A data-mining based analysis of traditional Chinese medicine in diagnosing and treating COVID-19

Abstract

Traditional Chinese Medicine (TCM) plays a vital role in preventing and treating COVID-19. In order to improve the therapeutic effect, we carried out this study to cope with the pandemic and discover the methods of treating COVID-19 with TCM. Our study 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 (457–221 BC) to the Republic of China era (1912 - 1949), so as to locate pandemic medical records according to inclusion criteria and exclusion criteria. Later, COVID-19 related manifestations and corresponding medications in those records were categorized by EXCEL. Last, Traditional Chinese Medicine Inheritance Support System (TCMISS) version 2.5 was used to build a medical record database of TCM treating COVID-19. Our study collected 263 pandemic medical records comprising COVID-19 related manifestations and found out that Chinese Materia Medica (CMM) combinations excavated from the 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 could offer valuable therapeutic strategies for COVID-19.

Chinese Abstract

中医药在预防和治疗新型冠状病毒肺炎中发挥至关重要的作用。为了提高对新型冠状病毒肺炎的治疗效果，开展研究并总结中医药治疗的方法。收集大量古代与该 病 症 状 相 似 的 医 案 ， 根 据 纳 入 标 准 和 排 除 标 准 ， 在 中 医 智 库 (https://www.zk120.com/) 中查找从战国 (公元前 457-公元前 221 年) 至中华民国 (1912-1949) 时期包含关键词瘟、疫、疠、瘴的医案。随后，用EXCEL分类医案中与该病相关的症状及其所使用的方药。最后，利用中医传承发展平台 (TCMISS) 2.5 版创建了中医治疗的医案数据库。研究共收集263份包含该病相关症状的医案，并根据挖掘出的药物组合锁定人参败毒散、五苓散、小柴胡汤、大承气 汤、大柴胡汤、苓桂术甘汤及清瘟败毒饮，同时发现治疗该病的高频次药物包括黄芩、白芍、茯苓及柴胡。研究表明，中医药为新型冠状病毒肺炎的治疗提供了有价值的策略 。

1 INTRODUCTION

The 2019 coronavirus disease (COVID-19) is a disease caused by coronavirus-2 (SARS-CoV-2) which induces severe acute respiratory syndrome (Stasi, Fallani, Voller, & Silvestri, 2020). It is an emerging pandemic with widespread and rapid infectiousness (Liu & Liu, 2020). On January 30, 2020, WHO declared COVID-19 as a pandemic, which has caused almost 100 million confirmed cases and more than 2.7 million deaths by March 22, 2021 and the number is still increasing (https://www.worldometers.info/coronavirus/). No sovereign remedy has been discovered to cure COVID-19. Supportive therapies and symptomatic treatment are primarily applied in western medicine, including antiviral agents, inflammation inhibitors, low-molecular-weight heparins, plasma, and hyperimmune immunoglobulins (Stasi et al., 2020). Currently, this serious epidemic has caused more than half a million deaths in the United States according to the Worldometer's COVID-19 data. In contrast, TCM has achieved great success in treating COVID-19 in China, benefiting from its unique characteristics of treatment based on syndrome differentiation. It was reported that TCM treatment was applied to 87% of COVID-19 cases in China and the effective rate was 92%, (Yang, Islam, Wang, Li, & Chen, 2020). Specifically, TCM treatment has shown its superiority in preventing infected patients escalate to severe cases as well as in reducing the number of patients admitted to the ICU. For example, in Jin-Chang Hospital, the effective rate in COVID-19 patients received TCM treatment achieved 99.2% (Lee, Li, Liu, & Efferth, 2021). Furthermore, TCM treatment has also shown greater safety and fewer side effects compared with antivirals, antibacterial drugs, and hormones (Du, Hou, Miao, Huang, & Liu, 2020).

With a long history, TCM has laid a solid theoretical foundation in fighting against epidemic diseases. The presence of Yi Bing(疫病), a name that is still used for pandemics so far, was already recorded 2000 years ago inthe Zhou Dynasty Compilation of Changes (Zhou Yi; Du, Hou, et al., 2020). Shuo wen jiezi, the origin of Chinese characters, explained yi(疫)as epidemic diseases among civilians (Ma et al., 2020; Ma, Ma, Lian, & Zheng, 2020). The manifestations of yi included a dry throat and myalgia and were first recorded in The Yellow Emperor's Inner Classic (Huang Di Nei Jing), which is the foundation of TCM. Aside from yi, many other words refer to epidemic diseases as well. Shi xingzhi qi (时行之气), described as similar manifestations among adults and children, was first brought into view by Zhang Zhongjing in Treatise on Cold Damage (Shang Han Lun). Zhou Hou Bei Ji Fang (Emergency Formulae to Keep Up One's Sleeve) first pointed outthat Li Qi (疠气) as the cause of contagious disease was combined with hidden toxins.Guai li zhi qi (乖戾之气) first appeared in the Zhu Bing Yuan Hou Lun (Treatise on the Origins and Manifestations of Various Diseases). This was developed into the Li Qi theory(戾气论)written in the Wen Yi Lun(Treatise on Warm-Heat Pestilence), which emphasized that Li Qi could spread from person to person through the mouth and nose as the pathogen of Yi Bing. TCM has accumulated thousands of years of experiences in the treatment of epidemic diseases. It is estimated that more than 100 TCM formulae were invented for combating epidemic infections throughout China's history (Lee et al., 2021). During the SARS (severe acute respiratory syndrome) epidemic in 2003, 3,104 of 5,327 clinically confirmed patients (58.27%) in China received TCM treatment, which demonstrated a remarkable therapeutic effect (Chen, Guo, Healy, & Zhan, 2007). According to the official reports (Chen et al., 2007), the mortality rate in China was approximately 6.5%, which was significantly lower than that the global mortality (9.6%). For example, among 112 SARS inpatients in Guangdong Province TCM Hospital, 105 cases were successfully cured with TCM treatment (Xiao & Zhang, 2014). The treatment effect of TCM (Zhou, HQ, ZD, & LT, 2011; Ding et al., 2017; Liu, Yin, & Liu, 2017) has also been confirmed in treating H1N1, H7N9 (H7N9 avian influenza) and EVD (Ebola Virus Disease). In addition to TCM formulae, Chinese herbal tea, acupuncture, moxibustion, and other TCM therapeutics also made great contribution to coping with pandemics.

Nowadays, data mining is widely used in TCM for analyzing medical records (Hsieh et al., 2020; You et al., 2019). Some studies recognized the significance of TCM in fighting pestilence through data mining and analyzed the related formulae (Ren et al., 2020). However, due to the diversity of pandemics it is hard to precisely identify the symptoms of COVID-19 patients amongst all pestilences. The CMMs and formulae applied to the similar manifestations as COVID-19 patients in ancient time might provide valuable information for combating the pandemic. Therefore, our current study mainly focused on the known manifestations of COVID-19 in time of a pandemic in more than 1800 ancient medical books containing effective formulae and CMM combinations. Based on the manifestations and symptoms of COVID-19, our study used the data mining method to summarize valuable therapeutic experience left by predecessors, in order to promote the inheritance and innovation of TCM theory.

2 METHODS

2.1 Data collection

ZhongyiZhiku (https://www.zk120.com/) is an online platform, which archives more than 1800 classical TCM books and over 40,000 medical cases from Warring States Period (457–221 BC) to the Republic of China era (1912–1949). Pandemic medical cases were retrieved by searching each key word, respectively, including wen (瘟), yi (疫), li (疠), and zhang (瘴).

2.1.1 Inclusion criteria and exclusion criteria

Medical records from Warring States Period (457–221 BC) to the Republic of China era (1912–1949) comprising complete symptoms and medication were included. Medical records referring to epidemic disease with incomplete symptoms and medication were not included. Follow-up visits with similar prescriptions were excluded.

2.2 Data processing

By analyzing the pandemic medical cases, researchers 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 effective cases. Later, COVID-19 related manifestations and corresponding medications were categorized by 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 Pharmacopoeia and Chinese Materia Medica (Commission, 2015; Zhong, 2016). After removing the duplicate cases, at least two researchers (Y.X.H., F.S., and M.Q.Z.) confirmed the data processing. At last, TCMISS version 2.5 was used to build a medical records database of TCM treating COVID-19.

2.3 Data analysis

Traditional Chinese Medicine Inheritance Support System (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, Shen, & Yang, 2019). The formula of the support degree is as below:

A represents one of the manifestations or CMM and B represents the other manifestation or CMM.

The support degree settings were changed according to the frequency of the specific manifestations, whilst the confidence coefficient was 1 in the current 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 as correlation degree = 8 and penalty degree = 2 are recommended by TCMISS.

3 RESULTS

3.1 Descriptive analysis

There were 263 pandemic medical records including COVID-19 manifestations in total. The distribution details of the pandemic medical records and COVID-19 manifestations are displayed in Figure 1. The manifestations with a frequency more than 15 times were considered as the core manifestations and subjected for the following study. The top 10 COVID-19 manifestations were fever, headache, thirst, aversion to cold, myalgia, vomiting, diarrhea, chest tightness, cough, and fatigue, as shown in Figure 3. 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.

[Image Omitted. See PDF.]

Two hundred and thirty-two CMMs were gained from the collected medical records (Data S1). 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), CitriReticulataePericarpium (Chen Pi, frequency = 52), Rhei Radix Et Rhizoma (Da Huang, frequency = 51), Platycodonis Radix (JieGeng, frequency = 47), and RehmanniaeRecens Radix (Sheng Di Huang, frequency = 47). Since GlycyrrhizaeRhizoma is mostly used as an envoy herb for harmonizing the actions of all other CMMs in a formula, we excluded it in the following study for analyzing the primary CMMs. As illustrated in Figure 2, 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 (20.28%). The CMMs were classified into 24 categories and the frequencies in each category are listed in Table 1. The details are provided in Data S2. Heat-clearing CMMs were the most commonly used in pandemic medical records. The total frequency of heat-clearing CMMs, exterior-releasing CMMs, and qi-tonifying CMMs has exceeded 50%.

[Image Omitted. See PDF.] TABLE 1. Frequency of CMMs categories

No.	CMMs category (quantity)	Frequency	Rate (%)	Cumulative frequency (%)
1	Heat-clearing CMMs (37)	606	22.82	22.82
2	Exterior-releasing CMMs (26)	451	16.99	39.81
3	Qi-tonifying CMMs (12)	317	11.94	51.75
4	Phlegm-resolving, cough-suppressing and panting-relieving CMMs (25)	184	6.93	58.68
5	Qi-regulating CMMs (12)	164	6.18	64.86
6	Dampness-draining diuretic CMMs (13)	150	5.65	70.51
7	Blood-tonifying CMMs (6)	129	4.86	75.37
8	Dampness-resolving CMMs (8)	119	4.48	79.85
9	Purgation-promoting CMMs (8)	85	3.20	83.05
10	Blood-activating and stasis-resolving CMMs (12)	70	2.64	85.69
11	Yin-tonifying CMMs (7)	67	2.52	88.21
12	Liver-calming and wind-extinguishing CMMs (11)	57	2.15	90.36
13	Interior-warming CMMs (9)	49	1.85	92.20
14	Orifices opening CMMs (5)	40	1.51	93.71
15	Mind-calming CMMs (5)	33	1.24	94.95
16	Astringent CMMs(8)	33	1.24	96.20
17	Wind-dispelling and dampness-resolving CMMs (8)	28	1.05	97.25
18	Digestion-promoting CMMs (4)	27	1.02	98.27
19	CMMs for resolving toxin, killing worms and relieving itching (4)	14	0.53	98.79
20	Worm-expelling CMMs (1)	13	0.49	99.28
21	Yang-tonifying CMMs (7)	9	0.34	99.62
22	Hemostatic CMMs (3)	5	0.19	99.81
23	CMMs for drawing out toxin, suppuration and promoting granulation (1)	4	0.15	99.96
24	Vomiting-inducing CMMs(1)	1	0.04	100.00

3.2 Association rule analysis

The analysis of the association rule was applied to study the collected manifestations in general. Figure 3 suggests a close relationship between fever, headache, aversion to cold, thirst, myalgia, and vexation.

[Image Omitted. See PDF.]

Afterward 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 were demonstrated in Table 3.

TABLE 2. The frequency of COVID-19 manifestations and non-COVID-19 manifestations in the pandemic medical records (frequency ≥15)

COVID-19 manifestations	Frequency	Non-COVID-19 manifestations	Frequency
Fever	186	Vexation	52
Headache	91	Rapid pulse	48
Thirst	86	Mental confusion	38
Aversion to cold	71	Delirious speech	27
Myalgia	57	Constipation	20
Vomiting	53	Surging pulse	20
Diarrhea	51	Thready pulse	19
Chest tightness	40	Wiry pulse	18
Cough	33	Yellow coating	18
Fatigue	31	Poor appetite	18
Abdominal pain	29	Cold limbs	16
Sore throat	27
Shortness of breath	22
Expectoration	16
Conjunctivitis	15

TABLE 3. Association rule analysis of common manifestations in yi bing medical records

Category	Manifestation	Association rule of CMMs	Confidence (%)	Support (%)
COVID-19	Aversion to cold	Ginseng Radix Et Rhizoma, Notopterygii Rhizoma Et Radix=>Platycodonis Radix	1	12
		Notopterygii Rhizoma Et Radix, Bupleuri Radix => Platycodonis Radix	1	12
	Myalgia	Aurantii Fructus=>Poria	1	14
		Chuanxiong Rhizoma, Bupleuri Radix => Platycodonis Radix	1	14
		Chuanxiong Rhizoma, Bupleuri Radix => Notopterygii Rhizoma Et Radix	1	14
		Chuanxiong Rhizoma, Bupleuri Radix and Platycodonis Radix => Notopterygii Rhizoma Et Radix	1	14
		Chuanxiong Rhizoma, Notopterygii Rhizoma Et Radix, Bupleuri Radix => Platycodonis Radix	1	14
		Chuanxiong Rhizoma, Bupleuri Radix => Notopterygii Rhizoma Et Radix, Platycodonis Radix	1	14
	Diarrhea	Alismatis Rhizoma => Poria	1	10
		Ginseng Radix Et Rhizoma, Bupleuri Radix => Scutellariae Radix	1	10
		Scutellariae Radix, Ginseng Radix Et Rhizoma => Bupleuri Radix	1	10
	Chest tightness	Gypsum Fibrosum => Scutellariae Radix	1	10
		Alismatis Rhizoma => Poria	1	10
		Zingiberis Rhizoma Recens, Scutellariae Radix => Pinelliae Rhizoma	1	10
	Cough	Notopterygii Rhizoma Et Radix => Chuanxiong Rhizoma	1	15
	Fatigue	Rhei Radix Et Rhizoma => Scutellariae Radix	1	13
		Aurantii Fructus Immaturus => Scutellariae Radix	1	13
	Abdominal pain	Natrii Sulfas => Rhei Radix Et Rhizoma	1	18
		Magnoliae Officinalis Cortex => Rhei Radix Et Rhizoma	1	18
	Sore throat	Rehmanniae Radix Recens, Scrophulariae Radix => Lonicerae Japonicae Flos	1	15
		Lonicerae Japonicae Flos, Scrophulariae Radix => Rehmanniae Radix Recens	1	15
		Lonicerae Japonicae Flos, Rehmanniae Radix Recens=> Scrophulariae Radix	1	15
Non-COVID-19	Vexation	Pinelliae Rhizoma => Scutellariae Radix	1	10
	Delirious speech	Natrii Sulfas => Rhei Radix Et Rhizoma	1	15
		Magnoliae Officinalis Cortex => Rhei Radix Et Rhizoma	1	15
	Constipation	Aurantii Fructus Immaturus => Rhei Radix Et Rhizoma	1	30
	Poor appetite	Zingiberis Rhizoma Recens => Scutellariae Radix	1	20
		Pinelliae Rhizoma => Scutellariae Radix	1	20

3.3 Network analysis of manifestations and CMMs

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 would be defined as a hub when the degree of the node was more than twofold of the median degree of all nodes in the same network (Li et al., 2007). There are four CMMs including Scutellariae Radix Paeoniae, Radix Alba, Poria, and Bupleuri Radix considered as hub nodes in this network.

[Image Omitted. See PDF.]

3.4 Formulae associated with Yi Bing manifestations

According to Formulae of Traditional Chinese Medicine (Li, 2006), seven classical formulae were acquired from the collected CMMs, as listed in Table 4. These formulae are 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.

TABLE 4. Formulas associated with yi bing manifestations

Formula	CMMs	Book	Author
Ren Shen Bai Du San	Bupleuri Radix Peucedani Radix Chuanxiong Rhizoma Aurantii Fructus ImmaturusNotopterygii Rhizoma Et RadixAngelicae Pubescentis RadixPoriaPlatycodonis RadixGinseng Radix Et RhizomaGlycyrrhizae Radix Et Rhizoma	Tai Ping Hui Min He Ji Ju Fang	Imperial Medical Bureau, revised by Chen Shi-wen
Wu Ling San	Polyporus Poria Atractylodis Macrocephalae Rhizoma Alismatis Rhizoma Cinnamomi Ramulus	Shang Han Za Bing Lun	Zhang Zhong-Jing
Xiao Chai Hu Tang	Bupleuri Radix Pinelliae Rhizoma Ginseng Radix Et Rhizoma Glycyrrhizae Radix Et Rhizoma Scutellariae Radix Zingiberis Rhizoma Recens Jujubae Fructus
Da Cheng Qi Tang	Rhei Radix Et Rhizoma Magnoliae Officinalis Cortex Aurantii Fructus Immaturus Natrii Sulfas
Da Chai Hu Tang	Bupleur Radix Scutellariae Radix Rhei Radix Et Rhizoma Aurantii Fructus Immaturus Pinelliae Rhizoma Paeoniae Alba Radix Jujubae Fructus Zingiberis Rhizoma Recens
Ling Gui Zhu Gan Tang	Poria Cinnamomi Ramulus Atractylodis Macrocephalae Rhizoma Glycyrrhizae Radix Et Rhizoma
Qing Wen Bai Du Yin	Gypsum Fibrosum Rehmanniae Recens Radix Bubali Cornu Coptidis Rhizoma Gardeniae Fructus Platycodonis Radix Scutellariae Radix Anemarrhenae Rhizoma Paeoniae Rubra Radix Scrophulariae Radix Forsythiae Fructus Glycyrrhizae Radix Et Rhizoma Moutan Cortex Lophatheri Herba	Yi Zhen Yi De	Yu Lin

4 DISCUSSION

TCM has played a unique role in the prevention and treatment of pandemics, such as SARS, H7N9, and EVD (Du, Hou, et al., 2020). Several reports point out that TCM makes great contributions to alleviating clinical manifestations and promoting pharmacological researches for COVID-19 (Luo et al., 2020; Zhang et al., 2020; Zhou et al., 2020). In ancient times, TCM mainly gets benefit from empirical treatment, which may lead to many useful potential applications to similar cases. One of the characteristics of Yi Bing is the similar manifestations among patients. Thus, the summary and analysis of the overall manifestations are particularly important (Chen et al., 2020).

The selected prescriptions are mainly distributed in the Song, Ming, and Qing dynasties as well as the Republic of China era, whereas the medical records in the Song dynasty have shown more manifestations of COVID-19. By collecting those medical records associated with pandemics, our study found out 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 anxiety is significant higher in COVID-19 patients compared to that in healthy people (Qin et al., 2020). Constipation could also be seen in patients with COVID-19 (Chow, Magnussen, Ip, & Su, 2020). A symptom like cold extremities mostly appears in the shock cases infected with COVID-19 (Li et al., 2020). 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 could be found in the COVID-19 literature, which suggests that the retrospective analysis of ancient medical records might be meaningful for mining the potential therapies.

Despite COVID-19 primarily presents as a respiratory illness, one-third of the confirmed cases could 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 are ranking the top four in the channel list, which is surprisingly consistent with the COVID-19 analysis given by renowned experts today (Gu et al., 2020). The CMMs with the functions of clearing heat, releasing the exterior, and tonifying qi belong to most of the components in the pandemic formulae. Exterior-releasing CMMs and heat-clearing CMMs were almost evenly used in the early stage of COVID-19. Heat-clearing CMMs were mostly used in the severe stage and tonifying CMMs were frequently applied to the recovery stage (Gu et al., 2020). Furthermore, several studies demonstrated that clearing heat is the primary treatment of COVID-19 (Fan et al., 2020; Yuan, Xin, Tang, & Cong, 2020).

Our study found several CMMs combinations (Table 3) for the specific manifestations in the collected medical records. Interestingly, almost all the combinations are comprised in classical 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 effective in the treatment of mild cases of COVID-19 (Wang et al., 2020; Wang, Kong, & Wang, 2020), since the mild cases mostly pertain to the combination of the exterior syndrome and interior syndrome. Wu Ling San and Xiao Chai Hu Tang were comprised in the formula Qing Fei Pai Du Tang which could prominently prevent the progression and shorten the duration of the symptoms (Zhong et al., 2020). Wu Ling San could unblock yang qi and promote urination, relieving the symptoms such as nausea, vomiting and heavy limbs. Xiao Chai Hu Tang, the representative formula for treating shaoyang syndrome could perfectly improve the symptoms as alternating chills, fever and chest tightness. Additionally, several studies have found that Xiao Chai Hu Tang could exert an anti-infection effect against SARS-CoV-2 (Kwon et al., 2020; Wang et al., 2020). Da Chai Hu Tang, a representative formula for yang ming and bowel excess syndrome, could remarkably improve the symptoms such as constipation and abdominal distention in the severe cases of COVID-19 (Chen et al., 2020), which could be explained by the interior-exterior relationship between Lung and Large Intestine.

Similarly, Da Cheng Qi Tang is recommended by official guidelines to inhibit inflammation by promoting bowel movement (Tang et al., 2020). With the function of activating qi and promoting purgation, Da Cheng Qi Tang could remove the heat accumulation and regulate the 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 (Committee, 2020). Qing Wen Bai Du Yin has an anti-inflammatory effect and is widely used in pandemics, such as H1N1 influenza and epidemic hemorrhagic fever (Zheng et al., 2020). Qing Wen Bai Du Yin is primarily applied to the patients with dual blazing of qi and blood syndrome, which is manifested as thirsty, headache and delirious speech. It is suggested that Qing Wen Bai Du Yin can alleviate the inflammatory reaction of COVID-19 patients and may have a protective effect on organ damage caused by inflammation (Wen et al., 2020). Moreover, LoniceraeJaponicaeFlos (Jin Yin Hua) a dominating CMM in Qing Wen Bai Du Yin, is frequently used in combination with Qing Wen Bai Du Yin to treat pneumonia (Nie, Zhang, Wang, & Guo, 2010). Water retention in the lung could worsen the dampness 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 GanTang in treating COVID-19 patients with yang qi deficiency and water retention syndrome is a unique TCM strategy (Dai, Zeng, & Ke, 2020).

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, Jiang, et al., 2020; Luo, Ni, et al., 2020). The major chemical constituents of Scutellariae Radix have been reported to possess anti-viral, anti-inflammatory, hepatoprotective and neuroprotective activities (Wang et al., 2018). Thirty compounds isolated from Scutellariae Radix were reported having potent anti-H1N1 activities, even more remarkable than oseltamivir phosphate (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 (Committee, 2020). Paeoniflorin, which is the most abundant compound in Paeoniae Alba Radix is also an ingredient of Xuebijing injection, which is reported to improve Lung injury in patients with severe or critical COVID-19 infection (Ma, Ma, et al., 2020; Ma, Qiu, et al., 2020). Furthermore, Poria is a popular CMM for the treatment of severe COVID-19 patients (Wang, Kong, & Wang, 2020; Wang, Ming, et al., 2020). Poriacocos polysaccharides have shown anti-inflammatory properties in previous studies (Liu, Wang, Xu, & Zhang, 2019; Zhao et al., 2020). One study shows that the extracts of Bupleuri Radix have an anti-viral effect on acute respiratory tract infections with H1N1 virus (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 has brought a good prognosis to COVID-19 patients (Zhong et al., 2020). Again, our findings support the results of previous studies, which indicates that Scutellariae Radix and Bupleuri Radix contain numerous potential compounds to eliminate or eradicate COVID-19 (Fang, Bie, Mu, Liu, & Chen, 2020; Ren et al., 2020).

The overlapped data of epidemic diseases in medical records and the manifestations of COVID-19 patients were creatively analyzed in our study. The effective CMMs corresponding to the COVID-19 symptoms with high frequency could provide some valuable information about treating this serious pandemic. In the future, further experimental researches are expected to validate the results of the current study.

5 CONCLUSION

In summary, CMM combinations extracted from medical records in Chinese ancient times are found in classical TCM formulae including 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 key CMMs for treating COVID-19 manifestations were Scutellariae Radix Paeoniae, Radix Alba, Poria, and Bupleuri Radix.

ACKNOWLEDGMENTS

Grant Sponsor: National Natural Science Foundation of China. Grant Number: 81873266; 81803973. Grant Sponsor: Project of Zhejiang Provincial Natural Science Foundation. Grant Number: LQ21H270005.

AUTHOR CONTRIBUTIONS

Yaxue Han: Data curation; formal analysis. Zi Yang: Software; writing-original draft. Shan Fang: Investigation; resources. Mengqing Zhang: Project administration; validation. Zhijun Xie: Project administration; writing-review & editing. Yongsheng Fan: Conceptualization. Ting Zhao: Conceptualization.

Supporting Information

Filename	Description
ar24677-sup-0001-supplement1.xlsxExcel 2007 spreadsheet , 18.6 KB	DATA S1: Supporting information
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