Can Yang, Xiao-Dong Lv, Li-Jian Pang, Lin-Lin Wang, Guo-Qian Cong, Hao-Yang Zhang, Jia-Ran Wang, Ye Sheng

1. Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China

2. Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China

Keywords:

ABSTRACT

1. Introduction

In December 2019, a novel coronavirus (2019-nCoV) infection was caused by a new type of coronavirus (2019-nCoV) in Hubei province. The epidemic spread rapidly and spread throughout the country and abroad. The novel coronavirus epidemic was declared as "Public Health Emergency of International Concern (PHEIC)" by WHO in January 31, 2020. Novel coronavirus pneumonia has been continuously improved in the joint efforts of the party and the central government under the leadership of Comrade Xi Jinping at the level of the government and the masses. As of 24 April 8th, 81865 new cases of pneumonia were diagnosed in China, 73 suspected cases, 64187 cured cases and 3215 death cases[1].In recent years, Chinese medicine has accumulated valuable and rich experience in the prevention and treatment of various diseases, especially in the prevention and treatment of SARS in 2003. According to the TCM novel coronavirus pneumonia, the epidemic characteristics of this new crown pneumonia are combined with the clinical manifestations of the patients. The disease belongs to the category of "epidemic diseases" in TCM. The disease is mainly due to the lung and spleen and stomach, and the mechanism of the disease is mainly "wet, hot, toxic, stasis, and vacuity"[2-4]. Recently, the novel coronavirus pneumonia novel coronavirus has been raging around the world, but there is no specific drug against the new coronavirus, and the vaccine is still under development. TCM novel coronavirus pneumonia has achieved remarkable clinical effects in treating new crown pneumonia with its multichannel and multi target antiviral effects and characteristics. According to the latest data, the rate of participation in treatment of TCM in many provinces has reached over 90%. Traditional Chinese medicine has the basic characteristics of syndrome differentiation and treatment, most of which are combined treatment. So it is meaningful to explore the law of Chinese medicine in the treatment of novel coronavirus pneumonia. This article collected the relevant diagnosis and treatment plans for new coronary pneumonia in the country and various provinces, autonomous regions and municipalities, Use Excle, SPSS25.0, SPSS Modeler18.0 data mining software to explore the rules of Chinese medicine treatment of new coronary pneumonia, with a view to providing reference for clinical medication.

2. Materials and Methods

2.1 Data source

By collecting the latest novel coronavirus pneumonia diagnosis and treatment plans released from January 26, 2020 to March 8th from the National Health Commission and the National Committee of the provinces, municipalities and autonomous regions , the official websites of the administration of traditional Chinese medicine and the China HowNet. A total of 24 novel coronavirus pneumonia related diagnosis and treatment plans were collected,159 prescriptions for treatment of r novel coronavirus pneumonia

2.2 Data processing

Referring to the 2015 edition of "Chinese Pharmacopoeia"[5] and the tenth edition of "Chinese Pharmacy" [6] to standardize the names of 189 traditional Chinese medicines involved. For example ,(1) Chinese medicine aliases and common names: White Cardamom is classified as Cardamom, Ling Yun is classified as Poria, Raw coix seed is classified as Coix seed.(2) Name of origin of traditional Chinese Medicine: Atractylodes lanceolata is classified as the Rhizoma atractylodis.(3)Synonymous expression of TCM name: For example, "liquorice" and "raw liquorice" are unified into "liquorice". The four properties and five tastes、meridian tropism and categories of traditional Chinese medicine are also regulated with reference to the 2015 edition of "Chinese Pharmacopoeia" and the tenth edition of "Chinese Pharmacy".

2.3 Data entry

The collected TCM compounds for the treatment of novel coronavirus pneumonia were recorded into Excle one by one,If the compound contains this flavored Chinese medicine, it will be marked as "1", if not, it will be marked as "0". Establishing a database for the treatment of new coronary pneumonia with TCM compounds, Sort out the four properties and five tastes 、meridian tropism and categories of all the included Chinese medicines. Data entry and data collation were completed by two people to ensure data integrity and accuracy. SPSS25.0 was used for cluster analysis. SPSS Modeler 18.0 was used for association rule analysis, in which "1" and "0" were replaced by "T" and "F", respectively.

2.4 Data analysis

Use Excel to make data statistics on the frequency, frequency, four properties and five tastes、meridian tropism and categories of traditional Chinese medicine, so as to know the distribution of traditional Chinese medicine in all aspects. Based on frequency analysis, SPSS25.0 was used for cluster analysis, using systematic clustering algorithm in cluster analysis to explore the usage rules of medicine pairs and medicine groups for the treatment of new coronary pneumonia. SPSS Modeler 18.0 was used for association rule analysis, Use Apriori algorithm to analyze the association of high-frequency drugs, and find out the commonly used drug pair combinationsThe Apriori algorithm was used to carry out correlation analysis of high-frequency traditional Chinese medicine and to dig out the combination of common traditional Chinese medicine.

3.Results

3.1 Analysis of the usage frequency and frequency of traditional Chinese medicine

Among the 159 TCM compounds included, a total of 189 of TCM were used, with a total medication frequency of 2049 times. Among them, licorice is the most frequently used drug 90 times, accounting for 4.39% of the total frequency of use. The 62 flavored traditional Chinese medicines with single-medicine usage frequency ≥ average frequency (used frequency ≥11 times) were classified as highfrequency drugs for data mining, The number of medicinal flavors accounts for 32.80% of the total number of medicinal flavors, and the total frequency of use was 77.99%, These medicines are the core medicines for the treatment of novel coronavirus pneumonia.(See Table1)

3.2 Frequency analysis of high-frequency Chinese medicine categories

Referring to the tenth edition of "Chinese Pharmacy" and "Chinese Pharmacopoeia" to classify the efficacy of drugs with a frequency of ≥11, a total of 17 drug categories are obtained, and the cumulative frequency of medication is 1598 times. Among them, the top three types with higher frequency of use are antipyretic medicine (332 times), tonic medicine (239 times), and humidifying medicine (210 times) .(See Table 2)

3.3 Frequency analysis of four properties and five tastes and meridian tropism of high frequency traditional Chinese medicine.

According to the standards of “Chinese Pharmacy” and “Chinese Pharmacopoeia,” the four Qi, five flavor and meridian tropism of high-frequency drugs are regulated, and the frequency was counted.(See Table3.Table4.Table5).Among them,the most frequent use of warm medicines (474 times), cold medicines ranked second, reaching 307 times. Among the properties of five flavor, the first three types are spicy, bitter and sweet drugs respectively. The use frequency of spicy drugs is the highest (765 times). Among the properties of five flavors, the top three are lung, stomach and spleen meridian.

Table 1 Chinese medicine frequency and frequency distribution (frequency of use ≥11 times)

Table 2 Frequency distribution table of Chinese medicine categoryries(frequency of use ≥ 11 times)

Table 3 Statistical analysis table of four properties frequency of traditional Chinese medicine (frequency of use ≥ 11 times)

Table 4 Statistical analysis table of frequency of five flavors of traditional Chinese medicine (frequency of use ≥ 11 times)

3.4 System cluster analysis of high frequency traditional Chinese medicine

SPSS25.0 was used for systematic cluster analysis of 62 high frequency drugs, Ward method was selected for clustering, Euclidean distance between variables was selected as the square distance. The results of cluster analysis were combined with the attending effect of traditional Chinese medicine. It is reasonable to group 62 traditional Chinese medicines into 7 categories(See Chart 1). Group I: Areca, Amomum tsao-ko, Atractylodes macrocephala, notopterygium root, ginger, Magnolia officinalis and Agastache; Group 2: Tangerine peel, Atractylodes macrocephala, Poria cocos, Pinellia ternata, Dried tangerine or orange peel, Codonopsis pilosula, Amomum villosum; Group 3: Radix Ophiopogonis, Radix Glehniae, Folium mori, Schisandra chinensis, Radix Scrophulariae, Radix Rehmanniae, bamboo leaf, Anemarrhena, Radix Paeoniae Rubra; Group 4: Mint, honeysuckle, Reed rhizome, Burdock, Periostracum cicada, Platycodon grandiflorum, Forsythia, Bupleurum chinense, Artemisia, Talcum, Cardamom, Coix seed; Group 5: Trichosanthes, Chinese rhubarb, Lepidium,peach seed,;Group 6:Ephedra, Almond, Gypsum, Liquorice; Group 7: Cinnabar, Realgar, Pearl, Bezoar, Borneol, Gardenia, Banksia rose, Syzygium aromaticum, Agarwood, Musk, Rithoma Curcuma, Cyperus, Sandalwood, Coptis, Buffalo horn, Myrobalan, Dogwood, Ginseng, Baikal Skullcap.

3.5 Analysis of high frequency traditional Chinese medicine association rules

Association rule analysis of high frequency traditional Chinese medicine by SPSS modeler 18.0, Algorithm selection Apriori algorithm. Set the correlation degree to 20%, the confidence degreeto 65%, and the maximum number of antecedents to 5, A total of 36 association rules were obtained, and the drug pairs were sorted according to the association degree. Among them, there are 20 groups of effective drugs in the association rules of the 2 flavor medicines. (See Chart 6); In the three-flavor medicine association rule, after the front-to-rear items are reversed, 9 effective medicine pair association groups are obtained, (See Chart 7); The highfrequency traditional Chinese medicine related network display map, (See Chart 2).

Table 5 Statistical analysis table of meridian tropism frequency of traditional Chinese medicine (frequency of use ≥ 11 times)

Table 6 Association rules analysis of novel coronavirus pneumonia 2 traditional Chinese medicine

Table 7 Association rules analysis of novel coronavirus pneumonia 3 traditional Chinese medicine

Chart 2 High frequency traditional Chinese medicine association network

4. Discussion

Novel coronavirus pneumonia is a newly discovered infectious disease. There is no corresponding disease in the existing Chinese medicine books. It is characterized by fever, strong infectivity and epidemic. It should belong to the epidemic category of febrile diseases in traditional Chinese medicine. In Shuowen, it is said that "epidemic, people all get sick" .The treatise on epidemic febrile diseases, compiled by Wu Youke of Ming Dynasty, is the first monograph in China that systematically studies the etiology, syndrome and pulse treatment of acute infectious diseases. It points out that”. The febrile disease is not the wind orthe cold. There is a different feeling between heaven and earth. Thus, the gas of epidemic disease is different from wind, cold, heat, dampness, dryness and fire. It has the main pathogenic characteristics of strong infectivity, easy epidemic and similar symptoms. The humidity is heavy all year round in Wuhan area, and the winter weather is abnormal this year. Many experts and scholars of traditional Chinese medicine believe that the disease is caused by dampness and toxin, and the core pathogenesis is "dampness, heat, toxin, stasis and deficiency". The location of the disease is mainly in the lung, spleen and stomach. Due to the different regional climate and individual constitution, the transformation of pathogenesis is also different. At present, most people think that at the initial stage, the dampness, poison and filthy Qi enter from the mouth and nose, or invade the lung, or straighten the spleen and stomach. In the middle stage, dampness stagnates and turns heat into heat, accumulating heat and steaming, and heat toxin closes the lung. In severe stage, pericardium was trapped by pathogenic factors. Recovery period evil to positive virtual, deficiency of Qi and Yin. Based on the classification and summary of TCM compounds for Novel coronavirus pneumonia in the relevant clinical diagnosis and treatment programs of China and 23 provinces, municipalities and autonomous regions, the drug use and compatibility rules of 159 TCM compounds were explored, so as to provide certain reference and reference for clinical drug use.

Traditional Chinese medicine in the treatment of Novel coronavirus pneumonia has a unique advantage and expertise, including theory of febrile diseases and pestilence theory is the traditional Chinese medicine an important theoretical base for research and treatment of Novel coronavirus pneumonia, at present, the treatment of Chinese medicine on the one hand, it can quickly improve patients with mild cough, sore throat, loss of appetite symptoms such as fatigue, on the other hand reduces severe to critical transformation, and higher chance to ordinary patients.

In response to the epidemic, many scholars and experts in China had put forward their own opinions on the treatment of novel coronavirus pneumonia. Zhou zhongying, a master of Chinese medicine, believed that novel coronavirus pneumonia belongs to the " pestilent toxicity”. In the treatment, it is suggested that both the exterior and the interior should be relieved, and the methods of diaphoresis, heat-clearing, purgative, reconciliation should be used.[7]Professor Jiang Liangduo[8] pointed out that " Qi Failing to Control Fluid” " is the key pathogenesis of the disease. In the treatment, it is advocated to take the care of Qi and Yin as the premise, by dispersing the upper warmer, middle warmer and lower energizer to drive out evil influence. Academician Wang Yongyan[9] believed that the new coronavirus pneumonia belongs to the category of "cold epidemic". According to the law of disease transmission, the treatment can be divided into the early, middle, critical and recovery phases, and will be treated according to syndrome differentiation. Follow the treatment of syndrome is the first rule of law. Academician Tong Xiaolin [10]thought novel coronavirus pneumonia belongs to the category of "cold damp epidemic", The treatment should be based on "Dispelling violence" and target on"improving environment".Du hongbo et al [11]considered the diagnosis and treatment of novel coronavirus pneumonia from the perspective of differentiation and treatment of liver and spleen, It is considered that liver stagnation and spleen deficiency can be considered as an important pathogenesis.To pay attention to the regulation of liver and spleen may be another entry point to improve clinical efficacy and prevent recurrence. Ren Peihua[12] believed that the treatment of new coronary pneumonia should be the first to protect the Yin fluid, and the main purpose is to clear the fire. Combining Sheng iang Powder at the right time to diffuse the lung and descendthe turbid. Although a large number of well-known Chinese medicine practitioners and scholars have similarities and differences in the treatment of new coronary pneumonia, they mainly proceeded from two aspects of strengthening and eliminating evil, and the treatment of new coronary pneumonia by treatment on stages and three measures had been agreed by the Chinese medicine community.

The frequency and frequency analysis results of this study show that the commonly used traditional Chinese medicine with drug frequency ≥ 11 times are licorice, almond, ephedra, gypsum, poria, baikal skullcap, agastache, etc. It can be seen from the highfrequency drugs that there are Maxing Shigan decoction, maxing Yigan Decoction, Huopu Xialing decoction, Dayuan decoction, etc. The analysis of high frequency drugs shows that there are 17 kinds of drugs involved in clinical use at present, among which four kinds of drugs are most frequently used: Antipyretic drugs,, tonic drugs, humidifying drugs and diaphoretic medicine. The analysis results of four properties and five tastes show that the main properties of novel coronavirus pneumonia are warm, cold, lukewarm,mild-natured. The main flavour is pungent,bitterness,sweet and slightly bitter. Bitter taste can relieve energy and dryness, and has the effects of clearing heat, purging fire, dampness, lowering gas and relieving asthma, The pungent flavor can disperse the energy, it has the effect of dissipating evil qi, promoting Qi and blood.Sweet taste can supplement energy and slow down. It has the function of harmonizing drug properties and tonifying deficiency and slowing down. The medicinal properties of cold temperature and the effects of bitter, pungent, sweet and sour flavors and high-frequency medicines together reflect the treatment of new coronary pneumonia with detoxification and dampness as well as nourishing qi and yin, besides ,it can disperse cold and dehumidification, or clear away heat and promot diuresis. According to the analysis of drug meridian, the main channel of drug meridian is lung, spleen and stomach, suggesting that the treatment of this disease mainly starts from the viscera such as lung, spleen and stomach, which is consistent with the knowledge and treatment experience of experts and scholars at present.

Using system cluster analysis and combining with the novel coronavirus pneumonia prescription and its efficacy. After clustering several times, the system cluster model showed that the clustering number of the new crown pneumonia formula was 7. There are 7 types of prescriptions with good effect for the treatment of novel coronavirus pneumonia. The first type is the combination of dampness-resolving and dampness-eliminating drugs with windcold-dispersing drugs, which can be given to patients with colddampness in the lung and unfavourable lung qi. Thereinto, betel nut, Magnolia officinalis and Amomum tsao-ko are important components of the membrane-source-opening beverage in the Treatise on Pestilence, and they constitute the common combination for the treatment of damp-pathogen block and hub dereliction. The second type includes drugs such as pinellia, Poria cocos, Atractylodes macrocephala and tangerine peel, and have the function of drying damp and strengthening spleen, they can also treat those with lung-spleen qi deficiency. The third type is the combination of qi-tonifying drugs and yin nourishing and heat clearing drugs, which can treat patients with remaining pathogenic qi and deficiency of both qi and yin. The fourth type is the combination of dampnessresolving drugs and heat-clearing drugs, including talcum, round cardamom, honeysuckle and fructus forsythiae, which are suitable for those with dampness and heat in the lung and heat toxin congestion. The fifth type is the combination of heat-clearing drugs and cathartic drugs, mainly including rheum officinale, trichosanthes kirilowii Maxim and rhizoma anemarrhenae, which are especially suitable for those with obstructed Fu-qi and domination of heat in middle jiao; the six type includes Chinese ephedra, bitter almond, gypsum and liquorice, which are the components of Maxingshigan Decoction in Zhang Zhongjing's Treatise on Febrile Diseases. The combination of the four drugs can disperse lung qi, clear away lung heat and relieve asthma, which are suitable for those with blocked lung by epidemic toxin or dyspnea cause by lung heat. In the seventh type, cinnabar, pearl and musk belong to the combination of awaking drugs, and ginseng, dogwood and monkshood are the common combination for rescuing from collapse by restoring yang. The cooperative use of the above drugs can treat inner blocking causing collapse in critical situation.

Compatibility is the main form of clinical application of traditional Chinese medicine. Usually more than two kinds of drugs are used together according to the needs of the disease and the different characteristics of the drugs to achieve the effect of increasing efficiency and reducing toxicity. From the results of association rules mining and drug association network graph, we can see that the common Chinese medicine pairs for COVID-19 include ephedraalmond, glycyrrhiza-gypsum, almond-glycyrrhiza-gypsum, Poria cocos-Agastache rugosus, Agastache rugosus-Pinellia ternata- Poria cocos, Agastache rugosus-Mangnolia officinalis, Amomum tsao-ko-Rhizoma Atractylodis, Rhizoma Atractylodis-Mangnolia officinalis, betel nut-Amomum tsao-ko, Mangnolia officinalis-Amomum tsaoko, and betel nut-Amomum tsao-ko-rhizoma atractylodis. The combination of ephedra, almond, liquorice and gypsum can dispel pathogenic qin, replenish lung qi and clear the stagnated hot-evil. They constitute the classic compatibility of medicines for treating damp evil blocking and fire and heat-transmission. Agastache rugosus, Pinellia ternata, Poria cocos and Mangnolia officinalis are components of the Huopu Xialing Decoction, which can remove dampness by means of aromatics. According to the Medical True Biography, “If the treatment of dampness cannot facilitate urination, then the point is not grasped”. The combination of Poria cocos and Agastache rugosus is the compatibility of dampness removing medicine and dampness-resolving medicine, which can remove the evil. Betel nut, Amomum tsao-ko and rhizoma atractylodis can eliminate damp and turbid qi. Betel nut can disperse dampness and evil by means of spiciness, Amomum tsao-ko can remove turbidity, and Mangnolia can resolve dampess with aromatics. The three medicines have a spicy smell and can directly reach the focus to dispel the evil.It can be seen that each pair of drugs can learn from each other and work together to achieve the best effect of disease treatment.

According to the results of the above data, the characteristics of the prescription medicine for the partial syndrome of new coronary pneumonia can be analyzed,In the early stage of dampness constraining the defensive qi in the lung, ephedra, the prescription containing ephedra, notopterygium root, honeysuckle, fructus forsythiae and gypsum can be used, which has the main effect of cooling and dispelling evil, accompanied by removing interior heat. In the middle stage, the evil enters qi fen, the blockage of dampness and heat is in the lung. Then the prescription can include ephedra, liquorice, gypsum, almond, rhizoma atractylodis, Mangnolia officinalis, rheum officinale and trichosanthes kirilowii Maxim, which can clear heat and free the lung, and dispel dampness and reduce phlegm. With the progression of the disease, the pathogen enters the interior and the noxious dampness blocks the lung. In this case, the prescription can include gypsum, rhizoma anemarrhenae, rhizoma coptidis, semen lepidii, rheum officinale, Mangnolia officinalis and rhizoma atractylodis, which has the effect of clearing heat and removing dampness, thereby relieve the poison stagnated in the lung. For critical disease with inner blocking causing collapse, ginseng, monkshood, cinnabar and pearl can be used to rescue from collapse by restoring yang, and tranquilize and allay excitement. After serious illness, the patients during convalescent period often have deficiency of both qi and yin, so they can take radix pseudostellariae, codonopsis pilosula, Astragalus membranaceus, Poria cocos and white atractylodes rhizome to nourish qi and yin and replenish vital qi.The clinical condition is complex, so we should distinguish deficiency and excess of cold and heat, differentiate syndrome by stages and adjust medication according to the characteristics of patients' symptoms.

In summary, this study used SPSS, SPSS Modeler, Excle and other software to analyze the traditional Chinese medicine compound for treating new coronary pneumonia. Dig out the commonly used traditional Chinese medicine and drug pairs for the treatment of new coronary pneumonia, and summarize some of the characteristics of traditional Chinese medicine in the treatment of new coronary pneumonia from the type, performance and frequency of the drugs used. Clearing heat, diverging, attacking, dehumidifying, dampening, wetting, and medicine all make wet evil go from all directions. The frequent use of drugs for invigorating qi and nourishing Yin also reflects that attacking pathogenic factors does not forget to strengthen the body, so as to prevent the occurrence of Internal closure and external detachment. At the same time, it can also be seen that the treatment of new coronary pneumonia with traditional Chinese medicine is mainly dehumidification and detoxification, and nourishing Qi and Yin. In summary, this study summarizes the medication rules of traditional Chinese medicine for the treatment of new coronary pneumonia through data mining, hoping that the results of this data mining can provide a certain reference and reference for further enriching and perfecting the clinical medication of new coronary pneumonia.