Fphar 14 1121580

TYPE Systematic Review
PUBLISHED 13 March 2023

DOI 10.3389/fphar.2023.1121580
Evidence synthesis of Chinese

OPEN ACCESS medicine for monkeypox:
EDITED BY
Myeong Soo Lee,
Korea Institute of Oriental Medicine
Suggestions from other
(KIOM), Republic of Korea
REVIEWED BY
contagious pox-like viral diseases
Yaolong Chen,
Lanzhou University, China
Stefka Krumova,
Hong-guo Rong 1,2,3, Xiao-wen Zhang 1,3, Mei Han 1,2,3, Xin Sun 3,
National Center of Infectious and Xiao-dan Wu 3, Xiao-zhen Lai 4, Chen Shen 1,3, Wei-jie Yu 3,
Parasitic Diseases (NCIPD), Bulgaria
Hai Fang 4, Yu-tong Fei 1,2,3 and Jian-ping Liu 1,5*
*CORRESPONDENCE
Jian-ping Liu, 1
Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China,
liujp@bucm.edu.cn 2
Institute for Excellence in Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine,
Beijing, China, 3School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing,
SPECIALTY SECTION
China, 4China Center for Health Development Studies, Peking University, Beijing, China, 5The National
This article was submitted
Research Center in Complementary and Alternative Medicine (NAFKAM), Department of Community
to Ethnopharmacology,
Medicine, Faculty of Health Science, UiT The Arctic University of Norway, Tromsø, Norway
a section of the journal
Frontiers in Pharmacology
RECEIVED 05 January 2023

ACCEPTED 27 February 2023
PUBLISHED 13 March 2023 Background: Monkeypox, a zoonotic disease caused by an Orthopoxvirus,
CITATION presents an etiology similar to smallpox in humans. Currently, there are no
Rong H-g, Zhang X-w, Han M, Sun X, licensed treatments for human monkeypox, so clear and urgent research on its
Wu X-d, Lai X-z, Shen C, Yu W-j, Fang H,
prophylaxis and treatment is needed.
Fei Y-t and Liu J-p (2023), Evidence
synthesis of Chinese medicine for
Objective: The purpose of this study was to explore the evidence of Chinese
monkeypox: Suggestions from other
contagious pox-like viral diseases. medicine for contagious pox-like viral diseases and provide suggestions for the
Front. Pharmacol. 14:1121580. multi-country outbreak management of monkeypox.
doi: 10.3389/fphar.2023.1121580
COPYRIGHT
Methods: The review was registered on INPLASY (INPLASY202270013). Ancient
© 2023 Rong, Zhang, Han, Sun, Wu, Lai, classics in China and clinical trials involving randomized controlled trials , non-
Shen, Yu, Fang, Fei and Liu. This is an RCTs, and comparative observational studies of CM on the prevention and
open-access article distributed under the
terms of the Creative Commons
treatment of monkeypox, smallpox, measles, varicella, and rubella were
Attribution License (CC BY). The use, retrieved from the Chinese Medical Code (fifth edition), Database of China
distribution or reproduction in other Ancient Medicine, PubMed, the Cochrane Library, China National Knowledge
forums is permitted, provided the original
author(s) and the copyright owner(s) are
Infrastructure, Chongqing VIP, Wanfang, Google Scholar, International Clinical
credited and that the original publication Trial Registry Platform, and Chinese Clinical Trial Registry until 6 July 2022. Both
in this journal is cited, in accordance with quantitative and qualitative methods were applied to present the data collected.
accepted academic practice. No use,
distribution or reproduction is permitted Results: The use of CM to control contagious pox-like viral diseases was traced
which does not comply with these terms.
back to ancient Chinese practice cited in Huangdi’s Internal Classic, where the
pathogen was recorded nearly two thousand years back. There were 85 articles
(36 RCTs, eight non-RCTs, one cohort study, and 40 case series) that met the
inclusion criteria, of which 39 studies were for measles, 38 for varicella, and eight
for rubella. Compared with Western medicine for contagious pox-like viral
diseases, CM combined with Western medicine showed significant
improvements in fever clearance time (mean difference, −1.42 days; 95%
CI, −1.89 to −0.95; 10 RCTs), rash/pox extinction time (MD, −1.71 days; 95%
CI, −2.65 to −0.76; six RCTs), and rash/pox scab time (MD, −1.57 days; 95%
CI, −1.94 to −1.19; five RCTs). When compared with Western medicine, CM
alone could reduce the time of rash/pox extinction and fever clearance.
Chinese herbal formulas, including modified Yinqiao powder, modified Xijiao
Dihaung decoction, modified Qingjie Toubiao decoction, and modified
Shengma Gegen decoction, were frequently applied to treat pox-like viral
Frontiers in Pharmacology 01 frontiersin.org

Rong et al. 10.3389/fphar.2023.1121580
diseases and also showed significant effects in shortening the time of fever
clearance, rash/pox extinction, and rash/pox scabs. Compared with Western
medicine (placental globulin) or no intervention, eight non-randomized trials
and observational studies on the prevention of contagious pox-like viral
diseases showed a significant preventive effect of Leiji powder among high-risk
populations.
Conclusion: Based on historical records and clinical studies of CM in managing
contagious pox-like viral diseases, some botanical drugs could be an alternative
approach for treating and preventing human monkeypox. Prospective, rigorous
clinical trials are urgently needed to confirm the potential preventive and treatment
effect of Chinese herbal formulas.
Systematic Review Registration: [https://inplasy.com/], identifier

[INPLASY202270013].
KEYWORDS
monkeypox, smallpox, measles, varicella, rubella, Chinese medicine, clinical studies
Introduction However, we can explore ways to prevent and treat monkeypox

from human experience in fighting against other contagious pox-
An outbreak of monkeypox is occurring in multiple countries like viral diseases. Throughout the 3000-year history of China,
across the world, showing the characteristics of wide coverage, fast Chinese medicine (CM) has been used as the routine treatment
transmission, unclear epidemic focus, mainly human transmission, regime for acute infectious diseases (Wu et al., 2021). For example,
and accelerated community transmission and virus variation when severe acute respiratory syndrome (SARS) was the most serious
(Guarner et al., 2022). The multi-country monkeypox epidemic infectious disease outbreak in China in 2003, Chinese herbal formulas
has become a serious public health emergency and requires a played a significant role in the prevention and treatment of SARS (Liu
coordinated international response (Wenham and Eccleston- et al., 2004; Liu et al., 2012). In 2022, facing the outbreak of monkeypox
Turner, 2022). The World Health Organization (WHO) around the world, the National Health Commission of China issued a
announced on 23 July 2022 that monkeypox outbreaks in several CM treatment program in the Guidelines for the Diagnosis and
countries and regions constituted a public health emergency of Treatment of Monkeypox (2022 Version) (Interpretation of
international concern (PHEIC). guidelines for diagnosis, 2022), which included six Chinese herbal
The most common symptoms of monkeypox identified during formulas based on different clinical symptoms.
the 2022 outbreak include fever, headache, muscle aches, back pain, At present, the multi-country outbreak of monkeypox has
low energy, and swollen lymph nodes, followed or accompanied by drawn worldwide attention, and it is necessary to find
the development of a rash that may last for 2 to 3 weeks (Patel et al., appropriate solutions as soon as possible. Therefore, we
2022). Caused by the monkeypox virus, monkeypox was recognized conducted this review to identify the historical and human
as the most significant Orthopoxvirus infection since the eradication research evidence and critically review the potential for CM to
of smallpox (Adler et al., 2022). Since the epidemic began to spread prevent and treat monkeypox.
in early May 2022, the WHO has attached great importance to this
special situation, rapidly releasing public health and clinical
guidelines, engaging with communities actively, and convening Methods
scientists and researchers to accelerate the study of new
diagnostic methods, vaccines, and treatments for monkeypox. At Data sources
present, there are three kinds of vaccines against monkeypox, but the
current supply is limited and there is a lack of data on the The protocol of this review has been registered on INPLASY
effectiveness of the new vaccine against monkeypox (Kumar (INPLASY202270013). Two types of data in the current study were
et al., 2022; Looi, 2022). It is urgent to find new approaches to searched, including historical classics records and human research
prevent and treat multi-country monkeypox outbreaks. evidence. Historical classics records are records on the prevention
At the time of writing, there are no specific treatments for and treatment of contagious pox-like viral diseases in ancient CM
monkeypox patients as per the WHO and US Center for Disease books, including history, treatment principles, medicines, and the
Control and Prevention, and the treatment is mainly for the application of CM to prevent or treat contagious pox-like viral
symptoms (Rizk et al., 2022). Monkeypox presents with fever, an diseases. Human research studies are studies to investigate the
extensive characteristic rash, and usually swollen lymph nodes preventive and therapeutic effects of CM on monkeypox,
(Adler et al., 2022; Orviz et al., 2022; Tarín-Vicente et al., 2022). smallpox, measles, varicella, and rubella were included. The
It is important to distinguish monkeypox from other contagious inclusion criteria were as follows: 1) study design: clinical trials,
pox-like viral diseases such as varicella, measles, bacterial skin clinical-controlled trials, cohort studies, cross-sectional studies,
infections, scabies, syphilis, and medication-associated allergies. case-control studies, case series, and clinical observations; 2)

Rong et al. 10.3389/fphar.2023.1121580
population: high-risk populations exposed to monkeypox, smallpox, When the data were available for pooling, meta-analysis would
measles, varicella, and rubella; 3) intervention: CM should be used be conducted by RevMan 5.3 software. Considering the trials usually
alone or combined with conventional treatment or healthcare; 4) applied different Chinese herbal formulas, we have to pool the data
control: conventional treatment, healthcare, placebo, or blank together to explore the overall effectiveness of CM, so a random-
control; and 5) outcome: outcomes included all-cause mortality, effects model was applied for all the pooled data. The mean
pathogen clearance rate or time, and improvement of overall difference (MD) was used for continuous data, and relative risk
symptoms, including but not limited to fever, frequency, and (RR) for dichotomous data, both with 95% confidence intervals (CI).
severity of pox.
Results
Literature search
General description of contagious pox-like
The retrieval strategies of the aforementioned two types of data were viral diseases in ancient CM classics
different. The Chinese Medical Code (fifth edition) and Database of
China Ancient Medicine were taken as the retrieval source of ancient Historically, CM has rich experience in treating contagious pox-like
literature. The list of literature retrieved was determined after discussions viral diseases (Figure 1). The first record of contagious pox-like viral
among all authors. PubMed, the Cochrane Library, China National diseases dated back to Huangdi’s Internal Classic, written about
Knowledge Infrastructure, Chongqing VIP, Wanfang, Google Scholar, 2,000 years ago. Huangdi’s Internal Classic reported that surplus qi
International Clinical Trial Registry Platform, and Chinese Clinical Trial of lesser yin led to skin impediment and urticaria, which was considered
Registry were taken as the retrieval source of modern literature. The to be the earliest record of the name and pathogenesis of contagious
search date was up to 6 July 2022. pox-like viral diseases. The Suwen Great Theory on Normality of Six-Qi,
Taking PubMed as an example, the retrieval terms were listed as part of Huangdi’s Internal Classic, reported that the occurrence of these
follows: diseases was marked by body fever, vomiting, cholera, carbuncles,
soreness, and ulceration. These theories had a profound impact on
#1 Monkeypox OR monkey pox OR monkeypox virus OR variole the treatment of contagious pox-like viral diseases.
du singe OR variole simienne OR smallpox OR variola OR Monkeypox virus and smallpox virus belonged to the genus
measles OR measles virus OR varicella OR chickenpox OR Orthopoxvirus of Poxviridae. The Handbook of Prescriptions for
varicellovirus OR rubella OR rubeola OR Rubella virus OR Emergencies written by Ge Hong in the Eastern Jin Dynasty first
german measles [title, abstract, keywords] described the symptoms of smallpox and the treatment methods
#2 traditional Chinese medicine OR Chinese medicine OR including internal and external use. A famous pediatrician in the
traditional medicine OR Chinese herbal medicine OR Northern Song Dynasty, Qian Yi wrote the Key to Therapeutics of
ethnological medicine OR Chinese materia medica OR Children’s Diseases and analyzed the different clinical symptoms of
Chinese patent medicine [title, abstract, keywords] varicella, measles, and smallpox. The name varicella was first proposed
#3 trial OR participants OR patients OR randomized controlled in General Theory of Pediatric Health in the Southern Song Dynasty, as,
trial OR random OR controlled clinical trial OR placebo OR “the skin of the sore is very thin, like blisters, and it dries quickly when
cohort study OR case-control study OR epidemiology OR cross- punctured, which is called varicella.” Medical books before the
sectional study OR descriptional study OR population-based OR Ming Dynasty, such as Essential Prescriptions Worth a Thousand
clinical observation [title, abstract, keywords]. Gold for Emergencies, Medical Secrets of an Official, and General
Treatise on Febrile Diseases, had a preliminary understanding of
the clinical manifestations of measles. General Treatise on Febrile
Data extraction and analysis Diseases also proposed the name “pockmarks” and distinguished it
from smallpox. Ancient and Modern Medical Guide written by
For CM classics, we summarized the text related to pox-like viral Gong Xin, a famous doctor in the Ming Dynasty, distinguished
diseases with a narrative description. For clinical trials, we designed a data measles from other pox diseases for the first time, proposed the
extraction form for study characteristics and outcome data, which we name measles, and recorded the diagnosis and treatment of
piloted on at least one study in the review. The study characteristics were measles in detail. The famous doctor Sun Simiao (541–682 AD)
extracted by two authors independently, including the characteristics of first put forward the name and cause of “rubella” in his book
the population (age), the type of therapies, treatment methods and Essential Prescriptions Worth a Thousand Gold for Emergencies,
courses, reported outcomes, and adverse events/reactions. According to which said that “when the wind pathogen invades the skin, the
the Convention on the Rights of the Child, our study defines children as deficiency itches then changed into rubella, itching, and sores.”
“every human being below the age of eighteen years.” Any disagreement
was solved by a third author to reach a consensus.
The following data were extracted and analyzed: source of evidence, Chinese herbal formulas for the prevention
time of publication or release, author, setting, the basis for the formulation and treatment of contagious pox-like viral
of CM prophylaxis and treatment strategy, the composition of CM diseases in ancient CM classics
prescription, target disease, course of prevention, effect, and adverse
reaction. The data were qualitatively described and presented, and if CM has been used to treat smallpox since ancient times, and
possible, quantitative or descriptive statistics were conducted. there were various methods. The famous doctor Ge Hong first

Rong et al. 10.3389/fphar.2023.1121580
FIGURE 1
Brief history of CM for prevention and treatment of contagious pox-like viral diseases.
proposed that smallpox could be treated by internal and external decoction could be used when the pox started to increase. If there
use of CM in his book Handbook of Prescriptions for Emergencies. was fever on the body surface but no sweat, Shengma Gegen
It could be taken orally with honey-fried Actaea cimicifuga L. and decoction was recommended. If the viscera were hot and sweaty,
scrubbed externally with boiled A. cimicifuga L. Essential Jiajian Xiaodu decoction was recommended. If herpes forms and
Prescriptions Worth a Thousand Gold for Emergencies was a the fever did not subside, Qingdu Huoxue decoction was
classic work of CM written by Sun Simiao, a Chinese recommended. If fever occurred after acne, Da Lianqiao
physician titled China’s King of Medicine in the Tang decoction was recommended. If convulsions occurred before
Dynasty. This book collected more than 10 prescriptions for the appearance of the rash, it was recommended to use Qingjie
treating acne. Most of the medicines used in these powder. If still had convulsive symptoms after the rash, it was
prescriptions were mainly cool feature medicines, such as recommended to use Daochi powder.
Coptis chinensis Franch., Indigofera suffruticosa Mill., Cornu For the ancient CM treatment of measles, the basic therapeutic
Bubali, Rheum officinale Baill., and Mangifera indica L. In the principles and methods for measles were clearing heat and
Song Dynasty, the treatment methods for smallpox became more promoting eruption. The earliest record of CM for measles can
abundant. A medical expert Zhu Zuo recommended the Mahuang be traced back to the Selections from Classic Formulae published in
decoction, Xijiao Dihaung decoction, and Shuijie powder to treat the Eastern Jin Dynasty. This book suggested that Gegen Jupi
smallpox. In the Song Dynasty, there were also monographs on decoction could be used to treat measles. In the monograph on
pox-like diseases, such as Xiaoer Banzhen Beiji Fanglun and the pediatrics of CM in the Southern Song Dynasty, Xiaoer
Xiaoer Douzhen Fanglun, which discussed the etiology, Weisheng Zongwei Lunfang opened a special column on disease
syndrome differentiation, treatment principles, and diagnosis and treatment of “acne and rash theory” and
presentations of children’s pox and rash and provided many recommended a variety of formulas to treat acne and rash
treatment approaches in this period. Thereafter, the prevention diseases. For example, Leiji powder has an effective effect on the
and treatment of smallpox with CM have been practiced in depth, treatment of children’s acne and rash characterized by irritability
improving its treatment methods. Zeng Shirong, a famous and thirst, soreness in the mouth and tongue, and obstruction of
pediatrician in the Yuan Dynasty, advocated that smallpox urine. Another famous medical book in the same period, Taiping
should be treated in three stages. When the pox rash did not Huimin Heiji Jufang (the first proprietary medicine standard
occur, Shengma Gegen decoction plus Ephedra sinica Stapf could compiled by the government in the world), established the
be used to promote the eruption. If the pox rash has occurred, Shengma Gegen decoction approach to treating pox-like diseases,
Zhonghe decoction could be used to smooth the appearance and which was widely used. The Ancient and Modern Medical Guide in
interior. If acne was easy to grow, Maogui decoction could be used the Ming Dynasty put forward the viewpoint of “warming and
to replenish qi, promote blood circulation, and detoxify. If the tonifying” to treat measles according to syndrome differentiation.
rash did not scab for a long time, Shengma Gegen decoction plus The formulas include modified Shengma Gegen decoction and
E. sinica Stapf could be used to promote scab formation. After a modified Siwu decoction. In the Qing Dynasty, there were more
rash scab, the Shengma Gegen decoction could be used for CM prescriptions for measles. In an important work on febrile
detoxification. The numbers of monographs on pox and rash diseases, the classic prescription Yinqiao powder was proposed in
appeared in the Ming and Qing dynasties. The theory was mature, Treatise on Differentiation and Treatment of Epidemic Febrile
and the description was complete. For example, the Qing Disease, a famous book about febrile diseases. As the basis of
Dynasty’s official medical book Golden Mirror of the Medical summing up predecessors’ experience, Golden Mirror of the
Ancestors proposed different treatment methods for smallpox Medical Ancestors in the Qing Dynasty provided rich formulas
patients with different clinical manifestations: Wuwei Xiaodu according to different syndrome types of measles, such as

Rong et al. 10.3389/fphar.2023.1121580
Shengma Gegen decoction, Maxing Shigan decoction, Sanhaung Evidence of Chinese herbal formulas for
Shigao decoction, and Siwei decoction. prevention and treatment of measles
The methods of CM treatment for varicella were clearing
heat, resolving dampness, and removing toxins. According to the Thirty-nine studies were identified, including 11 RCTs, seven
different syndromes of varicella, the methods of releasing non-RCTs, one cohort study, and 20 case series. Table 1 presents the
exterior and clearing interior, clearing qi aspect and cooling studies on the prevention of measles by CM, including one RCT,
nutrient aspect, eliminating dampness, and removing toxins four non-RCTs, and four case series. The Chinese herbal formulas of
were, respectively, used. In the Song Dynasty, although Xiaoer Leiji powder were widely used in the prevention of measles. The
Weisheng Zongwei Lunfang first proposed the name varicella, it is population comprised children who were directly or indirectly in
still considered a combination of pox-like viral diseases in terms contact with confirmed measles cases, with ages ranging from
of treatment. It mentioned a variety of treatments, such as 4 months to 15 years (three papers did not report the specific
Shengma Gegen decoction, Leiji powder, and Baidu powder. age of children). The total sample size was 15,566, with the largest
Baoying Cuoyao in the Ming Dynasty contains important one being 7,828. The course of taking Leiji powder for prevention
medical treatises from the Han to the Tang, Song, Jin, and was 3–30 days. The incidence rate of measles ranged from 1.7% to
Yuan dynasties, and down to the early Ming Dynasty, 71.7%. The results of one study (Chen, 1964) showed that the effect
reflecting the continuation and development of the history of of using Leiji powder to prevent measles is not evident. Other studies
pediatrics theory in CM. Baoying Cuoyao suggested that for have proved that Leiji powder could significantly reduce the
patients with the pathogenic qi light shallow, mainly exterior incidence rate of measles. Even after the occurrence of measles,
syndrome, Shengma Gegen decoction should be selected. In the the use of Leiji powder could significantly improve its clinical
Qing Dynasty, CM practitioners added the prescriptions of symptoms.
predecessors and skillfully applied them to treat varicella. For Table 2 shows the basic characteristics of studies (10 RCTs, three
example, the Golden Mirror of the Medical Ancestors mostly non-RCTs, and one cohort study) on CM treatment for measles. Most
adopted the formula of strengthening the body and resolving of the included studies had clear diagnostic criteria of CM or Western
the exterior, clearing away heat and diuresis to treat varicella. medicine for measles (Supplementary Table S1). The participants of
The methods of CM treatment for rubella were mainly based on those studies were adults and children, the youngest of whom was
clearing heat to release exterior, cooling blood and promoting 4 months old. The total sample size was 2,277, with the largest one being
eruption, and harmonizing nutrient and defensive aspects. Sun 899. The treatment therapeutic principles and methods of CM for
Simiao recorded the Mahuang decoction to treat rubella in his measles are based on clearing heat, detoxifying, and penetrating rash
book Essential Prescriptions Worth a Thousand Gold for (Supplementary Table S1). These included interventions comprise three
Emergencies. Peaceful Holy Benevolence Formulae was the first self-made prescriptions and 14 classic Chinese herbal formulas.
large-scale comprehensive prescription prepared by a government Modified Qingjie Toubiao decoction appeared most frequently in
organization in China, which collated the previous experience in the classic prescriptions of CM (3/14), followed by modified Yinqiao
treating diseases, and later generations’ empirical prescriptions, time powder, modified Yinqiao powder, and modified Maxing Shigan
prescriptions, exotic drugs, etc. Treatise on differentiation and decoction (all 2/14). The specific components of the prescription are
treatment of epidemic febrile disease, a treatise on febrile diseases shown in Supplementary Table S1. The conventional anti-symptomatic
in the Qing Dynasty, pointed out for the first time that although the treatment was generally used as a control. Five RCTs and one non-RCT
eruption was not difficult to treat, the treatment was urgent and the reported the course of formulas ranging from 3 to 10 days. The main
time limit was only 3 days, and said that the exterior should be outcome measures were the total effective rate, fever clearance time,
released with pungent cool medicine first and then recovered using time of rash disappearance, and complication rate. Two studies reported
sweet cool medicine. In another monograph on febrile diseases, the adverse events including nausea, vomiting, and bad appetite, while
Yizhen Yide recommended the Liangge powder and Qingwen Baidu two studies reported that no adverse events occurred, and the others did
powder to treat rubella. not report on this aspect.
Clinical studies’ search results Evidence of Chinese herbal formulas for

varicella
Across searches, 2,758 studies were retrieved. After
deduplication, 2,388 records remained. After screening titles Thirty-eight studies were identified, including 22 RCTs, one
and abstracts for relevance, 268 records remained. Two reports non-RCT, and 15 case series. All the studies were published in
were not retrieved. After reading the full text, 76 records Chinese. The details of the characteristics of included trials RCTs
remained. After reviewing reference lists, eight studies were and non-RCTs are presented in Table 3. More than half of the
added. In total, 85 articles met the inclusion criteria for the studies reported having clear diagnostic criteria of CM or Western
current study objective. Of the 85 studies, 36 were randomized medicine for varicella (Supplementary Table S2). The participants
controlled trials (RCTs), eight non-RCTs, one cohort study, and were children and adults, ranging from 4 months to 58 years old.
40 case series. There were 39 pieces of literature on measles, 38 on The total sample size of the included clinical studies was 2,015. The
varicella, eight on rubella, and none on monkeypox or smallpox. therapeutic principles and methods for varicella were clearing heat
The flow of articles through identification to final inclusion is and cooling blood and removing toxins and dampness
represented in Figure 2. (Supplementary Table S2). These included interventions

Rong et al. 10.3389/fphar.2023.1121580
FIGURE 2
Flow chart of the study selection process.
comprising 15 classic Chinese herbal formulas, three self-made Evidence of Chinese herbal formulas for
prescriptions, and one Chinese patent medicine (Lianhua rubella
Qingwen Capsules). Among these, modified Yinqiao powder was
applied most frequently (7/15), followed by Xijiao Dihaung For Chinese herbal formulas for rubella, three RCTs and five
decoction (5/15). Shengma Gegen decoction, Baihu decoction, case series were identified. The characteristics of included RCTs
and modified Wuwei Jiedu decoction appeared three times. are presented in Table 4. The subjects were children or adults with
Modified Qingjie Toubiao decoction, Sanren decoction, and confirmed rubella. The total sample size of the included clinical
modified Liuyi powder appeared two times. The specific studies was 255, with the average age ranging from 1 to 27.93 years
composition of the prescription is shown in Supplementary Table old. The tested interventions included modified Yinqiao powder,
S1. The control group was generally treated with Western medicine. Xijiao Dihaung decoction, and Chinese patent medicines
Eighteen RCTs reported the course of Chinese herbal formulas (Huanglan Granule). The control measures mainly included
ranging from 3 to 10 days. The main outcome measures included Western medicine antiviral treatment (ribavirin), classic
the total effective rate, fever clearance time, time of rash Chinese herbal formulas, and self-made prescription. Two
disappearance, rash scab time, and index tested by laboratory studies reported that the course of formulas lasted for 3–7 days
serological diagnosis. Twelve clinical studies reported adverse and 20 days, respectively. The main outcome measures included
events that occurred, including nausea, vomiting, and bad fever clearance time, the time of rash disappearance, and RuV-
appetite. Six studies reported that no adverse events occurred, IgM. One study reported that no adverse events occurred, while the
while the others did not report on this aspect. others did not report on this aspect.

Rong et al. 10.3389/fphar.2023.1121580
TABLE 1 Characteristics of clinical trials on Leiji powder preventing measles.
Study ID Study Sample Average Intervention Control Treatment Follow- Incidence Incidence
type size age (year) course (d) up (d) number (n) rate (%)
(case,
T/C)
Chen 1964 (Chen, RCT T: 53 T: Modified Leiji Blank 14 60 T: 38 T: 71.7%
1964) 6 months–15 powder
C: 50 C: C: 32 C: 64.0%
6 months–15
Zhang 1960 Non- T1: 847 0–10 T1 Blank 12–15 27–28 T1: 11 T1: 1.3%
(Zhang, 1960) RCT
T2: 259 Ferula T2: 13 T2: 5.0%
sinkiangensis
K.M.Shen
C: 205 T2: Leiji powder C: 26 C: 31.0%
Jinzhou 1959 Non- T1: 742 Not reported T1: Fangma Placental T1: not reported Not T1: 208 T1: 28.0%
(Jinzhou city RCT decoction globulin reported
hospital, 1959)
T2: 3,460 T2: Guanzhong T2: 3 T2: 692 T2: 20.0%
powder
T3: 1,595 T3: Goose egg T3: 45 T3: 479 T3: 30.0%
T4: 2031 T4: Leiji powder T4: 7–10 T4: 349 T4: 17.2%
C: not C: 45%
reported
Yan 1959 (Yan Non- T: 75 Not reported Leiji powder Placental 30 More than 41 T: 54.7%
and Su, 1959) RCT globulin and 1 month
C: 35 umbilical C: 71.4%
placenta
powder
Lu 1957 (Lu, 1957) Non- T1: 261 6 months–12 T1: Zicaogen Blank T1: 3 T1: 56 T1: 48 T1: 18.4%
RCT decoction
T2: 145 T2: Leiji powder T2: 5 T2: 30 T2: 9 T2: 6.2%
C: 60 C: 14.6%
Sheng 1957 (Lu, Case 1,086 4 months–10 Leiji powder Not reported 25 21 18 1.7%
1957) series
Zheng 1960 Case 4,468 Not reported Leiji powder Not reported 5 Not 648 14.5%
(Zheng, 1960) series reported
Qiang 1959 (Qian Case T1: 118 4 months–7 Leiji powder Not reported T1: 28 T1: 30 31 T1: 26.3%
et al., 1959) series
T2: 25 T2: 3 T2: 40 T2: 8.0%
T3: 92 T3: 5 T3: 30 T3: 3.3%
Xinxiangg 1959 Case 164 4 months–7 Leiji powder Not reported 7–10 15 3 1.8%
(Measles series
prevention and
control group of
Shengli road office
of Xinxiang City,
1959)
Notes: RCT, randomized controlled trial; T, treatment group; and C, control group.
General evidence of Chinese herbal time were pooled in the meta-analysis (Figure 3). The results showed
formulas for measles, varicella, and rubella that compared with Western medicine, CM combined with Western
medicine showed significant improvement in fever clearance time
In summary, we identified 39 clinical trials on the treatment of (MD, −1.42 days; 95% CI, −1.89 to −0.95; p < 0.00001; I2 = 91%;
measles, varicella, and rubella with CM. The data from 20 studies on 10 RCTs), rash/pox extinction time (MD, −1.71 days; 95%
fever clearance time, rash/pox extinction time, and rash/pox scab CI, −2.65 to −0.76; p = 0.0004; I2 = 91%; six RCTs), and rash/

Rong et al. 10.3389/fphar.2023.1121580
TABLE 2 Characteristics of included trials of Chinese herbal formulas for measles.
Study ID Design Population Average Sample Intervention Control Course Outcome Adverse
type age (year) size (d) reaction
(case,
T/C)
Xu 2020 (Xu, RCT Children T: 5.28 ± 1.11 80 (40/40) Modified Yinqiao Conventional 3–5 Total effective rate Not
2020) powder anti- and complication reported
C: 5.42 ± 1.06 symptomatic rate
treatment
Zhou 2019 RCT Children T: 60 (30/30) Self-made Conventional 7 Total effective rate, Not
(Zhou et al., 5 months–14 prescription anti- time of rash reported
2019) symptomatic disappearance,
C: treatment fever clearance
4 months–13 time, duration of
cough,
hospitalization
time, and
complication rate
Tu 2016 (Tu RCT Adult T1: 87 (30/ Modified Qingjie Conventional Not Total effective rate, Nausea and
et al., 2016) 35.79 ± 7.12 29/28) Toubiao decoction anti- reported fever clearance vomiting
symptomatic time,
T2: 36.46 ± treatment hospitalization
10.53 time, duration of
fever, and
C: complication rate
32.23 ± 7.38
Li 2015 (Li and RCT Adult 32.21 ± 1.83 100 (50/50) Self-made Conventional Not Hospitalization Not
Lei, 2015) prescription anti- reported time and total reported
symptomatic effective rate
treatment
Liu 2013 (Liu RCT Children T: 7.35 ± 3.12 60 (30/30) Self-made Combined Not Hospitalization Not
and Liang, prescription traditional reported time and reported
2013) C: 7.71 ± 2.54 Chinese and complication rate
Western
medicine
Zhang 2009 RCT Adult T: 22.7 ± 15.6 62 (32/30) Modified Conventional 5 Total effective rate, Not
(Zhang et al., Huanglian Jiedu anti- scores of clinical reported
2009) C: 23.5 ± 16.7 decoction and symptomatic symptoms and
modified Xijiao treatment signs,
Dihaung decoction normalization rate
of irritative cough
liver function
normalization rate,
hospitalization
time, and medical
cost
Niu 2006 (Niu RCT Children T: 4.58 ± 1.41 100 (50/50) Modified Qingjie Conventional Not Total effective rate, Not
et al., 2006) Toubiao decoction anti- reported fever clearance reported
C: 4.66 ± 1.50 symptomatic time, rash onset
treatment time, and the
disappearance time
of pulmonary rales
Zhang 2004 RCT Children/adult Not reported 86 (44/42) Modified Maxing Conventional 4–10 Fever clearance Not
(Zhao et al., Shigan decoction anti- time, time of rash reported
2004) symptomatic disappearance,
treatment markedly effective,
and complication
rate
Li 2000 (Li, RCT Children T: 3.48 ± 0.31 102 (60/42) Modified Xijiao Conventional Not Fever clearance Not
2000) Dihaung decoction anti- reported time, rash onset reported
C: 3.26 ± 0.54 symptomatic time, course of
treatment disease, and total
effective rate
Wang 1995 RCT Children/adult T: 1–25 142 (82/60) Modified Qingjie Conventional 7–10 Cure rate Not
(ang, 1995) Toubiao decoction anti- reported
(Continued on following page)

Rong et al. 10.3389/fphar.2023.1121580
TABLE 2 (Continued) Characteristics of included trials of Chinese herbal formulas for measles.
(case,
T/C)
C: not and modified symptomatic
reported ephedra, apricot, treatment
gypsum, and
licorice decoction
Zhao 2021 Non-RCT Children T: 3.58 ± 1.02 100 (50/50) Modified Xuanbai Routine general Not Time of rash Not
(Zhao, 2021) Chengqi decoction care reported disappearance, reported
C: 4.15 ± 1.01 fever clearance
time, duration of
cough, sleepiness
time, total effective
rate, and degree of
satisfaction
Ye 1962 (Ye Non-RCT Children Not reported 899 Modified Sangju Conventional 4.38 Fever clearance Not
et al., 1962) (818/81) decoction, anti- time, time of rash reported
modified Yinqiao symptomatic disappearance, cure
powder, and treatment time, and
modified Qianjin complication rate
Weijing decoction
303 Hospital Non-RCT Not reported Not reported 192 Zicao Fuping Western Not Rash onset time Not
1959 (Efficacy (155/37) decoction and medicine reported and complication reported
effect in Sanhaung Shigao antibiotic
155 cases, decoction treatment
1959)
Qi 2016 (Qi, Cohort Adult 33 80 (40/40) Modified Shengma Conventional Not Duration of fever, Bad
2016) study Gegen decoction anti- reported WBC, CRP, and appetite
symptomatic ALT, and
treatment complication
Notes: RCT, randomized controlled trial; T, treatment group; C, control group; WBC, white blood cell; CRP, C-reactive protein; and ALT, alanine transaminase.
pox scab time (MD, −1.57 days; 95% CI, −1.94 to −1.19; p < 0.00001; Toubiao decoction, and modified Shengma Gegen decoction
I2 = 62%; five RCTs). When compared with Western medicine, CM could reduce the time of rash/pox extinction and scab and fever
alone could fasten fever clearance (MD, −1.05 days; 95% clearance.
CI, −1.68 to −0.42; p < 0.00001; I2 = 98%; 4 RCTs) and reduce
the time of rash/pox extinction (MD, −1.39 days; 95%
CI, −1.78 to −1.00; p < 0.00001; I2 = 93%; 6 RCTs). However, no Discussion
significant difference was found in rash/pox scab time when
comparing CM alone with Western medicine (MD, −0.18 days; The emergence of a new outbreak caused by the monkeypox
95% CI, −1.21 to −0.85; p = 0.02; I2 = 82%; two RCTs). In virus raised concerns among public health authorities, and there
summary, whenever CM was used alone or combined with were no licensed treatments for patients with monkeypox virus
Western medicine, the symptoms of pox-like viral disease infection. It is urgent to investigate effective intervention strategies
probably cleared faster when compared with Western medicine from CM for its prevention and treatment. Our review integrated
alone, lessening the time of suffering for the patients. multiple lines of evidence from historical classics and clinical
Of the 39 clinical trials on the treatment of measles, studies, which suggested that modified Yinqiao powder, modified
varicella, and rubella with Chinese medicine herbal Xijiao Dihaung decoction, modified Qingjie Toubiao decoction,
interventions (11/39), modified Yinqiao powder (8/39), modified Shengma Gegen decoction, and Leiji powder were
modified Xijiao Dihaung decoction (5/39), modified Qingjie effective in preventing and treating smallpox, measles, varicella,
Toubiao decoction, and Shengma Gegen decoction (4/39) were and rubella. The evidence synthesis from other contagious pox-like
frequently studied and applied for pox-like viral diseases. We viral diseases was highly significant for exploring the intervention
pooled the data from the included RCTs (Table 5) and program for monkeypox.
found that when compared with Western medicine, the four The multi-country outbreak of monkeypox posed unique
formulas used alone or combined with Western medicine all challenges. At the time of writing, there are no specific
showed significant differences in the reduction of treatments for monkeypox patients. Two oral drugs (tecovirimat
fever clearance time, rash/pox extinction time, and rash/pox and brincidofovir) have been approved for the treatment of
scab time. In summary, modified Yinqiao powder, smallpox and have demonstrated efficacy against monkeypox
modified Xijiao Dihaung decoction, modified Qingjie based on animal models, while the clinical data regarding the

Rong et al. 10.3389/fphar.2023.1121580
TABLE 3 Characteristics of included trials of Chinese herbal formulas for varicella.
(case,
T/C)
Huang RCT Children T: 7.19 ± 2.10 84 (42/42) Huanglian Jiedu Western 5 Total effective rate, Diarrhea, thirst,
2022 decoction, Xijiao medicine CM syndrome nausea,
(Huang, C: 6.54 ± 2.23 Dihaung decoction, antiviral scores, CRP, TNF- vomiting,
2022) and modified Six- therapy α, and PCT, fever headache, and
one powder clearance time, time skin itching
of rash
disappearance, rash
scab time
Zhang 2021 RCT Children T: 5.70 ± 1.80 60 (30/30) Self-made Western 5 Total effective rate, No
(Zhang and prescription medicine CM syndrome
Zhou, C: 6.00 ± 2.13 antiviral scores, fever
2021) therapy clearance time, time
of rash
disappearance,
antipruritic time,
hospitalization
time, and Hamilton
anxiety scale
Din 2021 RCT Children T: 9.80 ± 3.04 60 (30/30) Self-made Western 5 Total effective rate, Not reported
(Ding, prescription medicine fever clearance
2021) C: 9.77 ± 3.09 antiviral time, and rash scab
therapy time
Guan 2020 RCT Children T: 4.5 ± 0.5 200 Yinqiao powder Western 7 Total effective rate, Not reported
(Guan, (100/100) and Three-nut medicine fever clearance
2020) C: 4.7 ± 0.7 decoction antiviral time, and time of
therapy rash disappearance
Tang 2019 RCT Adult T: 32.09 57 (28/29) Lianhua Qingwen Western 7 Total effective rate, Fever, headache
(Tang et al., (26–43) capsules medicine fever clearance and
2019) antiviral time, and rash scab gastrointestinal
C: 33.05 therapy time discomfort
(29–49)
Gao 2016 RCT Adult T: 22.9 ± 2.3 100 (50/50) Modified Yinqiao Western 10 Total effective rate, Not reported
(Gao et al., powder and medicine fever clearance
2016) C: 23.2 ± 2.1 modified six-one antiviral time, time of rash
powder therapy disappearance, and
cure time
Zhang RCT Children T: 5.7 ± 2.1 80 (40/40) Shengma Gegen Western 7 Total effective rate, Nausea,
2016a decoction, White medicine fever clearance vomiting,
(Zhang, C: 5.4 ± 1.4 Tiger decoction, antiviral time, rash scab proteinuria, and
2016) and Xijiao Dihaung therapy time, and mild stomach
decoction hospitalization time discomfort
Han 2016 RCT Children T: 4.3 ± 1.4 86 (43/43) Shengma Gegen Western Not Time of rash Nausea,
(Han, decoction, Baihu medicine reported disappearance, total vomiting, and
2016) C: 4.1 ± 1.7 decoction, and antiviral effective rate, and proteinuria
Xijiao Dihaung therapy hospitalization time
decoction
Wang 2015 RCT Children T: 3–8 60 (30/30) Modified Wuli Western Not Total effective rate, Not reported
(Wang, Huichun Pills medicine reported fever clearance
2015) C: 2–7 antiviral time, antipruritic
therapy time, rash scab
time, and cure time
Quan 2011 RCT Children T: 2–12 200 Kushen decoction Western 5 Total effective rate No
(Quan, (100/100) medicine
2011) C: 2–12 antiviral
therapy
Chen 2010 RCT Children T: 1–10 60 (30/30) Modified Yinqiao Western 7 Total effective rate Not reported
(Chen, powder medicine
therapy
(Continued on following page)

Rong et al. 10.3389/fphar.2023.1121580
TABLE 3 (Continued) Characteristics of included trials of Chinese herbal formulas for varicella.
(case,
T/C)
Zeng 2009 RCT Children T: 2–15 86 (44/42) Modified Yinqiao Western 5 Total effective rate Not reported
(Zeng et al., powder and medicine
2009) C: 2–15 modified Qingwen antiviral
Baidu decoction therapy
Zhu 2009 RCT Children T: 9.32 ± 2.15 85 (43/42) Modified Yinqiao Western 3 Total effective rate, No
(Zhu et al., powder and medicine fever clearance
2009) C: 9.28 ± 2.24 modified Three-nut antiviral time, time of rash
decoction therapy disappearance, and
rash scab time
Zhao 2009 RCT Adult T: 21.4 (19–24) 80 (40/40) Modified Qingjie Western Not Fever clearance No
(Zhao, Toubiao decoction medicine reported time, rash scab
2009) C: 21.6 (19–24) antiviral time, IL-6, IL-8, and
therapy TNF-α
Zhao 2007 RCT Children T: 7.55 ± 2.41 76 (42/34) Modified Qingjie Western 5 Total effective rate, Shivering,
(Zhao, Toubiao decoction medicine fever clearance headache,
2007) C: 7.25 ± 2.49 and modified antiviral time, antipruritic nausea,
Wuwei Xiaodu therapy time, and rash scab vomiting, and
decoction time bad appetite
Chen 2006 RCT Adult T: 18–58 86 (46/40) Modified Youlong Western 7 Total effective rate No
(Chen, decoction medicine
therapy
Zhang 2006 RCT Children T: 4.56 ± 1.28 48 (24/24) Modified Yinqiao Western 3 Total effective rate Not reported
(Zhang and powder, Wuwei medicine
Tao, 2006) C: 5.15 ± 1.42 Xiaodu decoction, antiviral
and Xijiao Dihaung therapy
decoction
Yang 2003 RCT Children T: 3–7 114 (60/54) Modified Yinqiao Western 3 Total effective rate, Not reported
(Yang, powder medicine fever clearance
2003) C: 3–7 antiviral time, antipruritic
therapy time, time of rash
disappearance, and
rash scab time
Li 2002 (Li RCT Children T: 68 (38/30) Modified Wuwei Western 5 Total effective rate No
and Zhang, 9 months–12 Xiaodu decoction medicine
2002) antiviral
C: 1–10 therapy
Li 1999 (Li, RCT Children 5.3 (3–14) 77 (45/32) Modified Coix and Western 3.1 Total effective rate, Not reported
1999) bamboo leaf medicine fever clearance
powder antiviral time, and rash scab
therapy time
Wan 1996 RCT Children 7 months–13 120 (60/60) Modified Qingwei Western Not Total effective rate Not reported
(Wan and powder medicine reported
Ye, 1996) antiviral
therapy
Lin 1994 RCT Children T: 7 48 (25/23) Self-made Western 6 Total effective rate, Not reported
(Lin, 1994) (4 months–13) prescription medicine and rash scab time
antiviral
C: 6.5 therapy
(6 months–11)
Ma 2017 Non-RCT Children 7 (3–11) 80 (40/40) Shengma Gegen Western Not Total effective rate Adverse event
(Ma, 2017) decoction, Baihu medicine reported rate
decoction, and antiviral
Xijiao Dihaung therapy
decoction
Notes: RCT, randomized controlled trial; T, treatment group; C, control group; CM, Chinese medicine; CRP, C-reactive protein; TNF-α, tumor necrosis factor-α; PCT, procalcitonin; IL-6;
interleukin-6; and IL-8, interleukin-8.

Rong et al. 10.3389/fphar.2023.1121580
TABLE 4 Characteristics of included trials of Chinese herbal formulas for rubella.
type age size (d) reaction
(Year) (case,
T/C)
Li 2012 (Li RCT Children/adult 11–28 43 (22/21) Modified Yinqiao Self-made 3–7 Time of rash No
and Zeng, powder and Xijiao prescription disappearance and
2012) Dihaung decoction total disease course
He 2008 RCT Adult T: 60 (30/30) Huanglan Granule Western 20 RuV-IgM Not

(He et al., 27.70 ± 3.44 medicine reported
2008) antiviral
C: therapy
27.93 ± 3.33
Zhou 1995 RCT Children 1–13 152 (122/30) Modified Yinqiao Chinese Not Fever clearance time, No
(Zhou, powder patent reported time of rash
1995) medicine disappearance, and
regression time of
lymphadenopathy
Notes: RCT, randomized controlled trial; T, treatment group: C, control group; and RuV-IgM, rubella virus-immunoglobulin M.
efficacy of these agents in humans against monkeypox were lacking

(Parker et al., 2012; Adler et al., 2022). Recorded literature showed
that the use of CM to prevent and treat epidemics of contagious pox-
like viral diseases can be traced back to ancient CM practice over
thousands of years, and its successful effects were preliminarily
substantiated by modern human clinical research when applied to
smallpox, measles, varicella, and rubella epidemics, which suggests
that historical CM experience is a worthwhile approach.
We are worried about a new threat posed by the outbreak of
monkeypox, but we still knew little about monkeypox, especially
in terms of in vivo viral kinetics and infectivity (Learned et al.,
2003; Mbala et al., 2017). The treatment and prevention of other
contagious pox-like viral diseases by Chinese herbal formulas
were of great significance to explore the intervention program
for monkeypox. Our results suggested that compared with
Western medicine, Chinese herbal formulas combined with
Western medicine and Chinese herbal formulas alone both
showed significant improvements in fever clearance time,
rash/pox extinction time, and rash/pox scab time, which
indicates that the symptoms of contagious pox-like viral
diseases may improve faster than those of Western medicine
alone, especially in reducing time rash/pox extinction and fever
clearance. The most frequently used Chinese herbal formulas
included modified Yinqiao powder, modified Xijiao Dihaung
decoction, modified Qingjie Toubiao decoction, modified
Shengma Gegen decoction, and Leiji powder. The use of
Chinese herbal formulas to prevent and treat other
contagious pox-like viral diseases may be effective in treating
monkeypox infections.
Yinqiao powder came from the Treatise on differentiation and
treatment of epidemic febrile disease in the Qing Dynasty. Yinqiao
powder was a classic prescription for treating exothermic febrile
diseases with clinical symptoms including fever and sore throat. It
FIGURE 3
Forest plot of RCTs on CM for pox-like viral diseases on (A) fever has the effect of releasing the exterior with pungent cool, clearing
clearance time; (B) rash/pox extinction time; (C) rash/pox scab time. heat, and removing toxins, mainly used in the early stage of epidemic
febrile diseases. The core components of Yinqiao powder, Lonicera

Rong et al. 10.3389/fphar.2023.1121580
TABLE 5 Meta-analysis of RCTs on four Chinese herbal formulas for contagious pox-like viral diseases.
Outcome Comparison No. of No. of Mean difference p-value I2

RCTs participant (95% CI)
Fever clearance time (days)

Modified Yinqiao powder (Zhou, 1995; Yang, CM vs. WM 3 296 −0.84 [−1.07, −0.60] p < 0.00001 61%
2003)
Modified Xijiao Dihaung decoction (Li, 2000) CM + WM vs. WM 1 102 −0.65 [−1.08, −0.22] p = 0.003 NA
Modified Qingjie Toubiao decoction (Niu et al., CM + WM vs. WM 1 60 −3.07 [−3.68, −2.46] p < 0.00001 NA
2006)
Modified Shengma Gegen decoction (Zhang, CM + WM vs. WM 1 80 −1.78 [−2.28, −1.28] p < 0.00001 NA
2016)
Rash/pox extinction time (days)

Modified Yinqiao powder (Zhou, 1995; Yang, CM vs. WM 3 296 −1.04 [−1.55, −0.53] p < 0.0001 92%
2003)
Modified Xijiao Dihaung decoction (Li, 2000; Li CM vs. WM 1 43 −2.38 [−2.83, −1.93] p < 0.00001 NA
and Zeng, 2012)
CM + WM vs. WM 1 102 −0.65 [−1.08, −0.22] p = 0.003 NA
Modified Qingjie Toubiao decoction (Niu et al., CM + WM vs. WM 1 60 −2.19 [−3.31, −1.07] p = 0.0001 NA
2006)
Modified Shengma Gegen decoction (Han, CM + WM vs. WM 1 86 −1.90 [−2.65, −1.15] p < 0.00001 NA
2016)
Rash/pox scab time (days)

Modified Yinqiao powder (Yang, 2003) CM vs. WM 1 114 −0.90 [−1.21, −0.59] p < 0.00001 NA
Modified Shengma Gegen decoction (Zhang, CM + WM vs. WM 1 80 −2.19 [−2.74, −1.64] p < 0.00001 NA
2016)
Notes: RCT, randomized controlled trial; CM, Chinese medicine; WM, western medicine; and NA, not applicable.
japonica Thunb. and Forsythia suspensa (Thunb.) Vahl were the appear which may last for 2 to 3 weeks (Petersen et al., 2019). Our
most powerful traditional medicines for heat-clearing and results found that Yinqiao powder could improve the time of rash/
detoxification. The other components including Platycodon pox extinction, rash/pox scab, and fever clearance.
grandiflorus (Jacq.) A. DC., Mentha canadensis L., Glycyrrhiza Shengma Gegen decoction was a classic prescription to treat pox-
glabra L., and Arctium lappa L. have effects for clearing the like viral diseases coming from the Formulary of the Bureau of Taiping
throat. Sesamum indicum L. and Glycine max L.) Merr. have the People’s Welfare Pharmacy in the Song Dynasty, which was composed
effects of inducing sweating to release the exterior. These medicines of A. cimicifuga L., Pueraria montana var. lobata (Willd.) Maesen and
were used together to give Yinqiao powder the ability to release the S.M.Almeida ex Sanjappa and Predeep, Paeonia lactiflora Pall., and G.
exterior with pungent cool, clear heat, and remove toxins (Wang glabra L. This prescription has an outstanding effect of releasing flesh
et al., 2011). At the initial stage of febrile disease infection, Yinqiao with pungent cool, removing toxins, and promoting eruption, and it
powder has a strong effect of blocking the progress of the disease. In was mainly used for measles, varicella, rubella and other eruptive
China, Yinqiao powder was widely used to treat viral pneumonia, diseases, viral pneumonia, herpes, and hepatitis C (Zhu et al., 1989;
COVID-19, measles, varicella, and rubella (Lyu et al., 2020; Xu and Niu, 1996; Li et al., 2015). Pharmacological research proved that A.
Jia, 2020; Guo et al., 2021a; Lin et al., 2021). An experimental study cimicifuga L. and P. montana var. lobata (Willd.) Maesen and
found that the effect of Yinqiao powder in preventing and treating S.M.Almeida ex Sanjappa and Predeep exhibited anti-osteoporosis,
upper respiratory tract infection could be explained by its antiviral, antitumor, antioxidant, and antiangiogenic activities (Guo
antibacterial and antiviral properties and improvement of the et al., 2017; Hu et al., 2021). The main effect of this prescription was
function of the upper respiratory mucosal immune system (Liu releasing exterior and promoting eruption. In clinical application, it
et al., 2015). A multicenter, large-scale, randomized trial found that can be used together with botanical drug M. canadensis L., L. japonica
Yinqiao powder plus another heat-clearing formula could reduce Thunb., and A. lappa L. to enhance the power of promoting eruption
time to fever resolution in patients with the H1N1 influenza virus and clearing heat. In the incubation period of monkeypox disease or
infection (Wang et al., 2011). Pharmacological studies have shown when clinical symptoms such as fever and rash appear, Yinqiao powder
that Yinqiao powder has an antitussive and expectorant effect, may be effective in improving clinical symptoms. Therefore, Shengma
improving lung function, alleviating acute lung injury, alleviating Gegen decoction could be combined with Yinqiao powder to treat
pulmonary fibrosis, enhancing the antiviral immune response, and monkeypox during the incubation period or when the patient has fever
alleviating the adverse effects of modern drugs (Rothan and symptoms and the rash does not appear completely. Meanwhile,
Byrareddy, 2020). The monkeypox identified during the Shengma Gegen decoction has been officially recommended in the
2022 outbreak begins with non-specific symptoms and signs that guidelines for the diagnosis and treatment of monkeypox
include fever, headache, muscle aches, back pain, low energy, and (2022 version) (Interpretation of guidelines for diagnosis, 2022) by
swollen lymph nodes; it can also begin with a fever before rashes the National Health Commission of the People’s Republic of China.

Rong et al. 10.3389/fphar.2023.1121580
Modified Qingjie Toubiao decoction, a famous empirical smallpox, which may be useful for monkeypox (Rizk et al., 2022).
prescription, comes from the Dictionary of Traditional Chinese While the safety information on vaccines (such as ACAM200)
Medicine. When measles patients have symptoms such as among children or pregnant women is limited, the vaccine
intensive measles, persistent high fever, and sore throat, Qingjie efficacy/effectiveness against monkeypox in the current epidemic
Toubiao decoction can be used to clear heat and detoxify and remains uncertain. Our results showed that Leiji powder had a
promote the penetration of rash (ang, 1995). Qingjie Toubiao significant effect on the prevention of pox-like viral diseases; Leiji
decoction has the effect of expelling pathogens through the powder comes from the Xiaoer Weisheng Zongwei Lunfang in the
exterior with pungent cool and ventilating lung, which has been Southern Song Dynasty. Historically, there were a lot of reports on
proven to be effective in the clinical practice of CM. Tamarix the use of Leiji powder to prevent and treat measles, scarlatina,
chinensis Lour. has effects of exterior releasing and promoting cholera, diarrhea, jaundice, dysentery, syncope, and other diseases in
eruption, expelling wind, and eliminating dampness. Pterocarpus China (Li and Li, 1959; Zhang, 1960; Zheng, 1960; Chen, 1964; Yu,
lucens Lepr. ex Guill. and Perr. and A. lappa L. could promote 1996). We searched nine literature reports on the use of Leiji powder
eruption and clear heat. Actaea cimicifuga L. and P. montana var. (nasal drip) to prevent measles. There was a report on the use of Leiji
lobata (Willd.) Maesen and S.M.Almeida ex Sanjappa and Predeep powder to prevent measles in 4,468 measles-susceptible children,
could release flesh and promote eruption. Compared with Shengma with an incidence rate of 14.5% (Zheng, 1960). Another non-RCT
Gegen decoction, Qingjie Toubiao decoction was more effective in including 2,031 subjects, reported that the incidence rate was 17.2%
removing toxins, relieving symptoms, cooling blood, and relieving (Jinzhou city hospital, 1959). The nasal drip of Leiji powder was
itching. It might be used in the early, middle, and even the late stages effective in preventing measles, which could significantly reduce the
of monkeypox infections and was of great help in relieving patients’ severity of the disease, shorten the course of the disease, reduce
clinical symptoms. Pharmacological research showed that F. suspensa complications, and have no adverse reactions (Zhang, 1960; Lu,
(Thunb.) Vahl, Morus alba L., and L. japonica Thunb. have the effects 1957; Qian et al., 1959; Measles prevention and control group of
of clearing heat and removing toxins. Pueraria montana var. lobata Shengli road office of Xinxiang City, 1959). Although one RCT study
(Willd.) Maesen and S.M.Almeida ex Sanjappa and Predeep, P. lucens (Chen, 1964) (n = 103) showed that Leijisan had no effect on measles
Lepr. ex Guill. and Perr., A. lappa L., and T. chinensis Lour. could help prevention, it might be related to the way of drug production,
in exterior releasing, ventilating lung, promoting eruption, and method used, and treatment course (Qian et al., 1959; Measles
relieving itching. Alternanthera sessilis L.) R. Br. ex DC. could be prevention and control group of Shengli road office of Xinxiang
used at any stage of rash outbreak and could clear heat and cool City, 1959). The main metabolite Gleditsia sinensis Lam. of Leiji
blood, remove toxins, and promote eruption. Qingjie Toubiao powder has the function of resolving phlegm for resuscitation,
decoction could effectively control body temperature, promote the reducing swelling, and alleviating pain (Dong et al., 2022).
appearance of skin rash, reduce serious complications, shorten the Angelica dahurica (Hoffm.) Benth. and Hook. f. ex Franch. and
course of the disease, and improve the curative effect when used at the Sav. and Atractylodes lancea (Thunb.) DC. have antiviral and
eruptive stage of contagious pox-like viral diseases. antibacterial effects and were effective in preventing measles and
Modified Xijiao Dihaung decoction was a classical prescription of influenza (Qian et al., 1959; Huang et al., 2022). Another metabolite,
CM derived from Important Prescriptions Worth a Thousand Gold for Liquidambar orientalis Mill., could resolve dampness and remove
Emergency by Sun Simiao in the Tang Dynasty. Xijiao Dihaung toxins. Modern pharmacological studies have proven that L.
decoction contains Cornu Bubali, Rehmannia glutinosa (Gaertn.) orientalis Mill. possesses potent anti-inflammatory effects,
DC., P. lactiflora Pall., and Paeonia × suffruticosa Andrews. Xijiao neuroprotective effects, anti-cancer effects, and antioxidant effects
Dihaung decoction has the effect of nourishing yin, reducing fever, (Guo et al., 2021b; Liu et al., 2021). The components of this
dispelling phlegm, and cooling the blood and was recommended to prescription can promote the disappearance of herpes in patients
patients who suffered from pneumonia, alimentary tract hemorrhage, with severe herpes eruptions. More prospective population studies
radiation enteritis, and sepsis. Animal experiments showed that Yinqiao are needed to further investigate the effect of Leiji powder in
powder combined with Xijiao Dihaung decoction has a therapeutic preventing monkeypox.
effect on influenza A virus infection, and the underlying mechanisms
might be related to regulating antiviral immunity and ameliorating
excessive inflammatory responses (Li et al., 2020). A pharmacological Limitations
study also suggested that Xijiao Dihaung decoction combined with
Yinqiao powder inhibits the inflammatory response mediated by the Our study had several limitations. Human monkeypox was first
MAPK signaling pathway to treat influenza viral pneumonia (Guo et al., reported in central Africa in 1970 (Marennikova et al., 1972) and has
2021a). Our review showed that Xijiao Dihaung decoction was mainly never broken out in Chinese history. There were no data on using
used for measles, varicella, and rubella patients with severe clinical CM for monkeypox in historical records and human research.
symptoms, such as persistent fever, skin rashes that do not scab, However, there are many studies on the use of CM to prevent
pneumonia, and other complications. For monkeypox patients, and treat contagious pox-like viral diseases in China. The
Xijiao Dihaung decoction may promote the crusting of patients’ skin suggestions from other pox-like viral diseases may be beneficial
rashes and shorten the fever time. for exploring the appropriate solutions for monkeypox. Second, we
People who lived with or had close contact (including sexual searched records of using CM for contagious pox-like viral diseases
contact) with someone who has monkeypox are most at risk. including monkeypox, smallpox, measles, varicella, and rubella in
Currently, there are three smallpox vaccines in the US Strategic the review. It might not be completely representative of respiratory
National Stockpile: JYNNEOS and ACAM2000 are licensed for viral diseases. Finally, as there was no direct clinical evidence for the

Rong et al. 10.3389/fphar.2023.1121580
prevention and treatment of the new breakout monkeypox, abstract screening and identified included studies. X-ZL, XS, CS, and
currently reported studies were from the previous literature on W-JY carried out the data extraction. HGR and X-WZ wrote a first
other contagious pox-like viral diseases which can only be draft of the manuscript, and PL, Y-TF, HF, and X-DW gave their
considered indirect evidence to refer to the current outbreak. input in subsequent drafts. All authors contributed to the
There is an urgent need for prospective studies with rigorous interpretation of the data and the revision of the manuscript.
design and a large sample to evaluate the effect of Chinese herbal
formulas on monkeypox infections.
Funding
Conclusion This work was supported by the Innovation Team and Talents
Cultivation Program of National Administration of Traditional Chinese
In conclusion, based on historical records and clinical studies of Medicine (No. ZYYCXTD-C-202006) and Fundamental Research
contagious pox-like viral diseases, the Chinese herbal formulas could Funds for the Central Universities (No. 2022-JYB-PY-013).
be considered an alternative approach for the prevention and
treatment of monkeypox. According to the principle of syndrome
differentiation and treatment of CM, Yinqiao powder, Shengma Conflict of interest
Gegen decoction, Qingjie Toubiao decoction, and Xijiao Dihaung
decoction had the potential to be useful for monkeypox treatment. The authors declare that the research was conducted in the
Leiji powder may be effective in preventing monkeypox infection. absence of any commercial or financial relationships that could be
The main limitation of this study is that there was no direct clinical construed as a potential conflict of interest.
evidence of the treatment of monkeypox with CM. We look forward
to real-world studies to verify our hypothesis. Furthermore,
prospective well-designed clinical studies are needed to Publisher’s note
investigate the effectiveness of Chinese herbal formulas for
monkeypox. All claims expressed in this article are solely those of
the authors and do not necessarily represent those of
their affiliated organizations, or those of the publisher,
Data availability statement the editors, and the reviewers. Any product that may
be evaluated in this article, or claim that may be made
The original contributions presented in the study are included in by its manufacturer, is not guaranteed or endorsed by the
the article/Supplementary Material, further inquiries can be directed publisher.
to the corresponding author.
Supplementary material
Author contributions
The Supplementary Material for this article can be found online
J-PL conceived the project. H-GR coordinated the data at: https://www.frontiersin.org/articles/10.3389/fphar.2023.1121580/
collection and analysis, and X-WZ, MH, and XS performed the full#supplementary-material
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TYPE Systematic Review

PUBLISHED 13 March 2023

Evidence synthesis of Chinese

RECEIVED 05 January 2023

Frontiers in Pharmacology 01 frontiersin.org

Systematic Review Registration: [https://inplasy.com/], identiﬁer

monkeypox, smallpox, measles, varicella, rubella, Chinese medicine, clinical studies

Introduction However, we can explore ways to prevent and treat monkeypox

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Clinical studies’ search results Evidence of Chinese herbal formulas for

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TABLE 1 Characteristics of clinical trials on Leiji powder preventing measles.

C: 205 T2: Leiji powder C: 26 C: 31.0%

T3: 92 T3: 5 T3: 30 T3: 3.3%

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TABLE 2 Characteristics of included trials of Chinese herbal formulas for measles.

(Continued on following page)

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TABLE 3 Characteristics of included trials of Chinese herbal formulas for varicella.

(Continued on following page)

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TABLE 4 Characteristics of included trials of Chinese herbal formulas for rubella.

He 2008 RCT Adult T: 60 (30/30) Huanglan Granule Western 20 RuV-IgM Not

efﬁcacy of these agents in humans against monkeypox were lacking

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Outcome Comparison No. of No. of Mean difference p-value I2

Fever clearance time (days)

Rash/pox extinction time (days)

Rash/pox scab time (days)

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