Received: 21 May 2021 Revised: August 2021 Accepted: August 2021 DOI: 10.1111/jebm.12444 GUIDELINE Integrating Chinese and western medicine for COVID-19: A living evidence-based guideline (version 1) Long Ge1,2,3,4 Yang Chen8 Hongfei Zhu1,2 Qi Wang1,2 Yaolong Chen3,4,9,10 Yutong Fei12 Jihong Feng13 Yuyong Jiang14 Guiwei Li15 Mengting Li1,2 Banghan Ding5 Jianxiong Cai5,6,7 Bangjiang Fang11 Xinfeng Guo5,6,7 Rongmeng Jiang14 Xiuhui Li16 Xucheng Li17 Qun Liang18 Jian Liu19 Jianping Liu12 Qingquan Liu20 Shaonan Liu5,6,7 Qing Miao22 Wensheng Qi23 Hongcai Shang24 Liqing Shi25 Xudong Tang27 Kehu Yang2,3,4,9 Junhua Zhang30 Darong Wu5,6,7 Xianbo Wang14 Lihong Yang5,6,7 Yun Lu21 XingHua Tan26 Xiaojun Wang16 Wenguang Xia28 Yongan Ye24 Qi Zhou10 Hongchun Zhang29 Zhiming Zhang31 Zhongde Zhang5 Xu Zou5 Department of Social Medicine and Health Management, School of Public Health, Lanzhou University, Lanzhou, China Evidence-Based Social Science Research Centre, School of Public Health, Lanzhou University, Lanzhou, China WHO Collaborating Center for Guideline Implementation and Knowledge Translation, Lanzhou, China Chinese GRADE Centre, Lanzhou University, Lanzhou, China Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China Key Laboratory of Evidence-Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China 10 Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China 11 Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China 12 Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China 13 Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China 14 Beijing Ditan Hospital Capital Medical University, Beijing, China 15 First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China 16 Beijing Youan Hospital, Capital Medical University, Beijing, China 17 Wuhan Hospital of Traditional Chinese Medicine, Wuhan, China 18 First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China 19 The First Hospital of Lanzhou University, Lanzhou, China 20 Beijing Traditional Chinese Medicine Hospital, Capital Medical University, Beijing, China 21 Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China 22 Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China 23 Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China 24 Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China Jun Li5 © 2021 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd J Evid Based Med 2021;14:313–332 wileyonlinelibrary.com/journal/jebm 313 314 GE ET AL 25 Department of Respiratory Medicine, Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China 26 Guangzhou Eighth People′s Hospital, Guangzhou, China 27 China Academy of Chinese Medical Sciences, Beijing, China 28 Hubei Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Wuhan, China 29 China-Japan Friendship Hospital, Beijing, China 30 Evidence-Based Medicine Center of Tianjin University of Traditional Chinese Medicine, Tianjin, China 31 Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Lanzhou, China Correspondence Jun Li, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China Email: lijun1401@163.com Darong Wu, The State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China Email: darongwu@gzucm.edu.cn Abstract Background: The coronavirus disease 2019 (COVID-19) has turned into a pandemic and resulted in huge death tolls and burdens Integrating Chinese and western medicine has played an important role in the fight against the COVID-19 pandemic Purpose: We aimed to develop a living evidence-based guideline of integrating Chinese and western medicine for COVID-19 Study design: Living evidence-based guideline Funding information China National Centre for Biotechnology Development, Grant/Award Numbers: 2019YFC1709805, 2019YFC1709802; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Grant/Award Numbers: ZH2019ZZ04, SZ2020ZZ09 Methods: This living guideline was developed using internationally recognized and Long Ge, Hongfei Zhu, Qi Wang, and Mengting Li are co-first authors Except the co-first and corresponding authors, the rest of authors were alphabetized by their last name and contributed equally were fully considered, and the Grading of Recommendations Assessment, Develop- accepted guideline standards, dynamically monitoring the release of new clinical evidence, and quickly updating the linked living systematic review, evidence summary tables, and recommendations Modified Delphi method was used to reach consensus for all recommendations The certainty of the evidence, resources, and other factors ment, and Evaluation (GRADE) approach was used to rate the certainty of evidence and the strength of recommendations Results: The first version of this living guidance focuses on patients who are mild or moderate COVID-19 A multidisciplinary guideline development panel was established Ten clinical questions were identified based on the status of evidence and a face-to-face experts’ consensus Finally, nine recommendations were reached consensus, and were formulated from systematic reviews of the benefits and harms, certainty of evidence, public accessibility, policy supports, feedback on proposed recommendations from multidisciplinary experts, and consensus meetings Conclusion: This guideline panel made nine recommendations, which covered five traditional Chinese medicine (TCM) prescription granules/decoction (MXXFJD, QFPD, XFBD, TJQW, and JWDY), three Chinese patent medicines (LHQW granules/capsule, JHQG granules, and LHQK granules), and one Chinese herbal injection (XBJ injection) Of them, two were strongly recommended (LHQW granules/capsule and QFPD decoction), and five were weakly recommended (MXXFJD decoction, XFBD decoction, JHQG granules, TJQW granules, and JWDY decoction) for the treatment of mild and moderate COVID-19; two were weakly recommended against (XBJ injection and LHQK granules) the treatment of mild and moderate COVID-19 The users of this living guideline 315 GE ET AL are most likely to be clinicians, patients, governments, ministries, and health administrators KEYWORDS COVID-19, evidence-based practice, living guideline, recommendation, SARS-CoV-2, traditional Chinese medicine INTRODUCTION Guidelines in Healthcare (RIGHT),17 and the Guidelines International Network (GIN).18 This is the first in a series of living guideline of “Inte- The coronavirus disease 2019 (COVID-19) pandemic continues to grating Chinese and Western Medicine for COVID-19.″ We developed spread globally As of August 2, 2021, more than 198.2 million peo- this guideline based on a linked living systematic review, to provide clin- ple have been confirmed to be COVID-19 caused by SARS coron- icians, patients, and other stakeholders with guidance for using TCM in avirus virus (SARS-CoV-2); of these, 4.22 million have died.1 Despite patients with mild and moderate COVID-19 The recommendations of global efforts to identify effective management for COVID-19, the lat- this version are summarized in Figure est World Health Organization (WHO) living guidance has suggested that there were no other interventions recommended for patients with COVID-19 regardless of disease severity except systemic corticos- METHODS teroids for severe and critical COVID-19.2,3 Traditional Chinese Medicine (TCM) has played and will continue to We developed a living guideline to optimize the development process play an important role in the fight against the COVID-19 pandemic, of the standard guideline, by dynamically monitoring the release of which has also brought increased attention and application of TCM in new clinical evidence and quickly updating the linked living systematic China and abroad.4 The combination of TCM and western medicine has review, evidence summary tables, and recommendations, aimed to pro- been documented to shorten the length of hospital conversion rate to severe cases,6 stay,5 reduce the improve clinical symptoms such as fever, cough, fatigue, and dry throat, and enhance immunity.7,8 Several clinical practice guidelines 8–10 for the treatment of COVID- vide timely and trustworthy recommendations for decision-makers.19 This guideline has been registered on the International Practice Guidelines Registry Platform (registration number: IPGRP2020CN164) 19 with TCM or integrating Chinese and western medicine have been developed; however, they were mainly based on indirect evidence or expert consensus (see Table 1) The lack of direct clinical evidence restricted their trustworthiness in the global fight against COVID- 2.1 Constitution of the guideline development panel 19 More than 20 randomized controlled trials (RCTs) of TCM for the treatment of COVID-19 have been published and assessed the effi- The guideline development panel was composed of a steering commit- cacy and safety of some TCMs such as Lianhua Qingwen (LHQW) gran- tee, an academic secretary group, an evidence review group, and an ules (or capsule), Toujie Quwen (TJQW) granules, and Jinyinhua Oral expert consensus group The consensus experts were all clinicians from Liquid.11–13 In addition, more than 60 trials on TCM interventions for the frontline of the fight against the COVID-19 pandemic in the field COVID-19 have been registered on the Chinese Clinical Trial Registry, of Chinese internal medicine, TCM emergency, western medicine, inte- and some of them still are ongoing With the rapidly evolving evidence grating Chinese and western medicine for infectious diseases, rehabil- landscape, it is extremely important to develop a trustworthy and expe- itation medicine, critical care medicine, TCM health care, and respira- ditious clinical practice guideline to guide clinicians, patients, govern- tory department, and supported by nine evidence-based TCM experts ments, ministries, and health administrators.2 and guideline development methodologists Relying on the “Demonstration application of the development of clinical guideline for 10 dominant diseases of traditional Chinese medicine,” which is the subproject of the key project of the China National Key Research and Development Program in 2019, we founded the Trust- 2.2 Declaration and management of conflicts of interest worthy traditional Chinese Medicine Recommendations (TCM Recs) working group, an international group aimed to develop the trustwor- All members filled out the conflicts of interest declaration form before thy and rapid TCM recommendations using internationally recognized they formally participate in the development of the guideline and and accepted guideline standards including the Institute of Medicine declared various actual or potential conflicts of interest, including (IoM),14 the Grading of Recommendations, Assessment, Development financial conflicts of interest and noneconomic conflicts of inter- and Evaluation (GRADE),15 Appraisal of Guidelines Research and Eval- est The steering committee independently checked all statements to uation II (AGREE II),16 Reporting Items of the Health Care for Practice determine whether there was a potential conflicts of interest.20 We 316 GE ET AL TA B L E Current guidelines on TCM for COVID-19 Title Recommendations Evidence basis Traditional Chinese medicine guidelines for coronavirus disease8 Strong recommendations of two TCMs, weak recommendations of 14 TCMs, and against the recommendation of one TCM for the treatment of COVID-19 Mainly based on published relative guidelines/statements/consensuses, indirect evidence, and expert consensus Only three TCMs used limited direct evidence A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)9 Recommendations of six TCMs for the prevention and nine for the treatment of COVID-19 Two TCMs in the medical observation period and seven TCMs in the clinical treatment period Mainly based on published relative guidelines, indirect evidence, and expert’s experience A clinical diagnosis & treatment rapid advice guideline for integrating Chinese and Western medicine of COVID-1910 Weak recommendations of 11 TCMs for the prevention Strong recommendations of 23 TCMs, weak recommendations of five TCMs for the adult treatment of COVID-19 Weak recommendations of 11 TCMs for the special populations (children) treatment of COVID-19 Mainly based on COVID-19 prevention and treatment protocol with TCM in various provinces and cities, ancient TCM books, experience, and consensus recommendation of National Celebrated Traditional Chinese Medicine Expert, expert’s evidence, and published clinical research literature excluded experts who declared a potential financial conflicts of inter- tions, symptomatic therapies, and oxygen therapy, and was determined est For experts with academic conflicts of interest, we managed them based on the latest guidelines of Diagnosis and Treatment of COVID- with WHO guidance No panel members stated any financial conflicts 19 (4) Outcomes: patient-important outcomes included the conver- of interest Since a regimen of TCM was developed by one of our sion rate of severe cases, the TCM symptom scores, the length of hospi- experts, and the relevant recommendation was supported only by this tal stay, the time for nucleic acid conversion, the duration of symptoms RCT, we finally did not count this expert’s vote for this recommenda- recovery, the effective rate, and adverse reaction We also considered tion All conflicts of interest declaration documents are filed by the sec- other outcomes reported in the included RCTs as a supplement We retary team and updated according to the actual situation decided the patient-important outcomes based on a combination of the Core Outcome Set for Clinical Trials on Coronavirus Disease 2019 (COSCOVID)21 of TCM and expert consensus More details can be found in 2.3 Development of living systematic review Section 2.6 (5) Study design: RCTs and observational studies We cooperated with McMaster University in Canada to conduct the linked living systematic review “Integrating Chinese and western medicine 2.3.2 Exclusion criteria for the treatment of COVID-19: a living systematic review and metaanalysis.” This systematic review aimed to update the ever-changing (1) TCM prescriptions with unclear ingredients; (2) The mixed results of new evidence of TCM in a timely manner and provide the best evidence multiple TCM prescriptions cannot distinguish the efficacy of a single support for the evaluation and decision-making activities of curative drug; (3) Protocols, case report, case report series, etc effect evaluation and guideline development of COVID-19 The details of methods can be found in the linked systematic review Here, we only provided a summary of the methods 2.3.3 Evidence retrieval and screening Based on the screening results of Drug treatments for covid-19: liv- 2.3.1 Inclusion criteria ing systematic review and network meta-analysis led by scholars from McMaster University in Canada,3 which started from April 2020 (1) Patients: confirmed COVID-19 cases (treatment), community, or and conducted daily evidence retrieval and literature screening, our high-risk population (prevention) The first version of this living guide- group selected and included RCTs of TCM for the prevention and line mainly focused on the treatment of mild and moderate COVID- treatment of COVID-19 The searched database of this living net- 19 patients with TCM (2) Intervention: TCM or integrating Chinese work meta-analysis included the WHO COVID-19 database (which and western medicine (3) Comparison: western medicine treatment consists of 26 databases published in different languages around generally consisted of supportive treatment such as antiviral medica- the world and the evidence sources of grey literature), six Chinese 317 GE ET AL FIGURE Visual summary of recommendations 318 FIGURE GE ET AL Continued databases and a dynamic evidence retrieval service platform devel- the WHO COVID-19 database, China National Knowledge Infras- oped by Epistemonikos foundation (including 40 databases and grey tructure (CNKI), and Chinese Medical Journal Network Two reviewers literature) Based on the results of the RCT searches, we searched of the evidence review group screened independently, and any con- observational studies as an additional evidence for the interven- flicts were resolved through discussion or consultation with a third tions identified by RCTs Observational studies were identified in reviewer 319 GE ET AL FIGURE 2.3.4 Continued Data extraction and Risk of bias assessment follow-up update process had Risk of bias assessment, data extraction, and synthesis Teams of two reviewers independently performed data extraction and Risk of bias assessment We used the Cochrane collaboration’s tool22 for assessing the risk of bias of RCTs and the Newcastle—Ottawa Scale 2.4 Summary table of living evidence (NOS)23 for the risk of bias of observational studies Different opinions were resolved through discussion or consultation with a third The evidence review group evaluated the certainty of evidence based reviewer on the GRADE system,15 mainly considering five downgrading factors (risk of bias, inconsistency, indirectness, imprecision, and publication bias) and three upgrading factors (large effect, dose–response gradi- 2.3.5 Evidence update ent, and plausible confounding) The final certainty of the evidence was classified in one of four levels—high, moderate, low, and very low.24 The search was regularly updated bimonthly to monitor and track clin- We presented the evidence through the evidence summary table, ical research evidence of TCM Based on the results of periodic living including the “Evidence Profile” and the “Evidence to Decision (EtD) evidence retrieval, new evidence would be included in time, and the table.”19 The “Evidence Profile” provided the reasons and detailed 320 GE ET AL information for the certainty evaluation of the evidence, and visu- tions and categorize the strength of recommendations as “strong” and ally displayed each outcome in the form of a forest diagram to deter- “weak” (sometime guideline panel may use terms such as “conditional” mine whether the intervention for a certain health problem is effec- or “discretionary” instead of weak),27 by comprehensively considering tive for the outcome indicators, and summarized the results of the the balance of benefits and harms, the certainty of evidence, cost, clin- meta-analysis of different outcomes and form the “Summary of Find- ical feasibility, accessibility, and clinical acceptability.28 When new evi- ings (SoFs) table.”25 The EtD table provides detailed information for dence emerged, the guideline development group would update the judging the strength and direction of each recommendation, such as linked systematic review, living summary table, and recommendations the reliability of the evidence, the application of resources, the impact in a timely manner in order to form living recommendations on fairness, and acceptability When new evidence appeared, the guide- We used the modified Delphi method to reach a consensus for all line evidence review group would update the above two tables in a recommendations The consensus rule was that more than 75% of timely manner to form a living summary table to determine new rec- experts agreed with the strength and direction of recommendation, ommendations which was deemed to have reached a consensus In the first round of Delphi consensus, we obtained the feedback regarding the recommendation from 30 experts, (LHQW granules, MXXFJD decoction, 2.5 Identification of clinical questions QFPD decoction, XFBD decoction, JHQG granules, and TJQW granules) of 10 recommendations were reached consensus Based on the Based on the RCTs evidence included in the above living systematic feedback of experts, we revised four recommendations (focusing on review, we structured the clinical questions as “Patient (P),” “Inter- XBJ injection, LHQK granules, Qingfei Touxie Fuzheng decoction, and vention (I) and Control (C),” and “Outcomes (O).” The secretary group JWDY decoction) which did not reach consensus, and designed the drafted the clinical questions based on the PICO, then we invited the questionnaire to perfume the second round of consensus In the sec- consensus expert group to rate the importance of clinical questions in ond round of Delphi consensus, we obtained feedback from 29 experts, the Kick-off meeting The secretary group collected experts’ feedback and three of four recommendations were reached consensus Consid- and discussed with the steering committee to determine the final clini- ering the discrepancies of experts’ opinions and insufficient evidence, cal questions When new evidence was included in the linked system- we decided that the present guideline did not include the recommen- atic review, the clinical questions to be updated were demonstrated dation of Qingfei Touxie Fuzheng decoction, which did not reach con- again based on the evidence sensus Finally, included nine recommendations in this version of the guideline (version 1) 2.6 Survey of the importance of clinical questions and outcomes 2.8 Development, external review, publication, and dissemination of the guideline The guideline consensus expert group determined important clinical questions and outcome indicators based on a face-to-face meeting The The guideline was conducted in a standardized, systematic, and trans- rules were as follows: (1) Score 1–5 points for the 19 clinical questions parent manner in strict accordance with the requirements of the inter- initially included, point means very unimportant, points means very national practice guidelines reporting standard RIGHT.17 Utilizing the important, and the top 10 clinical questions are included in the first resources of peer reviewers in journals, we transformed the external version of the living guideline; (2) The 30 outcome indicators initially review of the standard evidence-based clinical practice guideline into included are scored from to points The critical outcome is 7–9 the peer review of the journal with multiple peer reviewers When points, the important outcome is 4–6 points, and the general outcome the recommendations are determined to be updated, the journal and is 1–3 points (3) Finally, we decided patient-important outcomes based peer reviewers are notified to shorten the time consumed by external on the results of scores and the Core Outcome Set for Clinical Trials on review The guideline will be disseminated by peer-reviewed academic Coronavirus Disease 2019 (COS-COVID).21 According to the consensus journals, presented at conferences, and promoted in public media out- of the guideline expert group, the first version of the living guideline lets such as WeChat and Facebook only focused on the recommendations of mild and moderate COVID19 patients 2.9 2.7 Formulation of living recommendations Guideline update plan and standards We plan to conduct bimonthly surveillance for new clinical research evidence of TCM When there is new research evidence, the steering The evidence review group formed a living summary table based on committee evaluates the possibility that the evidence changes clinical the clinical questions identified by the expert consensus, and the sec- practice or previous recommendations to decide whether to initiate or retary group formulated the GRADE EtD table26 and drafted recom- update the guideline recommendations The main criteria considered mendations We used GRADE approach to formulate the recommenda- in the guideline update are: (1) New high-quality clinical researches, 321 GE ET AL including but not limited to RCT or observational studies of TCM for 3.1.2 Benefits and harms COVID-19 is published and/or does not include in the previous version of the guideline; (2) For TCM that has been included in the guideline, Our living SR included four RCTs11,30–32 involving 916 patients with the new evidence may change the direction or strength of the existing mild and moderate COVID-19, the results suggested that integrat- recommendations ing LHQW granules (capsule) and western medicine could significantly shorten the rate of conversion of severe cases11,30 (Risk Ratio (RR) = 0.59, 95%CI: 0.37, 0.94; moderate certainty), improve the effec- RECOMMENDATIONS tive rate30,32 (RR = 1.33, 95%CI: 1.06, 1.66; moderate certainty), the rate of recovery of chest CT manifestations11,30 (RR = 1.21, 95%CI: 3.1 Clinical question 1: What is the impact of integrating LHQW granules (capsule) and western medicine in the treatment of COVID-19? 1.02,1.43; moderate certainty), and the TCM symptom scores32 such as fever (Mean Difference (MD) = 0.48 scores, 95%CI: 0.39, 0.57; low certainty), fatigue (MD = 0.28 scores, 95%CI: 0.19, 0.37; low certainty), and chest tightness (MD = 0.37 scores, 95%CI: 0.24, 0.50; low cer- Recommendation 1: we recommend the integration of LHQW gran- tainty) Table presents GRADE assessment details and other out- ules (capsule) and western medicine to decrease the rate of conversion comes of severe cases, shorten the duration of symptoms recovery, improve A meta-analysis33 addressed 600 patients with moderate COVID- the effective rate, the TCM symptom scores, and the rate of recovery 19 suggested that compared to western medicine treatment, integrat- of chest CT manifestations for mild and moderate COVID-19 patients ing LHQW granules (capsule) and western medicine showed lower inci- (strong recommendation, moderate certainty evidence) dence of adverse events such as nausea, vomiting, diarrhea, and loss of appetite (overall adverse events, RR = 0.33, 95%CI: 0.13, 0.81; low certainty) 3.1.1 Recommendation statement LHQW granules/capsule shows important improvements in 3.1.3 Other considerations patient-important outcomes (the rate of conversion of severe cases, duration of symptoms recovery, and TCM symptom scores), Both LHQW granules and capsule are Class A medical insurance in can reduce the incidence of adverse events In China, LHQW China and are included in the National Essential Drug List of China and granules/capsule is Class A medical insurance drug with good Protection System for Varieties of TCM with good accessibility.34–37 accessibility The certainty of evidence is low to moderate There- Meanwhile, the Chinese National Medical Products Administration has fore, the panel suggested recommending the use of LHQW approved to include the treatment of COVID-19 in the drug indications granules/capsules strongly of LHQW granules and capsule.37 LHQW granules: g by mouth, three times per day LHQW capsule: capsules/time by mouth, three times per day for 7–14 days LHQW granules (capsule) is more suitable for COVID-19 patients with the syndrome of equal severity of dampness and heat LHQW granules is composed of lián qiào (Fructus Forsythiae), j¯ın yín hua¯ (Flos Lonicerae Japonicae), zhì má huáng (Herba Ephedrae 3.2 Clinical question 2: What is the impact of integrating Maxing Xuanfei Jiedu (MXXFJD) decoction and western medicine in the treatment of COVID-19? ˘ ku˘ xìng (Semen Armeniacae Praeparata cum Melle), chao ˘ lán gen Amarum) (fired), shí gao ¯ (Gypsum Fibrosum), ban ¯ (Radix Recommendation 2: we suggest integrating MXXFJD decoction and ˘ (Herba Houttuyniae), gu˘ang huò xiang Isatidis), yú x¯ıng cao ¯ (Herba western medicine to shorten the duration of symptoms recovery and Pogostemonis), dà huáng (Radix et Rhizoma Rhei), hóng j˘ıng tian ¯ improve the TCM symptom scores for moderate COVID-19 patients ˘ (Radix et Rhi(Radix et Rhizoma Rhodiolae Crenulatae), and gan ¯ cao (weak or conditional recommendation, low certainty evidence) zoma Glycyrrhizae).29 LHQW capsule is composed of lián qiào (Fructus Forsythiae), j¯ın yín 3.2.1 Recommendation statement hua¯ (Flos Lonicerae Japonicae), zhì má huáng (Herba Ephedrae ˘ lán gen Praeparata cum Melle), ban ¯ (Radix Isatidis), dà huáng MXXFJD decoction shows significant improvements in some ˘ (Radix et Rhizoma Glycyrrhizae), (Radix et Rhizoma Rhei), gan ¯ cao patient-important outcomes (the TCM symptom scores and dura- hóng j˘ıng tian ¯ (Radix et Rhizoma Rhodiolae Crenulatae), yú x¯ıng tion of symptoms recovery); however, no difference in the rate ˘ (Herba Houttuyniae), shí gao cao ¯ (Gypsum Fibrosum), mián ma˘ of conversion of severe cases No adverse reactions related to ˘ guàn zhòng(Dryopteridis crassirhizomatis rhizome), and bò he nao MXXFJD were found The certainty of the evidence is low In China, (Mentholum).29 MXXFJD decoction is Class B medical insurance drug with good MD = 0.48 scores (0.39, 0.57) MD = 0.28 scores (0.19, 0.37) MD = 1.10 scores (0.99, 1.21) MD = 1.40 scores (1.29, 1.51) MD = 0.37 scores (0.24, 0.50) MD = −0.46 ×109 /L (−0.55, −0.37) MD = −0.11×109 /L (−0.14, −0.08) MD = 1.88 mg/L (0.70, 3.06) MD = −0.19 ng/L (−0.20, −0.18) RR = 1.11 (1.01, 1.22) RR = 1.19 (1.03, 1.38) RR = 1.21 (1.02, 1.43) MD = −1.00 days (−1.17, −0.83) MD = −2.33 days (−2.88, −1.78) MD = −3.67 days (−0.42, −3.32) MD = −1.34 days (−1.96, −0.72) RR = 0.42 (0.19, 0.93) 147/148 (n = 1) 147/148 (n = 1) 147/148 (n = 1) 147/148 (n = 1) 147/148 (n = 1) 147/148 (n = 1) 147/148 (n = 1) 147/148 (n = 1) 147/148 (n = 1) 142/142 (n = 1) 142/142 (n = 1) 289/290 (n = 2) 142/142 (n = 1) 142/142 (n = 1) 142/142 (n = 1) 142/142 (n = 1) 142/142 (n = 1) Fever Fatigue Cough Dry throat and sore throat Chest tightness WBC LYM CSR PCT Rate of recovery at day 14 Rate of clinical recovery Chest CT manifestations Fever Fatigue Cough Diarrhea Adverse reaction Lowc,d Lowc,d Lowc,d Lowc,d Lowc,d Moderateb Lowc,d Lowc,d Lowb,d Lowb,d Lowb,d Lowb,d Lowb,d Lowb,d Lowb,d Lowb,d Lowb,d Moderateb Moderatea Quality of evidence I, Intervention group; C, Control group a Downgraded one level due to serious risk of bias (high or unclear risk of bias in random sequence generation, allocation concealment, blinding of participants and personnel, and funding resources) b Downgraded one level due to serious risk of bias (high or unclear risk of bias in allocation concealment, blinding of participants and personnel, and funding resources) c Downgraded one level due to serious risk of bias (high or unclear risk of bias in blinding of participants and personnel, and funding resources) d Downgraded one level due to serious imprecision (only included one study) / Time for nucleic acid conversion Duration of symptoms recovery Rate of recovery Inflammatory markers TCM symptom scores RR = 0.59 (0.37, 0.94) 289/290 (n = 2) / Rate of conversion of severe cases RR = 1.33 (1.06, 1.66) 177/178 (n = 2) / Effective rate Effect (estimates (95%CI)) Subgroup Sample sizeI/C (Number of study) Summary of evidence of integrating LHQW granules (capsule) and western medicine in the treatment of COVID-19 Outcomes TA B L E 322 GE ET AL 323 GE ET AL accessibility Comprehensively considering these factors, the panel indexes for mild and moderate COVID-19 patients (strong recommen- suggested recommending the use of MXXFJD decoction weakly dation, low certainty evidence) MXXFJD decoction: 150 ml by mouth, three times per day for 10 days MXXFJD decoction is more suitable for COVID-19 patients with the 3.3.1 Recommendation statement syndrome of external cold and internal heat MXXFJD decoction is composed of má huáng (Ephedrae Herba) QFPD decoction shows important improvements in patient- g, xìng (Armeniacae Semen Amarum) 12 g, shí gao ¯ (Gypsum important outcomes (the duration of symptoms recovery, time for Fibrosum) 15–30 g, zhè bèi muˇ (Fritillaria Thunbergii Bulbus) 12 g, nucleic acid conversion, and length of hospital stay) No adverse chán tuì (Cicadae Periostracum) 10 g, jiang cán (Bombyx Batry¯ reactions related to QFPD were found The certainty of the evi- ticatus) 15 g, jiang huáng (Curcumae Longae Rhizoma) 12 g, jié ¯ dence is low Although there is still a lack of RCTs for patients with ˇ (Platycodonis Radix) 12 g, zhˇı qiào (AurantiI Fructus) 12 g, cao geng ˇ mild and moderate COVID-19, the included observational study guoˇ (Tsaoko Fructus) g, and dòu kòu (Amomi Fructus Rotundus) indicates a large effect size In addition, the earlier the intervention 12 g.38 time, the better the effect The cost is low, and it is the only general therapeutic decoction for all stages of COVID-19 currently Considering all of these factors, the panel suggested strongly 3.2.2 Benefits and harms recommending using QFPD decoction in the early treatment QFPD decoction: one dose twice per day, once in the morning and Our living systematic review (SR) included one RCT38 involving 50 patients with moderate COVID-19; the results suggested that inte- once in the evening (40 minutes after dinner) by mouth, three doses for a course of treatment grating MXXFJD decoction and western medicine might significantly QFPD decoction is used for the COVID-19 patients characterized shorten the duration of symptoms recovery such as fever(MD = −1.68 as cold-dampness obstructing lung, and more suitable for COVID- days, 95%CI: −2.38, −0.98; low certainty) and cough (MD = −2.93 19 patients with the exterior syndrome of cold-dampness and pul- days, 95%CI: −4.02,−1.84; low certainty), improve the TCM symptom scores (MD = 5.99 scores, 95%CI: 3.61, 8.37; low certainty) There monary heat QFPD decoction is composed of má huáng (Herba Ephedrae) g, zhì were no significant differences on the improvement (RR = 2.50, 95%CI: ˘ (Radixet Rhizoma Glycyrrhizae Praeparata cum Melle) g, gan ¯ cao 0.53,11.70; low certainty), stability (RR = 0.94, 95%CI: 0.63,1.40; low xìng (Semen Armeniacae Amarum) g, sheng ¯ shí gao ¯ (Gypsum certainty) or lesion progression rate of chest CT (RR = 0.67, 95%CI: Fibrosum) 15–30 g (decocted first), guì zh¯ı(Ramulus Cinnamomi) 0.21, 2.08; low certainty), and the rate of conversion of severe cases g, zé xiè (Rhizoma Alismatis) g, zhu¯ líng (Polyporus) g, bái zhú (RR = 0.33, 95%CI: 0.01,7.81; low certainty) The study did not report (Rhizoma Atractylodis Macrocephalae) g, fú líng (Poria) 15 g, chái any adverse reactions related to MXXFJD hú (Radix Bupleuri) 16 g, huáng qín (Radix Scutellariae) g, jiang ¯ bàn According to the GRADE approach, all outcomes were downgraded xià (Rhizoma Pinelliae Praeparatum) g, sheng ¯ jiang ¯ (Rhizoma Zin- two levels because of serious risk of bias (allocation concealment and giberis Recens) g, zˇı wan ˇ (Radix et Rhizoma Asteris) g, kuan ˇ dong ¯ blinding) and imprecision (only one study with 50 patients or wide con- hua¯ (Flos Farfarae) g, shè gan ¯ (Rhizoma Belamcandae) g, xì x¯ın fidence interval/confidence interval crosses the null) (Radix et Rhizoma Asari) g, sh¯an yào (Rhizoma Dioscoreae) 12 g, zh˘ı shí (Fructus Aurantii Immaturus) g, chén pí (Pericarpium Citri Reticulatae) g, and huò xiang ¯ (Herba Agastachis) g.5 3.2.3 Other considerations MXXFJD decoction is Class B medical insurance in China and are 3.3.2 Benefits and harms included in the National Essential Drug List of China with good accessibility.34,35 Our living SR included one RCT39 involving 12 patients with severe COVID-19; the results suggested that days treatment of integrating QFPD decoction and western medicine might significantly shorten the 3.3 Clinical question 3: What is the impact of integrating Qingfei Paidu (QFPD) decoction and western medicine in the treatment of COVID-19? length of hospital stay (MD = −7.95 days, 95%CI: −14.66, −1.24; low certainty), improve the white blood cell count (MD = −4.47×109 /L, 95%CI: −7.12,−1.82; low certainty), partial pressure of carbon dioxide (MD = 8.86 mmHg, 95%CI: 3.23,14.49; low certainty), and partial Recommendation 3: we recommend the integration of QFPD decoc- pressure of oxygen (MD = −20.8 mmHg, 95%CI: −34.59,−7.01; low tion and western medicine in the early treatment (less than week certainty) The study did not report adverse reactions related to QFPD from the onset of symptoms) to shorten the duration of symptoms decoction recovery, the time for nucleic acid conversion, and the length of hos- Four retrospective studies40–43 involving 441 patients with pital stay, improve the inflammatory markers and the biochemical mild and moderate COVID-19, the results suggested that inte- 324 GE ET AL grating QFPD decoction and western medicine might significantly shorten the time for nucleic acid conversion41,42 (MD = −4.88 days, 95%CI: −5.29,−4.47; low certainty) and length of hospital stay40–43 3.4 Clinical question 4: What is the impact of integrating Xuebijing (XBJ) injection and western medicine in the treatment of COVID-19? (MD = −3.34 days, 95%CI: −5.48, −1.21; low certainty), improve the inflammatory markers,42 lymphocyte subsets indexes,42 and biochem- Recommendation 4: we suggest against the integration of XBJ injection and ical indexes40,42 (see Table 3) Included studies did not report adverse western medicine for mild and moderate COVID-19 patients (weak or con- reactions related to QFPD decoction ditional recommendation, very low certainty evidence) A retrospective multicenter cohort study5 addressed 782 patients with COVID-19 (91% were mild and moderate) According to the interval from the onset of symptoms to the initiation of the treat- 3.4.1 Recommendation statement ment with QFPD decoction, patients were divided into four groups: ≤1 week group, 1–2 weeks group, 2–3 weeks group, and >3 weeks XBJ injection shows slight improvements in the inflammatory mark- group The results indicated that compared with >3 weeks group, early ers and effective rate of lung CT absorption; however, the effects of treatment with QFPD decoction initiated after less than week, 1– patient-important outcomes are unclear The certainty of the evi- weeks, or 2–3 weeks is more likely to recover, with an adjusted dence is very low Therefore, the panel suggested against the use of hazard ratio (HR) of 3.81 (95%CI:2.65,5.48), 2.63 (95%CI:1.86,3.73), XBJ injection for mild and moderate COVID-19 patients and 1.92 (95%CI:1.34,2.75), respectively When QFPD decoction treatment was initiated less than week after the symptom appeared, the median course of the disease decreased from 34 to 24 days, 21 days, 3.4.2 Benefits and harms and 18 days (p < 0.0001) Compared with treatment in a later period, treatment within week was associated with a decrease in the length In an observational study53 involving 44 patients with moderate of hospital stay for 1–4 days (p < 0.0001) The study did not report COVID-19, the results suggested that integrating XBJ injection and adverse reactions related to QFPD decoction Since the early medica- western medicine might improve the effective rate of lung CT absorp- tion (within week) had a large effect on the improvement of patients’ tion (RR = 1.40, 95%CI: 1.04, 1.89; very low certainty), but there was no symptoms recovery, and the effect diminished with the delay of time, significant difference in the total effective rate of treatment (RR = 1.36, all outcomes were upgraded one level according to GRADE approach, 95%CI: 0.82, 2.26; very low certainty) There was no obvious adverse the certainty of the evidence is moderate reaction related to XBJ injection during treatment Seven retrospective studies44–50 involving 744 patients with mild, Our living SR included one RCT54 involving 22 patients with mild moderate, and severe COVID-19, compared the efficacy before and COVID-19; the results suggested that integrating XBJ injection and after treatment, and the results suggested that integrating QFPD western medicine might improve the LYM (MD = −0.53 ×109 /L, decoction and western medicine might significantly improve the TCM 95%CI: −0.80, −0.26; low certainty) and CRP (MD = 18.88 mg/L, symptom scores44,49 (MD = 41.48, 95%CI: 32.67,50.49; very low 95%CI: 9.33, 28.43; very low certainty), but there was no significant dif- certainty); increase the disappearance rate of clinical symptoms47 ference in the temperature returned to normal (MD = −0.08°C, 95%CI: such as fever (RR = 23, 95%CI: 1.5,353.64; very low certainty), sore −0.45, 0.29; very low certainty) throat (RR = 5.00, 95%CI: 1.35, 18.52; very low certainty), fatigue (RR = 1.59, 95%CI: 1.03,2.45; very low certainty), irritability and anxiety (RR = 2.08, 95%CI: 1.17, 3.68; very low certainty), and c-reactive 3.4.3 Other considerations protein (CRP)44–46,49 (MD = 20.00 mg/L, 95%CI: 15.90,24.11; very low certainty) XBJ injection is Class A medical insurance in China and are included in the National Essential Drug List of China with good accessibility.34 Meanwhile, Chinese National Medical Products Administration has 3.3.3 Other considerations approved to inclusion of the treatment of severe COVID-19 in the drug indications of XBJ.37 QFPD decoction has not been included in China medical insurance policy.51,52 QFPD decoction is the only general therapeutic decoction at present, which costs about 100 yuan (about $15) for a course of treatment in China.51 The Diagnosis and Treatment Protocol for Coronavirus Pneumonia (Trial version 8)52 recommends QFPD decoction for 3.5 Clinical question 5: What is the impact of integrating Xuanfei Baidu (XFBD) decoction and western medicine in the treatment of COVID-19? patients with mild, moderate, and severe COVID-19 in the clinical treatment period, and QFPD decoction can be used reasonably in the Recommendation 5: we suggest integrating XFBD decoction and west- treatment of critically ill patients according to actual conditions ern medicine to improve the cough symptom, CRP, and erythrocyte MD = −1.64 days (−1.91, −1.36) MD = −2.23 days (−2.46, −2.00) MD = −1.40% (−2.31, −0.49) MD = 10.17 pg/ml (8.47, 11.87) MD = −185.2×109/L (−208.71, −161.69) MD = 22.1×109/L (3.9, 40.3) MD = 24.8×109/L (12.91, 36.69) MD = 1.02×109/L (0.82, 1.22) MD = −11.64 U/L (−16.45, −6.82) MD = 1.12 U/L (0.25, 1.99) MD = 2.67μmol/L (2.05, 3.29) MD = −2.28% (−2.82, −1.74) MD = −0.35 g/L (−0.42, −0.28) MD = 0.99μg/L (0.65, 1.33) MD = 1.79 mg/L (0.79, 2.79) 30/30(n = 1) 30/30(n =(n = 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) 67/62(n = 2) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) Cough Chest CT NEU% IL-6 CD3 CD4 CD8 CD4/CD8 Creatine kinase (CK) Lactate dehydrogenase (LDH) Serum creatinine (sCr) Estimated glomerular filtration rate (eGFR) Fibrinogen (Fib) D-dimer (DD) Fibrinogen degradation products (FDP) I: Intervention group C: Control group a Downgraded one level due to serious risk of bias (high or unclear risk of bias in allocation concealment, blinding of participants, and personnel) b Downgraded one level due to serious imprecision (only including one study and/or small sample size) c Upgraded one level due to large effect Coagulation Biochemical indexes Immunocyte Inflammatory markers Duration of symptoms recovery MD = −1.51 days (−1.92, −1.09) 30/30(n = 1) / Time to antipyretic MD = −3.34 days (−5.48, −1.21) 110/102(n = 3) / Length of hospital stay MD = −4.78 days (−5.79, −3.77) 147/171 (n = 2) / Time for nucleic acid conversion RR = 1.26 (1.10, 1,43) 104/125(n = 1) / Rate of improvement of chest CT manifestations Effect (estimates (95%CI)) Subgroup Sample sizeI/C (Number of studies) Summary of evidence of integrating QFPD decoction and western medicine in the treatment of COVID-19 Outcomes TA B L E Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Very lowa,b Lowa,c Lowa,c Very lowa,b Quality of evidence GE ET AL 325 326 GE ET AL sedimentation rate (ESR) for mild and moderate COVID-19 patients disease.56 XFBD decoction has not been included in China medical (weak or conditional recommendation, very low certainty evidence) insurance policy.34,35 3.5.1 3.6 Clinical question 6: What is the impact of integrating JinHua Qinggan (JHQG) granules and western medicine in the treatment of COVID-19? Recommendation statement XFBD decoction is an effective prescription summarized in the first-line clinical treatment in Wuhan However, there was only one RCT with a small sample size shows important improvements in the Recommendation 6: we suggest integrating JHQG granules and west- cough symptom, CRP, and ESR The efficacy of patient-important ern medicine to improve the clinical symptoms such as fever and expec- outcomes is unclear The certainty of the evidence is very low toration, to increase the rate of nucleic acid conversion after days Based on its effectiveness in the fight against COVID-19 in Wuhan, for mild COVID-19 patients (weak or conditional recommendation, low the panel suggested recommending the use of XFBD decoction certainty evidence) weakly XFBD decoction: 200 ml one time, two times per day for week XFBD decoction is more suitable for COVID-19 patients with the 3.6.1 Recommendation statement syndrome of dampness and toxin stagnating the lung XFBD decoction is composed of má huáng (Ephedrae Herba) g, JHQG granules show important improvements in some patient- xìng (Armeniacae Semen Amarum) 15 g, Gypsum Fibrosum important outcomes (duration of symptoms recovery, rate of (sheng ¯ shí gao) ¯ 30 g, cang ¯ zhú (Atractylodis Rhizoma) 10 g, yì yˇı nucleic acid conversion after days), and is Class B medical insur- (Semen Coicis) 30 g, huò xiang ¯ (Agastachis Herba) 15 g, huˇ zhàng ance drug in China with good accessibility However, the incidence (Polygoni Cuspidati Rhizoma et Radix) 20 g, tíng lì zˇı (Lepidii seu of diarrhea is high, and the certainty of the evidence is low to very Descurainiae Semen) 15 g, maˇ bian ¯ cao ˇ (Verbenae Herba) 30 g, lú low Comprehensively considering these factors, the panel sug- gen ¯ (Phragmitis Rhizoma) 30 g, q¯ıng hao ¯ (Artemisiae Annuae Herba) gested recommending the use of JHQG granules weakly 25 g, jú hóng (Citri Grandis Rubrum Exocarpium) 20 g, and sheng ¯ gan ¯ JHQG granules: 10 g by mouth, two times per day for days cao ˇ (Glycyrrhizae Radix et Rhizoma) 10 g No evidence documented which syndrome differentiation is more suitable for the JHQG granules JHQG granules is composed of j¯ın yín hua¯ (Lonicera Japonicae Flos), 3.5.2 Benefits and harms ˘ ku˘ shí gao ¯ (Gypsum Fibrosum), má huáng (Ephedrae Herba), chao xìng (Semen Armeniacae Amarum) (fired), huáng qín (Radix Our living SR included one RCT55 involving 42 patients with mild Scutellariae), lián qiào (Fructus Forsythiae), zhè bèi muˇ (Fritillaria and severe COVID-19; the results suggested that integrating XFBD Thunbergii Bulbus), zh¯ı muˇ (Anemarrhe Naerhizoma), niú bàng zˇı decoction and western medicine could improve the cough symptom (Arctii Fructus), q¯ıng hao ¯ (Artemisiae Annuae Herba), bò he (Men- (RR = 1.97, 95%CI: 1.04, 3.72; low certainty), CRP (RR = 2.83, 95%CI: thae Haplocalyis Herba), and gan ¯ cao ˇ (Glycyrrhizae Radix et Rhi- 1.32, 6.09; very low certainty), and ESR (RR = 2.25, 95%CI: 1.16,4.35; zoma) very low certainty), but there was no significant difference in the disappearance rate of clinical symptoms, such as fever, fatigue, loss of appetite, shortness of breath, chest tightness, insomnia, pharyngalgia, 3.6.2 Benefits and harms chill, headache, nausea, vomiting, and diarrhea There was no obvious adverse reaction related to XFBD decoction during treatment Accord- Our living SR included one RCT57 involving 123 patients with mild ing to the GRADE approach, all outcomes were downgraded three lev- COVID-19; the results suggested that integrating JHQG and western els because of serious risk of bias (allocation concealment and blind- medicine could shorten the duration of symptoms recovery, such as ing), indirectness (unclear proportion of patients with mild and moder- fever(RR = 1.51, 95%CI: 1.07, 2.14; low certainty) and expectoration ate COVID-19), and imprecision (only one study with 42 patients and (RR = 1.85, 95%CI: 1.01, 3.38; low certainty), however, the incidence of wide confidence interval/confidence interval crosses the null) diarrhea in the treatment group was higher than in the control group (RR = 27.83, 95%CI: 1.74, 445.11; very low certainty), which might be explained by the use of high doses of JHQG granules 3.5.3 Other considerations One observational study58 involving 80 patients (65 mild and 15 severe) with COVID-19, the results suggested that integrating JHQG As an effective prescription summarized according to clinical obser- granules (6 g by mouth, two times per day) and western medicine could vation in the first-line clinical treatment in Wuhan, XFBD decoction shorten the time for nucleic acid conversion (MD = −3.00 days, 95%CI: shows an important clinical effect in blocking the development of −4.76, −1.24; very low certainty) and the time to pneumonia recov- disease, improving symptoms, especially in shortening the course of ery (MD = −2.00 days, 95%CI: −4.02, 0.02; very low certainty), and 327 GE ET AL increase the rate of nucleic acid conversion after days (RR = 2.05, 3.7.3 Other considerations 95%CI: 1.14, 3.68; low certainty) LHQK granules has not been included in China medical insurance policy.34,35 3.6.3 Other considerations JHQG granules is Class B medical insurance in China, and are included in the National Essential Drug List of China with good accessibility.34,35 Meanwhile, the Chinese National Medical Products Administration has 3.8 Clinical question 8: What is the impact of integrating TJQW granules and western medicine in the treatment of COVID-19? approved to include the treatment of COVID-19 in the drug indications of JHQG granules.37 Recommendation 8: we suggest integrating TJQW granules and western medicine to shorten the length of hospital stay, improve the TCM symptom score, the effective rate, and the inflammatory markers for 3.7 Clinical question 7: What is the impact of integrating LianHua QingKe (LHQK) granules and western medicine in the treatment of COVID-19? mild and moderate COVID-19 patients (weak or conditional recom- Recommendation 7: we suggest against the integration of LHQK granules 3.8.1 mendation, low certainty evidence) Recommendation statement and western medicine for mild and moderate COVID-19 patients (weak or conditional recommendation, very low certainty evidence) TJQW granules show an important improvement in some patient-important outcomes (length of hospital stays and TCM symptom scores), no adverse reactions related to TJQW 3.7.1 Recommendation statement were found The certainty of the evidence is low The panel suggested recommending the use of TJQW granules LHQK granules may improve the cough and expectoration symptoms, oxygen index, and rate of recovery of chest CT weakly TJQW granules: one dose per day, two times per day for 10–15 manifestations; however, no significant difference in improving the rate of conversion of severe cases The certainty of days, days as a course of treatment TJQW granules is suitable for COVID-19 patients with the the evidence is very low Considering the potential conflicts pathogen in lung-defence syndrome with dampness of interest of this study and the lack of relevant evidence, the TJQW granules is composed of lián qiào (Fructus Forsythiae) panel suggested against the use of LHQK granules for mild and 30 g, sh¯an cí gu(Cremastrae Pseudobulbus Pleiones Pseu¯ moderate COVID-19 patients dobulbus) 20 g, j¯ın yín hua¯ (Flos Lonicerae Japonicae) 15 g, huáng qín (Radix Scutellariae) 10 g, dà q¯ıng yè (Isatidis ˇ chái hú (Bupleuri Radix) g, q¯ıng hao Folium) 10 g, bei ¯ 3.7.2 Benefits and harms (Artemisiae Annuae Herba) 10 g, chán tuì (Cicadae Periostracum) 10 g, qián hú (Peucedani Radix) g, chuan ¯ bèi muˇ Our living SR included one RCT59 involving 57 patients with mild (Fritilariae Cirrhosae Bulbus) 10 g, zhè bèi muˇ (Fritillaria and moderate COVID-19; the results suggested that integrat- Thunbergii Bulbus) 10 g, fú líng (Poria) 30 g, wu¯ méi (Mume ing LHQK granules and western medicine shows no signifi- Fructus) 30 g, xuán shen ¯ (Scrophulariae Radix) 10 g, huáng cant difference in improving the rate of conversion of severe qí (Astragali Radix) 30 g, and tài zˇı shen ¯ (Pseudostellariae cases (RR = 0.16, 95%CI: 0.01, 3.14; very low certainty), but Radix) 15 g.12 could improve the cough symptom (RR = 1.42, 95%CI: 1.03, 1.93; very low certainty), expectoration symptom (RR = 1.66, 95%CI: 1.04, 2.64; very low certainty), the rate of recovery of 3.8.2 Benefits and harms chest CT manifestations (RR = 1.35, 95%CI: 1.05, 1.37; very low certainty), and oxygenation index (RR = 2.21, 95%CI: 1.03, Our living SR included four RCTs12,60–62 involving 303 patients with 4.78; very low certainty) The study did not report adverse mild and moderate COVID-19; the results suggested that integrating reactions related to LHQK Since the LHQK granules used in TJQW granules and western medicine might significantly shorten the this RCT was provided by the drug manufacturer, and the core length of hospital stay,60–62 improve the effective rate,60,61 inflamma- author of this study was also from the manufacturer, and the tory markers,12,60,62 and TCM symptom scores such as fever, cough, study did not state the role of the manufacturer in the study and dry throat and throat pain.12,60 GRADE assessment details and design, implementation, and report Accordingly, there might other outcomes are shown in Table No adverse reactions related to be a potential conflicts of interest in this study TJQW were found in the included studies 328 GE ET AL Other considerations TJQW granules has not been included in China medical insurance Lowb,c Lowb,c Lowa,c Lowa,c Lowa,c Lowa,c Lowa,c Lowa,c Lowb,c Lowa,c Quality of evidence 3.8.3 policy.34,35 I, Intervention group; C, Control group a Downgraded one level due to serious risk of bias (high or unclear risk of bias in random sequence generation, allocation concealment, blinding of participants and personnel) b Downgraded one level due to serious risk of bias (allocation concealment, blinding of participants and personnel) c Downgraded one level due to serious imprecision (small sample size) MD = −26.50 U/L (−53.35, 0.35) 55/43 (n = 2) / Lactate dehydrogenase (LDH) MD = 3.95% (2.76, 5.14) 32/33 (n = 1) NEU% MD = 7.74 mg/L (5.92, 9.55) 69/69 (n = 2) CSR MD = −2.12% (−0.45, −0.19) 69/69 (n = 2) LYM MD = −0.44×109 /L (−0.64, −0.25) 69/69 (n = 2) WBC Inflammatory markers MD = 0.53 scores (0.36, 0.70) 69/69 (n = 2) Dry throat and sore throat MD = 1.13 scores (0.81, 1.44) 69/69 (n = 2) Cough MD = 0.65 scores (0.48, 0.81) 69/69 (n = 2) Fever TCM symptom scores MD = −2.51days (−4.98, −0.04) 55/43 (n = 2) / Length of hospital stay RR = 1.31(1.11, 1.56) 69/69 (n = 2) / Effective rate Sample sizeI/C (Number of studies) Subgroup Outcomes TA B L E Summary of evidence of integrating TJQW granules and western medicine in the treatment of COVID-19 Effect (estimates (95%CI)) 3.9 Clinical question 9: What is the impact of integrating JiaWei DaYuan (JWDY) decoction and western medicine in the treatment of COVID-19? Recommendation 9: we suggest integrating JWDY decoction and western medicine to shorten the duration of symptoms recovery, improve the lung CT condition, and the inflammatory makers for moderate COVID-19 patients (weak or conditional recommendation, low certainty evidence) 3.9.1 Recommendation statement JWDY decoction shows significant improvement in the duration of symptoms recovery and inflammatory makers No adverse reactions related to JWDY were found However, the effect of other important outcomes is unclear The certainty of the evidence is low The panel suggested recommending the use of JWDY decoction weakly JWDY decoction: one dose per day by mouth, three times a day JWDY granules (capsule) is more suitable for COVID-19 patients with the syndrome of epidemic toxin blocking the lung JWDY decoction is composed of zhì má huáng (Herba Ephedrae Praeparata cum Melle) 10 g, xìng (Semen Armeniacae Amarum) 15 g, sheng shí gao ¯ ¯ (Gypsum Fibrosum) 20 g, gu¯a lóu pí (Trichosanthis Pericarpium)20 g, jiuˇ dà huáng (Rhubarb Extract) g, tíng lì zˇı (Lepidii seu Descurainiae Semen) 10 g, táo (Persicaese Men) 10 g, cao ˇ guoˇ (Tsaoko Fructus) g, b¯ıng láng (Arecae Semen) 10 g, and cang ¯ zhú (Atractylodis Rhizoma) 10 g 3.9.2 Benefits and harms Our living SR included one RCT63 involving 45 patients with moderate COVID-19, the results suggested that integrating JWDY decoction and western medicine might significantly shorten the duration of symptoms recovery, such as fever (MD = −2.52 days, 95%CI: −3.30, −1.74; low certainty), cough (MD = −2.52 days, 95%CI: −3.30, −1.74; low certainty), fatigue (MD = −2.35 days, 95%CI: −2.91, −1.79; low certainty), chest tightness and wheezing (MD = −2.48 days, 95%CI: −3.10, −1.86; low certainty), bloating and constipation (MD = −2.23 days, 95%CI: −2.78, −1.68; low certainty), and tongue characteristics (MD = −3.19 days, 95%CI: −3.86, −2.52; low certainty), improve the lung CT condition (RR = 2.51, 95%CI: 1.06, 5.95; low certainty), the inflammatory 329 GE ET AL indicators such as LYM (%) (MD = 14.90 %, 95%CI: 10.43, 19.37; low time constraints, and the lack of clinical evidence of TCMs, including certainty) and CRP (MD = −6.88 mg/L, 95%CI: −8.05, −5.71; low cer- “Three Medicines and Three Prescriptions”64 (LHQW granules/capsule, tainty) XBJ injection, JHQG granules, QFPD decoction, XFBD decoction, and The intervention group of included RCT showed no abnormal condi- Huashi Baidu Formula) recommended by many clinicians, we cannot tion related to JWDY decoction in blood routine examination, liver and fully consider all clinical questions for this acute infectious disease kidney function, and other laboratory examinations In particular, the Huashi Baidu Formula has shown obvious benefit in the frontline of the fight against the COVID-19 pandemic However, we did not include it in this version of the guideline because 3.9.3 Other considerations of the lack of direct evidence For other TCMs included in the “Three Medicines and Three Prescriptions,” we reached weak recommendations JWDY decoction has not been included in China medical insurance for JHQG granules and XFBD decoction Third, since the patients of policy.34,35 included studies were classified according to the diagnosis standard of western medicine (mild, moderate, severe, or critical), we only showed the corresponding TCM dialectical classification and could not obtain DISCUSSION more information on TCM symptoms Fourth, based on the consensus of expert group, the first version of this living guideline only focused The development of this living guideline was based on the best cur- on mild and moderate COVID-19 patients Accordingly, recommen- rently available direct evidence, aimed to provide timely clinical prac- dations related to severe COVID-19 were not included; for example, tice guidance, which made recommendations of integrating Chinese although we recommended against XBJ injection for the mild and mod- and western medicine used for mild and moderate COVID-19 patients erate COVID-19 patients, XBJ injection has been approved for the This living guideline, based on western medicine support treatment treatment of severe and critical COVID-19 patients by the National such as oxygen therapy, antiviral medications, antimicrobial medica- Medical Products Administration.65 The present recommendations were tions, or symptomatic therapies, strongly recommended LHQW gran- mainly based on RCT evidence, supplemented by observational stud- ules (capsule) and QFPD decoction; weakly recommended MXXFJD ies Therefore, some Chinese medicines that only were assessed in the decoction, XFBD decoction, JHQG granules, TJQW granules, and design of the observational study were not included in this version of JWDY decoction; recommended against XBJ injection and LHQK gran- the living guideline We will consider them in the updated versions We ules for the treatment of mild and moderate COVID-19 Considering may also consider enlarging the range of inclusion criteria, if more evi- the rapidly evolving evidence landscape, we suggested that western dences have shown the benefit of adopting Chinese medicine alone in medicine treatment should follow the latest guidelines of Diagnosis the treatment of mild or moderate COVID-19 In addition, the courses and Treatment of COVID-19 of these recommendations were based on currently available evidence; Our recommendations were developed with some strength First, in therefore, we suggest rational use in combination with clinical practice the linked systematic review, we conducted a series of meta-analyses Future research should focus on: (1) patient-important outcomes of of RCTs to adopt different clinical questions and rated the certainty of all TCMs used for COVID-19 patients using well-designed prospective evidence with GRADE approach Meanwhile, to enhance the evidence studies, especially some TCMs that are recognized to have good effi- base of supporting recommendations, we searched observational stud- cacy, such as “Three Medicines and Three Prescriptions.” (2) The effect for ies as a supplementary evidence for the interventions identified by a specific population such as children, pregnant, and perinatal women RCTs Second, we recruited 38 multidisciplinary experts to support (3) The effect differences of different TCM syndrome differentiation the development of this guideline Of them, all clinicians were partic- (4) Economic burden and accessibility of integrating Chinese and west- ipating in the frontline of the fight against the COVID-19 in Wuhan ern medicine in the whole course of treatment Third, the COVID-19 pandemic continues to spread globally; a living evidence-based guidance of the prevention and treatment of COVID- ACKNOWLEDGMENTS 19 is extremely important; our living guideline can fill this gap Fourth, We thank McMaster University in Canada for conducting evidence based on AGREE II and RIGHT statements, we assessed the quality retrieval and literature screening to identify randomized trials of of our guideline by three reviewers and found that the scores of six traditional Chinese medicine We thank Prof Youping Li (Chinese domains of AGREE II were as follows: 87.04% for domain (Scope and Evidence-based Medicine Center, West China Hospital, Sichuan Uni- purpose), 70.37% for domain (Stakeholder involvement), 84.03% for versity) for her constructive suggestions and supports during the domain (Rigor of development), 90.74% for domain (Clarity of pre- development of guideline This guideline was funded by National sentation), 98.15% for domain (Applicability), and 94.44% for domain Key R&D Program, China National Centre for Biotechnology Devel- (Editorial independence) opment (No.2019YFC1709805/2019YFC1709802) and the State However, this guideline also has some limitations First, most of the Key Laboratory of Dampness Syndrome of Chinese Medicine (NO evidence was low certainty, and the patient-important outcomes were ZH2019ZZ04/NO.SZ2020ZZ09) The funding is mainly used to pay reported seldom Therefore, we made weak or conditional recommen- for travel expenses and expert consultation expenses in the process of dations for most of the recommendations Second, due to resource and preparing the guideline 330 GE ET AL CONFLICTS OF INTEREST The guideline development was initiated by the international Trustworthy traditional Chinese Medicine Recommendations (TCM Recs) Working Group Guangdong Provincial Hospital of Chinese Medicine, Evidence-Based Medicine Centre of Lanzhou University, and Tianjin University of Traditional Chinese Medicine led the guideline development following the universal methodology by reaching the final consensus based on the latest research evidence and multidisciplinary expert opinions Every guideline panel member has completed the TCM Recs interest disclosure form Hongcai Shang and Yongan Ye participated in the G-CHAMPS Study, Xiuhui Li, Xianbo Wang, and Wenguang Xia published studies of TCM for COVID-19 which did not involve in the present guideline Zhongde Zhang published a retrospective study on effect and safety of Chinese herbal medicine granules in patients with severe COVID-19, which is ineligible with the population of the present guideline Rongmeng Jiang declared his participant in the Notice on Diagnosis and Treatment Protocol for Coronavirus Pneumonia (Trial version 1–8) of China, after discussion, the steering committee decided that he could participate in consensus voting Wensheng Qi and Yang Chen declared that their participation in the studies of COVID-19 is irrelevant with treatment Qun Liang declared that she participated in a guideline for the treatment of COVID-19 with integrated traditional Chinese and western medicine, and published a study on the treatment of COVID-19 with QFPD granules, however, the guideline and study have not been published In addition, Xinghua Tan declared that he has published clinical studies related to Toujie Quwen granules, therefore, we did not count his voting for the relevant recommendation The TCM Recs judged that no panel member had any financial conflicts of interest Professional and academic interests are minimized as much as possible Besides, we declare that the guideline will not be disseminated for commercial promotions ORCID Long Ge https://orcid.org/0000-0002-3555-1107 REFERENCES WHO WHO Coronavirus Disease (COVID-19) Dashboard https:// covid19.who.int/2021 Siemieniuk R, Rochwerg B, Agoritsas T, et al A living WHO guideline on drugs for covid-19 BMJ 2020;370:m3379 Siemieniuk RA, Bartoszko JJ, Ge L, et al Drug treatments for covid-19: living systematic review and network meta-analysis BMJ 2020;370:m2980 Luo H, Gao Y, Zou J, et al Reflections on treatment of COVID-19 with traditional Chinese medicine Chin Med 2020;15:94 Shi N, Liu B, Liang N, et al Association between early treatment with Qingfei Paidu decoction and favorable clinical outcomes in patients with COVID-19: a 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= 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1) 43/46(n = 1). .. Y, Yuan Y, et al Efficacy and safety of herbal medicine (Lianhuaqingwen) for treating COVID- 19: a systematic review and metaanalysis Integr Med Res 2021; 10 (1): 100644 Liu M, Gao Y, Yuan Y, et al