KMCRIC

Herbal medicine and pattern identification for treating COVID-19: a rapid review of guidelines

Lin Ang a,b, Hye Won Lee c, Jun Yong Choi d, Junhua Zhang e, Myeong Soo Lee a, b,*

a Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, Korea

b Korean Convergence Medicine, University of Science and Technology, Daejeon, Korea

c Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea

d School of Korean Medicine & Korean Medicine Hospital Lung Cancer & Pulmonology, Pusan National University, Busan, Korea

e Evidence-based Medicine Centre, Tianjin University of Traditional Chinese Medicine, Tianjin, China

* Corresponding author at: drmslee@gmail.com or mslee@kiom.re.kr

Clinical Medicine Division Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Korea; Tel. +82-42-868-9266

Abstract

Background: Coronavirus disease 2019 (COVID-19) is pandemic and has caused illness to many people worldwide. This review aimed to summarize and analyze the herbal formulae provided by the guidelines for their pattern identifications (PIs) and compositions of herbs to treat patients with COVID-19.

Methods: We searched 7 data sources for eligible traditional medicine guidelines up to March 6, 2020 and found a total of 28 traditional medicine guidelines that provide treatment measures for COVID-19.

Results: Of the 28 guidelines, there were 26 government-issued Chinese guidelines and 2 Korean guidelines. After standardizing the terminology of the PIs and herbal formulae, there were 8 PIs and 23 herbal formulae for the mild stage, 11 PIs and 31 herbal formulae for the moderate stage, 8 PIs and 21 herbal formulae for the severe stage, and 6 PIs and 23 herbal formulae for the recovery stage in the Chinese guidelines. In the Korean guidelines, there were 4 PIs and 15 herbal formulae for the mild stage, 3 PIs and 3 herbal formulae for the severe stage, and 2 PIs and 2 herbal formulae for the recovery stage. In the frequency analysis of herbs, Glycyrrhizae Radix et Rhizoma was found to be the herb with the highest frequency of usage in the Chinese guidelines. 

Conclusion: This review can be used as guidance for the traditional medicine treatment of COVID-19. Clinical evidence is needed in the future to evaluate the efficacy of traditional medicine.

Keywords: Coronavirus disease 2019; Pattern identification; Herbal medicine; Chinese medicine; Korean medicine

1. Introduction

Coronavirus disease 2019 (COVID-19) is a newly identified strain of coronavirus that causes illness ranging from effects similar to the common cold to fatal diseases in people across the world.[1] This disease was first identified in early December 2019, and by the middle of March 2020, the World Health Organization (WHO) assessed COVID-19 as a pandemic.[2] As of March 2020, there have been more than 178,700 confirmed cases in at least 140 countries. The majority of cases were reported in mainland China, followed by Italy, Iran, Spain and South Korea.[3]

The common symptoms of COVID-19 include fever, cough, and shortness of breath. In severe cases, pneumonia may occur and ultimately lead to organ failure and even death.[4] Currently, there are no available vaccines or specific medicines for the treatment of COVID-19. In light of the outbreak, various treatment modalities have been considered, including traditional medicine, which has been widely used during the past epidemic outbreaks, such as severe acute respiratory syndrome (SARS) and H1N1 influenza.[5] To date, 2 countries, China and South Korea, have issued traditional medicine treatment guidelines on the prevention and treatment of COVID-19. Up to March 2020, there have been 7 versions of diagnosis and treatment guidelines issued by the National Health Commission of China[6] and 2 versions of guidelines issued in South Korea.[7]

A recent systematic review suggested that “Based on historical records and evidence of SARS and H1NI influenza prevention, Chinese herbal formula could be an alternative approach for the prevention of COVID-19 in high-risk populations”[5] and it focused on prevention method but not treatment methods. Therefore, we aimed to systematically analyze the herbal formulae in the guidelines for pattern identifications and herbal compositions recommended for treating patients with COVID-19.

2. Methods

2.1. Data sources

The following data sources were searched on February 25, 2020 for eligible traditional medicine guidelines and searched up to March 6 to retrieve the updated version of the guidelines provided:

• Guidelines International Network (G-I-N)[8]

• “Chinese guidelines on Novel Coronavirus” resources[9] by Evidence Aid

• The official government websites of all 31 provinces in mainland China (including municipal and autonomous regions)

• The Centre for Health Protection of the Hong Kong Special Administrative Region[10]

• Association of Korean Medicine and Korean Association of Traditional Pulmonary Medicine

• Japanese Association for Infectious Diseases and Japanese Respiratory Society[11]

• Taiwan Centers for Disease Control[12]

2.2 Inclusion and exclusion criteria

This study focused on the recommended treatment modalities related to traditional medicine for COVID-19. All guidelines that provide traditional medicine treatment measures were included regardless of language, and publication types and years. Guidelines that only provide preventive measures without treatment measures were excluded. Herbal formulae related to folk medicine were excluded only and other herbal formulae in these guidelines were included. As the guidelines were outlined based on regional characteristics, regional folk medicines, such as Tibetan medicine in Tibet, Mongolian medicine in Inner Mongolia, and Miao medicine in Guizhou province, were integrated into their guidelines.

2.3 Data extraction and analyses

The data from each included guideline were extracted using a predefined data extraction table. The content of the data extraction tables comprised the stages of the disease, pattern identification, clinical symptoms, therapeutic principle, name and composition of herbal formulae, amount of herbs, and country or province of the provided guideline. The pattern identification and herbal formulae were analyzed according to the severity of the disease (mild, moderate, severe and recovered stages). The frequency of herbs recommended in the herbal formulae for each stage of disease was also computed and analyzed.

2.4 Terminology standardization

The terminology of pattern identification were standardized based on the clinical manifestation provided in the guidelines and Clinic Terminology of Traditional Chinese Medical Diagnosis and Treatment-Syndromes.[13] The herbal formulae with missing names were also renamed by comparing the compositions of these herbal formulae with other named herbal formulae and double-checked them with the Dictionary of Traditional Chinese Medicine Formula.[14] All the terminologies were also standardized based on the WHO international standard terminologies for traditional medicine.[15]

3. Results

A total of 28 traditional medicine guidelines that provide treatment measures for COVID-19 were found. Of the 28 guidelines, there were 26 government-issued Chinese guidelines and 2 Korean medicine-professional associations-issued Korean guidelines. The Japanese government did not officially issue any traditional medicine guidelines on COVID-19, but they adopted a translated version of the national guideline issued by the National Health Commission of China. There were no official traditional medicine guidelines issued in Hong Kong or Taiwan.

In mainland China, there are currently 7 versions of national diagnosis and treatment guidelines, and traditional medicine content has been included since the third version.[6] Using the government-issued national guidelines as a reference, 17 provinces, 4 municipalities and 4 autonomous regions in mainland China officially issued traditional medicine-related guidelines for the prevention and treatment of COVID-19. All the guidelines were devised by local health authorities according to regional characteristics and local prevalence of COVID-19 and have been continuously updated since the first issuance.[5]

In Korea, the Association of Korean Medicine and the Korean Association of Traditional Pulmonary Medicine each issued the first version of traditional medicine guidelines on the prevention and treatment of COVID-19 at the end of February 2020.[7] Both guidelines were drafted by clinical experts who were also regularly updated by both associations to provide clinical guidance for the prevention and treatment of COVID-19 in South Korea. 

In the frequency analysis of the herbs used in the herbal formulae for treating patients with COVID-19 according to the patients’ disease stages and PIs (Tables 1-5), the results showed that there were 8 PIs and 23 herbal formulae for the mild stage (Table 1); 11 PIs and 31 herbal formulae for the moderate stage (Table 2); 8 PIs and 21 herbal formulae for the severe stage (Table 3); and 6 PIs and 23 herbal formulae for the recovery stage (Table 4) in the Chinese guidelines. The Korean guidelines suggested 4 PIs and 15 herbal formulae for the mild stage, 3 PIs and 3 herbal formulae for the severe stage, and 2 PIs and 2 herbal formulae for the recovery stage (Table 5).

Among the Chinese guidelines, we also found that most of the herbal formulae were recommended once in the respective guidelines. However, 17 herbal formulae were recommended several times by different guidelines, with a slight difference in the herbal compositions. The herbal formulae with the highest frequency of recommendation were the herbal formula of Shen Fu Tang with Su He Xiang Pill or Angong Niuhuang Pill in the severe stage and the combined formula of Xiang Sha Liu Junzi Tang and Li Zhong Pill in the recovery stage. In particular, Angong Niuhuang Pill, Zhi Bao Dan, Zi Xue San, and Su He Xiang Pill were the only prescriptions that were not required in the form of decoction and were only prescribed in the severe stage.

On the other hand, the herbal formula of Qingfei Paidu Tang, which is a combination of 4 different herbal formulae with 21 herbs (Tables 1-4), was recommended by the Chinese national diagnosis and treatment guidelines in the treatment of COVID-19 regardless of disease stage or regional status. This herbal formula was also recommended for the treatment of severe stage in the Korean guidelines (Table 5).

In addition, the frequency of the herbs used in the herbal formulae recommended by the Chinese guidelines for every stage and in total were computed (Figure 1). The results showed that these formulae contain 12 herbs with a frequency of use 30 or more times in the treatment formulae in all stages. Both Armeniacae Semen Amarum and Ephedrae Herba were found to be the top 10 herbs with the highest frequency of use in the mild, moderate and severe stages. The Gypsum Fibrosum and Lepidii seu Descurainiae Semen were  also the top 10 most common herbs used in the moderate and severe stages. In addition, Agastachis Herba, Forsythiae Fructus, Atractylodis Rhizoma, and Scutellariae Radix were also highly used in both the mild and moderate stages. Notably, Glycyrrhizae Radix et Rhizoma was found in the top 10 herbs with the highest usage frequency in all four stages. It was also the herb with the highest frequency of usage in total.

4. Discussion

In this review, we systematically summarized and analyzed all the herbal formulae provided by the guidelines according to their pattern identification and herbal compositions. The Chinese medicine herbs used for the prevention of COVID-19 based on 23 provincial guidelines issued in mainland China were reviewed and analyzed in a recent publication.[5] With reference to it, but in contrast, our review focused on the traditional medicine treatment measures recommended by all available guidelines. We extended our search of guidelines to nearby countries and reviewed guidelines issued by mainland China (25 provincial guidelines and 1 national guideline) and South Korea to conduct a more comprehensive review.

For the frequency analysis of herbs used in every Chinese guideline for COVID-19, each stage has several herbs that were not shown in the list of top 10 frequently used herbs for other stages. For instance, Magnoliae Officinalis Cortex and Platycodonis Radix could only be seen for the mild stage. Magnoliae Officinalis Cortex is often prescribed for the treatment of various gastrointestinal problems, such as fullness in the stomach, vomiting, and diarrhea from dampness. Platycodonis Radix is usually prescribed for coughs with excessive phlegm and sore throat due to exogenous pathogens.[16] It could be inferred that gastrointestinal symptoms due to dampness and sore throat as well as coughing with sputum are the primary clinical manifestation in the mild stage of COVID-19. The active components contained in these 2 herbs also showed anti-inflammatory benefits in the in vivo studies of the acute lung injury model.[17, 18]

In the severe stage, Aconiti Lateralis Radix Praeparata and Rhei Radix et Rhizoma were identified to be frequently used but not in other stages. This could be due to the extreme PIs and clinical manifestations that are only found in severe patients. Aconiti Lateralis Radix Praeparata is known to treat heart failure and has anti-asthmatic and anti-epileptic properties.[19, 20] The combination of Aconiti Lateralis Radix Praeparata and Rhei Radix et Rhizoma is also highly compatible, and this combination is often used in various herbal formulae. As these herbs have a certain degree of toxicity, they have to be used in caution and preferably are reserved for extreme cases.[21]

Moreover, there are 4 herbal medicines available only in the severe stage. Angong Niuhuang Pill, Zhi Bao Dan, Zi Xue San, and Su He Xiang Pill played a significant role in the severe stage treatment. Angong Niuhuang Pill, Zhi Bao Dan, Zi Xue San belongs to the First Aid Three Treasures of Chinese Medicine[22], which is cold in nature and is used when the patient loses consciousness due to infectious disease-induced heat. In contrast, Su He Xiang Pill is an aromatic warm-natured medicine and is used when the patient loses consciousness due to a cold pathogen. All 4 herbal medicines were prescribed in different conditions of extremelysevere or critical stages based on the patients’ clinical manifestation, and they shared the same therapeutic principle to clear the orifices.

Pinelliae Praeparatum cum Zingiberis and Citri Reticulatae Pericarpium were only identified in the list of frequently used herbs in the recovery stage where patients may suffer from white and thin phlegm after their recovery. Pinelliae Praeparatum cum Zingiberis and Citri Reticulatae Pericarpium are major components of the herbal formula Er Chen Tang, which is usually prescribed to clear phlegm and dampness.[16] Another herb, Ophiopogonis Radix, is conventionally used for nourishing yin and promoting fluid production. This herb is prescribed for dry cough caused by yin deficiency and is especially suitable for patients in the recovered stage.[16]

Glycyrrhizae Radix et Rhizoma is the herb with the highest frequency use overall regardless of disease stage. It is one of the antiviral herbal medicine which is approved by the China Food and Drug Administration (SFDA). Many studies have reported that this herb inhibits viral attachment, entry and replication, which is previously used in combating SARS.[23, 24] Moreover, Glycyrrhizae Radix et Rhizoma also has an anti-inflammatory quality which is suitable for the treatment of inflammatory lung condition in COVID-19.[25]

The herbal formula Qingfei Paidu Tang was recommended by both Chinese and Korean guidelines. In the Chinese guidelines, this formula is recommended for all stages. According to a recent publication[26], this herbal formula increases immunology and reduces inflammation by targeting the lung and spleen, which are the disease pathways of COVID-19. However, the herb Farfarae Flos was removed in the Korean guidelines due to its safety and toxicity.[27]

This review has several limitations. First, the results of this review were obtained after standardizing the terms of the PIs and herbal formulae. Therefore, there might be a difference in the terms used in the provided guidelines. Second, this review does not include any direct evidence on the efficacy of traditional medicine in the clinical treatment of COVID-19. The results provided by this review are a summary of the traditional medicine guidelines, which can only be considered as guidance, and clinical verification is still required. Third, although this review summarized the most recent version of the national and provincial guidelines available up to March 6, 2020, the guidelines issued on COVID-19 by the Chinese government are constantly and frequently updated.

In conclusion, this review can be used as a reference in the traditional medicine treatment of COVID-19. Clinical studies are required to evaluate the efficacy and safety of traditional medicine and to provide clinical evidence. The integration of traditional medicine into conventional treatment may be an alternative approach for the treatment of COVID-19 in the future.

Acknowledgement

The authors thanks for the American Journal Experts for offering free editing services for this paper as COVID-19 article.

Author contributions

Conceptualization: HWL and MSL. Methodology: LA and MSL. Software: LA and MSL.

Validation: HWL, JYC, and JZ. Formal Analysis: LA and HWL. Investigation: LA, HWL and MSL. 

Resources: MSL. Data Curation: HWL and JYC. Original Draft: LA and HWL. 

Review & Editing: JYC, JZ and MSL. Visualization: HWL and MSL.

Supervision: MSL. Project Administration: MSL. Funding Acquisition: MSL

ORCID number

Lin Ang: https://orcid.org/0000-0002-7273-9600

Hye Won Lee: https://orcid.org/0000-0003-4248-1482

Jun Yong Choi: https://orcid.org/0000-0002-2854-3862/

Junhua Zhang: https://orcid.org/0000-0003-4043-1967/

Myeong Soo Lee: https://orcid.org/0000-0001-6651-7641

Conflict of interest

The authors declare no conflict of interest.

Funding

This study was supported by the Korea Institute of Oriental Medicine (KSN2013210).

Ethical statement

This research did not involve any human or animal experiment

Data availability

Data will be made available upon reasonable request.

Supplementary material

Supplement 1. English and Chinese terms of pattern identification, herbal formulae and herbs name.

References

[1] Centers for Disease Control and Prevention (CDC). Coronavirus Disease 2019 (COVID-19) Situation Summary, Available from: https://www.cdc.gov/coronavirus/2019-nCoV/summary.html. Accessed March 6, 2020.

[2] World Health Organization (WHO). WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020, Available from: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-themedia-briefing-on-covid-19---11-march-2020. Accessed March 11, 2020.

[3] Lai KKR, Wu J, Harris R, McCann A, Collins K, Watkins D, et al. Coronavirus Map: Tracking the Spread of the Outbreak, Available from: https://www.nytimes.com/interactive/2020/world/coronavirusmaps.html?action=click&module=RelatedLinks&pgtype=Article. Accessed March 17, 2020.

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[5] Luo H, Tang QL, Shang YX, Liang SB, Yang M, Robinson N, et al. Can Chinese Medicine Be Used for Prevention of Corona Virus Disease 2019 (COVID-19)? A Review of Historical Classics, Research Evidence and Current Prevention Programs. Chinese Journal of Integrative Medicine 2020.https://doi.org/10.1007/s11655-020-3192-6.

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[14] Peng HR. Dictionary of Traditional Chinese Medicine Formula. 2nd ed: People's Medical Publishing Press; 2015.

[15] World Health Organization (WHO), Regional Office for the Western Pacific. WHO international standard terminologies on traditional medicine in [the Western Pacific Region, Available from: https://apps.who.int/iris/handle/10665/206952. Published 2007.

[16] Xi SY, Gong YW. Essentials of Chinese materia medica and medical formulas: new century traditional Chinese medicine. 1st ed: Academic Press; 2017.

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[21] Wang L, Peng C. Study on compatibility source of Radix Aconiti Lateralis Praeparata and Radix et Rhizoma Rhei. Journal of Shandong University of Traditional Chinese Medicine 2006;30(2):100-04.

[22] Tong D. The necessity of having the "First Aid Three Treasures of Chinese medicine” at home Chinese health care 2010;4:50-21.

[23] Li T, Peng T. Traditional Chinese herbal medicine as a source of molecules with antiviral activity. Antiviral Res 2013;97(1):1-9.https://doi.org/10.1016/j.antiviral.2012.10.006.

[24] Chen F, Chan KH, Jiang Y, Kao RYT, Lu HT, Fan KW, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 2004;31(1):69-75.https://doi.org/10.1016/j.jcv.2004.03.003.

[25] Yang XL, Liu D, Bian K, Zhang DD. Study on in vitro anti-inflammatory activity of total flavonoids from Glycyrrhizae Radix et Rhizoma and its ingredients. Zhongguo Zhong Yao Za Zhi 2013;38(1):99-104.

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Table 1. Herbal medicines and pattern identification for treating mild stage patients with COVID-19

* Name of the herbal formula is originally not reported, and the authors named them based on Dictionary of Traditional Chinese Medicine Formula.

Table 2. Herbal medicines and pattern identification for treating moderate stage patients with COVID-19

* Name of the herbal formula is originally not reported, and the authors named them based on Dictionary of Traditional Chinese Medicine Formula.

Table 3. Herbal medicines and pattern identification for treating severe stage patients with COVID-19

* Name of the herbal formula is originally not reported, and the authors named them based on Dictionary of Traditional Chinese Medicine Formula.

Table 4. Herbal medicines and pattern identification for treating recovery stage patients with COVID-19

* Name of the herbal formula is originally not reported, and the authors named them based on Dictionary of Traditional Chinese Medicine Formula.

Table 5. Herbal medicines and pattern identifications for treating the patients with COVID-19 (Korean guidelines)

* Name of the herbal formula is originally not reported, and the authors named them based on Dictionary of Traditional Chinese Medicine Formula.