Role of Traditional Chinese Medicine in the Management of Viral Pneumonia

Viral pneumonia is one kind of acute respiratory tract infection caused by the virus. There have been many outbreaks of viral pneumonia with high contagiousness and mortality both in China and abroad, such as the great influenza in 1918, the severe acute respiratory syndrome (SARS) coronavirus in 2003, the Influenza A (H1N1) virus in 2009, and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) in 2012 and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019. These outbreaks and/or pandemic have significant impact on human life, social behaviors, and economic development. Moreover, no specific drug has been developed for these viruses. Traditional Chinese medicine (TCM) plays an important role in the treatment of viral pneumonia during these outbreaks especially in SARS and SARS-CoV-2 because studies suggest that TCM formulations may target several aspects of the disease and may have lesser side effects than manufactured pharmaceuticals. In recent years, a lot of clinicians and researchers have made a series of in-depth explorations and investigations on the treatment of viral pneumonia with TCM, which have understood TCM therapeutic mechanisms more specifically and clearly. But critical analysis of this research in addition to further studies are needed to assess the potential of TCM in the treatment of viral pneumonia.


INTRODUCTION
Viral pneumonia is an acute respiratory infectious disease caused by viruses with different degrees of contagiousness. The main clinical manifestation is fever, which may be accompanied by symptoms such as anhidrosis or sweating, nasal congestion, runny nose, sore throat and cough (Figueiredo, 2009). Common viruses that cause pneumonia include adenovirus, coronavirus, human metapneumovirus, rhinovirus, respiratory syncytial virus, influenza virus and parainfluenza virus (Jain, 2017). Among them, severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) in 2003, Influenza A (H1N1) virus in 2009, and middle east respiratory syndrome coronavirus (MERS-CoV) in 2012 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or called novel coronavirus in 2019 are highly contagious and fatal. As of 30 May 2020, there were 5,817,385 confirmed cases and 362,705 deaths in the coronavirus induced disease 2019  outbreak since December 2019, and the trend is still on the rise (World Health Organization, 2020). At present, the commonly-used antiviral drugs in western medicine are probavirin, acyclovir, interferon, adenosine arabine, etc., which are easy to produce drug resistance, have many side effects and poor efficacy as well as other disadvantages (Amarelle et al., 2017). Because no specific and effective antiviral drugs have been developed in western medicine and Chinese herbal medicine possess clinical features of targeting multiple components and having multiple approaches, traditional Chinese medicine (TCM) has unique advantages in relieving symptoms, shortening treatment time and reducing the development of severe pneumonia. In the fight against COVID-19, the State Administration of Traditional Chinese Medicine of China has actively promoted the therapeutic role of TCM. As the member of the Leading Group of the National Health Commission and Secretary of the Leading Group of the National Administration of Traditional Chinese Medicine of China, Dr. Yanhong Yu pointed out that among the confirmed COVID-19 cases in China, a total of 74,187 people have used Chinese medicine, which accounts to 91.5% of patients (National Administration of Traditional Chinese Medicine, 2020). Academician of Chinese Academy of Engineering Dr. Boli Zhang analyzed 52 patients with COVID-19 retrospectively and found the clinical effective rate of 91.2% in patients treated with integrated traditional Chinese and western medicine as compared to effective rate of 61.1% in patients treated with western medicine alone .
Although there is no name of "viral pneumonia" in TCM, it is mainly attributed to "exogenous diseases" or "exterior syndrome". Traditional Chinese medical physicians usually classified them as "cough" or "lung distention" according to its clinical manifestations. Moreover, viral pneumonia with strong infectivity and high fatality rate is usually classified as "epidemic disease" in TCM. There has been a long history in China that TCM has been used to treat "epidemic disease" and there are a lot of clinical experiences and excellent efficacy. Therefore  Xi et al., 2020). For the main clinical manifestations of viral pneumonia such as fever, cough and panting, Gypsum Fibrosum (Shengshigao) can clear and discharge lung-heat, and vent pathogen with acrid-cool (medicinals). Prunus armeniaca L. (Xingren) and Ephedra sinica Stapf (Mahuang) can diffuse the lung, relieve cough and calm panting. Glycyrrhiza uralensis Fisch. ex DC. (Gancao) and Ephedra sinica Stapf (Mahuang) have antiviral and immune regulating effect (Mantani et al., 2001;Cinatl et al., 2003). Lonicera japonica Thunb. (Jinyinhua), Forsythia suspensa (Thunb.) Vahl (Lianqiao), Artemisia annua L. (Qinghao), Pogostemon cablin (Blanco) Benth. (Huoxiang), and Scutellaria baicalensis Georgi (Huangqin) are also commonly used in the recommended prescription and have been reported to possess immunoregulatory and antiviral activities (Efferth et al., 2008;Duan et al., 2012;Shen et al., 2012;Xu et al., 2019).
The role of Chinese herbal medicine in antivirus is usually considered interfering the procession of virus pathogenesis to achieve anti-virus effects, such as suppressing the virus proliferation, preventing the adhesion of virus into susceptible host cells, promoting the immune response, suppressing the excessive abnormal inflammatory response and regulating the immune function of the body. These antiviral effects are often referred to as "detoxification" or "resolving toxins" in the theory of traditional Chinese medicine (Xi and Gong, 2017). In recent years, many researches and progresses have been made to understand the action and mechanism of TCM in the treatment of viral pneumonia for clinical purpose. Through the collection and analysis of nearly 20 years of literature, these actions and mechanisms were discussed from the perspective of direct and indirect antiviral effects as well as immunomodulatory effects in this report. diagnosis and treatment literatures and data related to viral pneumonia issued by the National Health Commission of China, the Health Commissions of provinces, autonomous regions and municipalities directly under the central government, the State Administration of Traditional Chinese Medicine of China and the Administration of Traditional Chinese Medicine of all provinces, as well as the opinions expressed from TCM masters, academicians and famous TCM clinical experts through open channels. These date were extracted into two tables by two independent researchers according to the inclusion and exclusion criteria after reaching a consensus. When there are differences in the process of screening and data extraction, it was submitted to the third party for joint decision. The inclusion criteria included the following: a. Clear literatures on the experimental and clinical research on the treatment of viral pneumonia with herbs, herbal extracts, or Chinese medical formulae. b. Literatures written in English and Chinese. The exclusion criteria were as follows: a. Literatures without control medicinals in experimental research; b. Literature review, individual case report, expert experience introduction and other types of literature; c. For the content of the repeatedly published literature or the repeatedly quoted literature, only one article is included.

Experimental Research
Animal or cell studies have found that some traditional Chinese herbal medicines and medical formulas have a variety of pharmacological effects in the treatment of viral pneumonia. In addition to the direct or indirect antiviral effect (See Tables 1 and 2), the best advantage of TCM is the regulation of immune function and low adverse effects (Ma et al., 2013).

Inhibition/Inactivation of Virus by TCM
The antiviral activity of TCM first manifests as the inhibition or inactivation of the virus. Studies have shown that a variety of TCM can directly inactivate or prevent the virus from adsorbing or penetrating into the cells, or induce the body to produce substances such as interferon, thereby inhibiting the replication of the virus.

Direct Inhibition of Viruses
Virus first attaches to membrane of host cells and then enters cells. After dissociation of virus particle, virus will employ host cells to replicate its genes and process proteins for viral assembly and release. In view of this series of processes, the use of drugs in the pre-infection stages of the virus can play a direct inhibitory effect on the virus. Studies showed by MTT method that the volatile oil from Cinnamomum cassia (L.) J. Presl and Cinnamic aldehyde could significantly inhibit the proliferation of influenza A virus (H1N1) in MDCK (Madin-Darby canine kidney) cells (p<0.05) . Ling Gou et al. confirmed that the medicated serum containing volatile oil from Nepeta tenuifolia Benth. and Cinnamomum cassia (L.) J. Presl also could significantly inhibit the proliferation of influenza A virus in MDCK cells (p<0.05) and show a certain degree of direct killing of virus . Studies have shown that Glycyrrhizic acid from Glycyrrhiza uralensis Fisch. ex DC. not only directly inhibits the replication of coronavirus, but also acts on the early stage of virus adsorption and membrane penetration, which may be related to its activation of protein kinase C, casein kinase II and nuclear transcription factor B (Cinatl et al., 2003). Arctiin and its aglucone, arctigenin from the fruits of Arctium lappa L. showed potent in vitro antiviral activities against influenza A virus (A/NWS/33, H1N1) (IFV). Based on the data from time-of-addition experiments and on release tests of progeny viruses, arctigenin was assumed to interfere the early event(s) of viral replication after viral penetration into cells, and to suppress the release of progeny viruses from the host cells (p<0.01 or p<0.001) (Hayashi et al., 2010). The classical Chinese medical formula, Pueraria Decoction (Gegen Tang) can play an antiviral role in the adsorption stage of virus (p<0.01), and Pueraria decoction and its antiviral activity are positively correlated with dose . Neuraminidase (NA) can be another target molecule    Ribavirin Inhibits neuraminidase activity, reduces virus replication, and decreases the protein expression of TLR3 and NF-kB and mRNA expression of TRIF, the protein and gene expression of proinflammatory cytokines TNF-a, IL-1 and IL-6 in lung tissue, and increases the protein and gene expression of antiinflammatory cytokine IL-10 and antiviral factor IFN-g in lung tissue after infection. Ding et al., 2014;Wang et al., 2014;Zhang and Yu, 2010;Xu et al., 2019 In    (Hsieh et al., 2012;Sun et al., 2014;Li et al., 2015).

Indirect Inhibition of Viruses
Interferon is a glycoprotein produced by cells stimulated by viruses or other interferon inducers. After binding to interferon receptors, it can induce cells to produce antiviral proteins with enzyme activity, such as protein kinase and 2',5'-adenosine kinase (Der and Lau, 1995;Min and Krug, 2006)  . Hongri Xu et al. showed that Scutellaria baicalensis Georgi could increase the expression of the antiviral factor IFN-g in lung tissue (p<0.05) (Xu et al., 2019). Cheng-Chuan Tsou pointed out that the antiviral effect of Arctium lappa L. was related to its ability to induce the organism to produce interferon (p<0.05 or p<0.01) (Tsou, 2007).

Regulatory Effects on Immune and Cellular Inflammatory Factors
Excessive immune response and release of inflammatory cytokines are important causes of viral pneumonia and lung injury. In patients infected with SARS, Influenza A (H1N1) virus and SARS-CoV-2 Casadevall and Pirofski, 2014;Huang et al., 2020), abnormally-elevated inflammatory cytokines so called cytokine storm can be detected and are closely related to disease severity. Therefore, inhibiting the overexpression of inflammatory factors and improving immune function have become important part in the treatment of viral pneumonia.

Regulation of the TLR-NF-kB Signaling Pathway
The TLR-NF-kB signaling pathway is an important pathway that mediates the expression of inflammatory factors. Toll-like receptor (TLR) is a transmembrane protein located on the cell membrane, which is composed of extracellular region, transmembrane region and intracellular region. At present, there are three kinds of TLR3, TLR7 and TLR8 which are closely related to the virus. These three receptors plus TLR9 have functional domain inside the cell, while the rest of the receptors are expressed outside the cell. Whether the different distribution of this functional domain is related to its antiviral effect needs further study. After virus invasion, both TLR3mediated MyD88 independent signaling and TLR7-mediated MyD88-dependent signaling ultimately activate the nuclear transcription factor NF-kB, which induces and promotes the expression of preinflammatory factors (Sanjeewa et al., 2020 (Lai et al., 2011;Liu et al., 2014;Li et al., 2018;Geng et al., 2019).

Regulation of the PI3K/Akt Signaling Pathway
The PI3K/Akt signaling pathway can also activate the nuclear transcription factor NF-kB, which induces the expression of inflammatory factors (Harikrishnan et al., 2018).  . Xiaoxue Liu showed that polysaccharides and flavonoids from Morus alba L. could significantly reduce the expressions of PI3K, AKT1/2 and NF-kBp65, as well as IL-4 and INF-g in serum of respiratory syncytial virus (RSV)-infected mice (p<0.05) (Liu, 2016 can reduce the excessive expression of NF-kB protein in the lung tissue, significantly improve the content of lung sIgA, IL-10, IL-IRa and sTNFR, reduce the serum IL-1b, IL-6, TNF-a content, inhibit proinflammatory factor and induce suppression of inflammatory factor expression to reduce pulmonary inflammatory injury (p<0.05 or p<0.01) (Nan et al., 2016a;Nan et al., 2016b). In addition, researchers found that hypericin and hyperoside extracted from Hypericum perforatum L. could reduce the expression of IL-6 and TNF-a in lung tissue and serum of mice infected with influenza A virus, and increase the expression of IFN-g and IL-10 protein (p<0.05 or p<0.01) ). Wei Luo et al. found that the levels of TNF-a and IL-10 in serum and lung tissues of mice infected with influenza virus were reduced by electroacupuncture and moxibustion at bilateral Feishu (BL 13) on the back of mice (p<0.01) (Luo et al., 2014).

Regulation of Lymphocyte Subsets
As one of the three lines of defense, cellular immunity plays an important role in eliminating pathogens. Experimental studies have shown that Andrographis paniculata (Burm.f.) Nees and Ilex asprella (Hook. et Arn.) Champ. ex Benth. can increase the percentage of CD3+ lymphocytes in the T-lymphocyte subsets in peripheral blood of mice infected with influenza virus, and regulate the CD4/CD8 ratio to enhance the immune function of mice (Chen et al., 2016;Wang et al., 2019). Hypericum perforatum L. extract can improve the immunologic function of influenza virus-infected mice by enhancing T and B lymphocyte conversion, phagocytic function of macrophages and NK killing activity (p<0.05 or p<0.01) . Gegen decoction can regulate the ratio of CD3+CD4+/CD3 +CD8+ and CD4+IFN-g+/CD4+IL-4+ in peripheral blood of virus-infected mice (p<0.01) . Shengjiang Power can increase the percentage of CD8+ in peripheral blood, regulate the radio of CD4+/CD8+, and improve the immune function of the body (p<0.05 or p<0.01) (Nan et al., 2016b). Other study results have shown that compared with ribavirin, the Haoqin Qingdan Decoction can improve the ratio of T lymphocyte subgroup and Th1/Th2 cell balance more effectively in rats with damp-heat syndrome of influenza viral pneumonia (Zhang et al., 2013).

TCM Protecting Host Cells
Some traditional Chinese medicines have been studied, which do not directly inhibit virus replication or regulate immune and inflammatory factors, but protect host cells and increase their tolerance to viruses. Shanshan Guo et al. found that the extract ZG from Gardenia jasminoides J. Ellis can improve the host cell membrane fluidity after infection of parainfluenza virus type 1 (PIV-1) (p<0.01) and maintain its normal function therefore to play an antiviral role (Guo et al., 2007).

Clinical Research
Compared with single herbs, traditional Chinese medical formulas are more widely used in the clinical prevention and treatment of viral pneumonia. Studies have shown that proprietary traditional Chinese medicine product or Chinese medical formula decoction plays a certain role in antiinflammatory, immune regulation, inhibition of viral replication, prevention of viral cytopathic disease and improvement of pathology (See Table 2).

TCM for the Treatment of SARS Coronavirus Pneumonia
Pneumonia caused by SARS coronavirus is a highly infectious pneumonia that can involve multiple organ lesions. The main clinical manifestations are fever, cough, headache, fatigue, aching pain of muscle and joint, oppression in chest, and dyspnea, etc. Tietao Deng, a master of Chinese medicine, considered that it belongs to the category of spring epidemic and damp-heat pestilence diseases, which pathogeneses are accumulation of damp-heat toxin, consumption of Qi and damage of Yin easily, and existance of blood stasis. According to Tietao Deng, SARS can be divided into early, middle, extreme and recovery stages (Deng, 2003). In the process of clinical treatment, therapeutic outcomes of combined treatment with TCM and western medicine are usually better than that of Western medicine alone in terms of release of clinical symptoms, improvements of pneumonia and blood oxygen saturation as well as the count of lymphocyte and T cell subsets.          and invigorate blood, boost qi and nourish yin, relieve cough and calm panting, Formula III for SARS during Convalescence (Feidian Huifuqi Sanhao Fang) with recovery to boost qi and nourish yin, fortify the spleen and harmonize the stomach. The results showed that the remission time of clinical symptoms and reduced hormone usage in the integrated TCM western medicine group were 2.52 days and 222.69 mg respectively, shorter than those in the control group, and the difference was statistically significant difference (p<0.05). Moreover, TCM also played an important role in promoting the recovery of immune function and reducing pulmonary inflammatory injury (Zhang R. L. et al., 2003). (Zhigancao)] with conventional western medicine to treat 40 patients with ordinary COVID-19, and found that after three days of treatment, IL-6 level significantly decreased compared with that before the treatment (p<0.05), and levels of AST, ALT and creatinine were normal. After 7 days of treatment, IL-6 level decreased to normal, hypersensitive C-reactive protein level decreased significantly, CD4+T and CD8+T cell count increased significantly compared with that before treatment (p<0.05), levels of AST, ALT and creatinine were still normal. The results showed that this modified decoction had a significant effect on common COVID-19 without significant hepatorenal toxicity (Qu Y. F. et al., 2020

DISCUSSION
In the treatment of viral pneumonia through syndrome differentiation, TCM plays a variety of roles in inhibiting the proliferation, replication, adsorption and membrane penetration of the virus, promoting the expression of interferon in vivo, inhibiting inflammatory reaction, enhancing immunity, etc., which is one of the theoretical bases for the clinical application of TCM in the prevention and treatment of viral pneumonia. Viruses with RNA genetic material, such as influenza virus and coronavirus, are more likely to mismatch and cause mutations in the replication process than DNA viruses (Woolhouse et al., 2016). Their high variability makes it more difficult to develop vaccines and more susceptible to drug resistance to single chemical drugs. Traditional Chinese herbal medicine and compound medicinals are characterized by multi-component, multi-pathway and multi-pathway complex networks. Therefore, drug resistance is relatively rare in the clinical practice of TCM. Moreover, in the process of diagnosis and treatment of TCM, treatment based on differentiation of symptoms and signs, especially treatment based on classification of symptoms and signs, can best reflect the overall concept of TCM. TCM has precise therapeutic activity and less adverse reactions.
Accumulating evidence has demonstrated the competent therapeutic effects of TCM against viral pneumonia with a prominent safety profile. TCM has obvious characteristics and great advantages on syndrome differentiation for the prevention and treatment of viral pneumonia before specific antiviral drugs and vaccines are developed and produced. However, TCM in treatment of viral pneumonia still have some problems. First, theoretical study of viral pneumonia in TCM, especially regarding the pathogenesis and changes of the virus are not comprehensive, systematic and in-depth; second, the complexity of traditional Chinese herbal medicine composition and its compound makes it difficult to understand mechanism and action and less specific; third, in the process of treatment of viral pneumonia, it is usually carried out by traditional and macroscopic methods, with strong subjectivity, which cannot be considered as microscopic and specific as modern medical diagnostic standards. There is still a lack of recognized and unified standards for the classification of TCM Syndrome of viral pneumonia; fourth, the basic research on prevention and treatment of SARS-CoV-2 and COVID-19 with TCM is less developed, which may be related to that case collection of infectious disease in different countries is different or may not be allowed, and/or lack of laboratories that meet the requirements for conducting research of contagious diseases. Furthermore, the TCM treatment was mainly based on decoction, which makes difficult to set up control group therefore, generate greater varieties. The basic treatment of medical formula and proprietary traditional Chinese medicine product are mainly based on the analysis of the whole process of the etiology and pathogenesis of viral pneumonia, which include grasping the basic pathogenesis, establishing the basic treatment method, and combining the viewpoint of modern medicine, formulating the basic prescriptions, or adding or subtracting along with the syndromes, or further changing the dosage form, and developing the treatment method for patent medicine. Although this kind of treatment often lacks the concept of TCM syndrome and the flexibility of syndrome differentiation and treatment, it has been proved to be effective in practice due to its grasp of the basic pathogenesis of the disease and the application of various methods. Moreover, it has been reported successful many times and seems to become a distinct alternative choice alongside the classical approach. Furthermore, in addition to oral administration of TCM decoction or pills, intravenous administration of TCM and other methods have been reported as another treatment of viral pneumonia. In addition, there are also many reports about the external treatment of patients with viral pneumonia, such as the atomizing inhalation of traditional Chinese medicine extract, external application of Chinese medicine powder or paste, foot reflexology, infantile massage, etc., all which reveal some new ideas and ways for TCM treatment of viral pneumonia.
In recent years, researches on viral pneumonia by TCM mainly focus on influenza virus, mainly on mice or cell models infected by influenza A (H1N1) virus, while researches on SARS-CoV and MERS-CoV are few. Studies on such viruses as SARS-CoV, MERS-COV, H1N1 and other viruses should be conducted in P3 laboratory (biosafety level 3 laboratory) or higher biosafety laboratory. Extensive and in-depth studies on the prevention and treatment of viral diseases with TCM are subject to certain conditions. Fortunately, in 2020, the Ministry of Science and Technology of China issued the "Guidance on Strengthening the Biosafety Management of Novel Coronavirus High-level Virus Microbiology Laboratory", requiring the laboratory to play a role as a platform to serve the needs of scientific and technological research. This will provide strong policy support for the in-depth study of the antiviral effect and mechanism of TCM. Although the research on the antiviral activity of TCM has been performed with molecular biology, the specific therapeutic effects of traditional Chinese herbal medicine or compound on virus and pneumonia remains to be further investigated because of its complex components. Therefore, in order to better treat viral pneumonia with TCM based on syndrome differentiation and the overall concept of theoretical system, we should adhere to the theory of TCM as the basis, actively combine with modern or western medicine, complement each other, and use modern science and technology to explore the role and mechanism of viral pneumonia and traditional Chinese medicine in a more comprehensive, systematic and in-depth way, deeply analyze the characteristics of viral pneumonia syndromes, unify evidence pattern classification standards, further standardize and unify the evaluation criteria of syndrome differentiation and efficacy in order to facilitate the communication of clinical and scientific research work, use new diagnostic techniques to prevent misdiagnosis and missed diagnosis, and establish positive drug control in a standardized way in the process of clinical research to improve the credibility of TCM treatment. In the future, the TCM treatment theory and clinical application of viral pneumonia should pay special attention to strengthen experimental research, especially the effective Chinese medicine compounds. The precise mechanism of Chinese medicine in the treatment of viral pneumonia should be scientifically clarified to achieve the synchronization of clinical research and experimental research. In this way, Chinese medicine can be better to treat patients with viral pneumonia in a scientific and standardized manner based on syndrome differentiation.

CONCLUSIONS
TCM has been widely used in basic and clinical researches of virus diseases especially viral pneumonia in human. Some Chinese medicine has shown certain therapeutic effect, but high-quality experimental design and randomized clinical controlled study are still needed. A wide variety of antiviral traditional Chinese herbal medicines also provides potential opportunity for further development in specific therapeutic agents to treat viral pneumonia around the world.

AUTHOR CONTRIBUTIONS
YL and SX wrote the manuscript. YL and LY helped in searching for related articles. Y'aY, LQ, TL, and SX proofread the manuscript. SX and YG guided the writing and critically revised the manuscript. All authors contributed to the article and approved the submitted version.