key: cord-0741804-9kea2qzg authors: Xiao, Mingzhong; Tian, Jiaxing; Zhou, Yana; Xu, Xi; Min, Xiaojun; Lv, Yi; Peng, Miao; Zhang, Ying; Yan, Dengying; Lang, Suping; Zhang, Qing; Fan, An; Ke, Jia; Li, Xiuyang; Liu, Binbin; Jiang, Manhong; Liu, Quan; Zhu, Jinyue; Yang, Lu; Zhu, Zheng; Zeng, Kun; Li, Chengyin; Zheng, Yujiao; Wu, Haoran; Lin, Jiaran; Lian, Fengmei; Li, Xiaodong; Tong, Xiaolin title: Efficacy of Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules in treatment of COVID-19: A randomized controlled trial date: 2020-08-08 journal: Pharmacol Res DOI: 10.1016/j.phrs.2020.105126 sha: 2c0d8b06224bbaba025ef60f857bd932e7de1fc8 doc_id: 741804 cord_uid: 9kea2qzg BACKGROUND: With the global epidemic of coronavirus disease (COVID-19), China has made progress in the prevention and control of the epidemic, and traditional Chinese medicine (TCM) has played a key role in dealing with the disease’s effects on the respiratory system. This randomized controlled clinical trial evaluated the clinical efficacy and prognosis of Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules in patients with COVID-19. METHODS: A total of 283 patients participated in this clinical trial, and participants were randomly assigned to receive either 1) Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules or 2) Linahua granules, both combined with western medicine, or 3) western medicine alone for 14 days. At the end of the trial, the improvement and resolution rates of clinical symptoms and the rate of patients who progressed to severe disease status were evaluated. RESULTS: After 14 days of treatment, there was no significant difference in the improvement rate of clinical symptoms among the three groups (P > 0.05). Huoxiang Zhengqi dropping pills combined with Lianhua Qingwen granules has advantages in the treatment of nausea, vomiting and limb soreness. During treatment, all participants were treated with western medicine, and there was a significant difference in the use of macrolides among the three groups (P < 0.05). Specifically, the utilization rate of antibiotics in the western medicine group was significantly greater than that of the other two groups. Among the 182 diagnosed patients who completed this clinical trial, 13 patients progressed to severe disease, including one case in the Huoxiang + Lianhua group (1.6%), five cases in the Lianhua group (8.6%), and seven cases in the western medicine group (11.1%). There was no statistical differences in this rate among the three groups (P > 0.05). However, the proportion of patients who progressed to severe disease in the Huoxiang + Lianhua group was the lowest, suggesting that the combination of TCM with western medicine has a potential advantage in improving the prognosis of patients with COVID-19. CONCLUSION: The use of Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules combined with western medicine may have clinical advantages for COVID-19 patients in improving clinical symptoms, reducing utilization rate of anti-infective drugs, and improving patient prognosis, which could pave the way for the use of complementary medicine in treating this infection. Coronavirus disease (COVID- 19) is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [1] . As of April 4, 2020, it has spread to 206 countries, with a total of 976 249 diagnosed cases and 50 489 deaths and has been declared a global pandemic [2] . As a public health emergency of international concern [3] , COVID-19 has had a serious socioeconomic impact worldwide [4] . The pathogen of COVID-19 is a novel coronavirus, which belongs to the β-coronavirus with severe acute respiratory syndrome-associated coronaviruses (Severe Acute Respiratory Syndrome-related coronavirus, SARS-CoV) [5] . The International Committee on Taxonomy of Viruses [6] announced the virus is classified as severe acute respiratory syndrome coronavirus 2 (Severe Acute Respiratory Syndrome Coronavirus-2, SARS-CoV-2). To date, the World Health Organization (WHO) has not recommended any specific vaccines or drugs for the prevention or treatment of COVID-19 [7] . Researchers are committed to developing new specialized treatments for COVID-19, but to date, they have little clinical evidence. At this stage, antiviral therapy is still the main treatment, which needs to be further optimized [8] . Measures to deal with the epidemic locally in China have obtained phased achievements, and traditional Chinese medicine (TCM) has been incorporated into COVID-19 treatment guidelines [9] , playing an indispensable role in the management of the disease. At the beginning of the epidemic in China, a clinical screening study on the effective prescriptions for the prevention and treatment of COVID-19 by TCM was rapidly launched. By February 17, 2020, a total of 60 107 diagnosed cases were treated with TCM, accounting for 85.20% of all cases. The proportion of cases who received TCM that were cured, discharged, and had symptom improvement accounted for 87%, demonstrating an optimum clinical efficacy of TCM in the treatment of COVID-19 [10] . As such, Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules have been recommended for the treatment of COVID-19 in China. They are highly recognized for their remarkable efficacy in fighting SARS [11] and influenza [12] , having significant effects on improving symptoms such as fever, cough, sputum production, and dsypnea [13, 14] . Therefore, this clinical trial A randomized, controlled, non-blinded design was used in this study. (2) Clinical manifestations include (a) fever and/or respiratory symptoms; (b) imaging characteristics of pneumonia: multiple small patchy shadows and interstitial changes were present in the early stage, especially in the extrapulmonary bands, which then develops bilateral multiple ground-glass infiltrates ; in severe cases, lung consolidation may occur, and pleural effusion is rare; (c) the total white blood cell count is normal or decreased in early onset, the lymphocyte count is normal or decreased. If the patient reported any one of those in the epidemiological history and meets any two of the clinical manifestations, or if there is no definite epidemiological history, but they meet all three of the clinical manifestations, the patient labeled as a suspected case of COVID-19. Patients who met the following criteria were included in this study: (1) suspected and diagnosed cases of COVID-19 meeting the diagnostic criteria mentioned previously; (2) 18-85 years old, regardless of sex; (3) provided informed consent. Patients who met any one of the following conditions were excluded from the study: (1) clear evidence of bacterial infection; (2) severe primary diseases, such as heart, kidney, lung, endocrine, blood, metabolism, or gastrointestinal tract diseases, which may affect the patient's participation in the trial or affect the outcome of the study; (3) family history of mental illness or previous mental illness; (4) allergies or multiple drug allergies; (5) pregnant or lactating women. In this study, a total of 292 patients were recruited from the isolation treatment site in Wuhan, Hubei Province from February 5 to 10, 2020. Aside from the criteria above, patients who met the following criteria were also excluded in the final data analysis: (1) those who did not meet the diagnosis and inclusion criteria; (2) those who were lost to follow up without any available data during observation; and (3) those who could not adhere to the prescribed treatment and did not complete observation period for any reason. Among the recruited patients, 5patients with severe illness were mistakenly initially accepted into the study and 4 patients were excluded because of refusal to cooperate. A total of 283 subjects who met the inclusion criteria entered this clinical trial. All patients were randomly divided into three treatment groups: Huoxiang + Lianhua group, Lianhua group, and western medicine group at a ratio of 1:1:1. J o u r n a l P r e -p r o o f All subjects underwent symptom assessment and body temperature and vital signs monitoring (blood pressure, heart and respiration rates). Medication compliance was recorded, as well as adverse events, before and after 14 days of treatment. The main outcome measures were clinical symptom improvement and disappearance rates after 14 days of treatment, and the secondary outcome measure was the proportion of patients who progressed to severe status despite the same duration of treatment. According to a clinical trial making use of Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules in the early treatment of influenza and other diseases, it was observed that their use was safe in these clinical populations. Therefore, safety-wise, the overall risk level of this study was low. As previously mentioned, all medications and adverse events were recorded in this study, taking note of their severity, occurrence, and remission time. FAS sets were used for statistical analysis. Data entry was carried out using SAS software (version 9.2), which was done independently by four staff members, twice. Analysis of variance was used for the comparison of measurement data between groups, and chi-square test was used for the comparison of grade data between groups. When P < 0.05, the results were statistically significant. General data of diagnosed and suspected patients are presented in Table 1 , and the data of diagnosed subjects are presented in Table 2 . Participants' past medical history were recorded, including hypertension, diabetes, hyperlipidemia, coronary heart disease, chronic obstructive pulmonary disease (COPD), and bronchial asthma. Primary initial symptoms included fever, fatigue, cough, and diarrhea. There was no significant difference in the baseline data of sex, age, height, weight, past medical history, initial symptoms, disease diagnosis, and medication between the patients diagnosed with and suspected to have COVID-19 among the three treatment groups (P > 0.05). Improvement in clinical symptoms of patients diagnosed with and suspected to have COVID-19 is presented in Table 3 . There was no significant difference in the improvement rate of clinical symptoms among the three groups before and after treatment (P > 0.05). All treatment schemes were found to improve patients' fever and diarrhea. Treatment utilizing Huoxiang Zhengqi dropping pills combined with Lianhua Qingwen granules had an advantage in the treatment of nausea, vomiting, and limb soreness. Table 4 presents the improvement in clinical symptoms of diagnosed patients alone. There was no significant difference in the improvement rate of clinical symptoms among the three groups before and after treatment (P > 0.05). All treatment schemes could improve these patients' fever and diarrhea. Treatment utilizing Huoxiang Zhengqi dropping pills combined with Lianhua Qingwen granules had an advantage in the treatment of anorexia, limb pain, fatigue, chest tightness, and shortness of breath over western medicine alone. The use of western medicines in diagnosed and suspected patients after treatment is shown in Table 5 . Both diagnosed and suspected patients were treated with antiviral drugs. There was a significant difference in the use of macrolides among the three treatment groups (P < 0.05). The utilization rate of anti-infective J o u r n a l P r e -p r o o f drugs in the western medicine group was significantly higher than the other two groups. The medication use of diagnosed patients after treatment is presented in Table 6 . All diagnosed patients were treated with antiviral drugs. In the use of anti-infective drugs, there is a significant difference in the use of macrolide antibiotics among the three groups (P < 0.05). The utilization rate of anti-infective drugs in the western medicine group was significantly higher than the other two groups. The time spent taking medication and prognosis of the 182 diagnosed patients who completed the trial are presented in Table 7 . Time spent taking medication ranged from 4 to 14 days. There were 13 patients who progressed to a severe status, including 1 case in Huoxiang + Lianhua group (1.6%), 5 cases in the Lianhua group (8.6%), and 7 cases in western medicine group (11.1%). There was no significant statistical difference in the proportion of severe disease status among the three groups (P > 0.05). While not reaching statistical significance, the proportion of patients who progressed to severe status is lowest in the Huoxiang + Lianhua group, while that in western medicine group is relatively high, suggesting that the combination of TCM has a potential advantage in improving prognosis of patients with COVID-19. For patients with COVID-19, fever, cough, fatigue, diarrhea, chest tightness, and shortness of breath are common initial symptoms, and could be classified as a "cold-dampness epidemic" in TCM theory. The influenza [15] . Furthermore, Huo Xiang Zhengqi dropping pills also play an important role in the treatment of acute respiratory infectious diseases caused by influenza virus such as fever, muscle soreness, and fatigue J o u r n a l P r e -p r o o f among other symptoms [16] . The results of this study also demonstrated that, with the lack of specific antiviral drugs for COVID-19, therapeutic characteristics and rational use of TCM have an important clinical value for the prevention and control of respiratory symptoms caused by the virus, confirming the scientific nature of the "cold-damp epidemic" theory and the potential of Lianhua Qingwen granules and Huoxiang Zhengqi dropping pills as treatment. Lianhua Qingwen granules has been widely involved and highly recognized in the fight against SARS and influenza in China. Previous pharmacodynamic studies have confirmed that Lianhua Qingwen granules can significantly inhibit the SARS-CoV activity cultured in vitro [17] . A recent study by the State Key Laboratory of Respiratory Diseases of the First Affiliated Hospital of Guangzhou Medical University found that Lianhua Qingwen granules could significantly stall the activity of a novel coronavirus, reducing the content of the virus in the cell membrane and cytoplasm and inhibiting excessive activation of cytokines [18] [19] [20] . At the same time, Huoxiang Zhengqi dropping pills have also achieved initial results in the battle against this epidemic [20] . For instance, application of Huoxiang Zhengqi dropping pills in treating SARS alleviated the inflammatory response and injury to the lung [22] , and Huoxiang Zhengqi caspules reduced the release of inflammatory cytokines stimulated by lipopolysaccharides [23] . One of the main components of Huoxiang Zhengqi, Radix Isatidis, has the following effects: anti-inflammation, anti-viral, antipyretic, and immunity-enhancing. Its antiviral effect is due to competitive adsorption with the virus on the cell surface, preventing invasion of normal, healthy cells. In addition, Herba Houttuyniae can block Madin-Darby Canine Kidney cells (MDCK) apoptosis induced by the influenza virus. Finally, patchouli ketone and patchouli alcohol in patchouli have an obvious inhibitory effect on adeno-, influenza A, and coxsackieviruses [24, 25] . This study demonstrated no significant difference in the improvement of clinical symptoms among the three treatment groups. However, utilization rate of anti-infective drugs and the proportion of patients who progressed to severe status was significantly higher in the western medicine group than the two groups treated with TCM. While this may suggest that the combination of TCM treatment had no significant advantage in the improvement of clinical symptoms in a short amount of time, TCM could reduce the utilization rate of anti-infective drugs. Furthermore, TCM has potential advantages in preventing aggravation while improving prognosis of the disease. This study has some limitations. There was a lack of viral nucleic acid detection data support, and a larger sample size and regular follow-up intervention for in-depth verification is required. Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules combined with western medicine treatment has potential clinical advantages for COVID-19 patients with improving clinical symptoms, not just by reducing the utilization rate of anti-infective drugs, but also by improving the prognosis of patients. This finding could set the precedence for complementary medicine treatment in COVID-19. 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TASLY Holding Group and Yiling Pharmaceutical Co., Ltd.provided the medications for the study, while they did not participate in research design, data collection, data analysis, data interpretation, nor article writing.