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/Seventh 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.
连花清瘟胶囊/颗粒（以下简称连花清瘟）是应用中医络病理论指导研发的治疗感冒、流感的专利新药（国药准字Z20040063），为SARS期间中国第一个通过国家药品监督管理局药品快速审批通道获批的新药品种，是中国唯一获国家科技进步二等奖的治疗流行性感冒中成药，是中国第一个进入美国FDA临床研究治疗流行性感冒的中成药。新冠肺炎暴发以来，该品种在包括湖北定点医院、方舱医院在内的全国疫区广泛应用，累计7000余万人使用该品种进行疫情防控。疫区临床研究证实可有效缓解确诊患者、疑似患者发热、咳嗽、咳痰、气促等症状，缩短发热时间，先后列入中国卫健委《新型冠状病毒感染的肺炎诊疗方案》（试行第四/五/六版/七版）及湖北、北京、上海等20个省卫健委、中医药管理局新冠肺炎诊疗方案推荐用药，成为推荐次数最多的中成药，在中国新冠肺炎疫情防控中发挥了举足轻重的作用。
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 [1], suggesting that this disease falls into the categories of pestilence and collateral disease in TCM [2]. 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 [3]. 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 [4].
1 连花清瘟治疗新冠肺炎的理论组方特色
新冠肺炎主要病变部位在肺，以发热、乏力、干咳为主要表现，病理表现为双侧弥漫性肺泡损伤伴细胞纤维粘液性渗出，肺间质内以淋巴细胞为主的炎性浸润[ ]，该病属于中医瘟疫、络病范畴[ ]。以中医络病理论阐述瘟疫的病机及传变规律，提出积极干预的原则——首重病因、驱逐毒邪；先证用药、积极干预；整体调节、多靶治疗[ ]，确立“清瘟解毒、宣肺泄热”的治疗方法。
连花清瘟胶囊/颗粒全方由连翘、金银花、炙麻黄、绵马贯众、板蓝根、石膏、薄荷脑、广藿香、红景天、鱼腥草、大黄、炒苦杏仁、甘草13味药物组成，汲取了中国汉代张仲景《伤寒杂病论》麻杏石甘汤，清代吴鞠通《温病条辨》银翘散，以及明代吴又可《温疫论》治疫病用大黄的用药经验，并在此基础上配伍红景天、藿香而成。麻杏石甘汤重在宣肺泄热，以解滞络热毒，银翘散透表解毒,大黄通腑清肺、通腑泻肺、通腑安肺，藿香芳香化湿、辟秽逐邪，红景天清肺化瘀、益气养阴，全方汇集了两千多年来中医药治疗瘟疫疾病最宝贵的经验[ ]。
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 cytopathy caused by novel coronavirus (2019-nCoV) infection, reduced the virus load in the infected cells in vitro, and significantly inhibited mRNA expression of inflammatory factors including TNF-α, IL-6, CCL2/MCP-1 and CXCL-10/IP-10 in a concentration-dependent manner. In addition, it has confirmed that LHQW significantly inhibited the weight loss, improved clinical symptoms and lung inflammation of hACE2 transgenic mice infected with 2019-nCoV by the Institute of Medical Experimental Animals, Chinese Academy of Medical Sciences.
The latest research by State Key Laboratory of Respiratory Diseases revealed that LHQW inhibited the influenza viruses including H3N2 via resisting their adhesion and proliferation and directly killing them [6]. 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 [6]. Moreover, accumulating evidence has shown that LHQW significantly regulated the immune response after virus infection [7] and exerted broad-spectrum antiviral effects against common respiratory viruses, such as FM1 virus, parainfluenza virus [8], respiratory syncytial virus (RSV) [9], enteric virus (EV) 71, and coxsackie virus [10], [11]. 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 [12], [15], [14].
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 [15]. 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 [16].
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.
2 连花清瘟治疗呼吸系统传染性疾病实验研究
2.1抗病毒、抑菌作用
广州医科大学附属第一医院呼吸系统疾病国家重点实验室最新研究证实，连花清瘟对新型冠状病毒（2019-nCoV）感染引起的细胞病变具有良好的抑制作用，减少细胞胞内病毒颗粒，明显抑制TNF-α、IL-6、CCL2/MCP-1和CXCL-10/IP-10等炎症因子mRNA表达，且具有剂量依赖关系。中国医学科学院医学实验动物研究所研究证实，连花清瘟明显抑制2019-nCoV感染hACE2转基因小鼠后动物体重下降，改善临床症状和肺部炎症病变。
由广州医科大学附属第一医院呼吸系统疾病国家重点实验室，连花清瘟可多环节抗甲型流感病毒H3N2，具有综合抑制、预防病毒吸附、抑制病毒吸附后复制增殖以及直接杀伤病毒作用[ ]。军事医学科学院微生物流行病研究所采用预处理、共处理、后处理三种不同给药方式，证实连花清瘟能延长H1N1病毒感染小鼠平均存活时间，减小感染小鼠肺指数，减轻肺组织炎症病变[ ]。研究发现连花清瘟胶囊对H7N9在内的一系列流感病毒具有广谱抑制作用，调节病毒感染免疫反应 [ ]。此外,研究证实连花清瘟明显抑制流感病毒FM1、副流感病毒 [ ],有效抑制呼吸道合胞病毒（RSV）[ ]、肠道病毒71（EV71）、柯萨奇病毒 [ ]、 [ ]。此外连花清瘟能有效抑制金黄色葡萄球菌、流感杆菌、肺炎球菌等，抑制金黄色葡萄球菌、表皮葡萄球菌甲氧西林耐药菌株细菌生物膜形成[ ]，[ ]，[ ]。
2.2 抗炎作用和减轻炎症风暴
炎症风暴是机体对病毒、细菌等外界刺激产生的一种过度免疫反应，成为新冠肺炎由轻症向重症和危重症发展的重要节点。广州医科大学附属第一医院呼吸系统疾病国家重点实验室研究发现，连花清瘟干预新型冠状病毒（2019-nCoV）提取细胞mRNA分析，对 TNF-α、 IL-6、 CCL2/MCP-1 和 CXCL-10/IP-10 等炎症因子的 mRNA 表达具有显著抑制作用，并呈剂量依赖关系，有效抑制细胞因子过度激活。连花清瘟还可可有效抑制FM1病毒感染小鼠多种组织细胞炎性因子（TNF-α、IL-1β、IL-4、IL-6、IL-12、IL-13等）表达[ ]。抑制脂多糖所致急性肺损伤小鼠炎症细胞浸润，改善肺泡上皮细胞和肺血管内皮细胞连接蛋白的表达，缓解肺组织损伤[ ]。
2.3改善症状、调节免疫
连花清瘟具有（1）退热作用：对三联菌苗致家兔发热有解热作用；（2）抗炎作用：可抑制二甲苯致小鼠耳肿胀，抑制角叉菜胶致大鼠足肿胀，降低醋酸所致小鼠腹腔毛细血管通透性；（3）止咳化痰作用：可增加小鼠气管段酚红排泌量；可延长氨水引咳小鼠的咳嗽潜伏期并减少其咳嗽次数，减少枸橼酸引咳豚鼠的咳嗽次数；（4）调节免疫作用：增强氢化可的松致免疫功能低下模型小鼠的迟发性超敏反应，提高环磷酰胺致免疫功能低下模型小鼠的腹腔巨噬细胞吞噬功能和血清溶血素抗体水平。
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
3.1.1 A prospective, randomized, controlled, multi-center clinical study of traditional Chinese medicine Lianhua Qingwen in the treatment of Corona Virus Disease 2019 (COVID-19)
In a prospective, randomized, controlled, multi-center clinical study of traditional Chinese medicine Lianhua Qingwen (LHQW) Capsule/Granule in the treatment of Corona Virus Disease 2019 (COVID-19), researchers of more than 20 hospitals from nine provinces, including Remin Hospital of Wuhan University, Jinyintan Hospital in Wuhan, the First Affiliated Hospital of Guangzhou Medical University, have made significant progress. Academician Zhong Nanshan, Academician Li Lanjuan and Academician Zhang Boli served as research consultants.
A total of 284 patients with COVID-19 who met the inclusion criteria were enrolled and randomly divided into a control group (conventional treatment) and a treatment group (conventional treatment supplemented with LHQW Capsule, 4 capsules each time, 3 times daily). The course of treatment was 14 d. The results of the study showed that (1) The cure rate (the percentage of patients recovering from fever, fatigue, and cough) of major clinical symptoms (fever, fatigue, and cough) was higher in the LHQW group (91.5\\%) than in the conventional treatment group (82.4\\%) (P <0.05). (2) The recovery time of clinical symptoms (fever, fatigue, and cough) was shorter in LHQW group (with a mean of 7 d) than in the control group (with a mean of 10 d). The duration of symptom disappearance, including fever (2 d vs. 3 d) and fatigue ( 3 d vs. 6 d), and cough (7 d vs. 10 d), was shortened in the LHQW group by 1 d, 3 d, and 3 d, respectively, as compared with the conventional treatment group (P <0.05).
(3) The improvement rate on CT was higher in the LHQW group than in the conventional treatment group (83.8\\% vs. 64.1\\%) (P <0.001). (4) The cure rate was significantly higher in the LHQW group than in the conventional treatment group (78.9\\% vs. 66.2\\%) (P <0.05). The duration of the disease was 15 d in the treatment group and 17 d in the control group (P <0.05). In addition, the nucleic acid negative conversion rate and duration of negative-to-positive conversion (76.8\\%, 11 d) of the treatment group showed a favorable trend, as compared with the control group (71.1\\%, 12 d). In terms of reducing the possibility of mild infections becoming severe, the treatment group was 50\\% lower than the control group (2.1\\% vs. 4.2\\%), showing a good trend. During the course of the trial, no severe adverse events were reported in either group. With respect to the experimental drug, no abnormalities were detected on laboratory examinations as well as on electrocardiogram in both groups, including routine blood test, markers of liver and kidney function, and myocardial enzymes. The results of this study confirmed that LHQW Capsule/Granule on the basis of conventional treatment could ameliorate clinical symptoms such as fever, fatigue, and cough in patients diagnosed with COVID-19. In addition, it could significantly improve CT characteristics of the lungs, shorten the duration of symptoms and treatment duration, and improve the cure rate, which is, therefore, safe and effective for patients with COVID-19.
3.1.2 Retrospective clinical study of Lianhua Qingwen in the treatment of Corona Virus Disease 2019 (COVID-19)
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 [17].
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 [18].
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 [19]. 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 [20].
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 [21]. 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 [21] 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 [22], [23].
3、连花清瘟治疗呼吸系统传染性疾病临床研究
3.1治疗新冠肺炎——有效缓解发热、咳嗽、咳痰、气促等症状，缩短发热时间
3.1.1连花清瘟治疗新冠肺炎前瞻性、随机对照、多中心临床研究
由钟南山院士、李兰娟院士、张伯礼院士担任顾问，武汉大学人民医院、武汉金银潭医院、广州医科大学第一附属医院等全国9个省份，20余家医院共同参与的，中药连花清瘟治疗新型冠状病毒肺炎前瞻性、随机、对照、多中心临床研究获重大进展。
该研究纳入符合要求的284名新型冠状病毒肺炎患者，随机分为对照组（常规治疗）和治疗组（常规治疗加用连花清瘟胶囊，4粒/次，3次/日），疗程14天。研究结果显示，（1）主要临床症状（发热、乏力、咳嗽）痊愈率（指发热、乏力、咳嗽均消失的患者百分比），连花清瘟组痊愈率（91.5\\\%）高于常规治疗组（82.4\\\%）（P＜0.05）。（2）临床症状（发热、乏力、咳嗽）痊愈时间，治疗组（平均7天）优于对照组（平均10天），从症状消失时间来看，发热（2天vs 3天）、乏力（3天vs 6天）、咳嗽（7天vs 10天），连花清瘟组较常规治疗组分别缩短了1天，3天，3天（P＜0.05）。（3）CT好转率连花清瘟组优于常规治疗组（83.8\\\% vs 64.1\\\%）（P＜0.001）。（4）疾病痊愈率，连花清瘟组明显高于常规治疗组（78.9\\\% vs 66.2\\\%），（P＜0.05），疾病持续时间治疗组15天，对照组为17天（P＜0.05）。此外，治疗组核酸转阴率及转阴时间（76.8\\\%，11天）与对照组（71.1\\\%，12天）比较显示出一定趋势。在降低转重型比例方面，治疗组较对照组降低50\\\%（治疗组2.1\\\% vs对照组4.2\\\%），显示出良好趋势。试验期间，两组均未发生不良事件。两组血常规、肝肾功能、心肌酶和心电图等检查，经研究者判断未见与试验药物相关异常。研究结果证实：在常规治疗基础上应用中药连花清瘟胶囊/颗粒可改善COVID-2019确诊患者发热、乏力、咳嗽等临床症状，明显改善肺部CT特征，缩短症状持续和治疗时间，提高临床痊愈率，应用于COVID-2019患者安全有效。
3.1.2连花清瘟治疗新冠肺炎回顾性临床研究
武汉市第九医院和华润武钢总医院42例COVID-19确诊普通型患者，纳入治疗组（21例，常规治疗联合连花清瘟颗粒，1袋/次，3次/日），对照组（21例，常规治疗），与对照组比较，治疗组发热症状消失率85.7\\\%（对照组57.1\\\%），咳嗽症状消失率46.7\\\%（对照组5.6\\\%），组间比较差异有统计学意义（P<0.05）；治疗组发热持续时间（4.6±3.2）d，较对照组发热持续时间（6.1±3.1） d，缩短1.5 d；与对照组比较，治疗组咳痰消失率64.3\\\%（对照组9.1\\\%），气促症状消失率77.8\\\%（对照组0），差异有统计学意义（P<0.05）。结论：中药连花清瘟能明显改善新型冠状病毒感染的肺炎确诊患者发热、咳嗽、咳痰、气促症状 [ ]。
武汉科技大学附属华润武钢总医院就诊的COVID-19疑似患者101例，联合应用连花清瘟治疗组63例，对照组38例，结果显示，与对照组比较，治疗组发热、咳嗽、乏力症状消失率分别为86.7\\\%、55.6\\\%、82.5\\\%，均明显优于对照组（分别为67.7\\\%、30.6\\\%、58.6\\\%，P<0.05）。治疗组中位发热持续时间6天，对照组7天。治疗组气促、湿啰音体征消失率分别为68.2\\\%、56.0\\\%，均明显高于对照组的20.0\\\%和20.0\\\%（P<0.05）。治疗组病情加重4例（6.4\\\%），对照组为6例（15.8\\\%），治疗组较对照组下降趋势明显[ ]。
武汉市普仁医院就诊的COVID-19普通型患者54例，治疗7天后发热、乏力、咳嗽症状消失率分别为80.0\\\%、75.7\\\%、76.7\\\%；发热、乏力、咳嗽消失天数分别为（3.6±2.14）天、（4.1±2.58）天、（5.3±2.63）天；治疗7天后，其他症状体征（胸闷、呼吸困难、湿啰音）消失率分别为84.6\\\%、100\\\%、89.5\\\%；有效率为81.6\\\%，且临床应用安全性良好[ ]。上述来自疫区的临床研究证实连花清瘟在改善新冠肺炎患者症状，缩短发热持续时间具有良好疗效。
3.2治疗流感H1NI——核酸转阴时间与达菲相当，改善临床症状疗效优于达菲
2009年甲型H1N1病毒爆发期间，由首都医科大学附属佑安医院担任组长单位8家医院完成的随机双盲、多中心244例临床试验证实，连花清瘟胶囊在病毒核酸转阴时间及流感症状缓解时间方面与磷酸奥司他韦无差异，但连花清瘟胶囊明显减少疾病的严重程度和症状的持续时间，包括退热及缓解咳嗽、肌肉酸痛、乏力；且药物安全性未见不良反应[ ]。
连花清瘟胶囊治疗甲型H1N1流感随机、阳性药物对照124例临床试验证实，连花清瘟胶囊对确诊患者病毒学检测病毒转阴时间与奥司他韦相当，咳嗽、咽痛、乏力、肌肉酸痛等症状缓解时间优于奥司他韦[ ]。此外，对北京地坛医院定点收治医院连花清瘟用药回顾性分析[ ]，亦证实应用连花清瘟退热、病毒核酸转阴时间与奥司他韦相当。完成的连花清瘟胶囊预防甲流密切接触者临床研究[ ]证实，对河北廊坊市密切接触者及周围人群20553人预防用药，连花清瘟组症状出现率1.2％，其他药物为6.8％，未用药为8.8％，显示出连花清瘟具有良好的预防作用。通过上述临床试验证实连花清瘟胶囊（颗粒）在治疗、控制、预防流感疫情方面具有确切的疗效。临床安全性方面，基于4906例患者的Meta分析显示清瘟胶囊（颗粒）有较好的安全性[ ]、 [ ]。
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 /Seventh 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 [26]. 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.
4、连花清瘟在中国新冠肺炎防控中应用广泛
“连花清瘟胶囊治疗流行性感冒研究”于2011年获得中国国务院颁发的国家科技进步二等奖，体现了在中医理论、原创组方、实验与临床研究方面的科技创新。自2003年上市以来，连花清瘟先后20余次列入国家卫健委、国家中医药管理局发布的甲流、乙流、禽流感、埃博拉出血热、中东呼吸综合征等传染性公共卫生事件诊疗方案或指南共识，已成为应对公共卫生事件的代表性中成药，纳入2019年《国家基本医疗保险、工伤保险和生育保险药品目录》甲类药品和2018年《国家基本药物目录》[ - ]。
此次新冠肺炎疫情中，连花清瘟胶囊/颗粒列为中国卫健委、国家中医药管理局联合颁布的《新型冠状病毒感染的肺炎诊疗方案》（试行第四/五/六版/七版）推荐用药，在全国推荐应用。同时纳入《儿童新型冠状病毒感染诊断、治疗和预防专家共识》、《妊娠期新型冠状病毒肺炎中医药治疗专家建议（试行）》推荐用药。先后列入包括湖北、北京、上海等20个省卫健委、中医局新冠肺炎诊疗方案推荐用药，成为推荐次数最多的中成药[ ]，同时列为13个省储备用药及应急医疗物资采购品种，全国200余个市县卫健委发文要求下辖医疗机构配备用于疫情防控。目前连花清瘟胶囊（颗粒）已在包括武汉方舱医院在内的湖北省1600余家医院社区应用，列入国家卫健委发布的《方舱医院工作手册》（第三版）中药治疗推荐用药。根据2020年1月到2月底销售额数据测算，约7000余万人在疫情暴发时使用连花清瘟胶囊/颗粒，显示该品种在疫情防控中发挥了积极的作用。
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