Complementary Therapies in Medicine 60 (2021) 102754

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Complementary Therapies in Medicine

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

A meta-analysis for Lianhua Qingwen on the treatment of Coronavirus

disease 2019 (COVID-19)
Jieqin Zhuang a, 1, Xingzhen Dai b, 1, Qihua Wu b, Hairong Cai a, Xue Fu a, Weizhang Zhang a,
Bojun Chen a, *
a
The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China
b
The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Traditional Chinese medicine (TCM) has been proven to played a great important role on the
Lianhua qingwen treatment of COVID-19. As one of the drugs recommended in Chinese guidelines, Lianhua Qingwen Granules or
COVID-19 Capsules (LQ) are widely used.This systematic review and meta-analysis amis to evaluate the clinical efficacy of
Traditional Chinese medicine
LQ on the treatment of COVID-19.
Meta-analysis
Methods: Seven databases (PubMed, EMBASE, CENTRAL, CNKI, VIP, CBM and Wanfang) were searched to
include all appropriate clinical trials that explore the efficacy of LQ on the treatment of COVID-19.
Result: A total of 3 trials including 245 COVID-19 patients were eventually enrolled.Compared with the control
group,the LQ group showed great significant difference on reducing the rate of clinical change to severe or
critical condition[RR = 0.38, 95 %CI (0.17,0.85), P < 0.05]and the fever time (SMD =-0.57,95 %CI (-0.96,-0.17),
P<0.05),as well as the significant improvement on the disappearance rate of the clinical symptoms: fever
[RR = 1.36,95 %CI (1.14,1.61), P < 0.05],cough[RR = 1.99,95 %CI (1.39,2.86), P < 0.05],fatigue[RR = 1.52,95
%CI (1.15,2.01), P < 0.05] and anhelation [RR = 4.18,95 %CI (1.99,8.81), P < 0.05], but no significance on
expectoration[RR = 2.46,95 %CI (0.81,7.51), P < 0.05].
Conclusion: The clinical application of LQ on the treatment of COVID-19 has significant efficacy in improving
clinical symptoms and reducing the rate of clinical change to severe or critical condition. Nevertheless, due to the
limited quantity and quality of the included studies, more and higher quality trials with more observational
indicators are expected to be published.

1. Introduction enormous impact and challenges in the global economy, the medical
industry, sports, transportation and many other fields. However, it is
Since being defined as a "Public Health Emergency of International also a great pity that there is no confirmed effective antiviral therapy for
Concern" by WHO,the epidemic of COVID -19 is still increasingly getting COVID -19,symptomatic and supportive treatment are still the main
worse at home and abroad.1 Until now, hundreds of thousands of cases approaches.3 Early detection, early diagnosis, early isolation and
have been confirmed in almost every countries and regions of the globe, adherence to the integrated treatment of traditional Chinese medicine
among them the death toll is still rising.2Undoubtedly,the situation (TCM) and western medicine are the most important therapeutic mea­
shows that it has formed the trend of global pandemic, causing sures for the China’s successful fight against the epidemic4 Especially for

Abbreviations: COVID-19, corona virus disease 2019; TCM, traditional Chinese medicine; LQ, Lianhua Qingwen Granules or Capsules; RCT, randomized controlled
trial; RR, relative risk; CI, confidence interval; SMD, standard mean variance; SARS, SevereAcuteRespiratorySyndrom; PRISMA, Preferred Reporting Items for
Systematic Review and Meta-Analyses; 2019-nCoV, 2019 novel Coronavirus; CNKI, Chinese National Knowledge Infrastructure; VIP, Chinese Scientific Journal
Database; CBM, Chinese Biomedical Literature Database; T, The treatment group; C, The control group; FO, Diagnosis and treatment of pneumonia caused by novel
coronavirus infection (Trial version 4); FI, Diagnosis and treatment of pneumonia caused by novel coronavirus infection (Trial version 5); CT, conventional treatment;
N, Not clear.
* Corresponding author at: 232 Waihuandong Road, University Town, Panyu District, Guangzhou, 510006, Guangdong, China.
E-mail addresses: [email protected], [email protected] (B. Chen).
1
These authors are contributed equally to this article.

https://doi.org/10.1016/j.ctim.2021.102754
Received 26 March 2020; Received in revised form 26 July 2020; Accepted 17 June 2021
Available online 19 June 2021
0965-2299/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
J. Zhuang et al. Complementary Therapies in Medicine 60 (2021) 102754

the mild and moderate patients who account for the majority of COVID that did not caused by 2019 novel coronavirus (2019-nCoV);(3)Any
-19,TCM can relieve clinical symptoms and prevent the transition to other chronic respiratory diseases or bacterial infections of the respira­
severe disease, reduce the medical pressure and psychological burden of tory system such as suppurative tonsillitis, acute tracheal-bronchitis,
patients,which is of great significance for the prevention and treatment. sinusitis, otitis media and other respiratory diseases that affect the
Thanks to the previous successful experience in the prevention and evaluation of clinical trials; (4)Asthma patients who need long-term
treatment of SevereAcuteRespiratorySyndrom(SARS) and influenza A treatment, chest X-ray or CT confirme the existence of serious lung
(H1N1), a large number of experimental and clinical meaningful studies interstitial lesions, bronchiectasis and other basic lung diseases;(5)Pa­
on the efficacy of TCM therapy for viral infections have been carried out tients with severe primary immunodeficiency disease, acquired immu­
in China.5 nodeficiency syndrome, congenital respiratory tract abnormalities,
LQ is a kind of compound Chinese patent medicine developed based congenital heart disease, abnormal lung development and other basic
on the theory of "plague" in TCM, which has been highly recommended diseases.
and widely used in clinical work for many years.6 It is made from two
very classic and effective formulae,Yinqiao Powder and Ma Xing Shi Gan 2.1.3. Types of interventions
Tang.7 It’s main ingredients are the following 13 traditional Chinese Follow the diagnosis and treatment guidelines,9all enrolled patients
medicines: Fructus Forsythiae (Lianqiao),Flos Lonicerae Japonicae in the control group were given symptomatic treatment, nutritional
(Jinyinhua), Herba Ephedrae (Mahuang),Semen Armeniacae Amarum support treatment, antiviral and antibacterial drugs and other routine
(Kuxingren), Gypsum Fibrosum (Shigao), Radix Isatidis (Banlangen), treatment;while patients in the LQ group were treated with LQ(6 g/ bag,
Rhizoma Dryopteridis Crassirhizomatis (Mianmaguanzhong), Herba Sig.6 g,Tid,PO) on the basis of treatment in the control group. The
Houttuyniae(Yuxingcao), Herba Pogostemonis (Guanghuoxiang), Radix observation time was 7 days.
et Rhizoma Rhodiolae Crenulatae (Hongjingtian), Radix et Rhizoma
Rhei (Dahuang) and Radix et Rhizoma Glycyrrhizae (Gancao),menthol 2.1.4. Types of outcome measures
(Bohe).Thanks to years of researches and development,LQ has been Primary outcome was the rate of clinical change to severe or critical
proved that has the curative effect of broad spectrum antivirus, condition.Secondary outcomes include
anti-bacterial, antipyretic and anti-inflammatory,reducing cough and the fever time, the disappearance rate of the major symptoms (fever,
expectoration, immune regulation on the respiratory system and so on.8 fatigue, cough) and secondary symptoms (expectoration,anhelation).
And because of that,LQ has been recommended over 20 times by the
National Health Commission and the State Administration of TCM for 2.1.5. Search strategies
the prevention and treatment of respiratory infectious diseases. Now For more comprehensive inclusion, the electronic databases from
being a representative Chinese patent medicine in response to respira­ November 2019 up to March 2020 we searched are listed below:CENTRAL
tory public health events, LQ has been listed as recommended drug for (2019–2020), EMBASE (2019–2020), PubMed (2019–2020),the Chinese
many times by the diagnosis and treatment program of COVID -19 (Trial National Knowledge Infrastructure (CNKI, 2019–2020), the Chinese Sci­
version 5),9 and even been delivered to some countries such as Italy as entific Journal Database (VIP, 2019–2020), the Chinese Biomedical
priority aid drugs.In the past, there are several Meta-analysis studies Literature Database(CBM, 2019–2020) and the Wanfang Database
have shown that LQ are more effective than oseltamivir on improving (2019–2020).By the means of using different relevant major medical
symptoms and reducing fever in people with influenza.10–12 Since the subject heading and without the limitations of country,region and lan­
outbreak of COVID -19, LQ combined with conventional treatment has guage,all relevant studies were retrieved. For avoiding some omissions,
also received a great deal of satisfactory clinical efficacy feedback from bibliography of all potential articles were also retrieved in detail.The key
the battle front. Thus, this Meta-analysis focused on the effectiveness of terms for literature searching were:(‘corona virus disease
LQ on the treatment of COVID-19 and summarized all the results of 2019′ OR‘COVID-19′ OR‘2019 novel coronavirus’ OR‘2019-nCoV’ OR‘no­
included trials, so as to provide further evidence for subsequent clinical vel coronavirus’) AND (‘Lianhua Qingwen Granules’ OR‘Lianhuaqingwen
treatment. Granules’ OR‘Lianhua Qingwen Capsules’ OR‘Lianhuaqingwen Capsu­
les’OR‘Lianhua Qingwen’OR‘Lianhuaqingwen’OR‘Traditional Chinese
2. Methods medicine’ OR‘combine traditional Chinese and western medicine’).

This study complied with the Preferred Reporting Items for Sys­ 2.1.6. Data extraction and analysis
tematic Review and Meta-Analyses (PRISMA) statement13 Two independent researchers (Master.Dai Xingzhen, Master.Wu
Qihua) reviewe and evaluate all retrieved literatures,and then deter­
2.1. Study selection mine the final studies that met the inclusion criteria. Afterwards,they
will extract some basic data from the included studies, including the first
2.1.1. Types of studies author’s name, publication date, sample size, intervention and obser­
All trials that reported the clinical application of LQ on the treatment of vation time of LQ group and control group, and outcome indicators.If
COVID-19 were included.There were no statistical differences in basic any disagreement happens,a third researcher (Dr. Hairong Cai) will
data such as age, sex ratio, previous medical history and body temperature participate in the discussion and resolve it together.
between the groups compared in the trials.Studies those meet the All outcomes were Meta analyzed by The RevMan 5.3 software.
following conditions will be excluded: (1)There were no comparisons Measurement data (continuous variables) were represented by standard
between the control group and the LQ group; (2)Duplicate studies; (3) mean variance (SMD) and 95 % confidence interval (95 % CI), while
There are other TCM drugs in the study except LQ; (4)There are obvious enumeration (binary variables) data were represented by relative risk
errors in data incomplete or unable to extract; (5)The outcomes do not (RR) and 95 % CI.I2 test was used for heterogeneity test. If P >0. 1 and
match. I2<50 %, Fixed Effect model was used for analysis,while P ≤0.1 and
I2≥50 %, heterogeneity between the included studies was indicated, and
2.1.2. Types of participants Random Effect model was used for analysis.
All enrolled patients must meet the diagnostic criteria of confirmed
COVID-19 or suspected,including symptoms and signs, past history, 2.1.7. Risk of bias assessment
laboratory examination, positive nucleic acid test or pulmonary CT Another two reviewers (Master.Zhang Weizhang,Dr. Huang
imaging examination, 9. Patients with the following conditions were Xiaoyan) independently evaluated the risk of bias of each study by using
excluded : (1)Severe or critical patients; (2)Acute respiratory diseases the assessment tool from the Cochrane Handbook. The criteria consisted

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J. Zhuang et al. Complementary Therapies in Medicine 60 (2021) 102754

of the following seven items: ① Allocation concealment (selection 3.3. Risk of bias within studies
bias);② Randonm sequence generation (selection bias); ③ Blinding of
participants and personnel (performance bias); ④ Blinding of outcome The methodological quality of the involved trials is shown in Figs. 2
assessments (detection bias); ⑤ Incomplete outcome data (attrition and 3.
bias); ⑥ Selective reporting (reporting bias); ⑦ Other sources of bias.
And egger analysis and funnel plot were used by the RevMan 5.3 soft­ 3.4. Outcome measures
ware to analyze the potential publication bias of the article.
3.4.1. Primary outcomes: the rate of clinical change to severe or critical
3. Results condition
2 studies14,15 reported the rate of clinical change to severe or critical
3.1. Study identification condition in the course of treatment.The Meta-analysis result showed
significant difference between two groups in the rate [RR = 0.38, 95 %CI
The process of study selection and identification was shown in Fig. 1. (0.17,0.85), P < 0.05; Fig. 4]with no significant heterogeneity (p = 0.90,
A total of 30 possibly relevant articles were selected by our study I 2 = 0%),which means that patients in the LQ group are less likely to
retrieval strategy,and all of them were first published online by Chinese change to severe or critical condition.
in various magazines without printed version.No duplicate studies were
found, so 30 articles were preliminarily screened. After reviewing titles 3.4.2. Secondary outcomes
and abstracts, 27 articles were excluded because they were theoretical
studies,pharmacology research,review or different intervention. Then 3.4.2.1. The fever time. 2studies14,16 assessed the effect of LG on
the remaining 3 articles were evaluated for full text. Ultimately,3 studies reducing the fever time compared with the control group.The combined
were assessed to be eligible in our review. among them 1 article 14 was effects of the independent trial results suggested that there was signifi­
randomized controlled trial (RCT) and 2 articles 15,16 were retrospective cant difference between two groups in the fever time[SMD =-0.57,95 %
case-control study. CI (-0.96,-0.17), P<0.05,Fig. 5], with no significant heterogeneity
(P = 0.68,I 2 = 0%).
3.2. Study characteristics
3.4.2.2. The disappearance rate of the major symptoms (fever, cough,
The basic characteristics of the included trials are summarised in fatigue). 3 studies 14–16 reported the difference in the disappearance rate
Table 1. A total of 245 COVID-19 patients were enrolled,and 135 in the of the major symptoms (fever, fatigue, cough) between the LQ group and
LQ group and 110 in the control group. The sample sizes for 3 studies the control group.And the meta-analysis results showed that LQ can
ranged from 42 to 102 and all participants were from China.Two diag­ significantly increase the disappearance rate of the major symptoms
nostic criteria source for COVID-19 were reported: Trial version 4 17 and (fever [RR = 1.36,95 %CI (1.14,1.61), P < 0.05, Fig. 6]; cough
Trial version 5 9 of the Diagnosis and Treatment of Pneumonia caused by [RR = 1.99,95 %CI (1.39,2.86), P < 0.05,Fig. 7]; fatigue[RR = 1.52,95
Novel Coronavirus Infection,which we found the diagnostic criteria %CI (1.15,2.01), P < 0.05, Fig. 8]) with no significant heterogeneity
were basically the same.Other details of interventions, course time and (fever[P = 0.80,I 2 = 0%]; cough [P = 0.29,I 2 = 18 %]; fatigue
outcomes are listed in the table. [P = 0.77,I 2 = 0%]).

Fig. 1. The process of studies selection and identification.

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Table 1
Basic characteristics of included Studies.
Studies Diagnosis standard n(T/C) LQ group Control group Course(d) Outcomes
14
Cheng Dz 2020 FI 51/51 LQ + CT CT 7 ①②③④⑤⑥⑦
Lv Rb 202015 FO 63/38 LQ + CT CT 7 ①③④⑤⑥⑦
Yao Kt 202016 FO 21/21 LQ + CT CT N ②③④⑤⑥⑦

T：
：The Treatment Group;C： ：The Control Group;FO： ：Diagnosis and Treatment of Pneumonia caused by Novel Coronavirus Infection (Trial version 4)；FI: Diagnosis
and Treatment of Pneumonia caused by Novel Coronavirus Infection (Trial version 5); LQ : Lianhua Qingwen Granules;CT:Conventional Treatment;N:Not clear；①：
The rate of clinical change to severe or critical condition；②：The fever time；③：The disappearance rate of fever；④：The disappearance rate of fatigue；⑤：The
disappearance rate of cough；⑥：The disappearance rate of expectoration；⑦The disappearance rate of anhelation.

groups. Compared with the control group, LQ group can significantly

improve the disappearance rate of the secondary symptoms (anhelation
[RR = 4.18,95 %CI (1.99,8.81), P < 0.05, Fig. 9] with no significant
heterogeneity (P = 0.78,I 2 = 0%),but no significant difference on
expectoration[RR = 2.46,95 %CI (0.81,7.51), P > 0.05, Fig. 10] with
significant heterogeneity (P = 0.04,I 2 = 69 %)and Fixed Effect model
was used for analysis.Meanwhile,sensitivity analysis was conducted by
removing these studies one by one since the heterogeneity was sub­
stantial with I2 = 69 %, resulting in significant changes when it’s turn to
one trial.16So heterogeneity may result from different research types
was considered.

3.4.2.4. Evaluation of publication bias. Because of the limited number of

included studies,there is no point in making funnel plot analysis to show
the risk of publication bias.

4. Discussion

COVID-19 is caused by the 2019-nCoV, which has now becoming a

global pandemic since it was first detected in Wuhan, China. 2019-nCoV
has a variety of transmission routes (droplets, contact, aerosol, fecal
mouth, etc.) and the characteristics of high infectivity in the general
population, 9that resulting in a large number of global human infections
with some major symptoms such as fever, cough, shortness of breath, 18
and even dyspnea, acute respiratory failure, renal failure or death in
some severe cases. 19 In the pathologic anatomy of COVID19 patients,
medical experts found the presence of diffuse alveolar injury with
Fig. 2. Risk of bias summary. cellular fiber mucous exudation, pulmonary interstitial lymphocyte
infiltration, and decreased lymphocytes in blood, indicating the
3.4.2.3. The disappearance rate of the secondary symptoms (expectoration, appearance of immune disorders. 20 Additionally,there was a large
anhelation). 3 trials14–16 recorded the comparison of the disappearance amount of white colloidal mucus in the trachea cavity and alveoli.21As a
rate of the secondary symptoms (expectoration, anhelation) among two result,many serious clinical consequences such as acute respiratory
distress syndrome, hypoxemia and metabolic acidosis will gradually

Fig. 3. Risk of bias graph.

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J. Zhuang et al. Complementary Therapies in Medicine 60 (2021) 102754

Fig. 4. The rate of clinical change to severe or critical condition.

Fig. 5. The fever time.

Fig. 6. The disappearance rate of fever.

come to the fore.Therefore, the rapid elimination of inflammatory cytoplasm, and inhibit the overactivation of cytokines.28Generally
response transmitters, blocking the diffuse lung injury caused by in­ speaking,a large number of previou and recent researches results have
flammatory storms, and the regulation of immune disorders are of great provided the experimental and clinical basis for the treatment of
significance for the control of patients’ conditions and the prevention of COVID-19 with LQ. Fortunately, this Meta analysis results also shows
the development of severe or critical illness22 that LQ plus routine therapy appears to improve the symptoms of fever,
In the absence of specific drugs and vaccines in China,the major fatigue, cough and anhelation in COVID-19 patients,as well as to reduce
clinical treatment is the integration of TCM and western medicine.23As a the rate of clinical change to severe or critical condition.
proprietary Chinese medicine strongly recommended by the guidelines However, from the perspective of research methodology, the limi­
in China, LQ playing an important role in this outbreak.A study on the tations of this Meta-analysis mainly include:(1)All included studies were
network pharmacology and preliminary evidence of LQ on the treatment only first published online without the print version;(2)Limited quan­
of COVID-19 speculates that many active ingredients of LQ have the tity, low quality and small sample of the included studies may lead to the
holistic therapeutic effect on broad-spectrum antiviral, antibiosis, selectivity bias;(3) All included studies were published by Chinese, so
reducing cough and phlegm, immune regulation through multi-targets there may be some regional differences and publication bias;(4)The
and multi-signal pathways. 24 In the past, some studies have proved included literatures include not only RCTs but also retrospective studies,
that LQ can inhibit the SARS-CoV25 and MERS-CoV activities in vitro. 26 which may result in some heterogeneity and reduce the persuasiveness
Recently,a study have shown that the components of LQ, honeysuckle of the results.In view of the current special epidemic period, many
and forsythia may alleviate the damage of the virus to host cells by reasons like the short time since the epidemic outbreak, the high pres­
blocking many binding sites of human angiotensin-converting enzyme sure of clinical work and the complexity and variability of treatment
to SARS-CoV-2.27Another recent study researched by the Key Laboratory option may lead to the emergence of these limitations.We are looking
of Respiratory Diseases in China found that LQ could inhibit the activity forward to more multicenter, large-sample and high-quality research
of 2019-nCoV,reduce the number of viruses in the cell membrane and reports are published in the future.

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J. Zhuang et al. Complementary Therapies in Medicine 60 (2021) 102754

Fig. 7. The disappearance rate of cough.

Fig. 8. The disappearance rate of fatigue.

Fig. 9. The disappearance rate of expectoration.

Fig. 10. The disappearance rate of anhelation.

5. Conclusions inflammatory factors, immune function and long-term follow-up of pa­

tients’ prognosis are expected to be published.
To sum up, the results of this systematic review and Meta analysis
support the clinical use of LQ on the treatment of COVID-19,which has PROSPERO registration
significant efficacy in improving clinical symptoms and reducing the
rate of clinical change to severe or critical condition. However, due to CRD42020182257
the insufficient quantity and quality of the included studies, more and
higher quality studies with more observational indicators such as

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epithelial cells of oral mucosa. Int J Oral Sci. 2020;12(1):8.
19 Ralph R, Lew J, Zeng T, et al. 2019-nCoV (Wuhan virus), a novel Coronavirus:
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Dev Ctries. 2020;14(1):3–17.
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