Integrated Lianhua-Qingwen and Western Medicine Versus Western Medicine-Only Therapies Against COVID-19: A Systematic Review and Meta-Analysis

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Introduction
Corona virus disease 2019 (COVID- 19) is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a disease with main clinical manifestations of fever, dry cough, fatigue, etc. In some patients, it involves the upper respiratory and digestive tracts with such clinical manifestations as nasal congestion, runny nose, diarrhea, etc. In severe cases, dyspnea usually occurs after one week. These severe cases rapidly develop into acute respiratory distress syndrome, septic shock, metabolic acidosis di cult to correct, coagulopathy, and multi-organ failure 1 . Globally, as of 11:09am CET, 16 January 2021, there have been 92,262,621 con rmed cases of COVID-19, including 1,995,037 deaths, reported to WHO (https://covid19.who.int/).
Although Lianhua-Qingwen and other therapeutic regimens of integrated traditional Chinese and Western medicine have been included in COVID-19 clinical treatment guidelines in China, the number of current clinical research reports is small in sample size. Comparing two therapeutic regimens, we will nd that there are uncertainties in the improvement of common symptoms and signs, and progressing to the critical cases, as well as the side effects in patients with  To this end, our study assessed multiple clinical trials to compare the effects of the therapeutic regimens of Lianhua-Qingwen combined with Western medicine versus the use of only Western medicine, and analyzed the issues of safety and e cacy of different therapeutic regimens in the clinical treatment of COVID-19. Our study aims to provide evidence-based medical indications for the clinical practice of applying Lianhua-Qingwen and other traditional Chinese medicines in the treatment of  Materials And Methods

Inclusion and exclusion criteria
The inclusion criteria for trials to study include the following: 1) The type of research should be clinical based studies, including randomized controlled experiments and single-arm experiments; 2) It reports the relevant information before and after the treatment of the patients; 3) It studies the integrated use of traditional Chinese medicine Lianhua-Qingwen and Western medicine in the treatment vs. Western medicine-only treatment.
The exclusion criteria include the following: 1) News, reviews, comments, methodology report, letters, conference articles about COVID-19 treatment were excluded; 2) Literature with incomplete data or literature unable to be extracted was excluded.

Data extraction and quality assessment
Two reviewers independently conducted literature screening, data extraction and quality assessment, and cross-checks were applied. In case of disagreement, the third reviewer would resolve it through discussion or consultation.
Literature screening was conducted in preliminary to exclude those not quali ed for our research by reading the title and abstract of a trial. Then the full text of the literature that meets the inclusion criteria was obtained. At that point the full text was read to check against the inclusion and exclusion criteria for further scrutiny. A self-made information extraction form was developed to collect information about the literature, including the title of the literature, the time of publication, the rst author or corresponding author, the total number of patients, the number of cases, sex ratio, age, body temperature, and observation duration in each treatment group. For the assessment of the quality of literature, the Cochrane bias risk assessment scale was used and independently conducted by two reviewers.

Risk of bias
The evaluation of the quality was based on the "bias risk assessment" tool that adopts the Cochrane systematic review, including random allocation, allocation concealment, the presence or absence of blindness, data integrity, the existence of selection bias, and other sources of bias. In the statistical analysis, the quality assessment was classi ed by a score system: a score of 5 or higher means low-level bias risks; 3 to 4 standards for medium-level bias risks; 3 or less indicates high-level bias risks.

Statistical analysis
Meta-analysis was performed using RevMan 5.3 software. The integrated approach of adopting Chinese herbal medicine Lianhua-Qingwen and Western medicines to treat COVID-19 patients was compared with the therapy administering only Western medicines to recover the disease improvement rate, CT imaging improvement rate, main disease improvement rate, duration of fever, rate of progressing to critical cases and rate of adverse reactions of patients with novel coronavirus infection; and the relationship between the main indicators and other indicators was analyzed. The relative risk (RR) was used to express the effect quantity, and the weighted mean difference (MD) or standardized mean difference (SMD) was used to express the measurement data. The con dence interval (CI) is 95%. If the heterogeneity test result P > 0.1 or I 2 ≤ 50% was included in the study, the xed effect model would be used for Metaanalysis; if the heterogeneity test result showed P ≤ 0.1 or I 2 > 50%, the random effect model would be used for Meta-analysis.

Eligible studies
A total of 123 studies were retrieved in this study, and 62 studies were obtained after excluding the duplicate articles. Through further reading the literature titles and reading abstracts, and checking against the inclusion criteria and exclusion criteria, nally, 13 reports 4-6, 8-13, 15-18 were included in the present research, of which 11studies were randomized controlled experiments, 2 studies were single-arm experiments, and the patients studied were mainly from Hubei and Anhui provinces in mainland China. The test group was given Lianhua-Qingwen mainly combined with Western medicine treatment, and the control group was treated with conventional Western medicine treatment, with a total of 1,182 cases of COVID-19; the intervention time range was 5-20 days. The basic characteristics and patient information of the included literature are shown in Table 1. Five studies report on the overall improvement rate, including 811subjects (405 patients were in the group of treatment using Lianhua-Qingwen and Western medicine, and 406 patients treated with only conventional Western medicine). The data showed that the therapy using Lianhua-Qingwen combined with Western medicine treatment improved the effectiveness of recovery of the patients with novel coronavirus by 18%, and the effective combined RR value was 1.18 (95% CI: 1.09, 1.21; I 2 = 37%, Fig. 2).

Chest CT imaging analysis
The rate of chest CT showing recovery was detected in 6 studies including 870 subjects (458 patients were in the group of taking Lianhua-Qingwen combined with Western medicine, and 412 patients were in the group taking conventional Western medicine). The data showed that Lianhua-Qingwen combined with Western medicine treatment showed a better chest CT result in patients with novel coronavirus. The RR value of CT image improvement rate was 1.12 (95% CI: 1.03, 1.23; I 2 = 38%, Fig. 3).

Disappearance rate of main symptoms
The main symptoms of patients with novel coronavirus pneumonia include fever, fatigue, and cough. We separately counted the effects of the two treatment methods on the disappearance rate of the main symptoms of fever, fatigue and cough, respectively.

Adverse reactions
Of the 13 studies included in our study, 11 studies reported treatment with Lianhua-Qingwen combined with Western medicine. Compared with the treatment by conventional Western medicine, no serious drug-related adverse reactions were seen in the group receiving Lianhua-Qingwen combined with Western medicine. Studies from 15 showed that in the group of conventional Western medicine, 38 cases complained of nausea, 5 cases of vomiting, and 3 cases of loss of appetite, the incidence of adverse reactions was 21.05%. However, in the group of Lianhua-Qingwen treatment with 63 patients, two cases complained of diarrhea, 1 case of loss of appetite, and the incidence of adverse reactions was only 4.76%, and the adverse reactions were improved in both groups after drug withdrawal. The research by Hu et al 11 . showed that the two groups of treatment showed abnormal liver function, renal dysfunction, headache, nausea, vomiting, diarrhea, loss of appetite and other adverse reactions, but there was no signi cant difference between the two groups 4 . Our analysis of the data also suggested that there was no signi cant difference in adverse reactions between the two groups: treatment with Lianhua-Qingwen combined with Western medicine vs. treatment with Western medicine treatment alone: (RR = 0.51 (95% CI: 0.14, 1.82; I 2 = 76%); Fig. 7).
Discussions the treatment of COVID-19, the method of adopting integrated Lianhua-Qingwen and Western medicine could signi cantly increase the improvement rate, the disappearance rate, and disappearance time of the main symptoms, improve the effect of chest CT on the patient, and reduce the risk of worsening of the disease. In addition, it has been found that there is no signi cant difference in adverse effects between the two treatment methods. The results of this study suggest that the treatment with Lianhua-Qingwen combined with Western medicine has a better synergistic effect on COVID-19.
The main symptoms of patients with COVID-19 are fever, fatigue and cough, and severe respiratory tract infections, and some patients also have a series of other symptoms such as diarrhea and nausea 28  combined with conventional treatment was higher, the CT recovery rate was better, and diarrhea occurred rate is low, but there is less analysis of the characteristic indicators of new coronary pneumonia, and only 4 articles include the conventional treatment group as a control; Zeng et al. 36 analyzed literature analysis as of May 2020 and found that: The combination of Lianhua Qingwen and traditional treatment is better than traditional treatment alone, but only 2 articles are included, and the data included is less; Fang et al. 37 analysis found that the combination of Lianhua Qingwen and Abido is more effective than using continuous treatment alone. Lianhua Qingwen has a good effect on the patient's recovery time, nucleic acid negative, improvement of chest CT time and hospital stay and other indicators, and there are no serious drug-related adverse events.
However, in this article, it should be noted that a large number of clinical trials were not published in time because the clinical trials had de ciencies in methodological design, such as randomization, hidden allocation, and insu cient reports on blinding, withdrawal, and sample size estimation. Therefore, subsequent reports of more randomized clinical trials will help to comprehensively analyze the effect of important preparations like Lianhua-Qingwen combined with Western medicine we have discussed above.
In summary, the conclusion of this systematic review is that Lianhua-Qingwen combined with Western medicine treatment has shown a better treatment e ciency and a more reassured clinical safety for patients with common type COVID-19, and has achieved well-demonstrated results in this anti-epidemic ght. None.