Paidu Decoction”—A Possible Choice of Phytotherapy for Severe Acute Respiratory Infection Caused by Coronavirus Disease-19

This work is aimed to study the therapeutics and pharmacology of the treatment of severe acute respiratory infection caused by coronavirus disease-19 (COVID-19) with traditional Chinese medicine (TCM) “Qingfei Paidu Decoction”. We analyze the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia” (Version I to Version VII) made by China, “Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected—Interim guidance” made by World Health Organization (WHO), “Therapeutic Guidelines: Respiratory” published by Australia, and the origin of classical prescription of Qingfei Paidu Decoction: “Shanghan Lun (Treatise on Febrile Diseases)” and “Jinkui Yaolue (Synopsis of Golden Chamber)”. We search the dictionary of traditional Chinese medicine (Version II) manually. We search literatures from 2001 to 2020 on Wiley online library. We conduct a comparative study on the therapeutic options and indications among Qingfei Paidu Decoction, COVID-19 and chronic ob-structive pulmonary disease (COPD). And we carry out pharmacological inquiry of Qingfei Paidu Decoction. The therapeutic options and indications of Qingfei Paidu Decoction in China, COVID- 19 and COPD are considered to be basically consistent. Qingfei Paidu Decoction has a definite therapeutic effect on the symptoms, basic diseases and complications for COVID-19 and COPD. Qingfei Paidu Decoction is a possible choice of phytotherapy for severe acute respiratory infection caused by COVID-19.

Severe cases: shortness of breath after mild activity, severe restriction of daily activities, frequent expectoration of sputum, chronic cough, acute exacerbation requiring glucocorticoids, FEV1 < 40% expected value Severe cases: Adults who conform to any of the following criteria: 1) Onset of shortness of breath, RRN30 times/min; 2) In resting state, oxygen saturation < 93%; 3) Arterial partial pressure of oxygen (PaO 2 )/fraction of inspired oxygen (FiO 2 ) < 300 mmHg (1 mmHg = 0.133 kPa) Cases with chest imaging that shows obvious lesion progression within 24 -48 hours > 50% shall be managed as severe Note: The symptoms and prescriptions described in TCM classics "Treatise on Febrile diseases" and "Synopsis of the Golden Chamber" have obvious correspondence with the clinical classification of COPD and Chinese protocol related clinical symptoms, which can also be compared with WHO temporary document: acute respiratory distress syndrome (ARDS). protection, gastrointestinal protection, immune activity, relief of cough, expectorant and bronchiectasis. Traditional Chinese medicines such as Chaihu (Radix Bupleuri), Gan Cao (Radix Glycyrrhizae), Huangqin (Radix Scutellariae), Fuling (Poria Cocos), Huoxiang (Herba Pogostemonis), Shegan (Rhizoma Belamcandae) have been shown to have strong anti-HCoV-229E activity, anti-human immunodeficiency virus, anti-hepatitis C virus, significant anti-inflammatory and antibacterial effects.
Ephedrine increases heart rate, glucose, and insulin concentrations without affecting systolic blood pressure [2]. Plant-based stimulants have similar disposition characteristics to drugs and can produce a significant cardiovascular response after a single dose [3]. Herbal ephedra can increase heart rate and blood pressure [4]. Ephedrine has indirect and direct effects on α1, β1, and β2 adrenergic receptors, resulting in cardiovascular effects. And it also interacts with β3 adrenergic receptors to promote thermogenesis [5]. The effect of ephedra and Xingren (Semen Armeniacae Amarum) on relieving asthma, relieving cough and eliminating phlegm is better than that of single use [6]. Phenylpropanolamine which is the stereoisomer of norpseudoephedrine has the effects of adrenalin, relieving asthma, expectorant, antitussive, sweating, diuretic, anti-inflammatory, antipyretic, antiallergic, and improving renal function [7]. Pseudoephedrine has been used as over-the-counter anti-cold drug and flu drug for more than 50 years as an oral decongestant [8] [9].

The Functions and Pharmacologic Basis of the Herbs of Xiaochaihu Decoction
The cough latency of mice is significantly prolonged after combined with the mixture of anti-inflammatory and antibacterial substances, which is positively correlated with the dose. The times of cough decrease significantly [70].
Mahuang (Herba Ephedrae) (  It also can inhibit the heart with high doses. The extract of Chenpi has the effect of scavenging oxygen free radicals, anti-lipid peroxidation, dilating trachea. The essential oil can make expectoration easy. The General flavone has antiallergic activity in vitro and in vivo [73]. Huoxiang (Herba Pogostemonis) It almost includes 1.5% volatile oil. It can promote the secretion of gastric juice, enhance the digestive power, and it has the antispasmodic effect on gastrointestinal tract. It also has antibacterial [74], antiviral effect. In addition, it has antidiarrheal effect, microvascular dilation effect, and slightly sweating effects.
Zhishi (Fructus Aurantii Immaturus) It includes hesperidin, neohesperidin, and naringin. It has significant promoting effect on gastrointestinal propulsive movement, and obvious anti-inflammatory effect. Its decoction has obvious hypertensive effect, anti-allergy effect, and anti-platelet aggregation effect.

Corresponding Relationship between the Herbs of "Qingfei Paidu Decoction" and the Important Organ Symptoms of COVID-19 Disease (Table 6)
According to pharmacological activity analysis, it is found that the traditional

Important Laboratory Parameters of COVID-19 and Traditional Chinese Herbal Medicine Functional
Groups with Clear Pharmacological Support (Table 7) According to the pharmacological activity analysis literature, it is found that the

Discussion
The Chinese treatment protocol "Qingfei Paidu Decoction" is based on the combination of classic prescriptions in "Treatise on Febrile and Miscellaneous Diseases" and "Synopsis of Golden Chamber" written by the medical saint Zhang Zhongjing of the Han Dynasty. According to historical records, the land of China suffered from a severe plague during the first year of Eastern Han Dynasty construction to the first ten years. Due to the plague, the population of the Zhang Zhongjing's family decreased from more than 200 to 60 -70 people, and about 100 of them died from typhoid fever. As a local official Changsha Taishou and medical scientist, Zhang Zhongjing actively organized rescue and medical treatment. During this period, "Treatise on Febrile and Miscellaneous Diseases" and "Synopsis of Golden Chamber" were born. This great work is extremely far-reaching, and it is the basic classic of traditional Chinese medicine, and Japanese Kampo Medicine is also based on this. "The Handbook of Prescriptions for Emergencies" clearly pointed out that "typhoid fever, shiqi, and plague have the same kind of characteristic". It can be seen that the so-called "typhoid fever" in "Treatise on Febrile and Miscellaneous Diseases" is the so-called "plague" in later generations. Zhang Zhongjing's classic herbal formulae of "Mahuang Xingren Gancao Shigao decoction", "Wuling Powder", "Xiaochaihu Decoction" and "Shegan Mahuang Decoction" in "Treatise on Febrile and Miscellaneous Diseases" and "Synopsis of Golden Chamber" can be used to treat fever and cough, gastrointestinal discomfort, chest tightness, shortness of breath, palpitation and dysuria, pulmonary emphysema, lung carbuncle, expectoration and hemoptysis, difficulty breathing and other disease symptoms caused by exogenous typhoid. The above-mentioned disease symptoms, the disease progression of COPD described in the guidelines and the development process of COVID-19 pneumonia disease from light to serious have a very high similarity. The dialectical treatment process adopted by classic herbal formulae also has a high similarity to the COPD treatment protocol in the respiratory disease guidelines. From a pharmacological point of view, the pharmacological treatments adopted by the "Mahuang Xingren Gancao Shigao decoction", "Wuling Powder", "Xiaochaihu Decoction", and "Shegan Mahuang Decoction" are basically consistent with the COPD treatment protocol in the respiratory disease guidelines.
The main efficacy of the Chinese treatment protocol "Qingfei Paidu Decoction" is clear. In response to the symptoms of fever, coughing, expectoration, and dyspnea symptoms in COVID-19 pneumonia, this formula has a clear antipyretic, relieving cough, eliminating phlegm, and bronchodilator effect. The formula has obvious anti-inflammatory, anti-bacterial and anti-viral effects on the inflammatory factor exudation present in COVID-19 pneumonia. It can ob-viously protect the gastric mucosa, promote bile secretion, and promote gastrointestinal tract symptoms against gastrointestinal discomfort symptoms caused by COVID-19 pneumonia. It has obvious protective effect on liver damage caused by COVID-19 pneumonia virus and obvious diuretic effect on the urinary system. It promotes blood microcirculation in the blood system and is conducive to self-repair of organs. It has a significant sedative effect on the central nervous system disease. The dosage of Chinese herbal medicine in the formula is sufficient to produce the effect, and the protection of the liver also reduces the damage of other drugs to the liver.
Among community-acquired COVID-19 patients, 64.3% had comorbidities, 30% had hypertension, 12.1% had diabetes, 5.7% had fatty liver and abnormal liver function, 5.0% had coronary heart disease, 5.0% had chronic gastritis and gastric ulcer [75]. The presence of comorbidities made the disease worse. The COVID-19 virus may attack multiple organs. The harmonious treatment of multiple organs in traditional Chinese medicine helps to alleviate the disease.
Traditional Chinese medicine generally works in the form of compound prescriptions. He Ping and other authors believe that it is a functional group. The method of herbal functional groups can be found in a large number of formulae recorded in Chinese medicine books. In the study of pharmacology, it is found that in the treatment of symptoms such as cough and sputum, several drugs are often used together. In the guidelines, the treatment of respiratory diseases and cardiovascular diseases is also in the form of combination drugs. At the same time, the relationship between dosage and therapeutic effect is also concerned in combination use. A controlled study found that in different stages of the disease, traditional Chinese medicine combines herbs with the same efficacy to enhance the effectiveness of treatment and increase the synergy of treatment. Shijun Wang and other scholars conducted a systematic study on the treatment of respiratory diseases with traditional Chinese medicine, and the article summarized the efficacy of COPD in detail [76]. The clinical treatment of COVID-19 pneumonia by traditional Chinese medicine in the Chinese protocol has also been widely recognized. Herbs in the Chinese treatment protocol "Qingfei Paidu Decoction" may have renal and hepatotoxicity, it is a big obstacle for the use of traditional Chinese medicine for medical personnel with non-traditional medical background. In particular, nephrotoxicity events caused by aristolochic acid such as Mutong (Caulis Akebiae) and Heshouwu (Multiflori Polygoni Radix) have a great impact on the use of traditional Chinese medicine. In this protocol, Xixin (Herba Asari) and Banxia (Rhizome Pinelliae) have a certain effect, but the overall drug toxicity is very low. The detoxification function of traditional Chinese medicine Gan Cao (Radix Glycyrrhizae) and the liver-protective effect of Chaihu (Radix Bupleuri), Fuling (Poria Cocos), Zhuling (Polyporus Umbellatus), Shanyao (Rhizoma Dioscoreae), Baizhu (Rhizoma Atractylodis Macrocephalae), etc. can alleviate the side effects caused by Xixin (Herba Asari) and Banxia (Rhizome Pinelliae). Traditional Chinese medicine emphasizes the detoxification of Gan Cao (Radix Glycyrrhizae) and its regulating functions of vari-ous medicines, which actually illustrates this effect.
Traditional Chinese medicine is based on thousands of years of history. It is an effective treatment method based on the extensive practice and use of the Chinese people in the fight against diseases. It is a scientific summary under the conditions at that time. The theory of traditional Chinese medicine is based on the yin and yang five elements theory of Chinese traditional philosophy "Zhouyi". In short, it is a universal connection and interaction theory of a simple phenomenon. Traditional Chinese medicine has made a universal connection between the etiology, symptoms, pharmacology, and medicinal properties, which is based on philosophy. After nearly 100 years of hard work, traditional Chinese medicine has obtained rich research results and made great progress in chemistry, pharmacology, experimental pharmacology, toxicology, and pharmacodynamics. Traditional Chinese medicine has the material basis. The artemisinin is extracted from the traditional Chinese herbal medicine Artemisia annua by the Chinese first Nobel Prize winner in medicine, the famous pharmacist, Ms. Tu Youyou. Baicalin in Huangqin (Radix Scutellariae), glycyrrhizic acid in Gan Cao (Radix Glycyrrhizae), ephedrine in Mahuang (Herba Ephedrae) and amygdalin in Xingren (Semen Armeniacae Amarum) all have clear material basis. In the same way, each herb in "Qingfei Paidu Decoction" has the relatively clear substance (chemical) basis and pharmacological effect. Qingfei Paidu Decoction is a possible choice to treat severe acute respiratory infection caused by COVID-19 in the case of the global epidemic crisis, and the vaccine and effective anti-COVID-19 drugs are still being studied.