Background: Coronavirus disease 2019 is still spreading all over the world and without any specific medicine. Traditional Chinese medicine has played an important role in the control of epidemics in China and accumulated many experiences. The aim of this study is to summarize the law of traditional Chinese medicine and provide reference for coronavirus disease 2019 traditional Chinese medicine treatment.

Methods: We collected the treatment plans of traditional Chinese medicine for coronavirus disease 2019 in 24 provinces of China to evaluate the basic Chinese medicine formulas, and the efficacy types, frequency, “Four Characters”, “Five Tastes”, “Channel Tropism” of herbal medicines. Combination rules between medicines were calculated by Apriori algorithm and Clementine12.0.

Results: The formulas for “Relieving Exterior Syndrome”, “Expelling Dampness”, “Clearing Heat” and “Supplementing” have highest proportion. In prevention period and medical observation period, the medicines mainly have effect for “Clearing Heat”, “Relieving Exterior Syndrome” and “Supplementing”. In treatment period, medicines for “Clearing Heat”, “Relieving Superficies” and “Relieving Dampness” had higher frequency. The “Four Characters” of Chinese medicines in all treatment plans were mainly “Cold” and “Warm”. Medicines in the treatment plans always belong to “Pungent Taste”, “Bitter Taste” and “Sweet Taste”. For “Channel Tropism”, most medicines turned over to the “Lung”, “Stoma” and “Spleen”. The common medicine combinations in the recommended formulas during the prevention period and medical observation period were medicines for “Qi-Supplementing” and “Relieving Superficies”. In treatment period (mild, moderate, severe/critical), medicines for “Dampness Expelling”, “Relieving Superficies” and “Qi-Supplementing” were combined in a high frequency. In recovery period, the medicines for “Dispelling Dampness” combined the medicines for “Promoting Blood Circulation” with highest frequency. Conclusions: We found the characteristics of medicine and prescription rules of traditional Chinese medicine for the treatment of coronavirus disease 2019 and provided scientificity and effectiveness of it. More importantly, it provides reference for the development of new clinical prescriptions for coronavirus disease 2019.

Key words: Coronavirus disease 2019, Formula of traditional Chinese medicine, Chinese medicine, Compositional analysis of formulas

Acknowledgment:

This study was funded by the National Natural Science Foundation of China (No. 81403040), Key Programs in Sichuan Department of Science and Technology (20ZDYF2376), Achievement Transformation Project of Chengdu Medical College (CYCG18-06).

Competing interests:

The authors declare no conflicts of interest.

Abbreviations:

COVID-19, coronavirus disease 2019; TCM, traditional Chinese medicine.

Citation:

Niu T, Zhong SH, Ding R, Bao X, Liu Q. Prescription analysis of traditional Chinese medicine for COVID-19 treatment. Drug Comb Ther. 2021;3(1):2. doi: 10.12032/DCT2021020502.

Executive editor: Xiao-Hong Sheng.

Submitted: 25 August 2020, Accepted: 12 December 2021, Online: 05 Febuary 2021.

© 2021 By Authors. Published by TMR Publishing Group Limited. This is an open access article under the CC-BY license (http://creativecommons.org/licenses/BY/4.0/).

 

Background

Coronavirus disease 2019 (COVID-19) is another acute infectious disease caused by severe acute respiratory syndrome coronavirus 2 after the outbreak of severe acute respiratory syndrome and middle east respiratory syndrome [1]. It was named by WHO on February 11, 2020 [2]. Most anxious is that epidemic situation spread all over the world at the end of February 2020 and regional or global risk levels had been upgraded to the highest level on February 28. Until March 11, the Director General of WHO Tedros Adhanom Ghebreyesus announced that this epidemic situation would be called a global pandemic [3]. Statistics showed that by February 01, there were more than 103.04 million cases had been reported to WHO, and more than 2,220,000 people had lost their lives. COVID-19 had a huge negative impact on people's lives and social and economic development [4]. Up to now, China has passed the peak period of the epidemic and gradually returned to normal life.

In order to alleviate the epidemic that is still spreading as soon as possibl，the WHO and partners launched an international clinical trial to help find an effective treatment for COVID-19 named “Solidarity” which contains 4 treatment options: local standard of care; local standard of care plus remdesivir; local standard of care plus lopinavir with ritonavir and local standard of care plus lopinavir with ritonavir plus interferon β-1a [5]. However, there are still no specific drugs although scientists all over the world have tried their best. The treatment plan of traditional Chinese medicine (TCM) is one of the unique methods in China that had been proven to have great therapeutic and preventive effects.

The recording about epidemic diseases in China starts from 221 B.C. [6], which provides lots of experiments to formulate a diagnosis and a treatment plan [7]. Combined the rainy and humid environment and the the fever and “Sticky Tongue” of patients, Chinese medicine experts believed that “Cold” and “Dampness” were the main causative factors of the epidemic [8]. The treatments for different clinical stages (preventive period, medical observation period, mild period, moderate period, severe/critical period, recovery period) were different [9]. In the prevention period, improving human immunity to prevent infection was firstly considered. In mild and moderate period, the formulas were mainly for symptoms of fever, coughing and vomiting. Patients in severe/critical period have symptoms such as coma, so Chinese medicines for resuscitation are used. All these above fully reflect the characteristics of treatment based on “Syndrome Differentiation”. Acupuncture, scraping, cupping therapy and point massage methods had also been promoted and used for patients in the recovery  period,  which  had  greatly  promoted  the rehabilitation of patients [10].

Traditional treatment had obvious clinical effects. In a study of 102 mild symptoms cases treated with TCM, the clinical symptom disappearance time, the recovery time of body temperature and the average length of stay in hospital was all shortened [11, 12], which were same as the view of academician of China engineering academy, Bo-Li Zhang. His research team had carried a study [13] to compare 52 COVID-19 patients treated by two plans: one treatment with integrated traditional Chinese, another with Western medicine and compared with treatment with Western medicine only. The results fully proved the positive role of treatment by TCM.

This study intends to analyze the formulas in treatment plans of TCM from different provinces in China, and find out the medicine association rules by Clementine12.0 to provide reference for the treatment and promotion of TCM plans about COVID-19.

Methods

Source of data

Search the government websites and the Chinese medicine administration website from 24 provinces to obtain the TCM treatment plans for COVID-19 (Table1).

Data pre-analysis

Many Chinese medicines in the treatment plans have different names due to different places of origin. We unified the names of one same medicines according to the Chinese Pharmacopoeia [14]. Such as ‘Sheng Gancao’ and ‘Zhi Gancao’ are all named ‘Gan Cao’ (Glycyrrhizae radix et rhizoma), ‘Yi Mi’ and ‘Yi Ren’ are all named ‘Yi Yiren’ (Coicis semen). According to different clinical stages, the recommended basic formulas and all Chinese medicines in the recommended formulas were analyzed.

Data analysis

We conducted a statistical analysis to evaluate the basic Chinese medicine formulas, and the efficacy types, frequency, “Four Characters”, “Five Tastes”, “Channel Tropism” of herbal medicines. Apriori algorithm and Clementine12.0 were used to calculate the combination rules between medicines. “Confidence” refers to the frequency of including medicine B in the formula containing medicine A, expressed as medicine A→medicine B, and “confidence” is an important indicator of association rules. Set the parameters of “number of support” and “confidence” in the software to conduct data mining analysis.

Results

Efficacy analysis of formula

We analyzed the type of formulas in different treatment periods and recovery periods based on their efficacy, as showed in Figure 1. In prevention and the medical observation period, the proportion of formula for “Relieving Superficies” was highest (50%). In mild case, formula for “Relieving Superficies” still had the highest proportion (39%) and the type of formula increased at the same time, obviously the “Desiccating” formula was used. In moderate case, the proportion of formula for “Clearing Heat” significantly increased (34%). The type of formula increased in severe and critical case, such as formulas for “Warming Interior”, “Supplementing” and “Resuscitation”. “Supplementing” formula had the highest proportion in recovery period (52%).

Frequency of Chinese medicine

The frequency of Chinese medicines (≥ 3%) in treatment plan for COVID-19 showed in Table2.

In prevention period, to improve body immunity and prevent  infection,  Huang Qi  (Astragali  radix), Jin Yinhua (Lonicerae japonicae flos), Fang Feng (Saposhnikoviae radix), Huo Xiang (Agastaches herba) and Glycyrrhizae radix et rhizoma were used mostly (frequency  =  19, 16, 15, 15, 15).  Those medicines mainly have the efficacy of “Supplementing Defensive Qi” and          “Relieving Superficies”. In medical observation period, patients usually showed symptoms of fever, weakness and so on, medicines have effect on “Desiccating” (Cang Zhu (Atractylodis rhizoma), Agastaches herba),  “Relieving Superficies” (Saposhnikoviae radix) and “Clearing Heat” (Lonicerae japonicae flos, Lian Qiao (Forsythiae fructus)) were mostly used. In mild and moderate period, the common symptoms such as fever and cough gradually became severe and the frequency of

Xing Ren (Armeniacae semen amarum), Forsythiae fructus, Ma Huang (Ephedrae herba), Shi Gao (Gypsum fibrosum) and Gua Lou (Trichosanthis fructus) which have stronger effects in “Relieving Cough and Clearing Heat” were used. In severe/ critical period, patients usually have severe symptoms of coma and shock. So medicines like Fu Zi (Aconiti lateralis radix praeparaia), Ren Shen (Ginseng radix et rhizoma) which have efficacy of “Tonifying Yang and Replenishing Qi” were mostly used (frequency = 23). Patients need to regain immunity during the recovery period, so Chen Pi (Citri reticulatae pericarpium), Astragali radix, Poria, Mai Dong (Ophiopogonis radix) and Dang Shen (Codonopsis radix) which can “Regulate, Replenish Qi and Yin” were used frequently.

Figure 1 Proportion of formulas based on efficacy in different clinical stages. A, preventive and medical observation period; B, mild period; C, moderate period; D, severe/critical period; E, recovery period.

 

The “Four Characters”, “Five Tastes” and “Channel Tropism” of herbs for COVID-19

The statistical analysis results of the “Four Characters” of medicines showed that medicines in the prevention period, treatment period and recovery period are mostly “Cold” and “Warm” (Figure 2). Herbs that “Taste Pungent, Bitter and Sweet” were used mostly in the treatment of COVID-19 (Figure 3). For “Channel Tropism”, most medicines were belong to “Lung, Stomach and Spleen Channel” (Figure 4).

 

Analysis of Chinese medicine efficacy

According to traditional Chinese pharmacology, we conducted statistics on the efficacy of Chinese medicines in TCM treatment plan (Table 3).

In prevention and medical observation period, the medicines mainly had efficacy of “Supplementing”, “Clearing Heat” and “Exterior-Effusing”. In treatment period (mild, moderate, severe and critical) and recovery period, the efficacy of medicines were concentrated in “Clearing Heat”, “Relieving Superficies”, “Clearing Dampness” and “Supplementing”. Especially medicines for “Supplementing” used. This fully reflects the treatment principle of TCM  was  “Eliminating  Pathogen and Strengthening Vital Qi” which different from Western medicine treatment.

 

Compositional analysis of formulas

Apriori algorithm was used in this study. “Number of support” refers to the frequency of a medicinal material in all formulas. “Confidence” is an important parameter of the association rule algorithm (medicine A→medicine B). For the formula containing A, the closer the confidence parameter is to 1, the greater the probability of B appearing. We set the support level to 20 and screened the medicine combination (n = 2, 3) with confidence = 1, the top ten medicines combinations in each period were shown in the Table 4.

Bai Zhu (Atractylodis macrocephalae rhizome), Saposhnikoviae radix→Astragali radix was the highest medicine combination in preventive period. Those 3 medicines compose a classic “Dispelling Wind” formula named Yupingfeng powder which outstanding effect is to prevent weak people from catching a cold. In medical observation period, Atractylodis macrocephalae rhizome,   Saposhnikoviae radix→Glycyrrhizae radix et rhizoma, Huang Qin (Scutellariae radix) → Forsythiae fructus and Scutellariae radix → Lonicerae japonicae flos had high frequency to appear in a same formula. The latter 3 medicines are main medicines of Chinese patent drug Shuang Huanglian which has excellent treatment effect on fever, cough and sore throat. In mild period, Cao Guo (Tsaoko fructus), Huo Pu (Magnoliae officinalis cortex)→Atractylodis rhizoma had high frequency, which often used together for “Removing Dampness”. And combination of Bing Lang (Arecae semen)→Tsaoko fructus is from a classic “Desiccating” formula named Dayuanyin. Armeniacae semen amarum→Gypsum fibrosum, Ephedrae herba had highest frequency in moderate period, these are main medicines of classic ancient prescription Maxing Shigan decoction which is one of the important basic formulas in this treatment of COVID-19 by TCM. Aconiti lateralis radix praeparaia→Zhi Zi (Gardeniae fructus) and Ginseng radix et rhizoma→Gardeniae fructus were main combinations in the severe/critical period. Aconiti lateralis radix praeparaia and Ginseng radix et rhizoma are the only 2 medicines in a famous first-aid formula in TCM named Shenfu decoction, which has great effect for symptoms such as shock and coma. In recovery period, Codonopsis radix, Citri reticulatae pericarpium→Poria and Poria→Codonopsis radix, Astragali radix are all belong to a classic formula Sijunzi decoction, a basic formula of “Supplementing Qi”. (The composition of the above formulas are all in the Supplementary Materials).

Figure  2  The  “Four  Characters”  of  medicines  in  traditional  Chinese  medicine  treatment  plan  for coronavirus disease 2019 

 

Figure 3 The “Five Tastes” of medicines in traditional Chinese medicine treatment plan for coronavirus disease 2019

Figure 4 The “Channel Tropism” of medicines in traditional Chinese medicine treatment plan for coronavirus disease 2019

Discussion 

TCM theory about COVID-19

The formation of the theoretical system of TCM was greatly influenced by ancient Chinese materialism and dialectics. It believed that disease arises as a combination of genetic, hormonal, environmental and other factors. TCM experts found that the epidemic initially outbreak during the heavy rainfall and dampness environment in Wuhan, and the tongue manifestation of patients at various stages of disease were all “Sticky, Greasy and Fur”[15], which could be summarized as “Cold” and “Dampness”. According to the theory of “Yin and Yang Balance” in TCM, the property of COVID-19 is “Yin Disease” and the main organs of injury are “Lung” and “Spleen”. Therefore, the treatment method is aimed at “Cold” and “Dampness”. Because of most patients have symptoms such as no appetite, nausea and vomiting, diarrhea or constipation, TCM experts recommend treatment should include gastrointestinal symptoms at the same time [16].

Formula and analysis by efficacy

The treatment of epidemic diseases in China starts very early. There has had recording about characteristics of epidemic diseases in the Yellow Emperor’s Inner Classic (written in 221 B.C.E.–220 C.E., unknown author), one of the four classics of TCM. There also had many famous TCM classic works in the long history of China. Such as Treatise on Cold Damage Diseases written by Zhongjing Zhang in the Late Eastern Han Dynasty and On Plague Diseases written by Youke Wu in Ming Dynasty [17]. And all formulas recommended in TCM treatment plan for COVID-19 are all based on classics of TCM. Such as Chinese patent drug Qingfei Paidu decoction, one of the most important TCM prescription in this COVID-19 campaign, was considered to be suitable for most of the clinical stages. It is based on several famous classic ancient prescription of Chinese medicine, such as Maxing Shigan decoction, Shegan Mahuang decoction and Xiao Chaihu decoction. Those are all from classic Treatise on Cold Damage Diseases or On Plague Diseases. it had been clinically proven have a good effect for treatment of COVID-19 [18].

Based on the classification of Chinese formula, the basic formulas in the treatment plan of TCM in 24 provinces were analyzed. The analysis showed that formula for “Relieving Superficial”, “Desiccating” and “Clearing Heat” were most used. As the main causes of COVID-19 are “Cold” and “Dampness”, which can cause fever, cough and phlegm et al., “Spleen and Stomach Symptoms” usually appeared at the same time. “Cold” has characters that being apt to “Attack Yang” and has property of “Coagulation and Stagnation” [19]. Therefore, by using the “Relieving Superficies and Clearing Heat” formula, it can relieve patients' fever, no sweat, sore throat and other symptoms caused by “Cold”. For the “Symptoms” caused by “Dampness” which can “Hamper Qi Movement” and be “Heavy and Turbid”, usually with “Phlegm and Sticky Greasy Fur”, the effect of “Desiccating” formula is needed. Besides, in severe/critical period, patients have symptoms of difficult breathing, fatigue and coma. Formulas for “Resuscitation” can treat the above symptoms. For strengthening body resistance in recovery period, increased use of “Supplementing” formula.

Analysis of Chinese medicines with high frequency In prevention period and medical observation period, the medicines mainly have effect for “Clearing Heat”, “Relieving Superficies” and  “Supplementting”. Such as Lonicerae japonicae flos, Saposhnikoviae radix and Astragali radix had high frequency. Lonicerae japonicae flos clinically widely used in acute diseases, pharyngitis, diarrhea and other diseases [20]. Saposhnikoviae radix has good antipyretic and anti-inflammatory effects [21]. Chromogenone glycosides of Saposhnikoviae radix can significantly reduce the temperature of rats [22]. The main ingredient of Astragali radix is saponin that can inhibit liver fibrosis, promote lymphatic proliferation and increase antibodies [23]. In treatment  period, medicines for  “Clearing  Heat”,  “Relieving Superficies” and “Relieving Dampness” had high frequency. For example, Armeniacae semen amarum, Ephedrae herba, Gypsum fibrosum, Agastaches herba and Platycodonis radix often used. Armeniacae semen amarum, Ephedrae herba and Gypsum fibrosum are common medicines combination in treatment of TCM. “Maxing Shigan decoction” is a classic ancient prescription of Chinese medicine for “Relieving Superficies” based on these 3 medicines [24]. Ephedrae herba has extremely sweating effect by “Relieving Superficies”, which often used  together with a “Clearing Heat” medicine named Gypsum fibrosum to greatly improve its “Heat Removal” effect. Armeniacae semen amarum is a representative medicine for “Resolving Phlegm, Cough and Asthma”. Agastaches herba is a representative medicine for “Expelling Dampness” by means of “Aromatics, Stopping Vomiting and Relieving Summer-Heat” [25]. Pharmacological studies have shown that high doses of extract of Platycodonis radix can effectively prolong the incubation period of asthmatic guinea pigs, significantly reduce the generation and release oxygen free radicals. At the same time, it can promote the secretion of IFN-γ in asthmatic guinea pigs, thereby indirectly regulating Th1/Th2 balance [26]. In addition, Ginseng radix et rhizoma as an  essential supplementing medicine and Aconiti lateralis radix praeparaia as a first-aid medicine are used for patients in severe/critical period. Finally, “Supplementing” medicine is mainly used in recovery period. For example, Ophiopogonis radix and Codonopsis radix.

 

Analysis of Chinese medicines characteristics (“Four Characters”, “Five Tastes”, “Channel Tropism” and efficacy)

In the basic theory of TCM, “Cold, Heat, Warm, Cool, (Plain)” are “Four Characters” and “Sour, Bitter, Sweet, Pungent, Salty, (Tasteless)” are “Five Tastes” of Chinese medicine which correspond to different efficacy. In addition, “Channel Tropism” is sites where TCM plays a therapeutic role on human body (“Heart, Liver, Spleen, Lung, Kidney, Stomach, Colorectal, Intestine, Bladder, Gallbladder, Triple Warmer, Pericardium) [27].

In  treatment  plan  of  TCM  for  COVID-19,  most medicines have characters of “Cold” and “Warm”, and most “Five Tastes” are “Pungent, Bitter and Sweet”. Medicines for “Relieving Superficies” (Ephedrae herba, Sheng Jiang (Zingiberis rhizoma recens), Bo He (Menthae haplocalycis herba)), “Clearing Heat” (Forsythiae fructus, Scutellariae radix, Gypsum fibrosum) and “Dampness-Eliminating” (Agastaches herba, Tsaoko fructus, Magnoliae officinalis cortex, Atractylodis rhizoma) always belong to “Pungent”, “Cold” and “Bitter”. Those medicines have great effect for symptoms such as fever, sore throat and so on caused by “Cold and Dampness”. The effect is closely related to the chemical composition of medicine. Such as patchouli alcohol in Agastaches herba and menthol in Menthae haplocalycis herba is a main component belongs to “Pungent” and play a role in “Sweating, Antipyretic and Resolving Dampness” [28, 29]. For “Channel Tropism”, most medicines belong to “Lung, Stomach and Spleen”, the same as the classical TCM theory of COVID-19.

 

Compositional analysis of formulas

TCM formulas are consisted by Chinese medicines following the combination principle named “Jun, Chen, Zuo, Shi”. “Jun” refers to the medicine that plays a major therapeutic role in a formula; “Chen” assist the main medicine to strengthen the therapeutic effect; “Zuo” is used to treat minor symptoms or restrict the toxicity of the main drug; “Shi” has effect to guide and harmonize medicines. Besides, the formula medicines can be adjusted according to different TCM syndromes in clinical application.

In this analysis, we set the support level to 20 that contain most medicines in the treatment plan of TCM, which can comprehensively showed the rules of the combination of medicines in formulas for COVID-19. The common medicine combinations in the recommended formulas during the prevention period and medical observation period were Atractylodis macrocephalae                                rhizoma-Astragali  radix, Saposhnikoviae radix-Atractylodis macrocephalae rhizoma, Saposhnikoviae radix-Atractylodis macrocephalae rhizoma-Astragali radix, Scutellariae radix-Forsythiae fructus, Perillae folium-Agastaches herba and so on. Those are all common medicines for improving body immunity and relieving superficies. Such as empirical formula of Chinese medicine Baizhu Huangqi decoction contains Atractylodis macrocephalae rhizoma, Astragali radix, Scutellariae radix, et al. Which can “Supplement Qi” and “Tonify Spleen” [30]. In treatment period (mild, moderate, severe/critical), Tsaoko fructus, Magnoliae officinalis cortex-Atractylodis rhizoma, Rhei radix et rhizoma-Gypsum fibrosum, Gua Lou (Trichosanthis fructus)-Armeniacae semen amarum, Ginseng radix et rhizoma-Aconiti lateralis radix praeparaia-Zhi Zi (Gardeniae fructus), Shan Zhuyu (Cornifructus), et al. were used together in a high frequency to have efficacy of “Clearing Heat”, “Dampness-Eliminating” and “Resuscitation”. Magnoliae officinalis cortex, Atractylodis rhizoma, Tsaoko fructus, Trichosanthis fructus often used in formula for “Damp-Heat” [31]. For example, they are main medicines in classic ancient prescription of Chinese medicine Ping Wei power and classic ancient prescription of Chinese medicine Da Yuan decoction [32, 33]. The combination of Ginseng radix et rhizoma, Aconiti lateralis radix praeparaia and Cornifructus always used for “Supplementing Yang Qi”. Pharmacological studies indicate the combination of Ginseng radix et rhizoma and Aconiti lateralis radix praeparaia can improve the myocardial energy metabolism disorder of chronic heart failure and the myocardial activity  of heart failure by increasing the activity of Na+, K+, ATPase in cardiomyocytes. At the same time, they play a synergistic and detoxifying role [34]. Finally, in recovery period, the main medicine combinations are Poria-Codonopsis radix-Astragali radix, Codonopsis radix-Poria-Citri reticulatae pericarpium and so on. Which are commonly used medicines for body recovery after illness. Classic ancient prescription of Chinese medicine Huanqi Sijunzi decoction contains Astragali radix, Poria, Codonopsis radix, Dang Gui (Angelicae sinensis radix), et al. which can improve patients’ immune function [35]. (The composition of the above formulas are all in the Supplementary Materials).

 

Conclusion

The TCM treatment plan of all provinces are based on the “Cold” and “Damp” pathogenic characteristics of COVID-19, combined with clinical symptoms and formulated according to the combination principle, and have played a good therapeutic effect on patients at different clinical stages. In this study, we combined with the theoretical knowledge of TCM and based on the analysis of formulas and Chinese medicines from treatment plans of TCM from 24 provinces in China, we found the characteristics of medicine and prescription rules of TCM for the treatment of COVID-19 and provided scientificity and effectiveness of it. More importantly, it provides reference for the development of new clinical prescriptions for COVID-19.

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Author Contributions

Zhong SH conceived of the design and Niu T carried out the study. Niu T, Bao X and Liu Q collected and organized data. Ding R conducted the medicine association analysis part. Niu T wrote the manuscript. Zhong SH assisted in writing and revise the article. All authors read and approved the final manuscript.

 

Ethical statement

No ethics committee approval was required as no human or animal research was conducted.

 

 

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This article is cited from Drug Comb Ther. 2021;3(1):2. doi: 10.12032/DCT2021020502.

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