Summary Report on Lianhua Qingwen Capsule/Granule for the Treatment of Influenza,Cold and Coronavirus Disease 2019 (COVID-19)
Lianhua Qingwen Capsule/Granule (hereinafter referred to as LHQW) is a new Chinese patent medicine (SFDA Approval No.: Z20040063) developed under the guidance of collateral disease theory in traditional Chinese medicine (TCM) for the treatment of cold and influenza. LHQW is the first new medicine approved through fast-track approval process by the National Medical Products Administration during the SARS epidemic, has been awarded with the second prize of “National Science and Technology Progress Award”, and also become the first Chinese patent medicine that enters Phase II clinical trial approved by FDA, the US for the treatment of influenza. Since the outbreak of coronavirus disease 2019 (COVID-19), LHQW has been widely used for the epidemic prevention and control of accumulated 70 million people in national epidemic areas including designated hospitals and mobile cabin hospitals in Hubei Province. The clinical research in the epidemic area has revealed that it is able to effectively relieve symptoms like fever, cough, expectoration, and polypnea in both confirmed and, suspected cases, and shorten the fever duration, making it successively included in the Guideline for the Diagnosis and Treatment of Novel Coronavirus (2019-nCoV) Pneumonia (On Trials, the Fourth/Fifth/Sixth Edition) issued by National Health Commission of the People’s Republic of China and also recommended by 20 provincial health commissions including Hubei, Beijing, and Shanghai as well as National Administration of Traditional Chinese Medicine for the treatment of COVID-19. As the most recommended Chinese patent medicine, LHQW plays a pivotal role in the prevention and control of COVID-19 in China.
1 Features of LHQW in the treatment of COVID-19
The main lesion of COVID-19 is in the lung, inducing such classical symptoms as fever, fatigue and dry cough. The pathological manifestations are bilateral diffuse alveolar damage, mucus exudate from cells and fibers, and lymphocytic infiltration in pulmonary interstitium , suggesting that this disease falls into the categories of pestilence and collateral disease in TCM . Its pathogenesis, transmission are identified based on the collateral disease theory in TCM, and then the corresponding therapeutic principles for active intervention are put forward as follows: exploration of the etiological factor for eliminating the toxic factors; drug formulation based on syndrome differentiation for active intervention; development of multi-target regimen for the regulation of the whole body . On this basis, the therapeutic methods of “eliminating pestilence, removing toxin, dispersing lung and clearing away heat” are therefore established.
LHQW is composed of 13 Chinese herbs, namely, Fructus Forsythiae, Flos Lonicerae, processed Herba Ephedrae, Cyrtomium Rhizome, Radix Isatidis, Gypsum Fibrosum, menthol, Herba Pogostemonis, Herba Rhodiolae, Herba Houttuyniae, Radix et Rhizoma Rhei, fried Semen Armeniacae Amarae, and Radix Glycyrrhizae. It is modified from Maxing Shigan Decoction in Treatise on Cold Damage and Miscellaneous Diseases by Zhang Zhongjing from the Han Dynasty,, Yinqiao Powder in Systematic Differentiation of Warm Diseases by Wu Jutong from the Qing Dynasty, as well as Radix et Rhizoma Rhei adopted for the treatment of pestilence by Wu Youke from Ming Dynasty in his book Treatise on Warm-Heat Pestilence. After further addition of Herba Rhodiolae and Herba Pogostemonis, it comes into being. Maxing Shigan Decoction is efficient in dispersing lung and clearing away heat, thereby relieving the accumulated heat-toxin in collaterals. Yinqiao Powder is effective for expelling pathogen through exterior and removing toxin. Radix et Rhizoma Rhei has the effect of relaxing bowels to clear, purge and quiet lung. Herba Pogostemonis is capable of resolving dampness, dispelling filth and eliminating pathogen due to its aroma. Herba Rhodiolae is good at clearing lung, resolving stasis, benefiting qi and nourishing yin. This formula is a collection of valuable experience for the treatment of pestilence with TCM over the past 2,000 years .
2 Experimental evidence for LHQW against respiratory infections
2.1 Anti-virus and anti-bacteria
The latest research by State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University has revealed that LHQW significantly inhibited the SARS-COV-2 replication, affected virus morphology and reduced the virus load in the infected cells in vitro. Another study by this State Key Laboratory of Respiratory Diseases has also revealed that LHQW inhibited the influenza viruses including H3N2 via resisting their adhesion and proliferation and directly killing them . According to Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, the pre-treatment, co-treatment, and post-treatment with LHQW would prolong the survival time of mice infected with H3N2 virus, reducing their lung index, and alleviated their lung inflammation . Moreover, accumulating evidence has shown that LHQW significantly regulated the immune response after virus infection  and exerted broad-spectrum antiviral effects against common respiratory viruses, such as FM1 virus, parainfluenza virus , respiratory syncytial virus (RSV) , enteric virus (EV) 71, and coxsackie virus , . Besides, LHQW exhibited definite antibacterial effects on Staphylococcus aureus, Hemophilus influenza, and Pneumococcus, and inhibited the biofilm formation of methicillin-resistant strains including Staphylococcus aureus and Staphylococcus epidermidis , , .
2.2 Anti-inflammation and alleviation of cytokine storm
Cytokine storm is known as a host overreaction to pathogens such as bacteria and viruses and is supposed to be an independent factor implicated in the progression of COVID-19 disease from mild to severe. To determine the efficacy of LHQW in suppressing the expressions of cytokines and chemokines induced by SAR2-CoV-2, the mRNA expression levels of TNF-α, IL-6, CCL-2/MCP-1, and CXCL-10/IP-10 were measured after LHQW treatment in the State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University. It was shown that the expression levels of these cytokines and chemokines were significantly inhibited by LHQW in a concentration-dependent manner. In addition, it exerted the effects in FM1- infected mice by inhibiting virus replication and reducing the expression levels of cytokines and chemokines including TNF-α, IL-4, IL-6, IL-1β, IL-12, and L-13 from several tissue cells . Besides, LHQW also attenuated the acute lung damage in mice induced by LPS through reducing the infiltration of inflammatory cells and increasing the expression levels of connexins in alveolar epithelial cells and pulmonary vascular endothelial cells .
2.3 Symptom improvement and immunoregulation
LHQW has been prescribed for treating bronchitis, pneumonia and early stage of measles due to its pharmacological activities like abatement of fever, anti-inflammation, anti-tussive effect, and immunoregulation. (1) Antipyretic effect: LHQW has been proved to be able to relieve the fever in rabbit induced by subcutaneous injection of triple vaccine. (2) Anti-inflammation: LHQW is capable of attenuating the ear edema in mice induced by xylene and paw edema induced by carrageenan, and decreasing the capillary permeability in the abdominal cavity of mice induced by acetic acid. (3) Anti-tussive effect: LHQW is able to increase the phenol red excretion in trachea of mice, prolong the incubation period of cough in mice induced by ammonium hydroxide and reduce its occurrence, and also decrease the cough frequency in guinea pigs induced by citric acid. (4) Immunoregulatory effect: LHQW is capable of enhancing the delayed hypersensitivity in mice with immune deficiency induced by hydrocortisone, improving the phagocytosis of peritoneal macrophages in mice with immune deficiency induced by cyclophosphamide and up-regulating the serum hemolysin antibody level.
3 Clinical studies on the treatment of respiratory infections with LHQW
3.1 Treatment of novel coronavirus pneumonia - effectively relieving the symptoms like fever, cough, expectoration, shortness of breath and shortening fever duration
Forty-two patients with COVID-19 confirmed by Wuhan Ninth Hospital and CR&WISCO General Hospital were included in this trial and then randomly divided into a treatment group (21 cases, conventional treatment combined with LHQW, one bag per time, three times per day) and a control group (21 cases, conventional treatment). Compared with the control group, the disappearance rates of fever, cough, expectoration, and shortness of breath in the treatment group were 85.7% (control group: 57.1%), 46.7% (control group: 5.6%), 64.3% (control group: 9.1%) and 77.8% (control group: 0), respectively, with statistically significant differences (P < 0.05). In addition, the duration of fever in the treatment group was (4.6 ± 3.2) d, which was 1.5 days shorter than (6.1 ± 3.1) d in the control group. Conclusion: Chinese patent medicine LHQW significantly alleviated fever, cough, expectoration and shortness of breath in patients with novel coronavirus pneumonia .
A total of 101 suspected COVID-19 patients in CR&WISCO General Hospital affiliated to Wuhan University of Science and Technology were included for anther clinical trial. They were randomized into a treatment group (63 patients provided with LHQW in combination with conventional treatment) and a control group (38 patients treated with only conventional treatment). The disappearance rates of fever, cough and fatigue in the treatment group were 86.7%, 55.6%, and 82.5%, respectively, which were significantly better than 67.7%, 30.6%, and 58.6% in the control group (P < 0.05). The median duration of fever in the treatment group was six days, while that in the control group was seven days. The disappearance rates of shortness of breath and moist rale in the treatment group were 68.2% and 56.0%, respectively, which were significantly higher than 20.0% and 20.0% of the control group (P < 0.05). During the study, four patients (6.4%) in the treatment group reported aggravation, while six patients (15.8%) in the control group suffered from aggravation, suggesting that the alleviation in the treatment group was significant as compared with that in the control group .
After seven days of treatment, fifty-four general patients with COVID-19 at Wuhan Puren Hospital exhibited the disappearance rates of 80.0%, 75.7%, and 76.7% for fever, fatigue, and cough, respectively. The remission of fever, fatigue, and cough after the treatment lasted for (3.6 ± 2.14), (4.1 ± 2.58), and (5.3 ± 2.63) days, respectively. Besides, the disappearance rates of other symptoms and signs such as chest tightness, dyspnea, and moist rale were 84.6%, 100%, and 89.5%, respectively. The effective rate was 81.6%, and it was safe for clinical application . The above-mentioned clinical research data from the epidemic area have confirmed that Lianhua Qingbing was effective for alleviating the symptoms of patients with novel coronavirus pneumonia and shortening the duration of fever.
3.2 Treatment of H1N1 influenza (swine flu) – negative conversion rate of viral nucleic acid test comparable to that of oseltamivir, while the effect of alleviating clinical symptoms better than that of oseltamivir
During the outbreak of the influenza A (H1N1) virus in 2009, a double-blind, randomized, multi-center, comparative clinical trial on 244 cases completed in eight hospitals, headed by Beijing Youan Hospital, Capital Medical University, has revealed that LHQW was not different from oseltamivir phosphate in inducing the negative conversion of viral nucleic acid test and alleviating flu symptoms. However, it significantly reduced the severity of the disease and shortened the duration of symptoms including fever, cough, muscular soreness, and fatigue. Also, no adverse reaction was reported .
A randomized, positive drug-controlled clinical trial concerning the treatment of 124 cases with H1N1 influenza by LHQW has shown that LHQW was similar to oseltamivir in inducing the negative conversion of viral nucleic acid test, but superior to oseltamivir in relieving cough, sore throat, fatigue, and muscular soreness . In addition, a retrospective analysis of the use of LHQW in the designated hospital (Beijing Ditan Hospita) has also confirmed that LHQW was equivalent to oseltamivir in alleviating fever and inducing the negative conversion of viral nucleic acid test. According to a completed clinical study  on the prevention of influenza A with LHQW, after the treatment of close contacts and surrounding populations (20,553 people) in Langfang City, Hebei Province, the symptom occurrence rate of the LHQW group was 1.2%, while the symptom occurrence rates of the other medication group and the non-medication group were 6.8% and 8.8%, respectively, verifying the good therapeutic effect of LHQW against H1N1 viral infection. The above clinical trial results have demonstrated that LHQW is effective for the treatment, control and prevention of influenza. In terms of clinical safety, a meta-analysis based on 4,906 patients revealed the good safety of LHQW , .
4 Wide application of LHQW for the prevention and control of novel coronavirus pneumonia in China
The research project of "LHQW for the treatment of influenza" was awarded with the second prize of “National Science and Technology Progress Award” by the State Council of the People’s Republic of China in 2011, which reflects the scientific and technological innovation in formulation as well as basic and clinical research based on TCM theory. Since its marketing in 2003, LHQW has been listed in various public health event diagnosis and treatment plans or guidelines for the diagnosis and treatment for infectious diseases such as influenza A, influenza B, avian influenza, Ebola hemorrhagic fever, and Middle East respiratory syndrome for more than 20 times [Annex 4], making it become a representative Chinese patent medicine in response to public health events and included in 2019 National Basic Medical Insurance, Work Injury Insurance and Maternity Insurance Drug List and 2018 National Essential Medicines List [24-26].
LHQW has been included in the Guideline for the Diagnosis and Treatment of Novel Coronavirus (2019-nCoV) Pneumonia (On Trials, the Fourth/Fifth/Sixth Edition) jointly issued by National Health Commission of the People’s Republic of China and National Administration of Traditional Chinese Medicine for the treatment of novel coronavirus pneumonia throughout the country. At the same time, it has also been recommended in the Expert Consensus on the Diagnosis, Treatment and Prevention of New Coronavirus Infection in Children and Recommendations form TCM Experts on Treatment of Novel Coronavirus Pneumonia in Pregnancy (On Trials). Consequently, it has also been listed in the treatment plans for novel coronavirus infection in 20 provincial health commissions including Hubei, Beijing, and Shanghai and the corresponding provincial administration of TCM, making it become the most frequently recommended Chinese patent medicine . Moreover, it has been classified as the standby medicine and listed in the inventory of emergency medical supplies by 13 provinces. In more than 200 cities and counties across the country, the corresponding health commissions requested the medical institutions under their management to stock LHQW for epidemic prevention and control. The designated hospitals and mobile cabin hospitals in Wuhan were ordered to stock LHQW, since it has been listed in Handbook for Mobile Cabin Hospitals (Third Edition) issued by the National Health Commission of the People’s Republic of China as a recommended Chinese patent medicine [Annex 4]. According to sales data from January to the end of February, 2020, about 70 million people have taken LHQW during the outbreak of novel coronavirus pneumonia, indicating that it has played an active role in epidemic prevention and control.
 Xu Z, Shi L, Wang YJ, et al. Wang, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome [J]. The Lancet Respiratory Medicine, Published online February 17, 2020 https: //doi. org / 10.1016 / S2213-2600 (20) 30076-X.
 Wu Yiling. Construction of collateral disease theory and its disciplinary value [J] .Frontier Science, 2007 (02): 40-46.
 Jia Zhenhua. Discussion on the Syndrome Treatment of New Coronavirus Pneumonia Guided by the Theory of Collateral Disease [J/OL] .Chinese Journal of Experimental Traditional Medical Formulae: 1-5 [2020-02-26] .https: //doi.org/10.13422/j.cnki. syfjx.20201146.
 JIA Zhenhua, LI Hongrong, CHang Liping, Wei Cong. Review on the history of Chinese medicine response to epidemics [J/OL] .Chinese Journal of Experimental Traditional Medical Formulae: 1-6 [2020-02-26] .https: //doi.org /10.13422/j.cnki.syfjx.20201071.
 Mo Hongyi, Ke Changwen, Zheng Jinping, et al. Experimental study of Lianhua Qingwen Capsules against influenza A virus in vitro [J].New Chinese Medicine and Clinical Pharmacology, 2007,18 (1): 6-9.
 Chinese Academy of Military Medical Sciences and Beijing Ditan Hospital have confirmed anti-H1N1 influenza virus: Chinese medicine Lianhua Qingwen Capsule has made a major breakthrough [J]. China Prescription Drugs, 2009,9 (90): 41-41.
 Yuewen Ding, Lijuan Zeng, Runfeng Li, et al. The Chinese prescription Lianhua Qingwen Capsules exerts anti-influenza activity through the inhibition of viral propagation and impacts immune function [J]. BMC Complement Altern Med, 2017, 17 (1): 130. doi: 10.1186 / s12906-017-1585-7.
 Guo Hai, Yang Jin, Gong Jiening, et al. Effect of Lianhua Qingwen Capsule on Lung Index after Mouse Infected by Virus [J] .Henan Traditional Chinese Medicine, 2007,27 (3): 35-36.
 Ding Yuewen, Zeng Lijuan, Li Runfeng, et al. Pharmacological effects of Lianhua Qingwen Granules against BALB / c mice infected with respiratory syncytial virus [J]. Journal of Guangzhou University of Traditional Chinese Medicine, 2016,33 (4): 541-544.
 Liu Xiaoyan. Preliminary Study on the Inhibitory Effect of Lianhua Qingwen Capsule on Virus [D]. Kunming: Kunming University of Science and Technology, 2015,11,28-45.]
 Liu Zhao, Shi Fuzhong, Yang Zhanqiu, et al. Experimental Study on the Effect of Lianhua Qingwen Capsule on Coxsackie B4 Virus [J]. Journal of Central South University for Nationalities (Natural Science Edition), 2012,31 (1): 21-24.
 Wang Yizhu, Wang Hongtao, Han Xue, Liu Chong, Sun Yining, Liu Bing, Wang Yi. Effect of Lianhua Qingwen Capsule Water Extract on Methicillin-resistant Staphylococcus Aureus Bacteria Biofilm [J] .Chinese Journal of Hospital Infectious Diseases, 2015, 25 (04): 727-729 + 790
 Shi Like, Wang Yue, Dong Xing, Liu Yan, Li Jihong, Wang Liyi, Wang Hongtao, Wang Shibo. In vitro bacteriostatic experiment of Lianhuaqingwen combined with meropenem on drug-resistant strains [J] . Chinese Journal of Nosocomiology, 2019 , 29 (08): 1172-1175.
 Wang Yizhu. Study on the inhibitory effect of Lianhua Qingwen Capsule on bacterial biofilms related to respiratory tract infection and preliminary exploration of its genetic mechanism [D]. Jilin University, 2014., which is beneficial to the treatment of secondary bacterial infection after viral infection.
 Mo Hongzhang, Yang Zifeng, Zheng Jinping, et al. Experimental Study on Lianhua Qingwen Capsules for Preventing and Treating Mice Infected with Influenza Virus FM1 [J] .Chinese Medicinal Materials, 2008,31 (8): 1230-1233.
 Cui Wenwen, Jin Xin, Zhang Yanfen, et al.Effects of Lianhua Qingwen Capsule on the Expression of Inflammatory Factors and Connexin in Mice with Acute Lung Injury Induced by Lipopolysaccharide [J] .China Journal of Pharmacology and Toxicology, 2015,29 (2): 213 -217.
 Yao Kaitao, Liu Mingyu, Li Xin, Huang Jihan, Cai Hongbin. Retrospective clinical analysis of Lianhua Qingwen in the treatment of 2019-ncov pneumonia[J/OL]. Chinese Journal of Experimental Pharmaceutics: 1-7[2020-02-26]. https://doi.org/10.13422/j.cnki.syfjx.20201099.
 Lu ruibing, Wang Wenju, Li Xin. Clinical observation of Lianhua Qingwen in treating 63 suspected cases of 2019-ncov pneumonia [J/OL]. Journal of Traditional Chinese Medicine:1-5[2020-02-27]. http://kns.cnki.net/kcms/detail/11.2166.R.20200215.1633.004.html.
 Cheng Dezhong, Li Yi. Clinical Analysis and typical case report of Lianhua Qingwen Granule in treating 54 patients with 2019-ncov pneumonia [J/OL]. World Traditional Chinese medicine:1-5[2020-02-27]. http://kns.cnki.net/kcms/detail/11.5529.R.20200218.1552.002.html.
 Duan Zhong-ping, Jia Zhenhua, Zhang Jian, Liu Shuang, Chen Yu, Liang Lianchun, et al. Natural herbal medicine Lianhuaqingwen capsule anti-influenza A(H1N1)trial; a randomized, double blind, positive controlled clinical trial.Chinese Medical Journal, 2011,124(18):2925-2933.
 Liu Gengxin, Zhang Yanxia, Yang Jiqing, etc.. A randomized controlled clinical study of Lianhua Qingwen capsule in the treatment of influenza a (H1N1) [J]. Chinese Journal of Difficult and complicated cases:2010,9(1):14-16.
 Wang Yuguang, Du Hongbo, Mao Yu, etc.. Analysis of clinical characteristics of 326 mild cases of influenza a (H1N1) [J]. Global Chinese traditional medicine,2011,4(01):31-34.
 Dou Ying, Yang Sanping. Lianhua Qingwen Capsule: Natural Antibiotic, Broad-spectrum Anti-virus [J]. Chinese community physician,2012,28(35):9.
 Wang Yanxun, Zhang Keyuan, Huang Jihan, etc.. Safety Evaluation of Lianhua qingwen preparation in clinical application [J]. Evaluation and analysis of drug use in hospitals,2013,13(8):676-680.
 Zhao P, Yang HZ, Lv HY, Wei ZM. Efficacy of Lianhuaqingwen capsule compared with oseltamivir for influenza A virus infection: a meta-analysis of randomized, controlled trials[J]. Altern Ther Health Med. 2014, 20(2): 25-30.
 Circular of the State Medical Insurance Bureau and the Department of Social Security on the publication and distribution of the catalogue of medicines under the State basic medical insurance, industrial injury insurance and maternity insurance. [2020-02-27]. http://www.nhsa.gov.cn/art/2019/8/20/art_37_1666.html
 National Board of Health, State Administration of Traditional Chinese Medicine. 2018 edition of the national essential drug list and its interpretation. http://www.gov.cn/fuwu/2018-10/30/content_5335721.htm
Pang Wuntai, Jin Xinya, Pang Bo, etc. . Analysis on the regularity of prescriptions and syndromes of TCM in preventing and treating 2019-ncov pneumonia [J/OL]. Chinese Journal of Chinese Traditional Medicine:1-8[2020-02-28]. https://doi.org/10.19540/j.cnki.cjcmm.20200218.502.