative and
Complementary Medicine, 13(6), 625–634.
Pongtuluran, O. B., & Rofaani, E. (2015). Antiviral and immunostimulant
activities of Andrographis paniculata. HAYATI Journal of Biosciences, 22
(2), 67–72.
Poolsup, N., Suthisisang, C., Prathanturarug, S., Asawamekin, A., &
Chanchareon, U. (2004). Andrographis paniculata in the symptomatic
treatment of uncomplicated upper respiratory tract infection: System-
atic review of randomized controlled trials. Journal of Clinical Pharmacy
and Therapeutics, 29(1), 37–45.
Prasad, K. (2013). Secoisolariciresinol diglucoside (SDG) isolated from flax-
seed, an alternative to ACE inhibitors in the treatment of hyperten-
sion. International Journal of Angiology, 22(04), 235–238.
Puggioni, F., Alves-Correia, M., Mohamed, M.-F., Stomeo, N., Mager, R.,
Marinoni, M., & Giorgis, V. (2019). Immunostimulants in respiratory
diseases: Focus on Pidotimod. Multidisciplinary Respiratory Medicine,
14(1), 1–10.
Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Tao, Y., & Wang, W. (2020).
Dysregulation of immune response in patients with COVID-19 in Wuhan.
Clinical Infectious Diseases: China.
Qiu, S.-X., Lu, Z.-Z., Luyengi, L., Lee, S. K., Pezzuto, J. M.,
Farnsworth, N. R., & Fong, H. H. (1999). Isolation and characterization
of flaxseed (Linum usitatissimum) constituents. Pharmaceutical Biology,
37(1), 1–7.
Racchi, M. L. (2013). Antioxidant defenses in plants with attention to Pru-
nus and citrus spp. Antioxidants, 2(4), 340–369.
Refaat, J., Desoukey, S. Y., Ramadan, M. A., & Kamel, M. S. (2015).
Rhoifolin: A review of sources and biological activities. International
Journal of Pharmacognosy, 2, 102–109.
remdesivir EUA Letter of Authorization - FDA. (2020). Retrieved from
https://www.fda.gov/media/137564/download
Ren, L.-L., Wang, Y.-M., Wu, Z.-Q., Xiang, Z.-C., Guo, L., Xu, T., … Li, H. (2020).
Identification of a novel coronavirus causing severe pneumonia in human:
A descriptive study. Chinese Medical Journal., 133, 1015–1024.
Riaz, G., & Chopra, R. (2018). A review on phytochemistry and therapeutic
uses of Hibiscus sabdariffa L. Biomedicine & Pharmacotherapy, 102,
575–586.
Rothan, H. A., & Byrareddy, S. N. (2020). The epidemiology and pathogen-
esis of coronavirus disease (COVID-19) outbreak. Journal of Autoimmu-
nity, 109, 102433. http://dx.doi.org/10.1016/j.jaut.2020.102433
JALALI ET AL.
Rowe, C. A., Nantz, M. P., Percival, S. S., Bukowski, J. F., & Bukowski, J. F.
(2007). Specific formulation of Camellia sinensis prevents cold and flu
symptoms and enhances γδ T cell function: A randomized, double-
blind, placebo-controlled study. Journal of the American College of
Nutrition, 26(5), 445–452.
Ryu, Y. B., Jeong, H. J., Kim, J. H., Kim, Y. M., Park, J. Y., Kim, D., &
Lee, W. S. (2010). Biflavonoids from Torreya nucifera displaying SARS-
CoV 3CLpro inhibition. Bioorganic and Medicinal Chemistry, 18(22),
7940–7947.
Saha, S., Nosál'ová, G., Ghosh, D., Flešková, D., Capek, P., & Ray, B. (2011).
Structural features and in vivo antitussive activity of the water
extracted polymer from Glycyrrhiza glabra. International Journal of Bio-
logical Macromolecules, 48(4), 634–638.
Salim, E., Kumolosasi, E., & Jantan, I. (2014). Inhibitory effect of selected
medicinal plants on the release of pro-inflammatory cytokines in
lipopolysaccharide-stimulated human peripheral blood mononuclear
cells. Journal of Natural Medicines, 68(3), 647–653.
Santos, U. P., Campos, J. F., Torquato, H. F. V., Paredes-Gamero, E. J.,
Carollo, C. A., Estevinho, L. M., & dos Santos, E. L. (2016). Antioxidant,
antimicrobial and cytotoxic properties as well as the phenolic content
of the extract from Hancornia speciosa Gomes. PloS One, 11(12),
e0167531.
Shah, S., Akhtar, N., Akram, M., Shah, P. A., Saeed, T., Ahmed, K., & Asif, H.
(2011). Pharmacological activity of Althaea officinalis L. Journal of
Medicinal Plants Research, 5(24), 5662–5666.
Shi, R., Xu, J. W., Xiao, Z. T., Chen, R. F., Zhang, Y. L., Lin, J. B., &
Su, W. W. (2019). Naringin and naringenin relax rat tracheal smooth
by regulating bkca activation. Journal of Medicinal Food, 22(9),
963–970.
Shin, J.-Y., Song, J.-Y., Yun, Y.-S., Yang, H.-O., Rhee, D.-K., & Pyo, S.
(2002). Immunostimulating effects of acidic polysaccharides extract of
Panax ginseng on macrophage function. Immunopharmacology and
Immunotoxicology, 24(3), 469–482.
Silva, G., Braga, F., Lima, M., Pesquero, J., Lemos, V., & Cortes, S. (2011).
Hancornia speciosa Gomes induces hypotensive effect through inhibi-
tion of ACE and increase on NO. Journal of Ethnopharmacology, 137(1),
709–713.
Sivagurunathan, A., Innocent, B. X., & Lakshmi, S. M. (2012).
Immunomodulatory effect of dietary Nelumbo nucifera (lotus) in
growth and haematology of Cirrhinus mrigala challenged with Pseu-
domonas aeruginosa. Journal of Applied Pharmaceutical Science, 2(7),
191–195.
Sivagurunathan, A., Meera, K. A., & Innocent, B. X. (2011). Investigation of
Immunostimulant potential of Zingiber officinale & Curcuma longa in
Cirrhinus mrigala exposed to P. aeruginosa-Haematological assess-
ment. International Journal of Research in Ayurveda and Pharmacy, 2(3),
899–904.
Song, Y. H., Kim, D. W., Curtis-Long, M. J., Yuk, H. J., Wang, Y.,
Zhuang, N., & Park, K. H. (2014). Papain-like protease (PLpro) inhibi-
tory effects of cinnamic amides from Tribulus terrestris fruits. Biologi-
cal and Pharmaceutical Bulletin, 37(6), 1021–1028.
Sood, R., Raut, R., Tyagi, P., Pareek, P. K., Barman, T. K., Singhal, S., &
Khanna, N. (2015). Cissampelos pareira Linn: Natural source of potent
antiviral activity against all four dengue virus serotypes. PLoS
Neglected Tropical Diseases, 9(12), e0004255. https://doi.org/10.
1371/journal.pntd.0004255
Stuart, R., Lefkowitz, D., Lincoln, J., Howard, K., Gelderman, M., &
Lefkowitz, S. (1997). Upregulation of phagocytosis and candidicidal
activity of macrophages exposed to the immunostimulant, acemannan.
International Journal of Immunopharmacology, 19(2), 75–82.
Sultana, S., Asif, H. M., Akhtar, N., & Ahmad, K. (2015). Medicinal plants
with potential antipyretic activity: A review. Asian Pacific Journal of
Tropical Disease, 5, S202–S208.
ul Qamar, M. T., Alqahtani, S. M., Alamri, M. A., & Chen, L.-L. (2020). Struc-
tural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery
13
from medicinal plants†. Journal of Pharmaceutical Analysis., 10,
313–319. https://doi.org/10.1016/j.jpha.2020.03.009
Utomo, R. Y., & Meiyanto, E. (2020). Revealing the potency of citrus and gal-
angal constituents to halt SARS-CoV-2 infection. https://doi.org/10.
20944/preprints202003.0214.v1
Votava, M., & Beran, J. The role of non-specific immunostimulant inosine
pranobex in the treatment of SARS-CoV-2 virus infection (n.d.).
Retrieved from https://www.researchgate.net/profile/Martin_Votava2/
publication/341043129_The_role_of_non-specific_immunostimulant_
inosine_pranobex_in_the_treatment_of_SARS-CoV-2_virus_infection/
links/5eaa96f7a6fdcc70509b1ed5/The-role-of-non-specific-immuno
stimulant-inosine-pranobex-in-the-treatment-of-SARS-CoV-2-virus-
infection.pdf
Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., … Peng, Z. (2020). Clini-
cal characteristics of 138 hospitalized patients with 2019 novel
coronavirus–infected pneumonia in Wuhan, China. JAMA, 323(11),
1061. http://dx.doi.org/10.1001/jama.2020.1585
Wang, W., Ma, X., Han, J., Zhou, M., Ren, H., Pan, Q., … Zheng, Q. (2016).
Neuroprotective effect of scutellarin on ischemic cerebral injury by
down-regulating the expression of angiotensin-converting enzyme
and AT1 receptor. PLOS ONE, 11(1), e0146197. http://dx.doi.org/10.
1371/journal.pone.0146197
Wen, C.-C., Shyur, L.-F., Jan, J.-T., Liang, P.-H., Kuo, C.-J., Arulselvan, P., &
Yang, N.-S. (2011). Traditional Chinese medicine herbal extracts of
Cibotium barometz, Gentiana scabra, Dioscorea batatas, Cassia tora,
and Taxillus chinensis inhibit SARS-CoV replication. Journal of Tradi-
tional and Complementary Medicine, 1(1), 41–50. https://doi.org/10.
1016/S2225-4110(16)30055-4
Wu, C., Liu, Y., Yang, Y., Zhang, P., Zhong, W., Wang, Y., & Li, H. (2020).
Analysis of therapeutic targets for SARS-CoV-2 and discovery
of potential drugs by computational methods. Acta Pharmaceutica
Sinica B., 10, 766–788. https://doi.org/10.1016/j.apsb.2020.
02.008
Xia, W, Shao, J., Guo, Y., Peng, X., Li, Z., & Hu, D. (2020). Clinical and CT
features in pediatric patients with COVID-19 infection: Different
points from adults. Pediatric Pulmonology, 55(5), 1169–1174. http://
dx.doi.org/10.1002/ppul.24718
Yan, Y.-M., Shen, X., Cao, Y.-K., Zhang, J.-J., Wang, Y., & Cheng, Y.-X.
(2020). Discovery of Anti-2019-nCoV agents from Chinese patent drugs
via docking screening. https://doi.org/10.20944/preprints202002.
0254.v2
Yang, Y., Ye-ping, M., Zhang, Z., Pei-lin, D., Li, P., & Wen-ge, L. (2018).
Effects of adding Rheum officinale to angiotensin-converting enzyme
inhibitors or angiotensin receptor blockers on renal function in
patients with chronic renal failure: A meta-analysis of randomized con-
trolled trials. Clinical Nephrology, 89(6), 445–454.
Yao, X. J., Yin, J. A., Xia, Y. F., Wei, Z. F., Luo, Y. B., Liu, M., & Dai, Y.
(2012). Puerarin exerts antipyretic effect on lipopolysaccharide-
induced fever in rats involving inhibition of pyrogen production from
macrophages. Journal of Ethnopharmacology, 141(1), 322–330. https://
doi.org/10.1016/j.jep.2012.02.038
Yi, L., Li, Z., Yuan, K., Qu, X., Chen, J., Wang, G., & Xu, X. (2004).
Small molecules blocking the entry of severe acute respiratory
syndrome coronavirus into host cells. Journal of Virology, 78(20),
11334–11339. https://doi.org/10.1128/JVI.78.20.11334-11339.
2004
Yu, J. S., Tseng, C. K., Lin, C. K., Hsu, Y. C., Wu, Y. H., Hsieh, C. L., &
Lee, J. C. (2017). Celastrol inhibits dengue virus replication via up-
regulating type I interferon and downstream interferon-stimulated
responses. Antiviral Research, 137, 49–57. https://doi.org/10.1016/j.
antiviral.2016.11.010
Zetterström, M., Sundgren-Andersson, A. K., Ostlund, P., & Bartfai, T.
(1998). Delineation of the proinflammatory cytokine cascade in fever
induction a. Annals of the new York Academy of Sciences, 856(1),
48–52.
14 JALALI ET AL.

Zhang, G.-H., Wang, Q., Chen, J.-J., Zhang, X.-M., Tam, S.-C., & A Perspective from China. Radiology, 296(2), E15–E25. http://dx.doi.
Zheng, Y.-T. (2005). The anti-HIV-1 effect of scutellarin. Biochemical org/10.1148/radiol.2020200490
and Biophysical Research Communications, 334(3), 812–816.
Zhang, H., Penninger, J. M., Li, Y., Zhong, N., & Slutsky, A. S. (2020). Angio-
tensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molec-
How to cite this article: Jalali A, Dabaghian F, Akbrialiabad H,
ular mechanisms and potential therapeutic target. Intensive Care
Medicine, 46(4), 586–590. http://dx.doi.org/10.1007/s00134-020- Foroughinia F, Zarshenas MM. A pharmacology-based
05985-9 comprehensive review on medicinal plants and phytoactive
Zhu, B., Qian, C., Zhou, F., Guo, J., Chen, N., Gao, C., & Ding, Z. (2020). Antipy- constituents possibly effective in the management of COVID-
retic and antitumor effects of a purified polysaccharide from aerial parts
19. Phytotherapy Research. 2020;1–14. https://doi.org/10.
of Tetrastigma hemsleyanum. Journal of Ethnopharmacology, 253, 112663.
Zu, Z. Y., Jiang, M. D., Xu, P. P., Chen, W., Ni, Q. Q., Lu, G. M., & 1002/ptr.6936
Zhang, L. J. (2020). Coronavirus Disease 2019 (COVID-19):