key: cord-1054152-c9ecid5e authors: Luo, Hui; Tang, Qiao-ling; Shang, Ya-xi; Liang, Shi-bing; Yang, Ming; Robinson, Nicola; Liu, Jian-ping title: Can Chinese Medicine Be Used for Prevention of Corona Virus Disease 2019 (COVID-19)? A Review of Historical Classics, Research Evidence and Current Prevention Programs date: 2020-02-17 journal: Chin J Integr Med DOI: 10.1007/s11655-020-3192-6 sha: 4c2d8626326664859db2a0500f70d6de736f5bfe doc_id: 1054152 cord_uid: c9ecid5e OBJECTIVE: Since December 2019, an outbreak of corona virus disease 2019 (COVID-19) occurred in Wuhan, and rapidly spread to almost all parts of China. This was followed by prevention programs recommending Chinese medicine (CM) for the prevention. In order to provide evidence for CM recommendations, we reviewed ancient classics and human studies. METHODS: Historical records on prevention and treatment of infections in CM classics, clinical evidence of CM on the prevention of severe acute respiratory syndrome (SARS) and H1N1 influenza, and CM prevention programs issued by health authorities in China since the COVID-19 outbreak were retrieved from different databases and websites till 12 February, 2020. Research evidence included data from clinical trials, cohort or other population studies using CM for preventing contagious respiratory virus diseases. RESULTS: The use of CM to prevent epidemics of infectious diseases was traced back to ancient Chinese practice cited in Huangdi’s Internal Classic (Huang Di Nei Jing) where preventive effects were recorded. There were 3 studies using CM for prevention of SARS and 4 studies for H1N1 influenza. None of the participants who took CM contracted SARS in the 3 studies. The infection rate of H1N1 influenza in the CM group was significantly lower than the non-CM group (relative risk 0.36, 95% confidence interval 0.24–0.52; n=4). For prevention of COVID-19, 23 provinces in China issued CM programs. The main principles of CM use were to tonify qi to protect from external pathogens, disperse wind and discharge heat, and resolve dampness. The most frequently used herbs included Radix astragali (Huangqi), Radix glycyrrhizae (Gancao), Radix saposhnikoviae (Fangfeng), Rhizoma Atractylodis Macrocephalae (Baizhu), Lonicerae Japonicae Flos (Jinyinhua), and Fructus forsythia (Lianqiao). CONCLUSIONS: Based on historical records and human evidence of SARS and H1N1 influenza prevention, Chinese herbal formula could be an alternative approach for prevention of COVID-19 in high-risk population. Prospective, rigorous population studies are warranted to confirm the potential preventive effect of CM. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at 10.1007/s11655-020-3192-6. In December 2019, a pneumonia associated with the corona virus disease 2019 (COVID- 19) emerged in Wuhan, Hubei Province, China. (1) It is highly contagious and has quickly spread to many other parts of China and some other countries within 1 month since the fi rst report emerged. As of February 11, 2020, 44,653 cases of confi rmed infections and 1,113 deaths have been reported in Chinese mainland. (2) Outside of China, there had been 395 confirmed cases and 1 death from 24 countries were reported as of February 11, 2020. (3) The outbreak of COVID-19 raised intense attention not only within China but internationally. (4) On 20 January 2020, the Chinese government added it to the Notifiable Communicable Disease List and gave the highest priority to its prevention and treatment. (5) On 30 January 2020, the World Health Organization : Based on historical records and human evidence of SARS and H1N1 influenza prevention, Chinese herbal Based on historical records and human evidence of SARS and H1N1 influenza prevention, Chinese herbal formula could be an alternative approach for prevention of COVID-19 in high-risk population. Prospective, rigorous formula could be an alternative approach for prevention of COVID-19 in high-risk population. Prospective, rigorous population studies are warranted to confi rm the potential preventive effect of CM. population studies are warranted to confi rm the potential preventive effect of CM. (WHO) declared a public health emergency of international concern for China's COVID-19. Although the WHO said: "To date, there is no specifi c medicine recommended to prevent or treat the novel coronavirus", (6) in China, historically, when the outbreak started, Chinese medicine (CM) approaches including oral administration of preventive herbal formulae, wearing CM sachets, indoor herbal medicine fumigation, etc. were recommended for prevention and treatment. (7, 8) For example, in 2003, CM approaches were used to prevent and treat severe acute respiratory syndrome (SARS), (9, 10) which was the most serious infectious disease outbreak in China prior to the COVID-19. In 2009, during the pandemic of H1N1 infl uenza around the world, the National Administration of Traditional Chinese Medicine of China issued a CM prevention program, which included 4 Chinese herbal medicine (CHM) formulae for adults of different CM body constitutions and one for children. (11) The current outbreak of COVID-19 resulted in many provinces in China issuing CM prevention and control programs, among which the prevention programs are mainly oral CHM formulae. This study has reviewed the historical and human research evidence on CM in preventing and control of infections in order to provide guidance for the prevention of COVID-19. Three types of data were searched, including historical classics records, human research evidence and current prevention programs. (Ⅰ) Historical classics records: records on the prevention of epidemic diseases in ancient CM books were searched, including history, treatment principles, medicines and application of CM to prevent epidemic disease. (Ⅱ) Human research studies: studies to evaluate the preventive effects of CM on contagious respiratory virus diseases were included. The inclusion criteria were as follows. (1) Study design: clinical trials, cohort studies, and other population studies without control. (2) Population: high-risk populations exposed to SARS or H1N1 infl uenza. (3) Intervention: oral CHM formulae, including decoction, granules, or patent medicine. (4) Control: placebo, blank or without control group. (5) Outcome: infection rate defi ned as laboratory-confi rmed incidence of disease. (Ⅲ) Current prevention programs: CM prevention programs for COVID-19 issued by the state or provincial health authorities in China. Considering that some provinces had regularly updated the programs according to the local prevalence and clinical practice, the most recent versions of the programs were included for analyses in this study. Retrieval strategy differed among the above three types of data. The fi rst type of data was based on mainly manual retrieval of ancient books of CM on epidemic diseases, supplemented by electronic database retrieval. The list of literature retrieved was determined by discussion among all authors. Secondly, 6 databases were searched including PubMed, Google Scholar, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and CQVIP database, with the key words of "severe acute respiratory syndrome" (or "SARS"), "infl uenza", "H1N1", "prevent*" and "Chinese medicine" (pinyin: zhongyi or zhongyao). Thirdly, government websites or offi cial media websites were searched for prevention programs on COVID-19. Two authors (Luo H and Tang QL) conducted the literature search independently. The search date was up to February 10, 2020. The following data were extracted and analyzed: source of evidence, time of publication or release, author, setting, basis for formulation of CM prevention strategy, composition of CM prescription, target disease, course of prevention, effect, and adverse reaction. The data was qualitatively described and presented, and if possible, quantitative or descriptive statistics were conducted. When the data were available for pooling, meta-analysis would be conducted by RevMan 5.3 software (https:// community.cochrane.org/help/tools-and-software/ revman-5/revman-5-download). The theory of prevention and treatment of "pestilence" (refers to fatal epidemic disease, pinyin: wenyi) in CM originated from Huangdi's Internal Classic (Huang Di Nei Jing), which was written about 2000 years ago. (12) It suggested two aspects which should be employed to prevent the spread of epidemics. One was to maintain and improve the healthy qi in the body by taking preventive medicine [Xiaojin Dan (小金丹) in Huangdi's Internal Classic, the first recommended formula of CM to prevent pestilence], healthy diet care, exercise and so on, so as to resist the invasion of external pathogen, and the other was to avoid the source of infection. (13) These two principles of epidemic disease prevention have been followed by CM practitioners till now. (12, 14) Since Huangdi's Internal Classic, a large number of formulae for preventing epidemic diseases have been recorded in other ancient CM classics, such as, the Handbook of Prescriptions for Emergencies (Zhou Hou Bei Ji Fang), Essential Prescriptions Worth a Thousand Gold for Emergencies (Bei Ji Qian Jin Yao Fang), Medical Secrets of an Official (Wai Tai Mi Yao), Compendium of Materia Medica (Ben Cao Gang Mu), etc. (15) The famous doctor SUN Si-miao (541-682 AD) expounded the basis of medicines to prevent "pestilence" in his book Essential Prescriptions Worth a Thousand Gold for Emergencies: "pestilence comes from nature, so to prevent it, we need to fi nd medicinal herbs that also come from nature. People would not be infected if they know and take preventive medicine." (16) A literature study compared the characteristics of medicinal formulae for preventing pestilence in different periods of ancient China, found that during the Jin and Tang Dynasties (3rd-10th century AD), medicinal formulae were mainly used to eliminate the pathogenic factors, while Ming and Qing dynasties (14-20th century AD) focused on fortifying Spleen (Pi), resolving dampness, clearing heat, and detoxifying. (17) A l t h o u g h m a n y f o r m u l a e f o r p e s t i l e n c e prevention were recorded in ancient CM books, the case description of prevention was relatively rare. Through limited literature searches, we found an interesting case report: SU Shi (1037-1101 AD), a famous poet in the Northern Song Dynasty, accidentally found a formula for preventing pestilence named Sheng San Zi (圣散子), a powder consisting of 22 herbs. (18) Later, when he was demoted to Huangzhou, Hubei Province, the pestilence had been outbreak for several years. He disclosed the prescription to the local people. After taking this formula, the number of patients with the disease was significantly reduced, and many lives were saved. This story was recorded by SU Shi himself, when he wrote a preface to his doctor friend PANG An-shi's book General Treatise on Febrile Diseases (Shang Han Zong Bing Lun). (18) Three studies were identified including 1 controlled study (19) and 2 single cohort studies (20, 21) conducted during the epidemic of SARS. Lau, et al (19) designed a controlled study to evaluate a herbal formula for prevention of SARS (no herbal intervention in the control group) and conducted it in Hong Kong SAR, China. The sample size was 16,437 (1,063 in the herbal group and 15,374 in the non-herbal group), and all participants were hospital care workers including doctors, nurses, and other staff. The result showed that none of the participants who took modifi ed formula of Yupingfeng Powder (玉 屏风散) plus Sangju Decoction (桑菊饮) contracted SARS, while 64 out of 15,347 (0.4%) in the non-herbal group were infected with SARS (P=0.035). Nineteen cases (1.8%) appeared minor adverse effects after 14 days taking herbal medicine, including diarrhea, sore throat, dizziness, and nausea. Both single cohort studies were conducted in Beijing, China with sample sizes of 3,561 (21) and 163, respectively. All participants were medical staff from two hospitals, where SARS patients were recruited and treated during the study period. Among them, Xu, et al's study (20) only included fi rst-line medical staff in treating SARS. The courses of taking herbal formulae for prevention were 6 days (20) and 12-25 days, (21) respectively. The formulae used in these studies were both classical formula Yupingfeng Powder plus some heat-clearing and detoxifying herbs. The results showed that none of the participants who took the preventive herbal medicine had contracted SARS in the two studies. Information on the safety of the herbal medicines was not reported. The details of the preventive herbal formulae of the three studies are presented in Table 1 . Four studies were identified, including 3 (22) (23) (24) randomized controlled trials (RCTs) and 1 (25) nonrandomized controlled clinical study. All the studies were conducted during the prevalence of H1N1 influenza in Chinese mainland and published in Chinese. In these studies, participants were exposed to high-risk environments, such as hospitals and schools where H1N1 influenza occurred. The total sample size was 25,636 with the largest one of 25, 329 . (25) The tested herbal interventions included self-made herbal formulae and Chinese patent medicines [Qingjie Fanggan Granule (清解防感颗粒), Kangbingdu Oral Liquid (抗病毒口服液); Ganmao Qingre Granule (感冒清热胶囊)]; while in the control group, 1 study used placebo and 3 used blank control. The course of herbal formulae ranged from 3 to 7 days, while the follow-up ranged from 5 to 30 days. The outcome measure was infection rate of H1N1 infl uenza tested by laboratory serological diagnosis. One study reported that no adverse events occurred, (22) while the others did not report. The details of the characteristics of included trials are presented in Table 2 . The data on infection rate of H1N1 influenza from 4 studies were pooled in meta-analysis. The results showed that the infection rate in the herbal formulae group was signifi cantly lower than that in the control group [relative risk (RR) 0.36, 95% confi dence Interval (CI) 0.24-0.52, P<0.01]. A sensitivity analysis was conducted to exclude non-RCT and the results showed similar effect (RR 0.36, 95% CI 0.21-0.62, P<0.01, Figure 1 ). Up to February 12, 2020, the National Health Commission of China has issued 5 versions of diagnosis and treatment programs for COVID-19, but none have included any content on CM prevention and control, but on treatment since the 3rd versions. (26) Of the 31 provinces (including autonomous regions, and municipalities) in Chinese mainland, health authorities in 23 provinces had offi cially issued programs recommending herbal formulae to preventing COVID-19. These 23 provinces cover 7 regions of mainland: Northeast, North, Central (including Wuhan, Hubei Province, the original outbreak of COVID-19), South, East, Northwest, and Southwest China. All programs were formulated by clinical experts organized by local health authorities according to local geographic and climate characteristics and COVID-19 prevalent conditions. The earliest program recommending CM for prevention was issued by Sichuan Province on January 21, 2019. Ten provinces have updated their programs since the fi rst announcement, 7 of them have issued the 2nd edition and 3 issued the third edition. The applicable population of preventive programs included general and special population (such as the elderly, children, pregnant women, patients with chronic comorbidity diseases). Different groups of populations had specifi ed preventive CM formulae. The programs issued by the 23 provinces included CM formulae ranging from 1 up to 10, with an average of 3.4 per program. With regard to the course of CM formulae for prevention, 11 provinces recommended from 3 to 14 days, while 12 provinces did not mention. In addition, Tibet Autonomous Region recommended Tibetan medicine and Guizhou province recommended Miao medicine formulae (one of the minority folk medicines). The basic characteristics of 23 provincial programs are shown in Appendix 1. We counted the frequency of the herbs used in CM formulae for prevention of general population issued by the 23 provinces. The results showed that these formulae contained 54 different herbs, of which 19 herbs with a frequency of use for 3 or more times in preventive formulae for general population ( Figure 2 ). The top two were Radix astragali (Huangqi) and Glycyrrhizae Radix Et Rhizoma (Gancao). As a new emerging acute respiratory infectious disease, COVID-19 lacks effective methods to control and treat the infection. It is urgent and reasonable to explore effective intervention strategies from traditional medicine for its prevention. This study examines the historical records for infection prevention in CM, as well as previous clinical evidence on CM prevention for similar public health emergencies such as SARS and H1N1 influenza. Recorded literature showed that the use of CM to prevent epidemics of infectious diseases can be traced back to ancient CM practice over thousands of years, and its successful effects were preliminarily substantiated by modern human clinical researches when applied to SARS and H1N1 influenza epidemics suggesting that historical CM experience is a worthwhile approach. Based on the comprehensive analyses of the prevention programs issued by 23 provinces since the COVID-19 outbreak, we found that the main CM principles in preventing COVID-19 were to tonify qi to protect and provide defense from external pathogens, disperse wind and discharge heat, and resolve dampness with aroma. It was also similar to the characteristics of CHM formulae for preventing "pestilence" in ancient times and SARS in 2003. (17, 19) The 6 most commonly used herbs were Astragali Radix (Huangqi), Glycyrrhizae Radix Et Rhizoma (Gancao), Saposhnikoviae Radix (Fangfeng), Atractylodis Macrocephalae Rhizoma (Baizhu), Lonicerae Japonicae Flos (Jinyinhua), and Forsythiae Fructus (Lianqiao). Astragali Radix (Huangqi), Saposhnikoviae Radix (Fangfeng), and Atractylodis Macrocephalae Rhizoma (Baizhu) are all ingredients of a classical herbal formula Yupingfeng Powder, for tonifying qi to protect from external pathogens. In Lao, et al's controlled study (19) of CM formula for preventing SARS, Yupingfeng Powder was also the main ingredients. Some studies have confirmed that Yupingfeng Powder has antiviral, anti-inflammatory and immunoregulatory effects. (27, 28) Japonicae Flos (Jinyinhua) and Forsythiae Fructus (Lianqiao) are the core components of Yinqiao Powder, which is a classical formula used to prevent and treat respiratory infectious diseases in ancient. (29) An experimental study found that the effect of Yinqiao Powder (银翘 散) in preventing and treating upper respiratory tract infection could be explained by its antibacterial and antiviral properties and improvement of the function of upper respiratory mucosal immune system. (30) A multicenter, large-scale, randomized trial found that Yinqiao Powder plus another heat-clearing formula could reduce time to fever resolution in patients with the H1N1 infl uenza virus infection. (29) At present, the National Health Commission of China has not issued a CM prevention program for COVID-19. The reasons may be, first, according to the CM theory of three-factors concerned treatment (Sanyin Zhiyi, 三因制宜), due to the differences of individual, regional, and seasonal factors in the occurrence and distribution of diseases, these factors should be considered in prevention and treatment, (31, 32) and second, lack of solid evidence of CM formula for COVID-19. By comparing and analyzing the prevention programs issued by provincial levels, we also found that there was slight regional difference in the recommended herbal formulae and prescription principles. For example, due to the dry climate in northern China, there are additional one or two herbs for nourishing yin in the formula, like Glehniae Radix (Shashen) and Ophiopogonis Radix (Maidong), while in the south, due to the humid climate, aromatic herbs with the function of resolving dampness and turbidity are used in the formulae, like Pogostemonis Herba (Huoxiang) and Eupatorii Herba (Peilan). Individual difference was also considered in the prevention programs in some provinces. There were two or more formulae recommended in 18 provinces' programs, which were applicable for different populations, such as the elderly, children, pregnant women, or patients with chronic comorbidity diseases, population in close contact with COVID-19 patients, etc. In addition, 7 provinces or provincelevel municipality (Beijing, Tianjin, Shanxi, Henan, Hunan, Shandong, Yunnan) recommended formulae according to the types of CM body constitutions of the population. This tailored prevention strategy might help to improve the preventive effect. We suggest that the safety should also be paid attention to when taking CHM formula to prevent COVID-19, especially when they are used for long period. The public should choose the prescriptions under the guidance of CM doctors according to the program issued by provincial health authorities, and avoid taking the prescriptions or herbs with unknown origin and without offi cially approval. It should also be noted that the prevention advice for taking decoction were not reported in the 12 provinces' program. According to the programs of other provinces, it is appropriate to take the decoction for 1 week. Based on the consideration of health economics and balance of risks and benefits, we do not recommend that all people should take CHM to prevent COVID-19. Due to the highly contagion, (33, 34) high-risk populations exposed to COVID-19 patients, including medical personnel, family members, and other people who are in close contact with COVID-19 patients, as well as residents living in COVID-19 outbreak areas, would probably benefit from taking CHM formulae for prevention. These formulae recommended in the prevention programs are easily available in pharmacies and hospitals across the country. There are some limitations within this study. Firstly, historical records of using CM for "pestilence" prevention were examined in the review, however, the term "pestilence" might be a broad concept in ancient CM books, including infectious diseases transmitted through respiratory tract, digestive tract and other ways, so it might not be completely representative of the respiratory viral diseases especially the COVID-19. Secondly, as there is no direct clinical evidence for the prevention of the new emerging COVID-19, currently reported researches were from previous literature on the prevention of SARS and H1N1 influenza by CM which can only be considered as indirect evidence to refer to the current outbreak. Thirdly, the prevention programs for preventing COVID-19 were issued shortly after the outbreak, which were formulated by CM experts based on their previous experience in the prevention and treatment of similar diseases and their initial understanding of the disease; therefore, the actual effect of these programs needs to be verifi ed in clinical application, and updated and improved according to the evidence of new researches on COVID-19. For future studies, we recommend prospective cohort studies, RCTs or registry studies to evaluate the effect of CHM formulae in prevention of COVID-19. At present, as the COVID- 19 has not yet been controlled, we expect that a series of prospective population studies with rigorous design and large sample should commence with protocol registration, ethical approval, and implementation in a timely manner, to produce reliable evidence for CM prevention of COVID-19 or similar emerging respiratory infectious diseases in the future. In conclusion, based on historical records and clinical evidence of SARS and H1N1 infl uenza prevention, CHM formula could be an alternative approach for the prevention of COVID-19 in high-risk population while waiting for the development of a successful vaccine. Prospective well design population studies are needed to evaluate the preventive effect of CM. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study National Health Commission of the People's Republic of China Novel coronavirus (2019-nCoV) situation report -22 A novel coronavirus outbreak of global health concern National Health Commission of the People's Republic of China. Announcement of the National Health Commission of the People's Republic of China World Health Organization. Q&A on coronaviruses An overview of the thoughts and methods of epidemic prevention in ancient Chinese Medicine Hygiene and preventive medicine in ancient China Chinese herbal medicine for severe acute respiratory syndrome: a systematic review and meta-analysis SARS: clinical trials on treatment using a combination of traditional Chinese medicine and Western medicine National Administration of Traditional Chinese Medicine. Prevention program of traditional Chinese medicine for 2009 H1N1 infl uenza A brief analysis on the understanding of pestilence in Huangdi's Internal Classic Therapeutic thoughts and academic contributions of 13 formulas in Huangdi's Internal Classic What happened in China during the 1918 infl uenza pandemic? Epidemic disease prevention in traditional Chinese medicine Essential prescriptions worth a thousand gold for emergencies (Bei Ji Qian Jin Yao Fang) Beijing: China Medical Science and Technology Press Finishing and Research of Plague Preventing between Jin and Tang Dynasties and the Ming and Qing Dynasties Beijing: People's Medical Publishing House The use of an herbal formula by hospital care workers during the severe acute respiratory syndrome epidemic in Hong Kong to prevent severe acute respiratory Clinical observation of Yinhua Yupingfeng Decoction in preventing SARS: analysis of 163 fi rst-line medical staff. Conference on the prevention and treatment of SARS in integrated traditional Chinese and Western medicine in five provinces of North China Analysis of fangdu decoction on SARS and zero infection in hospital Clinical observation of prevention of influenza A (H1N1) by Qingjie Fanggan Granules Preliminary observation on the prevention of infl uenza A (H1N1) by the formula of Jialiu Yufang Formula Effect of Kangbingdu Oral Liquid and Ganmaoqingre Granule on prevention of influenza A (H1N1) Clinical observation on the prevention of infl uenza A H1N1 with the prevention theory of TCM Diagnosis and treatment of pneumonia caused by the 2019 new coronavirus (2019-nCoV). 2020/1/22 Yu Ping Feng San, an ancient Chinese herbal decoction, induces gene expression of anti-viral proteins and inhibits neuraminidase activity Antiinfl ammatory and immunoregulatory effects of total glucosides of Yupingfeng Powder Oseltamivir compared with the Chinese traditional therapy Maxingshigan-Yinqiaosan in the treatment of H1N1 Infl uenza-a randomized trial The effects and mechanism of Yinqiao Powder on upper respiratory tract infection Theoretical study of three factors-concerned treatment [dissertaion Analysis on the Chinese medicine syndromes and demographic characteristics of patients with infl uenza-like illness in clinics of China Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China The epidemic dynamics of 2019 novel coronavirus (2019-nCoV) infections in China by 28 The authors declare that they have no competing interest. Luo H, Tang QL, and Liu JP conceived of the design and