key: cord-0770800-rteysj8j authors: Liu, Ming; Gao, Ya; Yuan, Yuan; Yang, Kelu; Shi, Shuzhen; Zhang, Junhua; Tian, Jinhui title: Efficacy and Safety of Integrated Traditional Chinese and Western Medicine for Corona Virus Disease 2019 (COVID-19): a systematic review and meta-analysis date: 2020-05-11 journal: Pharmacol Res DOI: 10.1016/j.phrs.2020.104896 sha: 9520fb2dad004a2905b08047768bab315ff57890 doc_id: 770800 cord_uid: rteysj8j COVID-19 has now spread to all parts of the world and almost all countries are battling against it. This study aimed to assess the efficacy and safety of Integrated Traditional Chinese and Western Medicine (Hereinafter referred to as “Integrated Medicine”) to corona virus disease 2019 (COVID-19). We searched six major Chinese and English databases to identify randomized controlled trials (RCTs) and case-control studies (CCSs) of Integrated Medicine on COVID-19. Two reviewers independently screened, identified studies, and extracted data. Cochrane Risk of Bias tool and the Newcastle-Ottawa Scale were used to assess the quality of included RCTs and CCSs, respectively. Stata (version 13.0; StataCorp) was used to perform meta-analyses using the random-effects model. Risk ratio (RR) was used for dichotomous data while the weighted mean difference (WMD) was adopted for continuous variables as effect size, respectively, both of which were demonstrated in effect size and 95% confidence intervals. A total of 11 studies were included. Four were RCTs and seven were CCSs. The samples of including studies ranged from 18 to 100 (total 982). The traditional Chinese medicine included Chinese medicine compound drugs (QingFei TouXie FuZhengFang) and Chinese patent medicine (such as Shufeng Jiedu Capsule, Lianhua Qingwen granules). Compared with the control group, the overall response rate [RR = 1.230, 95%CI (1.113, 1.359), P = 0.000], cure rate [RR = 1.604, 95%CI (1.181, 2.177), P = 0.002], severity illness rate [RR = 0.350, 95%CI (0.154, 0.792), P = 0.012], and hospital stay [WMD = -1.991, 95%CI (-3.278, -0.703), P = 0.002] of the intervention group were better. In addition, Integrated Medicine can improve the disappearance rate of fever, cough, expectoration, fatigue, chest tightness and anorexia and reduce patients’ fever, and fatigue time (P < 0.05). This review found that Integrated Medicine had better effects and fewer adverse drug reactions for COVID-19. More high-quality RCTs will be needed in the future. against it. This study aimed to assess the efficacy and safety of Integrated Traditional Chinese and Western Medicine (Hereinafter referred to as "Integrated Medicine") to corona virus disease 2019 . We searched six major Chinese and English databases to identify randomized controlled trials (RCTs) and case-control studies (CCSs) of Integrated Medicine on COVID-19. Two reviewers independently screened, identified studies, and extracted data. Cochrane Risk of Bias tool and the Newcastle-Ottawa Scale were used to assess the quality of included RCTs and CCSs, respectively. Stata (version 13.0; StataCorp) was used to perform meta-analyses using the random-effects model. Risk ratio (RR) was used for dichotomous data while the weighted mean difference (WMD) was adopted for continuous variables as effect size, respectively, both of which were demonstrated in effect size and 95% confidence intervals. A total of 11 studies were included. Four were RCTs and seven were CCSs. The samples of including studies ranged from 18 to 100 (total 982). The traditional Chinese medicine included Chinese medicine compound drugs (QingFei TouXie FuZhengFang) and Chinese patent medicine (such as Shufeng Jiedu Capsule, Lianhua Qingwen granules). Medicine can improve the disappearance rate of fever, cough, expectoration, fatigue, chest tightness and anorexia and reduce patients' fever, and fatigue time (P<0.05). This review found that Integrated Medicine had better effects and fewer adverse drug reactions for COVID-19. More high-quality RCTs will be needed in the future. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f As a member of coronavirus subfamily Coronaviridae, the coronavirus can infect human beings, many kinds of mammals and birds. Some coronavirus can spread between humans, livestock, and poultry. In December 2019, many cases of Novel Coronavirus Pneumonia China has been gradually controlled, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Traditional Chinese Medicine (TCM) has a history of thousands of years and has saved the Chinese from major infectious diseases on many occasions. Now, TCM has been practiced worldwide. During the SARS epidemic in 2003, TCM played a huge role [6] [7] [8] . belongs to the category of "Pestilence" in TCM. Its main clinical manifestations are fever , 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 fatigue, dry cough, and the disease is situated in the lung and related to the spleen, stomach, and heart. Like during the SARS period, TCM played a major role in the "Fight against the Pestilence in China", saving many people's lives [5, 9, 10] . There is now evidence that compared with the simple treatment of Western Medicine; Integrated Traditional Chinese and Western Medicine (Hereinafter referred to as "Integrated Medicine") for COVID-19 may have better effects [11] [12] [13] [14] [15] . However, these studies have small sample sizes, and no convincing evidence is available to demonstrate the benefits and risks of Integrated Medicine for COVID-19. This study summarized controlled trials and methods of Integrated Medicine treatment of COVID-19, including the changes of clinical symptoms. The secondary outcome is the changes of laboratory indicators and the safety of Integrated Medicine of COVID-19. This meta-analysis was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [16] . In addition, because this study is linked to TCM, we also performed according to some other reporting guidelines [17] [18] [19] . The protocol for this study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42020177097). A pre-developed search strategy was used to identify all relevant clinical trials, regardless of languages or types of publication (excluded unpublished). We searched the following six Chinese medicine", "Western medicine", "Integrated traditional Chinese and Western medicine", "novel coronavirus pneumonia", "2019-nCoV", "COVID-19", "SARS-CoV-2" and "NCP". The search strategy of the PubMed database is presented in Appendix Table 1 . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f further assessment. Finally, resolve any differences through discussion between two reviewers or consultation with a third reviewer. A pre-formed data form was used to extract the relevant information, such as the author, journal, study type, study location, study time, interventions, the dose of drugs, outcomes. Primary outcomes including the changes of clinical symptoms, such as cure rate, total effective rate, nausea disappearance rate, fever disappearance rate and fatigue disappearance rate. Second outcomes including the changes of laboratory indicators and the safety of Integrated Medicine of COVID-19, such as CRP, TNF-α, WBC count, Liver damage and Diarrhea. The Risk of Bias (RoB) assessment tool from the Cochrane Handbook was used to assess the methodological quality of RCTs [20] , and the Newcastle-Ottawa Scale (NOS) was used to assess the quality of CCSs [21] . Each RCT was assessed at low risk, high risk, or unclear risk relating to the following items: sequence generation, allocation concealment, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. The NOS assesses the quality of CCSs with eight questions in three broad categories: (1) patient selection; (2) comparability of study groups; (3) assessment of the outcome. The total score is 9, the higher the score, the better the quality of the study. Two reviewers independently completed the data extraction and quality assessment. Any disagreement between reviewers was resolved by discussion or consultation with a third reviewer . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 Stata (version 13.0; StataCorp) was used to perform the statistical analysis. Risk ratio (RR) was used for dichotomous data while weighted mean difference (WMD) was adopted for continuous variables as effect size, respectively, both of which were demonstrated with effect size and 95% Confidence Intervals (CI). Considering heterogeneity of drugs used in different trials, we calculated all results based on the random effect model. We assessed statistical heterogeneity in each pairwise comparison with I 2 statistic, and value of <25%, 25-50%, and >50% considered as low, moderate, and high level of heterogeneity, respectively [22] . We would perform subgroup analyses and sensitivity analyses to explore sources of heterogeneity if enough data were available. The Egger's test and funnel plots were used to detect the potential publication bias if the number of included trials was larger than ten for an outcome. Statistical significance was set at P<0.05. Figure 1 showed the study selection process. A total of 11 studies were included in our study. All the articles were published by Chinese, among them, four studies were RCTs [12, [23] [24] [25] and seven were CCSs [11, 12, [26] [27] [28] [29] [30] . The detail of these studies is shown in Table 1 . Except for two studies that did not provide the range of study time [23, 24] , the study time was from January 01, 2020 to March 02, 2020. The samples of the included studies ranged from 18 to 100 (total 982). The duration of treatment ranges from 5 to 30 days, with an average of 13.55 days. Two studies did not 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f provide specific Chinese medicine compound drugs and Chinese patent medicine [11, 13] . One studies intervention groups were Chinese medicine compound drugs (QingFei TouXie FuZhengFang) [24] . And the other studies were Chinese patent medicine (such as Shufeng Jiedu Capsule, Lianhua Qingwen granules). The drugs used in the control group were Lopinavir, Ribavirin, Arbidol and et al. The RoB of the included RCTs is shown in Table 2 [12, [23] [24] [25] . Fours RCTs described the adequate random sequence generation process, but only one RCT [25] described the methods used for allocation concealment. Only one RCT [25] described the blinding of participants and personnel and blinding of outcome assessment (High risk), and none described how the incomplete outcome data were processed and reported selective outcome reporting. Overall, the quality of the included RCTs was low. Seven CCSs were assessed for quality by the NOS [11, 13, [26] [27] [28] [29] [30] . The maximum quality score is 9 and the range of scores was 3 to 7 (Table 3) , with a median of 6 (5.4±1.4). Only one study did not report the Case Definition [13] , and all study report the Definition of Controls and Comparability of Cases and Controls [11, 13, [26] [27] [28] [29] [30] . None of the studies were reported Representativeness of the Cases and Selection of Controls [11, 13, [26] [27] [28] [29] [30] . The reporting for exposure was better, but only one study reported Non-Response Rate [30] . These studies showed a moderate quality sufficient to conduct a meta-analysis. We The common Adverse Drug Reactions of Integrated Medicine were Nausea and Vomit, Diarrhea, Liver damage, and reduced blood cell count. As showed in Table 6 , there was no significant difference in the Adverse Drug Reactions caused by the two different interventions (P>0.05). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Results of the subgroup analysis of the Chinese medicine compound drugs and Chinese patent medicine for the primary outcome were shown in Appendix Since the number of studies in any comparative analysis did not exceed ten, we did not conduct a risk assessment of publication bias . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 to Critical [11, 24] . However, the use of these traditional herbs has been controversial due to unclear composition and lack of scientific evidence [32] . In our study, we found that the quality of these studies was low. In the treatment of many diseases, TCM is only used as 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 adjuvant therapy [33, 34] . So, standard treatment and outcome index need to be developed. In this way, the best evidence can be systematically reviewed, summarized and disseminated to better provide evidence-based TCM decision-making. TCM is superior to western medicine in improving the symptoms and quality of life of patients. This study found that Integrated Medicine can improve the disappearance rate of fever, cough, expectoration, fatigue, chest tightness and anorexia and reduce patients' fever, and fatigue time. This is related to TCMs can affect immune cells and cytokine production associated with immune responses [35] . Immune regulation maintains the homeostasis of the immune system, protects the body from sources of infection or other harmful substances, thereby alleviating the clinical symptoms. It is essential for normal health. However, we found that the outcome indicators were not uniform in the included studies. This situation is dangerous and increases the waste of research resources, may cause some ineffective or adverse interventions to be applied clinically [36] . The diversity of outcome indicators also exists in the laboratory indicators and the adverse reaction indicators. Although we found that the Integrated Medicine may change the inflammation index and have fewer adverse drug reactions than western medicine. But these are not enough, we found that many important indicators cannot be analyzed due to outcome indicators were not uniform. Such as Erythrocyte Sedimentation Rate, each Interleukin type, Macrophage ratio [13, 24] . As a new kind of respiratory disease, COVID-19 has many unknown factors to be solved. We found that included studies had a short duration, the ranges from 5 to 30 days. COVID-19 is likely to require a longer period of follow-up. In this way, the efficacy and possible adverse drug reaction of COVID-19 can be better observed. Besides, adverse events should be 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 monitored through standardized and effective reporting systems, and some serious adverse events should be observed through epidemiological studies [37, 38] . However, this study also has the following limitations. The TCM and Western Medicine used in the intervention group and the control group is different. But we did not perform subgroup analysis or sensitivity analysis. And many merger statistical analysis studies have more heterogeneity. In addition, most of the included trials had flaws in the methodological design, including randomization, concealment of allocation, and inadequate reports on blinding, withdrawal, and sample size estimates. We also tried to contact the authors who participated in the trial for detailed information; however, we did not get a response at the end. Above all, COVID-19 is a sudden outbreak disease. There are difficulties for clinicians to conduct RCTs, especially in the acute or critical period. So we included both RCTs and CCTs in this study. Therefore, some high-quality RCTs are needed to evaluate the effect of Integrated Medicine for COVID-19. The study results showed that compared with Western Medicine, the Integrated Medicine for COVID-19 has better effects and fewer Adverse Drug Reactions. However, due to the low number of included studies, low quality, and inadequate methodologies, high-quality RCTs are needed to evaluate the effect of Integrated Medicine for COVID-19. Acknowledge: None . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Clinical experience of treating SARS in Guangdong hospital of TCM Some research clues on Chinese herbal medicine for SARS prevention and treatment On the rational exertion for the prescriptions and drugs of TCM in prevention and treating SARS To explore the value of Chinese medicine in the treatment of COVID-19 from the perspective of Treatment of COVID-19 by Pneumonia No.1 Prescription and Pneumonia No.2 Prescription Clinical study on 34 cases of COVID-19 treated by integrated Chinese and western medicine Clinical study on 37 cases of COVID-19 treated by integrated Chinese and western medicine Clinical observation of 49 cases of non-critical COVID -19 treated by integrated traditional Chinese and western medicine in Shanghai Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2) Traditional Chinese medicine for COVID-19 treatment Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement The methodological and reporting quality of systematic reviews from China and the USA are similar Network meta-analyses could be improved by searching more sources and by involving a librarian The reporting characteristics and methodological quality of Cochrane reviews about health policy research The Cochrane Collaboration's tool for assessing risk of bias in randomised trials The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomised studies in metaanalysis Measuring inconsistency in meta-analyses Clinical value of glycyrrhizinate in the treatment of patients with common new coronavirus pneumonia Clinical Effect and Mechanism of Qingfei Touxie Fuzheng Recipe in the Treatment of Novel Coronavirus Pneumonia Clinical Observation of Jinhua Qinggan Granule in Treating Pneumonia Infected by New Coronavirus Observation on the clinical effect of Shufeng Jiedu Capsule combined with Arbidol Hydrochloride Capsules in the treatment of COVID-19 Retrospective Clinical Analysis on Treatment of Novel Coronavirus-infected Pneumonia with Traditional Chinese Medicine Lianhua Qingwen Analysis of the value of Shufeng Jiedu capsules combined with Abidol in the treatment of mild new type of coronary toxin pneumonia Analysis of 51 cases of new coronavirus pneumonia treated with traditional Chinese medicine Lianhua Qingwen: a multicenter retrospective study Multi-center Clinical Observation of Reyanning Mixture in Treatment of Novel Coronavirus Pneumonia Effect of integrated traditional Chinese and Western medicine on SARS: a review of clinical evidence Atheroprotective Effects and Molecular Targets of Bioactive Compounds from Traditional Chinese Medicine Recent Advances in Traditional Chinese Medicine for Kidney Disease Anti-ageing active ingredients from herbs and nutraceuticals used in traditional Chinese medicine: pharmacological mechanisms and implications for drug discovery The immunopharmaceutical effects and mechanisms of herb medicine Standardising outcomes for clinical trials and systematic reviews Adverse event: cochrane The revised consort statement for reporting randomized trials: explanation and elaboration Appendix Table 1 Search strategy Appendix Table 2 Results of subgroup meta-analysis for COVID-19 about the primary outcome (dichotomous data) Appendix Table 3 Results of subgroup meta-analysis for COVID-19 about the primary outcome (continuous variables) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65