BACKGROUND: Over 65 million people have long COVID. Evidence for using Chinese herbal medicine (CHM) to treat long COVID is growing. A systematic review of evidence for guiding clinical decision is warranted. OBJECTIVE: To examine the effects and safety of CHM in alleviating the severity of dyspnea, fatigue, exercise intolerance, depression, anxiety and insomnia in long COVID adults based on registered randomized clinical trials (RCT). SEARCH STRATEGY: World Health Organization International Clinical Trials Registry Platform and Chinese Clinical Trial Registry were searched for registered trial protocols from database inception to February 10, 2023. English (PubMed, Embase, AMED and CINAHL) and Chinese databases (CNKI, Wanfang Data and CQVIP) were then searched to identify relevant publications from December 2019 through April 6, 2023. INCLUSION CRITERIA: Registered RCTs that compared the effects of Chinese herbal medicines or Chinese herbal formulas against a control treatment (i.e., the placebo or usual care) in adults with persistent symptoms of long COVID. The primary outcome of dyspnea, and secondary outcomes of fatigue, exercise intolerance, depression, anxiety and insomnia were measured using validated tools at the end of the treatment. DATA EXTRACTION AND ANALYSIS: Data were extracted, and eligible RCTs were evaluated using version 2 of the Cochrane risk-of-bias tool for randomized trials and Grading of Recommendations, Assessment, Development and Evaluations independently by two researchers. Effect sizes were estimated by random-effects modelling and mean difference (MD). Heterogeneity between trials was quantified by I². RESULTS: Among the 38 registered clinical trials we identified, seven RCTs (1,519 patients) were included in the systematic review. One RCT had a low overall risk of bias. Compared to the control, CHM reduces dyspnea on the Borg Dyspnea Scale score (MD = -0.2, 95% confidence interval [CI] = -0.65 to 0.25) with moderate certainty, and reduces fatigue on the Borg Scale (MD = -0.48, 95% CI = -0.74 to -0.22) with low certainty. CHM clinically reduces depression on Hamilton Depression Rating Scale score (MD = -6.00, 95% CI = -7.56 to -4.44) and anxiety on Hamilton Anxiety Rating Scale score (MD = -6.10, 95% CI = -7.67 to -4.53), and reduces insomnia on the Insomnia Severity Index (MD = -4.86, 95% CI = -12.50 to 2.79) with moderate certainty. Meta-analysis of two RCTs (517 patients) showed that CHM clinically improves exercise intolerance by increasing 6-minute walking distance (MD = -15.92, 95% CI = -10.20 to 42.05) with substantial heterogeneity (I² = 68%) and low certainty. CONCLUSION CHM is associated with a post-treatment clinical reduction in depression and anxiety in long COVID adults, compared to the control, but it does not have a strong treatment effect on dyspnea and insomnia. Effects of CHM on exercise intolerance and fatigue are uncertain, and the safety of using CHM remains questionable. Please cite this article as: Tsang MS, Zhou IW, Zhang AL, Xue CC. Chinese herbal medicine for dyspnea and persistent symptoms of long COVID: A systematic review and meta-analysis of randomized controlled trials. J Integr Med. 2025; 23(2): 126-137.
Humans ; Dyspnea/etiology* ; Drugs, Chinese Herbal/therapeutic use* ; Randomized Controlled Trials as Topic ; COVID-19/complications* ; Fatigue/drug therapy* ; SARS-CoV-2 ; Anxiety/drug therapy* ; Depression/drug therapy* ; Sleep Initiation and Maintenance Disorders/drug therapy* ; Betacoronavirus

Betacoronavirus ; COVID-19 ; Coronavirus ; Coronavirus Infections/epidemiology* ; Humans ; Liver/pathology* ; Liver Diseases/virology* ; Pandemics ; Pneumonia, Viral/epidemiology* ; SARS-CoV-2

Betacoronavirus ; COVID-19 ; Coronavirus Infections/complications* ; Disseminated Intravascular Coagulation/etiology* ; Humans ; Pandemics ; Pneumonia, Viral/complications* ; SARS-CoV-2

Betacoronavirus ; Blood Coagulation Disorders/therapy* ; COVID-19 ; Coronavirus Infections/complications* ; Humans ; Pandemics ; Pneumonia, Viral/complications* ; SARS-CoV-2

The coronavirus disease 2019(COVID-19) is raging in China and more than 20 other countries and regions since the middle of December 2019. Currently, there is no specific drug or vaccine besides symptomatic supportive therapy. Taking full advantage of the clinical experience of traditional Chinese medicine(TCM) in preventing and controlling major epidemics such as SARS, it is an important mission for TCM to propose effective formula with immediate response and solid evidence by using modern biomedical knowledge and techniques(molecular docking assisted TCM formulation for short). In view of the high homology between the gene sequences of the novel coronavirus and SARS virus, and the similarities between the two in terms of pathogenic mechanism and clinical manifestations, our team established a rapid screening and optimization model for the prevention and treatment of the novel coronavirus based on clinical experience and molecular docking technology. Firstly, the clinical team and the research team pre-developed and screened TCM formula by using "back-to-back" manner. Then, the formula was optimized and determined by comparing and analyzing the results of the two groups. The results showed that the research team screened out 46 active ingredients from candidate TCMs that could act on the novel coronavirus S-protein-binding site of human ACE2 protein, which were mainly attributed to 7 herbs such as Lonicerae Japonicae Flos and Mori Folium. The result was largely consistent with the formula raised by the clinical group, verifying and supporting its rationality. This provides evidence for the scientific and potential efficacy of the TCM prescription from the perspective of treatment target analysis, and also suggests that the TCM prescription has the potential to directly inhibit viral infection in addition to improving clinical symptoms or syndromes. Based on this, our team optimized and formed a new anti-coronavirus TCM prescription "Keguan Yihao", immediately providing the TCM prescription with certain clinical experience and objective evidence support for the prevention and treatment of new emergent infectious diseases in our hospital. The TCM prescription was combined with modern medicine symptomatic supportive treatment for clinical treatment, preliminary results showed better effect than symptomatic supportive therapy alone. This research has innovated the method mode in clinical practice and basic research integration of traditional Chinese medicine for the prevention and control of new emerging infectious diseases. It is of great significance to further improve the rapid response mechanism of TCM in face of major epidemics, and further improve the capability level of TCM to prevent and treat new emerging infectious diseases.
Angiotensin-Converting Enzyme 2 ; Angiotensin-Converting Enzyme Inhibitors/pharmacology* ; Betacoronavirus ; COVID-19 ; China ; Coronavirus Infections/drug therapy* ; Drugs, Chinese Herbal/pharmacology* ; Humans ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Pandemics ; Peptidyl-Dipeptidase A/chemistry* ; Pneumonia, Viral/drug therapy* ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/chemistry* ; COVID-19 Drug Treatment

With the rapid outbreak of COVID-19, traditional Chinese medicine(TCM) has been playing an active role against the epidemic. However, the screening of TCM is limited by the development cycle and laboratory conditions, which greatly limits the screening speed. This study established optimization docking models and virtual screening to discovery potential active herbs for the prevention and treatment of the novel coronavirus based on molecular docking technology. The crystal structures of 3 CL protease(Mpro) and papain-like protease(PLP) were obtained from PDB database and homologous modeling respectively, and were used to conduct virtual screening of TCMD 2009 database by CDOCKER program. The ingredients scored in the top 100 were selected respectively, and the candidate herbs were ranked by the numbers of hit molecules. Based on Mpro inhibitors screening, 12 322 potential active components were obtained, and the representative active components included aster pentapeptide A, ligustrazine, salvianolic acid B, etc., and Zingiberis Rhizoma Recens, Asteris Radix et Rhizoma, Notoginseng Radix et Rhizoma, Chuanxiong Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Zingiberis Rhizoma, Dianthi Herba, Rhei Radix et Rhizoma, Cistanches Herba were obtained. While 11 294 potential active ingredients were obtained by PLP inhibitor screening, representative active ingredients included gingerketophenol, ginkgol alcohol, ferulic acid, etc., and Codonopsis Radix, Notopterygii Rhizoma et Radix, Zingiberis Rhizoma Recens, Ginkgo Semen, Chuanxiong Rhizoma, Trichosanthis Fructus, Paeoniae Radix Alba, Psoraleae Fructus, Sophorae Flavescentis Radix, Notoginseng Radix et Rhizoma, Angelicae Sinensis Radix were chosen. By combining the diagnosis and treatment scheme of Hunan province's and angiotensin converting enzyme 2(ACE2) inhibitors screening from literature, present study also discussed the rational application of candidate herbs to this epidemic situation. Trichosanthis Fructus obtained by PLP inhibitors screening and Fritillaria verticillata obtained by ACE2 inhibitors screening were parts of the Sangbei Zhisou Powder and Xiaoxianxiong Decoction, which might be applicable to the syndromes of cough and dyspnea. Rhei Radix et Rhizoma screened by Mpro and Trichosanthis Fructus screened by PLP were contained in Maxing Shigan Decoction and Xuanbai Chengqi Decoction, and could be applied to the syndromes of epidemic virus blocking lung. Mori Folium, Lonicerae Japonicae Flos and Forsythiae Fructus obtained by ACE2 inhibitors screening were included in the Sangju Decoction and Yinqiaosan, which might be applicable to the syndromes of warm pathogen attacking lung and cough and dyspnea. The results of this study are intended to provide a reference for the further development of traditional Chinese medicine to deal with the new epidemic.
Angiotensin-Converting Enzyme 2 ; Angiotensin-Converting Enzyme Inhibitors/pharmacology* ; Betacoronavirus/drug effects* ; COVID-19 ; Coronavirus Infections/drug therapy* ; Drug Evaluation, Preclinical ; Drugs, Chinese Herbal/pharmacology* ; Humans ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Pandemics ; Peptidyl-Dipeptidase A ; Pneumonia, Viral/drug therapy* ; SARS-CoV-2 ; COVID-19 Drug Treatment

Since the outbreak of 2019-nCoV, the epidemic has developed rapidly and the situation is grim. LANCET figured out that the 2019-nCoV is closely related to "cytokine storm". "Cytokine storm" is an excessive immune response of the body to external stimuli such as viruses and bacteria. As the virus attacking the body, it stimulates the secretion of a large number of inflammatory factors: interleukin(IL), interferon(IFN), C-X-C motif chemokine(CXCL) and so on, which lead to cytokine cascade reaction. With the exudation of inflammatory factors, cytokines increase abnormally in tissues and organs, interfering with the immune system, causing excessive immune response of the body, resulting in diffuse damage of lung cells, pulmonary fibrosis, and multiple organ damage, even death. Arachidonic acid(AA) metabolic pathway is principally used to synthesize inflammatory cytokines, such as monocyte chemotactic protein 1(MCP-1), tumor necrosis factor(TNF), IL, IFN, etc., which is closely related to the occurrence, development and regression of inflammation. Therefore, the inhibition of AA metabolism pathway is benefit for inhibiting the release of inflammatory factors in the body and alleviating the "cytokine storm". Based on the pharmacophore models of the targets on AA metabolic pathway, the traditional Chinese medicine database 2009(TCMD 2009) was screened. The potential herbs were ranked by the number of hit molecules, which were scored by pharmacophore fit value. In the end, we obtained the potential active prescriptions on "cytokine storm" according to the potential herbs in the "National novel coronavirus pneumonia diagnosis and treatment plan(trial version sixth)". The results showed that the hit components with the inhibitory effect on AA were magnolignan Ⅰ, lonicerin and physcion-8-O-β-D-glucopy-ranoside, which mostly extracted from Magnoliae Officinalis Cortex, Zingiberis Rhizoma Recens, Lonicerae Japonicae Flos, Rhei Radix et Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Scutellariae Radix, Gardeniae Fructus, Ginseng Radix et Rhizoma, Arctii Fructus, Dryopteridis Crassirhizomatis Rhizoma, Paeoniaeradix Rubra, Dioscoreae Rhizoma. Finally the anti-2019-nCoV prescriptions were analyzed to obtain the potential active prescriptions on AA metabolic pathway, Huoxiang Zhengqi Capsules, Jinhua Qinggan Granules, Lianhua Qingwen Capsules, Qingfei Paidu Decoction, Xuebijing Injection, Reduning Injection and Tanreqing Injection were found that may prevent 2019-nCoV via regulate cytokines. This study intends to provide reference for clinical use of traditional Chinese medicine to resist new coronavirus.
Arachidonic Acid/metabolism* ; Betacoronavirus ; COVID-19 ; Coronavirus Infections/immunology* ; Cytokines/immunology* ; Drugs, Chinese Herbal/pharmacology* ; Humans ; Medicine, Chinese Traditional ; Metabolic Networks and Pathways ; Pandemics ; Pneumonia, Viral/immunology* ; SARS-CoV-2 ; COVID-19 Drug Treatment

To analyze the registered clinical trial protocols of traditional Chinese medicine(TCM) for the prevention and treatment of coronavirus disease 2019(COVID-19), in order to provide information for improving the quality of research design. The website of the Chinese Clinical Trial Registry(www.chictr.org.cn) and the American Clinical Trial Registry(clinicaltrials.gov) were searched to collect protocols of TCM for COVID-19. Documents were screened following the inclusion criteria, and data were extracted in regard to registration date, study objective, type of design, sponsor, patient, sample size, intervention, and evaluation index. Descriptive analysis was conducted. A total of 49 clinical trial protocols of TCM for COVID-19 were included. Primary sponsors were mainly hospitals or universities in places like Hubei, Beijing, Zhejiang and other regions. The implementation units are mainly in Hubei, Guangdong, Zhejiang, Henan and other regional hospitals. The types of study design were mainly experimental studies(40), including 30 randomized parallel controlled trials, 7 non-randomized controlled trials, 2 single arm trials and 1 consecutively recruited trial; besides, there were also 6 observational studies, 2 health service studies and 1 preventive study. The sample size reached a total of 30 562 cases, with a maximum of 20 000 for a single study and a minimum of 30. The 49 trials subjects included healthy people(3), isolation and observation cases(1), suspected cases(10),confirmed COVID-19 patients(31) and COVID-19 recovery patients(4). Of the 31 trials planned to include confirmed COVID-19 patients, 16 protocols no definite disease classification, 3 with a clear exclusion of severe subjects, 4 with common subjects, 2 with light, common or severe subjects, 1 with light and common subjects, 1 with common or severe subjects, 3 with severe subjects, and 1 with severe or critical subjects. The experimental interventions included Chinese patent medicine(Lianhua Qingwen Capsules/Granules, Huoxiang Zhengqi Dropping Pills/Oral Liquid, Babao Dan, Gubiao Jiedu Ling, Jinhao Jiere Granules, Compound Yu-xingcao Mixture, Jinye Baidu Granules, Shufeng Jiedu Capsuless, Shuanghuanglian Oral Liquid, Tanreqing Injection, Xuebijing Injection, Reduning Injection, Xiyanping Injection), Chinese medicinal decoction and taichi. The primary evaluation outcomes mainly included antipyretic time, clinical symptom relief, novel coronavirus nucleic acid turning to negative, conversion rate of severe cases and chest CT. There was a quick response of clinical research on the prevention and treatment of COVID-19 with TCM, with the current registered protocols covers the whole process of disease prevention, treatment and rehabilitation. However, issues need to be concerned, including unclear definition of patient's condition, unclear research objectives, unclear intervention process and inappropriate outcomes, etc. In addition, researchers should consider the actual difficulties and workload of doctors in epidemic response environment, and make effort to optimize the process and improve the operability of research protocols under the principle of medical ethics.
Betacoronavirus ; COVID-19 ; China ; Clinical Trial Protocols as Topic ; Coronavirus Infections/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Medicine, Chinese Traditional ; Pandemics ; Pneumonia, Viral/drug therapy* ; Randomized Controlled Trials as Topic ; Research Design ; SARS-CoV-2 ; COVID-19 Drug Treatment

To investigate the regularity of prescription and clinical syndromes by analyzing the diagnosis and treatment protocols of traditional Chinese medicine(TCM) for coronavirus disease 2019(COVID-19), so as to provide references for syndrome differentiation and relevant researches. The diagnosis and treatment protocols of COVID-19 published by national and regional health authorities were searched, and information was extracted in regard to disease stages, type of syndromes, and prescriptions, etc. Frequency statistics and relative analysis were used to analyze the rule of syndrome differentiation and prescription with TCM, and further discussion on the pathogenesis and progress of the disease. A total of 26 diagnosis and treatment protocols of TCM for COVID-19 were retrieved after screening(including 1 national scheme and 25 regional ones), among which 16 contained aspects of both prevention and treatment, 7 only involved treatment contents and 3 were prevention schemes. The courses of COVID-19 can be divided into early stage, middle stage, severe stage and recovery stage. The pathogeny of COVID-19 in TCM is damp-toxin, with the core pathogenesis of damp-toxin retention in lung and Qi repression. Its pathological features can be summarized as "damp, toxin, obstruction, deficiency". The location of the disease is lung, always involving spleen and stomach, and may further affect heart and kidney in severe cases. The major treatments for each course are Fanghua Shizuo, Xuanfei Touxie(early stage); Qingre Jiedu, Xuanxie Feire(middle stage); Kaibi Gutuo, Huiyang Jiuni(severe stage); Qingjie Yure, Yiqi Yangyin(recovery stage). There were many diagnosis and treatment protocols for COVID-19 have been published, which generally followed the national edition, through with certain personalities in different regional protocols. There were common features with respect to the disease stage, syndrome differentiation, therapeutic principles and methods, as well as prescriptions; the treatment were generally carried out against the core pathogenesis and progress of the disease. Along with the deepening recognition of COVID-19, the diagnosis and treatment protocols are still need further concretization and standardization. We hope researchers and decision-makers can pay more attention to the treatment of Huayu Tongluo in severe and recovery period.
Betacoronavirus ; COVID-19 ; COVID-19 Testing ; Clinical Laboratory Techniques ; Coronavirus Infections/prevention & control* ; Humans ; Medicine, Chinese Traditional ; Pandemics/prevention & control* ; Pneumonia, Viral/prevention & control* ; SARS-CoV-2 ; COVID-19 Drug Treatment

The coronavirus disease 2019(COVID-19) is developing rapidly and posing great threat to public health. There is no specific medicine available for treating the disease. Luckily, traditional Chinese medicine has played a positive role in the fighting against COVID-19. In this paper, We collected and sorted the prescriptions of modern Chinese medicine for COVID-19 released by national government, different provinces, autonomous regions and municipalities, as well as online databases, such as CNKI, WanFang medical network, and VIP database. These prescriptions were combined with the inheritance of traditional Chinese medicine auxiliary V2.5, and the complex system entropy clustering method was used to determine the association rules and frequency of single drug and drug combination in the prescription. In the end, 96 effective prescriptions were included. Among them, the four properties were mainly concentrated in temperature, cold and level, the five tastes were mainly concentrated in bitter, hot and sweet, and the meridians were mainly concentrated in lung, stomach and spleen. The high-frequency drugs were Glycyrrhizae Radix et Rhizoma, Armeniacae Semen Amarum, Gypsum Fibrosum, etc., and the high-frequency combinations are Gypsum Fibrosum-Armeniacae Semen Amarum, Gypsum Fibrosum-Glycyrrhizae Radix et Rhizoma, Armeniacae Semen Amarum-Glycyrrhizae Radix et Rhizoma, the core combinations are Lepidii Semen-Armeniacae Semen Amarum-Gypsum Fibrosum, Pogostemonis Herba-Zingiberis Rhizoma Recens-Magnoliae Officinalis Cortex, Ophiopogonis Radix-Armeniacae Semen Amarum-Scutellariae Radix and so on. Form new prescriptions Lepidii Semen, Armeniacae Semen Amarum, Gypsum Fibrosum, Pogostemonis Herba, Zingiberis Rhizoma Recens, Magnoliae Officinalis Cortex. Ophiopogonis Radix, Armeniacae Semen Amarum, Scutellariae Radix, Schisandrae Sphenantherae Fructus, Panacis Quinquefolii Radix. From the medicinal properties to high-frequency drugs and new prescriptions, it could be seen that the overall treatment of COVID-19 by traditional Chinese medicine was to strengthen body resistance, eliminate pathogenic factors, and give attention to Qi and Yin.
Betacoronavirus ; COVID-19 ; Coronavirus Infections/drug therapy* ; Data Mining ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Medicine, Chinese Traditional ; Pandemics ; Pneumonia, Viral/drug therapy* ; SARS-CoV-2 ; COVID-19 Drug Treatment