Journal of Traditional Chinese Medical Sciences 8 (2021) 101e109

Contents lists available at ScienceDirect

Journal of Traditional Chinese Medical Sciences

journal homepage: www.elsevier.com/locate/jtcms

Clinical applications and pharmacological research progress of

Lianhua Qingwen capsules/granules
Zhenhua Jia a, b, c, d, *, Yiling Wu b, c, d
a
Hebei Yiling Hospital, Shijiazhuang, 050091, China
b
State Key Laboratory of Collateral Disease Research and Innovative Chinese Medicine Medicines, Key Laboratory of National Administration of Traditional
Chinese Medicine, Shijiazhuang, 050035, China
c
Key Laboratory of National Administration of Traditional Chinese Medicine (Cardiovascular & Cerebrovascular Collateral Disease), Shijiazhuang, 050035,
China
d
Hebei Academy of Integrated Traditional Chinese and Western Medicine, Shijiazhuang, 050035, China

a r t i c l e i n f o a b s t r a c t

Article history: Lianhua Qingwen capsule/granule is an innovative Chinese medicine developed under the guidance of
Received 9 April 2021 the traditional Chinese medicine (TCM) collateral disease theory. It has the effect of “clearing heat and
Received in revised form removing toxin, ventilating the lungs and discharging heat”. In 2003, it was approved as a new drug by
6 May 2021
the China National Medical Products Administration, through expedited approval during severe acute
Accepted 6 May 2021
Available online 10 May 2021
respiratory syndrome, and now, it has become a representative proprietary Chinese medicine for the
treatment of infectious diseases of the respiratory system. Pharmacodynamic studies have revealed that
Lianhua Qingwen has broad-spectrum antiviral, antibacterial and anti-inflammatory, antipyretic, cough-
Keywords:
Collateral disease theory
relieving, and immunoregulation effects. Clinically it has been used in the treatment of communicable
Lianhua Qingwen and infectious respiratory diseases such as Coronavirus Disease 2019, influenza, colds, pulmonary in-
COVID-19 fections, etc. and has achieved remarkable curative effects, showing the important clinical guidance of
Influenza the TCM collateral disease theory.
Pneumonia © 2021 Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V. This is an open
Traditional Chinese medicine access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction Lianhua Qingwen capsule/granule (hereinafter referred to as

Coronavirus Disease 2019 (COVID-19) has become a public
health emergency of international concern worldwide. It is
considered the most destructive respiratory public health event
following the severe acute respiratory syndrome (SARS), H1N1
influenza, and the Middle East respiratory syndrome outbreaks
since the beginning of the 21st century.1 There are over 4 million
deaths and millions of hospitalizations each year due to acute viral
respiratory diseases worldwide,2 and every year, 294 000 to 518
000 people die from seasonal influenza,3 which poses a serious
threat to human health, social stability, and economic develop-
ment. Therefore, exploring new and effective treatment approaches
has important clinical value and application prospects for breaking
through the limitations of current antiviral drugs in the treatment
of novel or recurring viral respiratory infections.
* Corresponding author.
E-mail address: jzhjiazhenhua@163.com (Z. Jia).
Peer review under responsibility of Beijing University of Chinese Medicine.
Lianhua Qingwen) is an innovative Chinese medicine for the
treatment of colds and influenza developed under the guidance of
the traditional Chinese Medicine (TCM) collateral disease theory. It
is composed of 13 herbs including forsythia fruit (Forsythia sus-
pensa (Thunb.) Vahl), honeysuckle flower (Lonicera japonica
Thunb.), fried ephedra stem (Ephedra sinica Stapf), dryopteris root
(Dryopteris crassirhizoma Nakai), isatis root (Isatis indigotica Fort.),
gypsum (Crystalline gypsum), patchouli (Pogostemon cablin
(Blanco) Benth.), integripetal rhodiola herb (Rhodiola saera (Prain)
Fu), houttuynia (Houttuynia cordata Thunb.), rhubarb root and
rhizome (Rheum palmatum L.), fried apricot seed (Prunus armeniaca
L. var. ansu Maxim.), licorice root (Glycyrrhiza uralensis Fisch.), and
menthol. It has the efficacy of clearing heat and removing toxin,
ventilating the lungs and discharging heat. In 2003, it was approved
as a new drug by the China National Medical Products Adminis-
tration through expedited approval during the SARS outbreak.
Since marketing, Lianhua Qingwen has been listed in China's na-
tional guidelines or consensus on the prevention and control of
respiratory communicable diseases more than 20 times, and has
become a representative proprietary Chinese medicine for

https://doi.org/10.1016/j.jtcms.2021.05.001
2095-7548/© 2021 Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
Z. Jia and Y. Wu
responding to respiratory public health events caused by viruses;
especially during the 2009H1N1 influenza pandemic and during the
COVID-19 epidemic in 2020, it played an important role and
received much attention both domestically and internationally. In
this article, the applications of Lianhua Qingwen in respiratory
diseases are reviewed based on its clinical uses and pharmacolog-
ical effects.
Theoretical basis and pharmacodynamic characteristics of Lianhua
Qingwen prescriptions based on the theory of collateral disease in
TCM
The collateral disease theory is an important part of the aca-
demic system of TCM and an applied theory for studying the
occurrence and development of collateral disease and the law of
differentiation therapy. Collateral disease is a pathological state and
process with a variety of miscellaneous diseases due to internal
injury and severe exogenous diseases.4 The Yellow Emperor's Inner
Classic is the theoretical foundation for the theory of collateral
disease; Zhang Zhongjing's Treatise on Cold Damage and Miscella-
neous Diseases in the Eastern Han Dynasty lays a foundation for
clinical patterns and treatment of collateral diseases; Ye Tianshi, in
the Qing Dynasty, proposed “chronic diseases going into the col-
laterals” and “long-term pains going into the collaterals”, and
developed collateral diseases into an important pathogenesis
concept in Chinese medicine. However, due to the excessive
emphasizing on the meridian over the collaterals in the history of
the development of TCM, the collaterals and the theory of collat-
erals have not received sufficient attention and in-depth research,
nor was a systematic theoretical system formed, therefore it has
become a major topic in the contemporary era.5,6 Academician
Yiling Wu has been devoted to the theoretical research of collateral
disease since the 1980s. He proposed the theoretical framework
“three-dimensional network system” of collateral diseases and
pointed out the spatial-temporal and functional differences be-
tween collaterals and meridians, to guide the studies on the onset,
pathogenesis, pattern identification, and treatment of collateral
diseases. He has formed the theory of systemic collateral disease for
the first time in the history of the development of TCM, and
established the system of “pattern and therapeutic principles of
collateral diseases”,7 laying a theoretical foundation for the estab-
lishment of the discipline of collateral disease in Chinese medicine.
The studies on cardiovascular and cerebrovascular diseases,
arrhythmia, chronic heart failure, diabetes mellitus, tumors, influ-
enza, and cold under the guidance of the theory of collateral dis-
eases have explored a new approach for effective treatment, to
improve clinical efficacy, and to promote the development of
innovative Chinese medicines.
Based on the theoretical framework of collateral disease, i.e.
“three-dimensional network system”, it is considered that collat-
erals are a network system that separates from the meridian
branches and spreads throughout the body, to be widely distrib-
uted as the reticular system between organs and viscera, present-
ing a spatial distribution of the “external (yang collaterals on the
body surface)emiddle (meridians)einternal (yin collaterals in the
internal organs”.8 In the Chapter 66 The Occurrence of All Diseases
in Spiritual Pivot, it is proposed that “the deficiency and evils start
from the skin, and the skin and muscle textures are open, then evils
enter from the hair …. then will pass on to the collaterals …...and
then pass on to the meridians … to accumulate in the minor veins
and collaterals”.9 It is proposed that the external evils invade the
human body from the outside, and invade the yang collaterals and
then the meridians, and finally affect the yin collaterals in the in-
ternal organs, which offers an important guidance on revealing the
common progress of viral respiratory infectious diseases such as
102
Journal of Traditional Chinese Medical Sciences 8 (2021) 101e109
SARS, influenza, COVID-19, etc. According to the concept of collat-
eral spaces, the pathogenesis characteristics of external evils (SARS,
influenza virus, etc.) from the yang collaterals to the meridians, and
the rules of progress of the disease to the yin collaterals of the
viscera are revealed, and an “active intervention” treatment strat-
egy is proposed. Simultaneous treatment of defensive qi, releasing
evils from both the exterior and the interior: the epidemic febrile
disease starts from the yang collaterals on the body surface, with
the Wei symptoms of aversion to cold and fever, and the exterior
syndromes are not solved. Then evils rapidly spread to the merid-
ians, when the qi symptoms like hyperpyrexia occur. Simultaneous
treatment of defensive qi and releasing evils from both the exterior
and the interior allow the disease to be controlled at the early stage.
Medication for proceeding disease and cutting off the disease
progression trend: In view of the characteristics of the epidemic
virus that is very virulent and spreads quickly, Wu Youke proposed
the epidemic treatment philosophy of “eliminating the evil as the
first principle”, attaching importance to the attack on the disease
evils as early as possible, and pointed out that “everyone's evil
should be treated as early as possible … early elimination of the
root cause of the disease is the key” (Treatise on Pestilence).10 In
view of the rapid spread of the disease caused by the epidemics, Wu
Youke proposed the active intervention philosophy of treatment
within one day over several days, to play a role of “ventilating all
orifices through one orifice” using prompt treatment on acute
symptoms, and “power of rhubarb” clarified that rhubarb relaxes
the bowel to play the role of active intervention. Overall regulation,
multi-target therapy: While actively expelling toxins, attention
should be paid to the injury to the viscera and tissues caused by the
pathogens of the epidemic invading the human body. With medi-
cines for heat-clearing and phlegm-relieving, and cough-removing
and stasis-removing, they can supplement healthy qi, regulate
immunity, and enhance rehabilitation ability to block the trans-
formation of diseases into severe and critical diseases. “By
observing the pulses and patterns, the disease can be known, and
then treated according to the patterns”.11
Based on the “active intervention” strategy, the therapeutic
method of “clearing heat and removing toxin, ventilating the lungs
and discharging heat” is established, and the prescriptions of
Lianhua Qingwen are determined. Using the Maxing Shigan
decoction in the Treatise on Cold Damage and the Yinqiao powder in
the Systematic Differentiation of Warm Diseases as the basic formula,
the simultaneous treatment of defensive qi and releasing evils from
both the exterior and the interior can be achieved. According to the
experiences in expelling evils and toxins with rhubarb in the
“Treatise on Pestilence” by Wu Youke in the Ming Dynasty, medi-
cation for proceeding disease and cutting off the disease progres-
sion trend is adopted; and with the interior-exterior relationship
between the lungs and the large intestine, the rhubarb clears the
lungs and soothes the lungs. It is compatible with rhodiola to clear
the lungs and resolve stasis, regulate immunity, and is compatible
with patchouli to resolve the dampness with aroma, and dispel filth
and ward off evils.6 The prescription draws on the essence of
medications for external-contraction febrile disease and epidemic
syndrome from the development history of Chinese medicine
across two thousand years, and reflects the characteristics of the
active intervention prescription. Pharmacodynamic studies have
confirmed that Lianhua Qingwen has a broad-spectrum antiviral
effect and significantly inhibits the SARS virus activity in African
green monkey kidney cells (Vero-E6),12 and apparently inhibits the
SARS-CoV-2,13 influenza virus H1N1,14 H3N2,15 avian influenza vi-
ruses H7N9,16 H9N2,13 enterovirus 71, Coxsackie B4 virus,17,18 respi-
ratory syncytial virus (RSV),19 adenovirus type 3 and type 7, Herpes
simplex virus type 1 and type 2, etc.; in addition, it can effectively
inhibit Streptococcus pneumoniae, Escherichia coli, Pseudomonas
Z. Jia and Y. Wu
aeruginosa,20 and Klebsiella pneumonia.21 By inhibiting the forma-
tion of Staphylococcus aureus biofilm,22 the resistance of bacteria to
carbapenem antibiotics is increased. Lianhua Qingwen has anti-
pyretic, anti-inflammatory, cough-relieving and phlegm-resolving
effects, and can alleviate influenza-like symptoms, as well as
regulate immunity to enhance the body's ability to resist disease
and enhance rehabilitation.
Clinical applications and pharmacodynamic research of Lianhua
Qingwen in respiratory diseases
Study on the treatment of COVID-19 with Lianhua Qingwen
Clinical study on in the treatment of COVID-19 with Lianhua Qingwen.
In a randomized, controlled, multi-center clinical study of Lianhua
Qingwen in the treatment of COVID-19 patients, a total of 284
eligible subjects was included and randomized into a control group
(142 cases, conventional treatment) and a treatment group (142
cases, conventional treatment þ Lianhua Qingwen), with a treat-
ment duration of 14 days. Results showed that Lianhua Qingwen
could enhance the disappearance rate and shorten the duration of
the main clinical symptoms of COVID-19 (fever, fatigue, cough)
(P < .05); and computerized tomography imaging showed that the
inflammation in the lung was alleviated (P < .001), the clinical cure
rate was increased (P < .05), and the progression to severe cases
was decreased by 50%, compared to the control group, showing a
good tendency but without statistical significance (P > .05).
Furthermore, no adverse reactions related to the study drug were
observed, which confirmed that Lianhua Qingwen was safe and
effective in the treatment of COVID-19.23 In addition, clinical
studies that reported on the treatment of COVID-19 with Lianhua
Qingwen were perused, and the clinical efficacy of Lianhua Qing-
wen in the treatment of common type COVID-19 was analyzed
using retrospective study methods, which confirmed that Lianhua
Qingwen could significantly alleviate the symptoms of COVID-19,
shorten the duration of symptoms and reduce the rate of pro-
gression to severe cases.24,25
A meta-analysis including seven randomized controlled trials
(RCT) of Lianhua Qingwen in the treatment of COVID-19 with a total
sample size of 665 patients showed that, compared to Western
medicine (WM) treatment alone (symptomatic supportive treat-
ment, antiviral and antibacterial therapy, etc.), Lianhua Qingwen
combined with WM treatment could significantly improve the
response rate of the main clinical symptoms of COVID-19 patients
[relative risk (RR) ¼ 1.24, 95% confidence interval (CI) (1.12, 1.38),
P < .05], computerized tomography imaging improvement
[RR ¼ 1.14, 95% CI (1.02, 1.28), P < .05], and reduce the ratio of
progression to severe cases [RR ¼ 0.48, 95% CI (0.31, 0.72), P < .05];
in addition, Lianhua Qingwen combination therapy could effec-
tively shorten the duration of fever [standardized mean difference
(SMD) ¼ 0.87, 95% CI (1.22, 0.52), P < .05], the time to disap-
pearance of clinical symptoms [SMD ¼ 1.19, 95% CI (1.56, 0.82),
P < .05] and the duration of hospitalization [SMD ¼ 0.61, 95% CI
(0.91, 0.30), P < .05],26 which further confirmed the clinical ef-
ficacy of Lianhua Qingwen in the treatment of COVID-19.
Basic study on the treatment of COVID-19 with Lianhua Qingwen.
The SARS-CoV-2 virus binds to the angiotensin converting enzyme
2 (ACE2) receptor on the surface of host airway epithelial cells to
invade cells for replication and proliferation. Therefore, the lung is
the main target organ of SARS-CoV-2. In the early stage of viral
infection, the inflammatory process is initiated at the injury site,
which is a defense response of the body against infectious or non-
infectious factors. If the homeostasis of pro-inflammatory and anti-
inflammatory reactions is disrupted, the release of pro-
inflammatory factors in a cascading fashion is manifested as
“cytokine storm”, with the coexistence of excessive inflammations
103
Journal of Traditional Chinese Medical Sciences 8 (2021) 101e109
and immunosuppression. This high inflammatory state is an
important pathogenesis of COVID-19 immune response imbalance,
and is closely related to the severity of the disease.27 Vero E6 is an
aneuploid cell with its ACE2 highly similar to the human cells. Li
et al used SARS-CoV-2 virus to infect Vero E6 and Huh-7 cells.8 The
cytopathic effect inhibition assay and plaque reduction assay
showed that the median inhibitory concentration (IC50) of Lianhua
Qingwen for SARS-CoV-2 virus-induced cytopathic changes was
411.2 mg/mL. When the dose was administered at 150, 300, and
600 mg/mL, it significantly inhibited the expression of SARS-CoV-2
in a dose-dependent manner, and inhibited the formation of pla-
ques in virus-infected cells, confirming that Lianhua Qingwen
significantly inhibited SARS-CoV-2 activity in vitro. When Lianhua
Qingwen was used to intervene Vero E6 cells infected with the virus
for 48 h, the results showed that it inhibited the expression level of
intracellular virus and changed the morphology of the intracellular
virus, confirming that Lianhua Qingwen could inhibit intracellular
virus replication. Lianhua Qingwen apparently inhibited the over-
expression of pro-inflammatory cytokines induced by Huh-7 cells
with virus infection (tumor necrosis factor (TNF)-a, interleukin (IL)-
6, C-C motif chemokine ligand 2 (CCL-2)/monocyte chemo-
attractant protein-1 (MCP-1) and C-X-C motif chemokine ligand-10
(CXCL-10)/interferon gamma-induced protein-10 (IP-10)) (P < .05)
in a concentration-dependent manner. This revealed that Lianhua
Qingwen significantly inhibited the SARS-CoV-2 activity, intracel-
lular virus replication, and the inflammatory response after virus
infection.
Furthermore, the network pharmacology revealed the acting
targets and signal pathways of Lianhua Qingwen in the treatment of
COVID-19. Results showed that hyperoside, rutin, and forsythiaside
E, the main components of forsythia in Lianhua Qingwen, were the
most possible inhibitor of the main proteases of SARS-CoV-2. An
active ingredient-gene target-pathway network was constructed,
which confirmed that COVID-19 was treated by Lianhua Qingwen
mainly through improving human immunity and inhibiting in-
flammatory pathways such as FcεRI, ErbB, and MAPK.28 Lianhua
Qingwen achieved the treatment of COVID-19 through, among
others, multi-component, multi-target, and multi-pathway in-
terventions such as broad-spectrum antiviral, antibacterial and
antipyretic, cough-relieving and sputum-reducing, and immune
regulation effects.29‒31
In terms of the pharmacodynamic material basis of Lianhua
Qingwen in the treatment of COVID-19, Chen et al conducted
analysis and evaluation on the exposure components of Lianhua
Qingwen in humans, based on high-resolution mass spectrometry
and intelligent non-targeted data mining technology.32 The ACE2
biochromatographic stationary phase was synthesized for the first
time, to screen the effective ingredients of Lianhua Qingwen.
Through this, eight ingredients were successfully identified that
were exposed to the human body at high concentrations, and
which had potential ACE2 targeting activity, including neo-
chlorogenic acid and its isomers, amygdalin, prunasin, glycyrrhizic
acid, forsythin A, forsythin I, rhein, and aloe-emodin. Further sur-
face plasmon resonance (SPR) analysis and molecular docking
simulation analysis showed that rhein, forsythoside A, forsythoside
I, neochlorogenic acid and its isomers had inhibitory effects on the
enzyme activity of ACE2. By blocking the binding of SARS-CoV-2 S
protein to the ACE2 receptor, Lianhua Qingwen played the role in
preventing and treating COVID-19. This article reported human
exposure information of Lianhua Qingwen and ACE2 targeting
components for the first time, providing a chemical and biological
basis for the study of its pharmacologically active ingredients and
mechanism against SARS-CoV-2.
Z. Jia and Y. Wu
Study on treatment of influenza virus with Lianhua Qingwen
Clinical studies on the treatment of influenza with Lianhua Qingwen.
In a randomized double-blind, multi-center, controlled clinical
study of Lianhua Qingwen vs oseltamivir phosphate in the treat-
ment of influenza A H1N1, 244 patients were included and
randomly assigned to the Lianhua Qingwen group (122 cases) and
the oseltamivir phosphate group (122 cases). The results showed
that Lianhua Qingwen was not different from oseltamivir phos-
phate in terms of the negative-conversion time of viral nucleic acid
and the flu symptom remission time (P > .05). However, Lianhua
Qingwen significantly reduced the severity of the disease and the
duration of symptoms, including fever, cough, sore throat, and fa-
tigue (P < .05). No serious adverse events related to drugs were
observed during the study.9 In another randomized, positive drug-
controlled clinical trial, Lianhua Qingwen was used to treat 124
cases with influenza A H1N1. The results showed that the time to
negative-conversion of the virus in confirmed patients treated with
Lianhua Qingwen was comparable to that of oseltamivir, while the
time of symptom relief such as cough, sore throat, fatigue, and
muscle soreness treated with Lianhua Qingwen was superior to
that of oseltamivir.33
A meta-analysis of five RCTs for comparing the efficacy of
Lianhua Qingwen and oseltamivir in the treatment of influenza A
virus infection with a total sample size of 620 influenza A (H1N1)
patients showed that, compared to the oseltamivir group, patients
in the Lianhua Qingwen group had shorter duration of symptoms,
with the time to abatement of fever [weighted mean difference
(WMD) ¼ 4.65, 95% CI (8.91 to 0.38), P ¼ .03]; cough
[WMD ¼ 9.79, 95% CI (14.61 to 4.97), P < .0001]; sore throat
[WMD ¼ 13.01, 95% CI (21.76 to 4.27), P ¼ .004]; and body pain
[WMD ¼ 16.68, 95% CI (32.33 to 1.03), P ¼ .04] all being shorter
than the oseltamivir group, confirming that Lianhua Qingwen is
superior to oseltamivir in improving the symptoms of influenza A
virus infections.34
A meta-analysis of 10 RCTs on the treatment of influenza Lian-
hua Qingwen with a total sample size of 1525 patients showed that
Lianhua Qingwen was superior to oseltamivir in relieving influenza
symptoms, in particular, and shortening the time to headache
disappearance [SMD ¼ 0.25, 95% CI (0.48, 0.01)], the time to
disappearance of sore throat [SMD ¼ 0.53, 95% CI (0.72, 0.34)],
the time to cough disappearance [SMD ¼ 0.39, 95% CI
(0.57, 0.21)], the time to disappearance of body soreness
[SMD ¼ 0.49, 95% CI (0.78, 0.21)], the time to disappearance of
fatigue [SMD ¼ 0.56, 95% CI (0.82, 0.29)], and the time to
abatement of fever [SMD ¼ 3.47, 95% CI (6.27, 0.67)]. Lianhua
Qingwen was superior to ribavirin in clinical efficacy [RR ¼ 1.53,
95% CI (1.24, 1.90)], and superior to paracetamol, caffeine, artificial
cow-bezoar, and chlorphenamine maleate capsules in the abate-
ment of fever [RR ¼ 1.37, 95% CI (1.19, 1.57)], with statistically sig-
nificant difference (P < .05), confirming that Lianhua Qingwen is
effective in treating influenza, with superior results than oselta-
mivir, ribavirin, caracetamol, caffeine, artificial cow-bezoar, and
chlorphenamine maleate capsules.35
Zhu et al used oseltamivir phosphate combined with Lianhua
Qingwen to treat children with influenza A.36 Patients were
randomly assigned into the control group (110 cases, oseltamivir
phosphate alone) and the test group (110 cases, oseltamivir phos-
phate combined with Lianhua Qingwen), with a treatment duration
of three days. Results showed that, in the group treated with
Lianhua Qingwen combined with oseltamivir phosphate, the time
to abatement of fever, time to disappearance of cough, time to
disappearance of sore throat, and time to negative-conversion of
virus were shortened (P < .01), and the levels of C-reactive protein
(CRP), TNF-a, IL-6, and IL-8 were reduced after comparing to those
in the control group (P < .01). In another study, when used in the
104
Journal of Traditional Chinese Medical Sciences 8 (2021) 101e109
treatment of children with influenza A, Lianhua Qingwen combined
with oseltamivir phosphate can shorten the time to negative-
conversion of virus, time to disappearance of sore throat, time to
disappearance of cough, and time to abatement of fever (P < .05), it
can also reduce the expression levels of pro-inflammatory factors
such as IL-8, IL-6, TNF-a, and CRP (P < .05),37 and alleviate the in-
flammatory reactions. This demonstrates that Lianhua Qingwen
combined with basic medication has a confirmed effect in the
treatment of children with influenza A and can effectively reduce
the inflammatory reactions.
Basic study on Lianhua Qingwen in the treatment of influenza.
Mo et al determined the in vitro inhibition of Lianhua Qingwen on
influenza A virus (H3N2) and its time-effect relationship using four
administration methods for treatment and prophylaxis, namely, 1)
adding the drug and virus to Madin-Darby canine kidney cells
simultaneously; 2) pretreating with drugs for 24 h; 3) adsorbing
virus before addition of drug; 4) infecting cells with virus after drug
pretreatment. All of them exhibited good effect in inhibiting
influenza A virus (H3N2), with effective rate up to 80%, and the
preventive medication showed the most significant effect of
inhibiting virus proliferation.15 The antiviral EC50 of the four
administration methods was 0.042, 0.031, 0.051, and 0.050 g/mL,
respectively. The ER value decreased with the decrease of the drug
concentration, and Lianhua Qingwen showed a time-dependent
resistance to H3N2 virus. Lianhua Qingwen achieved its effect
against influenza A virus through multiple aspects, such as
comprehensive inhibition, prevention of virus adsorption, inhibi-
tion of virus replication and proliferation after virus adsorption,
and direct virus killing.
The Institute of Microbiology and Epidemiology, Academy of
Military Medical Sciences has completed the study on the effect of
three administration methods on anti-influenza A H1N1 virus. The
administration methods included pretreatment with Lianhua
Qingwen (pretreatment of Madin-Darby canine kidney cells for
24 h with the drug, and virus infection for 1 h); co-treatment with
Lianhua Qingwen (co-incubation of cells with the drug and viral
solution for 1 h); and post-treatment with Lianhua Qingwen (in-
cubation of cells with viral solution for 1 h, then incubation with
drug). Results showed that, the therapeutic indexes of the three
different administration methods were 15.431, 15.735 and 8.942
respectively, confirming that Lianhua Qingwen has a definite
antagonistic effect on influenza A (H1N1) virus, and the therapeutic
index of Lianhua Qingwen is about 1 time higher than that of
oseltamivir phosphate.38
Ding et al conducted in vitro studies and found that, Lianhua
Qingwen could inhibit the in vitro proliferation of different strains
of influenza viruses, such as H1N1, H3N2, H6N2, H9N2, and H7N9, and
inhibited the nuclear export of viral nucleocapsid protein in
infected cells.16 The early intervention (0e2 h) could block the virus
infection, inhibit virus-induced nuclear factor kB (NF-kB) activa-
tion, and reduce the expressions of virus-induced IL-6, IL-8, TNF-a,
IP-10, and MCP-1 genes in a dose-dependent manner, confirming
that Lianhua Qingwen has a broad-spectrum anti-influenza A virus
effect.
Mo et al found that Lianhua Qingwen could downregulate the
expression levels of TNF-a, IL-6, and IL-1b in lung tissues of mice
infected with mouse-adapted influenza A strain (FM1) via nasal
drip (P < .05), alleviate the inflammatory lesions of lung tissue,
reduce lung index (P < .05), improve clinical symptoms of infected
mice, and prolong the average survival time (P < .05),39 confirming
that Lianhua Qingwen could reduce the inflammatory injury to
lungs of mice caused by the FM1 influenza virus by regulating the
expression of inflammatory cytokines. Studies by Ding et al showed
that Lianhua Qingwen could reduce the virus titer and inflamma-
tory cytokine levels in the lungs of BALB/c mice infected with the A/
Z. Jia and Y. Wu
PR/8 (H1N1) virus.19
Study on treatment of other respiratory diseases with Lianhua
Qingwen
Study on the treatment of upper respiratory infections with Lianhua
Qingwen
Clinical study on the treatment of upper respiratory infections with
Lianhua Qingwen. In a clinical study on Lianhua Qingwen in the
treatment of acute upper respiratory infections, a total of 203 acute
upper respiratory infection (AURI) patients was included and
randomly assigned to the treatment group (Lianhua Qingwen, 101
cases) and the control group (azithromycin, 102 cases). Results
showed that the treatment group was superior to the control group
in terms of overall curative effect, body temperature reduction, and
serum interferon (IFN)-g reduction (P < .05), suggesting that
Lianhua Qingwen could alleviate the clinical symptoms of AURI.40
In a completed study on the treatment of AURI with Lianhua
Qingwen, a total of 1000 patients diagnosed with external-
contraction wind-heat by TCM pattern identification were ran-
domized into the observation group (Lianhua Qingwen, 500 cases)
and the control group (vitamin C Yinqiao tablets, 500 cases) with a
treatment duration of 3 days. Results showed that the overall
response rate and improvement of symptoms and signs in the
Lianhua Qingwen group were better than those in the control group
(P < .05), confirming the clinical efficacy of Lianhua Qingwen in the
treatment of AURI.41
A meta-analysis including 21 articles regarding treatment of
upper respiratory infection (URI) with Lianhua Qingwen including
a total sample size of 3249 patients revealed that, compared to the
control group, the response rate was increased [RR ¼ 1.22, 95% CI
(1.18, 1.25), P < .00001], the time to abatement of fever was
shortened [MD ¼ 1.03, 95% CI (1.52, 0.53), P < .00001]; the rate
of improvement of aversion to cold was increased [RR ¼ 1.24, 95% CI
(1.17, 1.31), P < .00001], and the rate of improvement of muscle
soreness was increased [RR ¼ 1.28, 95% CI (1.19, 1.38), P < .00001],
confirming the clinical efficacy of Lianhua Qingwen in the treat-
ment of URI.42 A meta-analysis including eight articles regarding
the studies on the efficacy of Lianhua Qingwen in the treatment of
viral influenza with a total sample size of 955 cases showed that the
Lianhua Qingwen group was superior to the control group in the
overall response rate [RR ¼ 1.20, 95% CI (1.09, 1.32), P ¼ .70]; the
body temperature recovery rate [RR ¼ 1.13, 95% CI (1.02, 1.24),
P ¼ .001]; and the symptom improvement rate [RR ¼ 1.18, 95% CI
(1.12, 1.24), P ¼ .16], confirming that Lianhua Qingwen is superior to
the control group in the treatment of viral influenza.43
In a clinical study on Lianhua Qingwen in the treatment of
children with viral URI, 112 children with URI were randomized into
the control group (ribavirin ibuprofen granules, 56 cases) and the
observation group (Lianhua Qingwen, 56 cases). The results
showed that the overall response rate in the observation group was
significantly higher than that of the control group (P < .05). Lianhua
Qingwen could shorten the time to body temperature reduction,
the time to recovery of normal body temperature, the time to
disappearance of throat soreness, the time to disappearance of
cough, and the time to disappearance of lung rales (P < .05). It could
also significantly reduce serum amyloid A level, regulate the levels
of CRP, TNF-a, SIL-2R, IL-6, IL-2, and IFN-g (P < .05), and promote
the abatement of fever and other symptoms.44
Basic study on the treatment of upper respiratory infections with
Lianhua Qingwen. URI is a general term for acute inflammation of
the nose, pharynx or throat caused by various viruses and/or bac-
teria. It is mainly caused by viruses, accounting for approximately
70%e80% of cases, mainly including influenza virus, parainfluenza
virus, RSV, adenovirus, rhinovirus, echovirus, coxsackie virus,
measles virus, and rubella virus. The infections caused by bacteria
105
Journal of Traditional Chinese Medical Sciences 8 (2021) 101e109
account for approximately 20%e30%, mainly including Strepto-
coccus hemolyticus, followed by Haemophilus influenzae,
S. pneumoniae, and staphylococcus, and occasionally gram-negative
bacilli.45 Lianhua Qingwen may achieve its clinical efficacy in the
treatment of upper respiratory infections by inhibiting coxsackie
virus,17 RSV,19 and adenovirus, etc.
Study on the treatment of community-acquired pneumonia with
Lianhua Qingwen
Clinical study on the treatment of community-acquired pneu-
monia with Lianhua Qingwen. In a study on the clinical effect and
safety evaluation of Lianhua Qingwen in the treatment of
community-acquired pneumonia (CAP), a total of 120 CAP patients
were included and randomly assigned to the control group (basic
treatment, 60 cases) and the treatment group (basic treatment plus
Lianhua Qingwen, 60 cases), with a treatment duration of 14 days.
The results showed that Lianhua Qingwen could increase the
overall response rate, shorten the duration of fever, the time to
disappearance of cough and expectoration, and the time to disap-
pearance of pulmonary rales (P < .05), confirming that the basic
anti-infective therapy combined with Lianhua Qingwen could
achieve effective and synergistic treatment of CAP.46 In a study on
Lianhua Qingwen combined with cefuroxime sodium for injection
in the treatment of CAP, a total of 104 CAP patients were included
and randomly assigned to the control group (intravenous drip of
cefuroxime sodium for injection, 52 cases) and the treatment group
(intravenous drip of cefuroxime sodium for injection combined
with Lianhua Qingwen, 52 cases), with a treatment duration of 10
days. Results showed that, in the treatment group, the overall
response rate was increased compared to the controls, the time to
abatement of cough and fever, the time to subsidence of rales, the
length of hospital stay, and the time to recovery of white blood cell
count to normal were shortened (P < .05), and the patients’ levels of
TNF-a, high-sensitivity CRP (hs-CRP), brain natriuretic peptide
(BNP) and procalcitonin (PCT) were decreased (P < .05), confirming
that Lianhua Qingwen combined with cefuroxime sodium for in-
jection had confirmed curative effect in the treatment of CAP, could
effectively relieve the clinical symptoms, and reduce the levels of
serum markers, with clinical promotion and application values.47
A meta-analysis including 22 RCTs of Lianhua Qingwen in the
treatment of pneumonia with a total sample size of 2007 patients
showed that, compared with the control group, the Lianhua Qing-
wen group showed improved overall response rate [RR ¼ 1.11, 95%
CI (1.08, 1.15), P < .001], shortened time to abatement of fever [mean
difference (MD) ¼ 1.81, 95% CI (2.39, 1.22), P < .001], shortened
duration of cough [MD ¼ 2.32, 95% CI (2.89, 1.76), P < .001] and
the duration of rales [MD ¼ 2.19, 95% CI (2.74, 1.63), P < .001],
shortened time to imaging outcome [MD ¼ 2.17, 95% CI
(2.76, 1.58), P < .001], and improved CRP [MD ¼ 4.07, 95% CI
(6.39, 1.75), P < .001]. Results showed that Lianhua Qingwen
combined with conventional WM therapy could increase the clin-
ical response rate, shorten the time to abatement of fever, the
duration of cough and rales, and the time to imaging outcome, and
improve CRP and speed up the recovery of patients with
pneumonia.48
In a study of Lianhua Qingwen combined with azithromycin in
the treatment of children with mycoplasma pneumoniae pneu-
monia (MPP), a total of 157 MPP children were included, and
assigned into the control group (azithromycin, 78 cases) and the
observation group (azithromycin combined with Lianhua Qingwen,
79 cases). In the observation group, the overall response rate was
increased (P < .05), the time to disappearance of shortness of
breath, cough, high fever, and other symptoms was shortened
(P < .05), the serum IL-6, hs-CRP, and TNF-a levels were reduced
(P < .05), the forced expiratory volume in 1 s (FEV1), peak
Z. Jia and Y. Wu
expiratory flow (PEF), forced vital capacity (FVC), FEV1/FVC
(P < .05), CD4þ, and CD4þ/CD8þ levels were increased, and CD8þ
level was decreased (P < .05). T lymphocytes mediated the cellular
immune response, and the helper/inducible T lymphocytes (CD4þ)
recognized antigen fragments through their surface antigen re-
ceptors, promoted humoral and cellular immunity, suppressed
cytotoxic T cells (CD8þ), exerting a role in eliminating infected cells.
The subset count (CD4þ, CD8þ) was an independent predictor of
disease severity and treatment effect after viral infection.49 The
results confirmed that Lianhua Qingwen combined with azi-
thromycin has a significant effect in the treatment of MPP, which
can effectively improve clinical symptoms, improve lung functions
and immune functions, and reduce the level of in vivo inflammatory
cytokines.50
Basic study on the treatment of acquired pneumonia with Lianhua
Qingwen. Epidemiological survey results showed that Mycoplasma
pneumoniae and S. pneumoniae are important pathogens of CAP.
Other common pathogens of CAP include H. influenzae, Chlamydia
pneumoniae, K. pneumonia, and Staphylococcus aureus. With the
development and application of virus detection techniques, the
virus detection rate can be up to 15%e34.9% in CAP patients, mainly
including influenza virus, parainfluenza virus, rhinovirus, adeno-
virus, and RSV, etc.51 Studies showed that Lianhua Qingwen could
reduce the viral titers in the lungs of BALB/c mice infected with RSV,
reduce the mRNA expressions of inflammatory cytokines such as IL-
6 and IL-1b in the lungs of mice, alleviate the pathological
inflammation in lung tissues and reduce the area of alveolar infil-
tration, indicating that Lianhua Qingwen can inhibit lung inflam-
mation in RSV-infected mice.39 Lianhua Qingwen possibly exerts its
clinical efficacy for lung infections through its confirmed inhibitory
effect on S. pneumoniae, RSV,19 P. aeruginosa,20 K. pneumonia,21 etc.,
and slowing down the resistance of bacteria to carbapenem
antibiotics.
Acute lung injury (ALI) is a pulmonary inflammatory disease
with the main clinical features of pulmonary edema, pulmonary
hemorrhage and respiratory depression.52 Lipopolysaccharide
(LPS), the main component of endotoxin, is an important factor in
causing ALI. The study on the LPS-induced ALI mice showed that
Lianhua Qingwen inhibited the inflammatory cell infiltration,
improved the expressions of connexins in alveolar epithelial cells
and pulmonary vascular endothelial cells, and reduced LPS-induced
lung injury through suppressing the IKK/IkB/NF-kB signaling
pathway.53,54
The impact of environmental factors on respiratory diseases
cannot be ignored. Fine particulate matters in the air (PM 2.5) have
a small diameter, a large surface area, and strong toxin absorption
capacity, which will easily cause injury to the respiratory system. A
study on lung inflammatory injury caused by acute exposure to PM
2.5 in rats showed that, Lianhua Qingwen reduced the rat alveolar
lavage fluid and the serum IL-1, IL-6, and TNF-a levels (P < .05), and
exhibited an antagonistic effect on lung inflammatory injury caused
by acute exposure to PM 2.5 suspension.55 In a study on lung injury
caused by exposure to automobile exhaust in mice,56 Lianhua
Qingwen inhibited the accumulation of neutrophils in the airway
and lung tissues, and alleviated the pathological injury of lung
tissues through lowering the expressions of inflammatory cyto-
kines in lung tissues such as IL-6, IL-1b, IL-4, IL-12, IL-13, and TNF-a,
demonstrating that Lianhua Qingwen could inhibit the pulmonary
infections caused by various pathogenic factors.
Treatment of chronic obstructive pulmonary disease with Lianhua
Qingwen.
Thymopentin combined with Lianhua Qingwen in the treatment
of patients with acute exacerbation of chronic obstructive pulmo-
nary disease (AECOPD) could significantly enhance lung functions
106
Journal of Traditional Chinese Medical Sciences 8 (2021) 101e109
and improve T lymphocyte subsets CD4þ, CD8þ, CD4þ/CD8þ,
immunoglobulin (IG), and enhance the immune functions of pa-
tients (P < .05).57 In a study on Lianhua Qingwen combined with
vitamin D in the treatment of chronic obstructive pulmonary dis-
ease (COPD), 100 COPD patients were included and randomly
assigned into the control group (calcitriol capsules, 50 cases) and
the observation group (calcitriol capsules combined Lianhua
Qingwen, 50 cases). Results showed that the combined use of
Lianhua Qingwen significantly reduced serum Th17 cytokines
(P < .05). Th17 secrets IL-17, IL-6, and other early initiating factors of
inflammatory reaction to promote the inflammatory cascade.
Combination with Lianhua Qingwen increased the levels of Treg
cytokines (IL-10, TGF-b), and improved the lung functions of pa-
tients by regulating the balance of Th17/Treg cytokines in the body
(P < .05).58 Lianhua Qingwen could significantly improve the clin-
ical efficacy of AECOPD patients, shorten the time to wheezing re-
lief, the time to disappearance of cough, and the time to
disappearance of wheezing, and significantly increased FEV1, FVC,
FEV1/FVC, the mechanism of which may be possibly related to the
inhibition of inflammatory cytokines IL-8 and TNF-a.59,60 This
confirmed that the basic treatment combined with Lianhua Qing-
wen has a good clinical efficacy in the treatment of AECOPD, which
can apparently improve the clinical symptoms and lung functions
and reduce the body's inflammatory responses of patients; there-
fore, it has clinical promotion and application values.
Pharmacodynamic mechanism of Lianhua Qingwen's effect of
“homotherapy for heteropathy”
The common pathogenesis of different viral respiratory infec-
tious diseases such as influenza A and COVID-19 is the imbalance of
the immune response, i.e. the coexistence of excessive inflamma-
tion and immunosuppression, which is closely related to the
severity of the disease and has become an important part in
intervening and blocking the disease progression. In TCM, the viral
respiratory infectious diseases are classified into the category of
“febrile diseases caused by external-contraction pathogenic fac-
tors”. Its pathological nature is the conflict between healthy qi and
pathogenic qi. The healthy qi resists the invasion of external evils
and eliminates pathogens, and is highly compatible with immune
defense functions. Pathogenic qi refers to the external toxins and
evils, i.e. the virus, which also refers to the endogenous toxins such
as phlegm, stasis, and toxins that are produced during the fighting
process between the healthy qi and pathogenic qi, such as the
excessive release of cytokines, etc. This process is consistent with
the unbalanced immune response characteristics of viral respira-
tory system infectious diseases coexisting with excessive inflam-
mation and immunosuppression. It is also the internal basis of
external-contraction febrile disease that develops to the later
stage of different diseases sharing same pattern”. Therefore, Zhang
Xichun pointed out that “the treatment methods for cold damage
and febrile disease are different at the beginning but achieving the
same effect in the end”.61
Based on the characteristics of the common immune mecha-
nism for different viral respiratory infectious diseases, immuno-
modulatory therapy has become a research hotspot. However,
because of the ubiquitous immunosuppressive effect of related
drugs, it has become a bottleneck for achieving the expected
curative effect. Lianhua Qingwen can not only be used for the
treatment of viral respiratory infectious diseases such as influenza
A and COVID-19, but also for the treatment of infectious diseases
such as CAP. Past studies have preliminarily revealed that its
pharmacodynamic mechanism of “homotherapy for heteropathy”
may be related to anti-inflammatory and immunoregulation.
Lianhua Qingwen apparently inhibited the overexpression of pro-
Z. Jia and Y. Wu
inflammatory cytokines induced by SARS-CoV-2 virus infection in
Huh-7 cells,13 downregulated the expression of inflammatory cy-
tokines in lung tissue of mice infected with FM1 via nasal drip to
reduce lung inflammatory injury,39 inhibited virus-induced NF-kB
activation, and reduced the gene expression of virus-induced pro-
inflammatory cytokines in a dose-dependent manner.14 It also
decreased the expression of inflammatory cytokines in the lungs of
RSV-infected BALB/c mice.19 In addition, Lianhua Qingwen has an
immunomodulatory effect on the body's viral infections, increases
the expression levels of CD4þ and CD4þ/CD8þ T cells after FM1
infection, and enhances the level of g-IFN in the lung tissues after
infected influenza viruses in mice.62 The correlation between the
components of Lianhua Qingwen prescription and its pharmaco-
dynamic effects was studied by network pharmacology. It is
confirmed that Lianhua Qingwen mainly treats COVID-19 by
improving human immunity and inhibiting inflammatory path-
ways such as FcεRI, ErbB, and MAPK.28 The network pharmacology
and transcriptomics prediction revealed that IL-6 and COX-2 are
important candidate indicators for the anti-inflammatory biolog-
ical evaluation of Lianhua Qingwen. The metabonomics study in
mice elucidated the rationality of COX-2 as an anti-inflammatory
biological evaluation index of Lianhua Qingwen. Studies have
confirmed that COX-2 is the main biomarker for Lianhua Qingwen
in exerting its anti-inflammatory effect, suggesting that Lianhua
Qingwen has an anti-inflammatory effect similar to that of cele-
coxib, which selectively inhibits COX-2. The multi-component,
multi-channel, and multi-target interventions of Lianhua Qing-
wen have an effect of “homotherapy for heteropathy”. In different
stages of respiratory infectious diseases, Lianhua Qingwen exerts its
effects of “directly inhibiting virus, regulating inflammation and
immune response after virus infection and enhancing patients'
recovery ability”. Furthermore, conducting studies on the mecha-
nism of Lianhua Qingwen's intervention in viral respiratory infec-
tious disease based on immune regulation will have important
clinical value and application prospect for breaking through the
limitations of antiviral drugs in the treatment of viral respiratory
infectious diseases and improving the treatment level.
Safety study
Safety analysis of clinical studies
The safety of clinical medication of Lianhua Qingwen prepara-
tions was systematically evaluated using systematic reviews and
Meta-analysis. A total of 40 RCTs were included, with 2592 cases in
the test group and 2314 cases in the control group; the diseases
involved influenza, AURI, lung infection, adjuvant therapy of acute
bronchitis, etc. There were 63 cases of adverse reactions in the test
group, with an adverse reaction rate of 2.4%, and there were 100
cases of adverse reactions in the control group, with an adverse
reaction rate of 4.3%, indicating that Lianhua Qingwen preparations
have good safety.63
Adverse drug reaction monitoring data after drug marketing
According to the data from China's National Adverse Drug Re-
action Monitoring and Direct Reporting System from January 2010
to January 2021, the cumulative sales of Lianhua Qingwen are about
17.1 billion capsules, and a total of 5738 cases of adverse drug re-
actions (ADRs), with a reporting rate of 0.12/10 000. Common
adverse reactions include nausea, diarrhea, vomiting, abdominal
pain, dry mouth, skin rash, itching, dizziness, etc.64 According to the
recommended standards of the Council for International Organi-
zation of Medical Sciences, the occurrence of Lianhua Qingwen
107
Journal of Traditional Chinese Medical Sciences 8 (2021) 101e109
adverse reactions is very rare. Based on the above data, it shows
that clinical medication of Lianhua Qingwen has good safety.
Rhubarb in the components is bitter in taste and cold in nature, and
the patients with a deficiency-cold of the spleen and stomach are
prone to gastrointestinal adverse reactions such as diarrhea,
abdominal pain, nausea, and vomiting65; Dryopteris root is slightly
cold in nature, which is prone to cause dizziness, diarrhea, nausea,
vomiting and other gastrointestinal adverse reactions. It is recom-
mended that people with deficiency-cold of the spleen and stom-
ach, and the elderly and infirm should use with caution, and the
dosage should be reduced as appropriate.66 If adverse reactions
occur, the mild symptoms can be relieved spontaneously, or
symptomatic treatment can be given.
Discussion and prospect
In recent years, the incidence of viral respiratory infectious
diseases has been increasing, which poses a serious threat to hu-
man life safety, social stability and economic development. Lianhua
Qingwen, developed under the theory of collateral disease, has
played a major role in fighting against H1N1 influenza and COVID-
19, and has become a representative proprietary Chinese medi-
cine for responding to public health events in the respiratory sys-
tem caused by viruses. It has been listed in the “three Chinese
patent medicines and three TCM prescriptions” of national major
achievement for national epidemic prevention and control, playing
an important role in international epidemic prevention and control.
The drug registration has been completed in 17 countries and re-
gions including Singapore, the Philippines, Thailand, Kuwait,
Romania, and Kenya, etc. It is the sole proprietary Chinese medicine
in the “three Chinese patent medicines and three TCM pre-
scriptions” to obtain drug registration in Europe, and also the first
proprietary Chinese medicine for the treatment of influenza to
enter clinical research approved by Food and Administration,
United States, which significantly improves the international in-
fluence of TCM and promotes its process of internationalization.
The common immune characteristics of viral respiratory infec-
tious diseases such as influenza and COVID-19 are the keys for their
development and aggravation. Lianhua Qingwen has the confirmed
efficacy with evidence-based medical evidences in the treatment of
COVID-19 and influenza. In the future, in-depth studies are pro-
posed to clarify its common mechanism of action in different viral
respiratory infectious and communicable diseases, which will not
only facilitate to identify the scientific connotation of Lianhua
Qingwen but will also play an important role in promoting the
modernization and internationalization of Chinese medicines.
Funding
This study was supported by special major project for technol-
ogies of innovative manufacturing of major new drugs
(2018ZX09737002).
CRediT authorship contribution statement
Zhenhua Jia: Conceptualization, data curation, project admin-
istration, funding acquisition, and writing e original draft. Yiling
Wu: Conceptualization and writing ereview & editing.
Declaration of competing interest
Prof. Zhenhua Jia formulates the prescription of Lianhua Qing-
wen based on the theory of collateral disease, and participates in
the research projects of Lianhua Qingwen against H1N1 and COVID-
Z. Jia and Y. Wu
19. Academician Yiling Wu systematically constructs the theory of
collateral disease, provides theoretical guidance for the formulation
of Lianhua Qingwen, and gives valuable advices on designing the
research project of Lianhua Qingwen against H1N1.
References
1. World Health Organization. Coronavirus disease (COVID-2019) situation reports;
2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/
situation-reports. Accessed January 1, 2020. Accessed.
2. Çelik I, Saatçi E, Eyübog lu AF. Emerging and reemerging respiratory viral in-
fections up to Covid-19. Turk J Med Sci. 2020;50(SI-1):557e562.
3. Paget J, Spreeuwenberg P, Charu V, et al. Global mortality associated with
seasonal influenza epidemics: new burden estimates and predictors from the
GLaMOR Project. J Glob Health. 2019;9(2), 020421.
4. Wu YL. Synopsis of collateral disease. Chin J Difficult Complicated Cases.
2004;3(1):37e39 [Chinese].
5. Wu YL. Three milestones in the formation and development of collateral dis-
ease theory (1). Chin J Difficult Complicated Cases. 2004;3(2):89e91 [Chinese].
6. Wu YL. Three milestones in the formation and development of collateral dis-
ease theory (2). Chin J Difficult Complicated Cases. 2004;3(3):149e151 [Chinese].
7. Wu YL. The construction of collateral disease theory system. Chin J Difficult
Complicated Cases. 2005;4(6):349e350 [Chinese].
8. Wu YL. TCM collateral disease theory and three-dimensional network system.
J Tradit Chin Med. 2003;44(6):407e409 [Chinese].
9. Li ZG, Liu XR. Trans. Baibing Shisheng: the occurrence of all diseases. In:
Yang MZ, ed. Yellow Emperor's Canon of Medicine · Spiritual Pivot. Xi’an, China:
Xi’an World Publishing Corporation; 2005:787e789.
10. Jia ZH. Discussion about guidance of diagnosis and treatment of COVID-19 by
Luobing Theory. Chin J Exper Tradit Med Formul. 2020;26(12):18e22 [Chinese].
11. Jia ZH, Wu YL. The research of exogenous febrile disease guided by the
collateral disease theory. Glob Tradit Chin Med. 2010;3(1):26e28 [Chinese].
12. Zhu SY, Li XY, Wei YL, Yang PY, Qin ED. Inhibitory effects of three prescriptions
of traditional Chinese medicine on SARS-associated coronaviruses in vitro. Lett
Biotechnol. 2003;14(5):390e392 [Chinese].
13. Li RF, Hou YL, Huang JC, et al. Lianhuaqingwen exerts anti-viral and anti-
inflammatory activity against novel coronavirus (SARS-CoV-2). Pharmacol
Res. 2020;156, 104761.
14. Duan ZP, Jia ZH, Zhang J, et al. Natural herbal medicine Lianhuaqingwen
capsule anti-influenza A (H1N1) trial: a randomized, double blind, positive
controlled clinical trial. Chin Med J (Engl). 2011;124(18):2925e2933.
15. Mo HY, Ke CW, Zheng JP, Zhong NS. Anti-viral effects of Lianhua Qingwen
capsule against influenza A virus in vitro. Tradit Chin Drug Res Clin Pharmacol.
2007;18(1):5e9 [Chinese].
16. Ding YW, Zeng LJ, Li RF, et al. The Chinese prescription lianhuaqingwen capsule
exerts anti-influenza activity through the inhibition of viral propagation and
impacts immune function. BMC Compl Alternative Med. 2017;17(1):130.
17. Liu XY. Preliminary Study of Lianhua Qingwen Capsule on Virus Inhibition
[master's Thesis]. Kunming, China: Kunming University of Science and Tech-
nology; 2015 [Chinese].
18. Liu Z, Shi FZ, Yang ZQ. Antiviral activity of Lianhua Qingwen capsules against
coxsackie B4 in vitro. J South-Central Univ Nationalities Nat Sci Ed. 2012;31(1):
20e24 [Chinese].
19. Ding YW, Zeng LJ, Li RF, et al. Pharmacological action of Lianhua Qingwen
granules on BALB/c mice infected with respiratory syncytial virus. J Guangzhou
Univ Tradit Chin Med. 2016;33(4):541e544 [Chinese].
20. Shi LK, Wang Y, Dong X, et al. In vitro antibacterial experiment of Lianhua
Qingwen capsules combined with meropenem against drug-resistant strains.
Chin J Nosocomiol. 2019;29(8):1172e1175 [Chinese].
21. Wang YZ. Inhibitory Effect of Genetic Mechanism of Lianhua Qingwen Capsule on
Respiratory Infection Related Bacterial Biofilm [master's Thesis]. Changchun,
China: Jilin University; 2014 [Chinese].
22. Lei HT, Liu MY, Ouyang JF, et al. Study on Lianhua Qingwen capsule resisting
Staphylococcus aureus biofilm. Chin J Exper Tradit Med Formul. 2013;19(22):
161e164 [Chinese].
23. Hu K, Guan WJ, Bi Y, et al. Efficacy and safety of Lianhuaqingwen capsules, a
repurposed Chinese herb, in patients with coronavirus disease 2019: a multi-
center, prospective, randomized controlled trial. Phytomedicine. 2021;85:
153242.
24. Cheng DZ, Wang WJ, Li Y, Wu XD, Zhou B, Song QY. Analysis of the efficacy of
Chinese medicine Lianhua Qingwen in 51 patients with COVID-19: a multi-
center retrospective study. Tianjin J Tradit Chin Med. 2020;37(5):509e516
[Chinese].
25. Yao KT, Liu MY, Li X, Huang JH, Cai HB. Retrospective clinical analysis on
treatment of novel coronavirus-infected pneumonia with traditional Chinese
medicine Lianhua Qingwen. Chin J Exper Tradit Med Formul. 2020;26(11):8e12
[Chinese].
26. Wang SX, Li MY, Chen XL, Ma MY, Hu JH. Clinical efficacy of Lianhua Qingwen
integrated with Western medicine on COVID-19 by meta-analysis. Chin Tradit
Herb Drugs. 2020;51(14):3763e3769 [Chinese].
27. Cardone M, Yano M, Rosenberg AS, Puig M. Lessons learned to date on COVID-
19 hyperinflammatory syndrome: considerations for interventions to mitigate
SARS-CoV-2 viral infection and detrimental hyperinflammation. Front Immunol.
108
Journal of Traditional Chinese Medical Sciences 8 (2021) 101e109
2020;11:1131.
28. Ye CH, Gao MN, Lin WQ, Yu KQ, Li P, Chen GH. Theoretical study of the anti-
NCP molecular mechanism of traditional Chinese medicine Lianhua-Qingwen
Formula (LQF). ChemRxiv; 2020. https://chemrxiv.org/articles/preprint/
Theoretical_Study_of_the_anti-NCP_Molecular_Mechanism_of_Traditional_
Chinese_Medicine_Lianhua-Qingwen_Formula_LQF_/12016236/1. Accessed
March 21, 2020. Accessed.
29. Wang L, Yang ZH, Zhang HR, et al. Study on the network pharmacology and
preliminary evidence of Lianhua Qingwen in the treatment of Novel Corona-
virus (2019-nCoV) pneumonia. J Chin Med Mater. 2020;43(3):772e778
[Chinese].
30. Ling XY, Tao JL, Sun X, Yuan B. Exploring material basis and mechanism of
Lianhua Qingwen Prescription against coronavirus based on network phar-
macology. J Chin Med Mater. 2020;51(7):1723e1730 [Chinese].
31. Wang FC, Shen BX, He CY, Zhao WC, Nie SL. Clinical efficacy and mechanism of
Lianhua Qingwen granule on COVID-19 based on network pharmacology
research. Pharmacol Clin Chin Mater Med. 2020;36(2):93e101 [Chinese].
32. Chen XF, Wu YL, Chen C, et al. Identifying potential anti-COVID-19 pharma-
cological components of traditional Chinese medicine Lianhuaqingwen capsule
based on human exposure and ACE2 biochromatography screening. Acta Pharm
Sin B. 2021;11(1):222e236.
33. Liu GX, Zhang YX, Yang JQ, Gao ZQ, Meng YC. The randomized controlled
clinical study of Lianhuaqingwen capsule in treating A/H1N1 influenza. Chin J
Difficult Complicated Cases. 2010;9(1):14e16 [Chinese].
34. Zhao P, Yang HZ, Lv HY, Wei ZM. Efficacy of Lianhuaqingwen capsule compared
with oseltamivir for influenza A virus infection: a meta-analysis of randomized,
controlled trials. Alternative Ther Health Med. 2014;20(2):25e30.
35. Niu QQ, Chen Y, Liu Y, et al. Efficacy and safety of Lianhua Qingwen capsule for
influenza: a systematic review. China J Chin Mater Med. 2017;42(8):1474e1481
[Chinese].
36. Zhu SJ, Li SJ, Li WB. Lianhua Qingwen granule combined with oseltamivir
phosphate in the treatment of influenza A in children. Chin J Clin Res.
2019;32(8):1099e1101 [Chinese].
37. Liu Y, Yang J, Zhao XK, Zhou MY. Clinical analysis of Lianhua Qingwen granule
combined with oseltamivir phosphate in the treatment of pediatric influenza
A. J Chin Prescript Drug. 2020;18(11):128e130 [Chinese].
38. The Chinese Academy of Military Medical Sciences and Beijing Ditan Hospital
confirmed that the anti-H1N1 influenza virus: a major breakthrough in the
traditional Chinese medicine Lianhua Qingwen capsules. J Chin Prescript Drug.
2009;9(90):41 [Chinese].
39. Mo HY, Yang ZF, Zheng JP, Mo ZY, Zeng YM, Xiao ZL. Experimental study of
Lianhua Qingwen capsule in preventing and treating influenza virus FM1
infection in mice. J Chin Med Mater. 2008;31(8):1230e1233 [Chinese].
40. Wei M, Song HX, Zhou H. Effect of Lianhuaqingwen capsule on acute upper
respiratory infection and their impact on IFN-g. Chin J Difficult Complicated
Cases. 2014;13(4):345e348 [Chinese].
41. Zhao MJ, Zhao XQ, Zhao W. Clinical effects of Lianhua Qingwen capsule in the
treatment of acute respiratory infections. Chin J Nosocomiol. 2015;25(4):
839e841 [Chinese].
42. Liu HK, Hou L, Huang HL, Han T. Meta-analysis of the clinical efficacy of Lianhua
Qingwen capsule in the treatment of acute upper respiratory infection. Paper
Presented at: 15th Annual Conference of Chinese Medicine Prescriptions of
Chinese Society of Chinese Medicine; May 1, 2015; Xianyang, China [Chinese].
43. Wang SH, Liu JF, Zhang YL, Dong Z. Systematic review of the efficacy and safety
of Lianhua Qingwen capsules in the treatment of viral influenza. China J Chin
Mater Med. 2019;44(7):1503e1508 [Chinese].
44. Li B, Sun YS, Li HY. Efficacy of Lianhua Qingwen granule on children with viral
upper respiratory infection and fever and its impact on the expressions of
serum amyloid A and inflammatory factors. J Chin Med Mater. 2020;43(6):
1490e1493 [Chinese].
45. Jain N, Lodha R, Kabra SK. Upper respiratory tract infections. Indian J Pediatr.
2001;68(12):1135e1138.
46. Jiang X, Wang ZP, Yu T, et al. Clinical observation of Lianhua Qingwen capsule
in the treatment of community-acquired pneumonia. Chin J Clin Rational Drug
Use. 2014;7(4A):59e60 [Chinese].
47. Hu XQ, Wan Y, Lu Q, et al. Clinical study of Lianhua Qingwen capsules com-
bined with cefuroxime in treatment of community acquired pneumonia. Drugs
Clin. 2018;33(12):3216e3220 [Chinese].
48. Lu ZJ, Wu LY, Mou YY, et al. Meta-analysis and systematic review of efficacy
and safety of Lianhua Qingwen in adjuvant treatment of adult pneumonia.
China J Chin Mater Med. 2021;46(4):1000e1009 [Chinese].
49. Zhou JG, Yang M, Cao HT, Hua C. The clinical application of detection of
lymphocyte subsets, 321 Military Med J Southeast China. 2015;17(3):298e300
[Chinese].
50. Chen Y, Han CQ, Zhao FL, Fu HL, Xi YF. Effects of Lianhua Qingwen granules
combined with azithromycin on children with mycoplasma pneumoniae
pneumonia. World Chin Med. 2020;15(1):76e80 [Chinese].
51. Respiratory Society of Chinese Medical Association. Guideline on diagnosis and
treatment of community acquired-pneumonia in Chinese adults (2016 Edi-
tion). Chin J Tuberc Respir Dis. 2016;39(4):253e279 [Chinese].
52. Zhang Y, Cheng C, Su JC, et al. Preparation of rat model of acute lung injury and
comparison of injury at different periods. Acta Lab Anim Sci Sin. 2021;29(1):
27e34 [Chinese].
53. Cui WW, Jin X, Zhang YF, Chang LP, Wang HT. Effects of Lianhua Qingwen
capsules on IKK/IkB/NF-kB signaling pathway in mouse with LPS-induced acute
Z. Jia and Y. Wu
lung injury. Chin Tradit Patent Med. 2015;37(5):953e958 [Chinese].
54. Cui WW, Jin X, Zhang YF, Wang HT, Mi Y, He QL. Effects of Lianhuaqingwen
capsules on inflammatory cytokines and junction protein expression in mice
with acute lung injury induced by lipopolysaccharides. Chin J Pharmacol Toxicol.
2015;29(2):213e219 [Chinese].
55. Xu N, Ping F, Xu X, Zhuge MN, Zhang FR, Han SZ. Antagonistic effects of
Lianhuaqingwen on rats' pulmonary inflammatory injury induced by airborne
fine particulate matters. Chin General Pract. 2015;18(27):3355e3359 [Chinese].
56. Tang SW, Zhang YF, Liu KJ, Xu DF, Wang HR, Li ZJ. Effects of Lianhua Qingwen
capsule on lung tissue injury and expression of inflammatory cytokines in mice
exposed to automobile exhaust. Chin J Exper Tradit Med Formul. 2015;21(13):
139e143 [Chinese].
57. Bai R, Yang C. Effects of thymopentin combined with Lianhua Qingwen capsule
on AECOPD patients and its influence on immune function. Lab Med Clin.
2018;15(5):592e595 [Chinese].
58. Tian JX, Chen XX, Wang JP. Effect of Lianhua Qingwen capsule combined with
vitamin D on CAT, mMRC score and Th17/Treg cytokine balance in the treat-
ment of chronic obstructive pulmonary disease. Modern J Integr Tradit Chin
West Med. 2018;27(32):3554e3557 [Chinese].
59. Dong L, Xia JW, Gong Y, Chen XD. Clinical effect of Lianhua Qingwen capsules
109
Journal of Traditional Chinese Medical Sciences 8 (2021) 101e109
on patients with acute exacerbation of chronic obstructive pulmonary disease
and its mechanism. Chin Tradit Patent Med. 2014;36(5):926e929 [Chinese].
60. Wei H. Clinical study of Lianhua Qingwen capsules combined with terbutaline
and budesonide in treatment of acute exacerbation of chronic obstructive
pulmonary disease. Drugs Clin. 2016;31(7):973e977 [Chinese].
61. Zhang XC, Liu XH. In: Records of Chinese Medicine with Reference to Western
Medicine. Beijing, China: People’s Medical Publishing House; 2006 [Chinese].
62. Guo H, Zhang QH, Yang J, Gong JN, Zhao YS, Zhou XP. Effect of Lianhua Qingwen
capsule on immunity of mice infected with flu virus. J Nanjing Tradit Chin Med
Univ. 2007;23(2):106e108 [Chinese].
63. Wang YX, Zhang KY, Huang JH, Han SL, Zhao JH, Xu ZJ. Clinical drug safety of
Lianhuaqingwen preparation: a systematic evaluation. Eval Analys Drug Use
Hospitals Chin. 2013;13(8):676e681 [Chinese].
64. Shi LX, Chen S, Zhou J, Liu LQ. Analysis of 69 adverse reaction reports of Lianhua
Qingwen preparation. Strait Pharmaceut J. 2020;32(12):263e265 [Chinese].
65. Hu P. Side effects of rhubarb should not be ignored. Capital Med. 2002;4:42
[Chinese].
66. Zhao XY, Liang Y, Kong DW, Zhang L, Du GH. The historical cognition and
evaluation of Cyrtomium fortunei. Pharmacol Clin Chin Mater Med. 2019;35(2):
156e159 [Chinese].