key: cord-0951308-jb68dipx
authors: Han, Yaxue; Yang, Zi; Fang, Shan; Zhang, Mengqing; Xie, Zhijun; Fan, Yongsheng; Zhao, Ting
title: Data‐mining‐based of ancient traditional Chinese medicine records from 475 BC to 1949 to potentially treat COVID‐19
date: 2022-03-08
journal: Anat Rec (Hoboken)
DOI: 10.1002/ar.24888
sha: 840a06bf592c4916d9f84f5fb1ea4ba3b48cea14
doc_id: 951308
cord_uid: jb68dipx

Traditional Chinese Medicine (TCM) plays a role in preventing and treating COVID‐19 in China. Based on the manifestations and symptoms of COVID‐19, our study used the data mining method to summarize related therapeutic experience left by predecessors who used TCM to treat epidemics in their eras. Initially, we collected abundant medical records with similar manifestations of COVID‐19 in Chinese ancient times. The key words including wen (瘟), yi (疫), li (疠), and zhang (瘴) were searched in ZhongyiZhiku (https://www.zk120.com/) from Warring States Period (475 BC–221 BC) to the Republic of China era (1912–1949) to locate ancient medical records according to inclusion criteria and exclusion criteria. Moreover, COVID‐19‐related manifestations and corresponding medications in those records were categorized. Eventually, Traditional Chinese Medicine Inheritance Support System version 2.5 was used to build a medical record database of TCM treating COVID‐19. Our study collected 263 epidemic medical records comprising COVID‐19 related manifestations and found that Chinese Materia Medica (CMM) combinations excavated from ancient medical records included Ren Shen Bai Du San, Wu Ling San, Xiao Chai Hu Tang, Da Cheng Qi Tang, Da Chai Hu Tang, Ling Gui Zhu Gan Tang, and Qing Wen Bai Du Yin. The recurrent CMMs with a high frequency for treating COVID‐19 manifestations were Scutellariae Radix (Huang Qin), Paeoniae Alba Radix (Bai Shao), Poria (Fu Ling), and Bupleuri Radix (Chai Hu). Our study suggests that TCM might offer new therapeutic strategies for COVID‐19.

TCM has accumulated 1,000 of years of experience in the treatment of epidemic diseases. An estimate is that more than 100 TCM formulae were invented for combating ancient epidemic infections throughout China's history (Lee et al., 2021) . Recently, during the SARS epidemic in 2003, TCM was used as an auxiliary therapy to Western Medicine which was applied for the treatment of SARS, with 3,104 of 5,327 clinically confirmed patients (58%) in China received TCM treatment had a therapeutic beneficial effect (Chen et al., 2007) . According to the official reports (Chen et al., 2007) , the mortality rate in China was about 7%, which was lower than the global mortality (about 10%). For example, among 112 SARS inpatients in Guangdong Province TCM Hospital, under the treatment of TCM, the symptoms of 105 patients were improved (Xiao & Zhang, 2014) . The treatment effect of TCM (Ding et al., 2017; Liu et al., 2017; Zhou et al., 2011) also happened in treating patients infected with H1N1, H7N9 (H7N9 avian influenza), and EVD (Ebola Virus Disease). In addition to TCM formulae, Chinese herbal tea, acupuncture (Zhu et al., 2021) , moxibustion, Qigong (Da et al., 2021) , and other TCM therapeutics also play a part in the treatment of theses pandemics.

Today, data mining is widely used in TCM for analyzing medical records (Hsieh et al., 2020; You et al., 2019) . Some studies recognized the contribution of TCM in fighting pestilence through data mining and analyzed the related formulae (Ren et al., 2020) . However, due to the diversity of pandemics, precise identification of the symptoms of COVID-19 patients among ancient epidemics is difficult. The Chinese Materia Medica (CMMs) and formulae applied to the similar manifestations as COVID-19 patients in ancient times might provide valuable information for combating the COVID-19 pandemic. Therefore, our study used known manifestations of COVID-19 to look back in ancient times in China during epidemics, using more than 1,800 ancient medical books containing effective formulae and CMM combinations during ancient epidemics. We used data mining methods to summarize therapeutic experience, using ancient TCM left by predecessors that may provide suggestions for clinical application of TCM to treat patients with COVID-19.

ZhongyiZhiku (https://www.zk120.com/) is the largest online library of ancient Chinese medicine books, supervised by the expert group of China Academy of Chinese Medical Sciences, which archives more than 1,800 classical TCM books and over 40,000 medical cases from Warring States Period (475 BC-221 BC) to the Republic of China era . Epidemic medical cases were retrieved by searching each key word, respectively, including wen (瘟), yi (疫), li (疠), and zhang (瘴).

Medical records from Warring States Period (475 BC-221 BC) to the Republic of China era comprising complete symptoms and medication were included. Medical records referring to epidemic diseases with incomplete symptoms and medication were not included. Followup visits with similar prescriptions were excluded.

By analyzing ancient epidemic medical cases, we extracted the known COVID-19 manifestations according to several literary sources (Du et al., 2020; Inomata et al., 2020; Jin et al., 2020) . Other clinical manifestations and corresponding medications were also acquired from the cases. Later, the data of COVID-19 related manifestations and corresponding medications in each ancient epidemic medical case was input into a database (Excel). Then, the clinical manifestations were standardized by Standard Terminology for Common Symptoms in Chinese Medicine Clinical Practice (Li & Ma, 2015) and CMMs were unified according to the Chinese Pharmacopeia and Chinese Materia Medica (National Pharmacopoeia Commission, 2015; Zhong, 2016) . After removing duplicate cases, at least two of our team (Y.X.H., F.S., and M.Q.Z.) confirmed accuracy of the data processing. Finally, Traditional Chinese Medicine Inheritance Support System (TCMISS) version 2.5 was used to build a medical records database of ancient TCM to potentially treat COVID-19.

TCMISS version 2.5, recommended by the Academy of Chinese Medical Sciences, was used. This system is specialized in the analysis of TCM data by integrating the association rules algorithm and complex-system entropy method. Among them, the frequency of manifestations and CMMs were analyzed by the association rules algorithm of the statistical analysis, which was assessed by the support degree and confidence coefficient (Tang et al., 2019) . The formula of the support degree is as below:

where A represents one of the manifestations or CMM and B represents the other manifestation or CMM. P (A[B) represents that the probability of A and B occurrence at the same time in the transaction set. The support degree settings were changed according to the frequency of the specific manifestations. The confidence coefficient was 1 for this study. The networks were visualized and analyzed by Cytoscape 3.7.1 (Shannon et al., 2003 ). The complex system entropy method, an unsupervised learning algorithm, was applied for mining composition patterns with the maximum amount of information by setting the variables of correlation degree and penalty degree. The correlation degree implies the relevance between one CMM with the other ones, while a penalty degree is set for shielding interfering information (Wang, 2020) . The settings of correlation degree = 8 and penalty degree = 2 are recommended by TCMISS.

We found 263 ancient epidemic medical records, including with COVID-19 manifestations (Data S1). The distribution details of the ancient epidemic medical records and COVID-19 manifestations are presented in Figure 1 . The manifestations with occurrence more than 15 times were considered as the core manifestations and subjected for the following study. The top 10 COVID-19 manifestations in the ancient TCM records were fever, headache, thirst, aversion to cold, myalgia, vomiting, diarrhea, chest tightness, cough, and fatigue, as shown in Figure 2 . The top 10 non-COVID-19 manifestations were vexation, rapid pulse, mental confusion, delirious speech, constipation, a surging pulse, a thready pulse or a wiry pulse, a yellow tongue coating, and poor appetite.

Two hundred and thirty-two CMMs were identified from the collected ancient medical records (Data S2). The 10 most frequently used CMMs were Glycyrrhizae Radix Et Rhizoma (Gan Cao, frequency = 158), Scutellariae Radix (Huang Qin, frequency = 87), Paeoniae Alba Radix (Bai Shao, frequency = 66), Bupleuri Radix (Chai Hu, frequency = 61), Ginseng Radix Et Rhizoma (Ren Shen, frequency = 58), Poria (Fu Ling, frequency = 57), Citri Reticulatae Pericarpium (Chen Pi, frequency = 52), Rhei Radix Et Rhizoma (Da Huang, frequency = 51), Platycodonis Radix (JieGeng, frequency = 47), and Rehmanniae Radix Recens (Sheng Di Huang, frequency = 47). Since Glycyrrhizae Rhizoma is mostly used as an envoy herb for harmonizing the actions of all other CMMs in a formula, we excluded Glycyrrhizae Rhizoma in the following study for analyzing the primary CMMs. As illustrated in Figure 3 , the frequency of the CMMs channel entry into the Lung, Spleen, Stomach, and Heart channels surpassed 65%, among which the frequency of the Lung channel was the highest (20%). The CMMs were classified into 24 categories and the frequencies in each category are listed in Table 1 . The details are provided in Data S3. Heatclearing CMMs were the most commonly used in ancient epidemic medical records. The total frequency of heat-clearing CMMs, exterior-releasing CMMs, and qi-tonifying CMMs exceeded 50%.

The analysis of the association rule was applied to study the collected manifestations in general. Figure 2 suggests

The distribution of pandemic medical records and COVID-19 manifestations. The numbers above represent the mean number of COVID-19 manifestations in each medical record of the specific period F I G U R E 2 The network of the common manifestations in medical records. The red circles represent the manifestations of COVID-19, while the green circles represent the non-COVID-19 manifestations. The size of the circles represent the frequency of the manifestation. The width of the lines represents the cooccurrence frequency of the two connected manifestations. The support was degree ≥ 10% a close relationship between fever, headache, aversion to cold, thirst, myalgia, and vexation.

Next, the association rule of CMMs was analyzed for each manifestation listed in Table 2 . Twenty-eight association rules corresponding to eight COVID-19 manifestations and four non-COVID-19 manifestations are shown in Table 3 .

To further understand the associations between the core manifestations and the high-frequency CMMs (frequency ≥ 20), the network of manifestations and CMMs was constructed, as illustrated in Figure 4 . A node is defined as a hub when the degree of the node is more than twofold of the median degree of all nodes in the same network (Li et al., 2007) . Four CMMs, including Scutellariae Radix Paeoniae, Radix Alba, Poria, and Bupleuri Radix are classified as hub nodes in this network.

According to Formulae of Traditional Chinese Medicine (Li, 2006) , seven classical formulae were acquired from the collected CMMs, as listed in 

TCM has guided prevention and treatment of pandemics, such as SARS, H7N9, and EVD (Du et al., 2020) . Several reports point out TCM contributions to alleviating clinical manifestations of and promoting pharmacological investigations for COVID-19 Luo, Ni, et al., 2020; Zhang et al., 2020; . In ancient times, TCM used empirical treatment, which may lead to useful potential applications to COVID-19 cases. One of the characteristics of Yi Bing is the similar manifestations among patients with COVID-19. Thus, the summary and analysis of ancient TCM treatments may be particularly important for today's pandemic . The selected prescriptions are mainly distributed in the Song, Ming, and Qing dynasties as well as the Republic of China era. Ancient medical records in the Song dynasty show similar manifestations of COVID-19. By collecting medical records associated with ancient epidemics, our study found that some manifestations might be ignored in COVID-19 clinical diagnoses, such as vexation, constipation, cold limbs, pulse manifestation, and tongue appearance. The level of vexation (anxiety) is higher in COVID-19 patients compared to healthy people (Qin et al., 2020) . Constipation may occur in patients with COVID-19 (Chow et al., 2020) . A symptom such as cold extremities mostly appears in shock cases of COVID-19 . A clinical study of COVID-19 reported that a yellow tongue coating is associated with severe cases (Pang et al., 2020) . Most manifestations in our study are found in the COVID-19 literature, which suggests that the retrospective analysis of ancient medical records might be meaningful for mining potential therapies.

While COVID-19 primarily presents as a respiratory illness, one-third of the confirmed cases may also have gastrointestinal symptoms and neurological manifestations (Ahmadirad & Ghasemi, 2020; Rajan et al., 2020) . Our study shows that the frequencies of CMMs channel entry into the Lung, Spleen, Stomach, and Heart channels rank as the top four in the channel list, which is surprisingly consistent with the COVID-19 analysis (Gu studies demonstrated that clearing heat is the primary treatment of COVID-19 Yuan et al., 2020) . Our study found several CMM combinations (Table 3) for the specific manifestations in the collected ancient medical records. Interestingly, almost all the combinations are included in ancient formulae, as shown in Table 4 . Ren Shen Bai Du San, a popular formula used for the treatment of Yi Bing, has the function of boosting healthy qi, expelling wind, removing dampness, and resolving toxins, especially for treating the inward invasion of exterior pathogens. It is reported that Ren Shen Bai Du San is helpful for the treatment of mild cases of COVID-19 (Wang, Kong, & Wang, 2020) , apparently because the mild cases mostly pertain to the combination of the exterior syndrome and interior syndrome. Wu Ling San and Xiao Chai Hu Tang were included in the formula Qing Fei Pai Du Tang, which may prevent progression and shorten duration of symptoms of COVID-19 . Wu Ling San could unblock yang qi and promote urination, relieving symptoms such as nausea, vomiting and heavy limbs. Xiao F I G U R E 4 The network of the core manifestations and the high-frequency CMMs. The red circles represent the manifestations of COVID-19, while the blue-green circles represent the non-COVID-19 manifestations. The yellow-green diamonds represent CMMs. The width of the lines represents the co-occurrence frequency of the two connected manifestations Chai Hu Tang, the representative formula for treating shaoyang syndrome, including alternating chills, fever, and chest tightness. Additionally, several studies found that Xiao Chai Hu Tang may exert an anti-infection effect against SARS-CoV-2 (Kwon et al., 2020; Wang, Ming, et al., 2020) . Da Chai Hu Tang, a representative formula for yang ming and bowel excess syndrome, may improve symptoms such as constipation and abdominal distention in severe cases of COVID-19 , which could be explained by the interior-exterior relationship between Lung and Large Intestine. Similarly, Da Cheng Qi Tang is recommended by official TCM guidelines to inhibit inflammation by promoting bowel movement . With the function of activating qi and promoting purgation, Da Cheng Qi Tang may remove heat accumulation and regulate qi flow in the bowel. The enema treatment of Da Cheng Qi Tang is applied in severe cases of COVID-19 for relieving symptoms like constipation and abdominal distension (Shanghai Association of Integrated Chinese and Western Medicine respiratory Diseases Professional Committee, 2020). Qing Wen Bai Du Yin has an antiinflammatory effect and is widely used in pandemics, such as H1N1 influenza and epidemic hemorrhagic fever . Qing Wen Bai Du Yin is primarily given to patients with dual severe qi and blood syndrome, which is manifested as thirst, headache, and delirious speech. Another suggestion is that Qing Wen Bai Du Yin may alleviate the inflammatory reaction in COVID-19 patients and may have a protective effect on organ damage caused by inflammation . Moreover, Lonicerae Japonicae Flos (Jin Yin Hua), a prominent CMM in Qing Wen Bai Du Yin, is frequently used in combination with Qing Wen Bai Du Yin to treat pneumonia (Nie et al., 2010) . Water retention in the lung could worsen pulmonary edema and phlegm, which could be alleviated by Ling Gui Zhu Gan Tang with the function of warming yang qi and dissolving fluid retention, The application of Ling Gui Zhu Gan Tang in treating COVID-19 patients with yang qi deficiency and water retention syndrome is a unique TCM strategy .

As for the four hub nodes in the network analysis, Scutellariae Radix is reported as one of the most frequently used CMMs for COVID-19 Luo, Ni, et al., 2020) . The major chemical constituents of Scutellariae Radix have anti-inflammatory, antibacterial, antiviral, neuroprotective effects, and enhance body immunity (Wang et al., 2018) . Thirty compounds isolated from Scutellariae Radix have anti-H1N1 activities (Ji et al., 2015) . Paeoniae Alba Radix is recommended to prevent inflammation as well as to enhance the body's immunity to inhibit a SARS-CoV-2 infection (Shanghai Association of Integrated Chinese and Western Medicine respiratory Diseases Professional Committee, 2020). Paeoniflorin, which is the most abundant compound in Paeoniae Alba Radix, is also an ingredient of Xuebijing injection, which reduces lung injury in patients with severe COVID-19 infection (Ma, Qiu, et al., 2020) . Furthermore, Poria is a popular CMM for treatment of severe COVID-19 patients (Wang, Ming, et al., 2020) . Poriacocos polysaccharides has a variety of pharmacological activities such as regulating immunity, and has anti-inflammatory, antioxidation, antitumor, and liver protection . Bupleuri Radix has the functions of antipyretic, anti-inflammatory, enhancing immunity, and analgesia (Su et al., 2021) . One study shows that the extracts of Bupleuri Radix have an effect on H1N1 (Su et al., 2011) . The three-fourth of the hub nodes, that is, Scutellariae Radix, Poria, and Bupleuri Radix in our study are also included in the formula Qing Fei Pai Du Tang. This formula is associated with better prognosis for COVID-19 patients . Again, our findings support the results of other studies that indicate that Scutellariae Radix and Bupleuri Radix contain numerous potential compounds to potentially treat COVID-19 Ren et al., 2020) .

However, there are some limitations to our current study. Although our results found that TCM has a role in preventing and treating COVID-19. TCM and western medicine have their own advantages, the combination of them may be more effective. Moreover, because the current COVID-19 pandemic persists, we will continue to focus on this pandemic for further study. In the future, further experimental researches are expected to validate the results of this study.

In summary, the overlapped data of epidemic diseases in ancient medical records and the manifestations of COVID-19 patients today were analyzed in our study. CMM combinations from ancient medical records are found in classical TCM formulae. The effective CMMs corresponding to the COVID-19 symptoms with high frequency may provide new insights and opportunities to treat the COVID-19 pandemic.

AUTHOR CONTRIBUTIONS yaxue Han: Data curation (equal); investigation (equal); methodology (equal); software (equal). ZI YANG: Investigation (equal); validation (equal); writingoriginal draft (equal); writingreview and editing (equal). shan Fang: Investigation (equal); methodology (equal); resources (equal). mengqing Zhang: Conceptualization (equal); data curation (equal); investigation (equal). zhijun Xie: Supervision (equal); validation (equal).

Yaxue Han https://orcid.org/0000-0002-2935-1774 Zi Yang https://orcid.org/0000-0002-0329-3254

COVID-19 and central nervous system: Entry routes and. Basic and Clinical Neuroscience

National TCM master XIONG Jibo's differentiation and treatment of COVID-19

Effect of integrated traditional Chinese medicine and western medicine on the treatment of severe acute respiratory syndrome: A meta analysis

Research progress on chemical structures and pharmacological activities of Poria cocos polysaccharide and its derivatives

Acute transverse myelitis in COVID-19 infection

Potential therapeutic effect and methods of traditional Chinese medicine on COVID-19-induced depression: A review

Treating Covid-19 from the perspective of fluid metabolism and qi disorder

The Chinese prescription lianhuaqingwen capsule exerts antiinfluenza activity through the inhibition of viral propagation and impacts immune function. BMC Complementary and Alternative Medicine

Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study

Analysis of medication characteristics of traditional Chinese medicine in treating coronavirus disease-19 based on data mining

Research on the mechanism of ChaihuHuangqin medicine based on integrated pharmacology to improve the clinical symptoms of covid-19

Analysis of property and efficacy of traditional Chinese medicine in staging revention and treatment of coronavirus disease 2019

Combination of acupoints in treating patients with chronic obstructive pulmonary disease: An apriori algorithm-based association rule analysis. Evidence-based Complementary and Alternative Medicine

Clinical and prodromal ocular symptoms in coronavirus disease: A systematic review and meta-analysis

Anti-H1N1 virus, cytotoxic and Nrf2 activation activities of chemical constituents from Scutellaria baicalensis

Epidemiological, clinical and virological characteristics of 74 cases of coronavirus

Could herbal medicine (Soshihotang) be a new treatment option for COVID-19? A narrative review

Traditional Chinese herbal medicine at the forefront battle against COVID-19: Clinical experience and scientific basis. Phytomedicine: international journal of phytotherapy and phytopharmacology

SARS-CoV-2 and viral sepsis: Observations and hypotheses

Formulae of traditional Chinese medicine

Standard terminology for common symptoms in Chinese medicine clinical practice Beijing

Understanding ZHENG in traditional Chinese medicine in the context of neuro-endocrine-immune network

The management of coronavirus disease 2019 (COVID-19)

Zero health worker infection: Experiences from the China Ebola treatment unit during the Ebola epidemic in Liberia

The interpretation of human body in traditional Chinese medicine and its influence on the characteristics of TCM theory

Analysis on herbal medicines utilized for treatment of COVID-19

The addon effect of Chinese herbal medicine on COVID-19: A systematic review and meta-analysis

The study on the treatment of Xuebijing injection (XBJ) in adults with severe or critical Corona virus disease 2019 and the inhibitory effect of XBJ against SARS-CoV-2

Occurrence and prevention of novel coronavirus pneumonia from the theory of plague

Chinese pharmacopoeia

Qingwenbaidu decoction used for curing mild cases of community acquired pneumonia

Efficacy and Safety of Traditional Chinese Medicine for Patients with Mild or Common COVID-19: A Metaanalysis

Tongue features of patients with coronavirus disease 2019: A retrospective cross-sectional study

Mental health status of patients with coronavirus disease 2019 in Changsha

Association of search query interest in gastrointestinal symptoms with COVID-19 diagnosis in the United States: Infodemiology study

Identifying potential treatments of COVID-19 from traditional Chinese medicine (TCM) by using a datadriven approach

Shanghai Association of Integrated Chinese and Western Medicine respiratory Diseases Professional Committee

Cytoscape: A software environment for integrated models of biomolecular interaction networks

Treatment for COVID-19: An overview

Effect of dietary Xiao-Chaihu-decoction on growth performance, immune response, detoxification and intestinal microbiota of pacific white shrimp (Litopenaeus vannamei)

In vitro anti-influenza a H1N1 effect of extract of Bupleuri radix

Application of the theory of "lung and intestine forming an exterior and interior relationship"to the treatment of severe COVID-19. Shangai

Analysis on composition rules of Chinese patent drugs treating pain-related diseases based on data mining method

Analysis of medication regularity and pharmacodynamic characteristics of traditional Chinese medicine treatment in 444 severe cases of COVID-19

The application of Renshen Baidu san in the treatment of COVID-19

Study on the rules of syndrome and treatment of infantile diarrhea treated by the modern name doctor of traditional Chinese medicine based on traditional Chinese medicine inheritance support system

A comprehensive review on phytochemistry, pharmacology, and flavonoid biosynthesis of Scutellaria baicalensis

Potential therapeutic effect of Qingwen Baidu decoction against Corona virus disease 2019: A mini review

Review of advantages on TCM in treatment of emergent infections diseases and system of infectious diseases based on doctrine of epidemic febrile disease

Treatment of COVID-19 guided by holistic view of traditional Chinese medicine: Therapy aimed at both viral and host

Therapeutic options of TCM for organ injuries associated with COVID-19 and the underlying mechanism

Holistic quality evaluation of Qingwen Baidu decoction and its anti-inflammatory effects

Chinese Materia Medica. China Press of Traditional Chinese Medicine

A review of QingFei Pai Du Tang and its major herbs. American Journal of Chinese Medicine, 48, 1051 -1071 . Zhou, H., Huang, H. Q., Zhang, Z. D., & Tao, L. T. (2011 

Additional supporting information may be found in the online version of the article at the publisher's website.How to cite this article: Han, Y., Yang, Z., Fang, S., Zhang, M., Xie, Z., Fan, Y., & Zhao, T. (2022) . Data-mining-based of ancient traditional Chinese medicine records from 475 BC to 1949 to potentially treat COVID-19. The Anatomical Record, 1-13. https://doi.org/10.1002/ar.24888