Traditional Chinese medicine for treating novel coronavirus (2019-nCoV) pneumonia: protocol for a systematic review and meta-analysis

Background: A new type of coronavirus, 2019 novel coronavirus (2019-nCoV), is causing an increasing number of cases of pneumonia and has been declared a Public Health Emergency of International Concern by the World Health Organization on 30 January 2020. The virus first appeared in Wuhan, China in late December 2019 and traditional Chinese medicine (TCM) is being used for its treatment. This systematic review and meta-analysis will assess studies of the effects of TCM in 2019-nCoV-infected pneumonia (NCIP). Methods: We will search electronic databases including PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP) and Wanfang database using keywords related to NCIP and TCM. Reference lists of relevant trials and reviews will be searched. We will manually search grey literature, such as conference proceedings and academic degree dissertations, and trial registries. Two independent reviewers will screen studies, extract data and evaluate risk of bias. Data analysis will be conducted using Review Manager software (version 5.3.5) and R software (version 3.6.1). Discussion: This study will provide a high-quality synthesis of the effects of TCM for NCIP. The use of TCM for treatment or prevention of these novel viral infections affecting the respiratory tract will be investigated. assess the limitations of available we conduct our based on PRISMA and checklist to achieve as high a level of quality as possible in reporting and methodology. help

grey literature, such as conference proceedings and academic degree dissertations, and trial registries. Two independent reviewers will screen studies, extract data and evaluate risk of bias. Data analysis will be conducted using Review Manager software (version 5.3.5) and R software (version 3.6.1).
Discussion: This study will provide a high-quality synthesis of the effects of TCM for NCIP.
The use of TCM for treatment or prevention of these novel viral infections affecting the respiratory tract will be investigated. identified in Wuhan, China, before being detected in other Chinese cities and in more than a dozen countries around the world by early February 2020. [5] The outbreak was declared a Public Health Emergency of International Concern by the WHO on 30 January 2020. The 2019-nCoV-infected pneumonia (NCIP) is characterized by flu-like symptoms including fever, cough, severe acute respiratory distress syndrome, and in some cases death. [6][7][8] Human-to-human transmission has been confirmed for the virus, [9][10][11] which is considered related to severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). Like SARS-CoV and MERS-CoV, the 2019-nCoV is a serious threat to human health. [7,12] As of 6 February 2020, nearly 30,000 people have been diagnosed with NCIP in the world.
[13] Effective prevention and treatment are crucial in this situation.
Traditional Chinese medicine (TCM) therapy is a mixture of Chinese herbs prescribed by Chinese herbalists depending on the differentiation of the patient's syndrome according to Chinese diagnostic patterns (inspection, listening, smelling, inquiry and palpation).
Studies have reported that Chinese herbal formula, such as San Wu Huangqin Decoction, Lianhuaqingwen Capsule and Yinhuapinggan granule, possess antiviral effects, which might be associated with blocking of the proliferation and replication of the viral particles, and that they might be able to improve lung damage by influenza viruses. [14][15][16] During the SARS epidemics, TCM treatments were reported to have successfully prevented and treated SARS. [17][18][19] Furthermore, TCM combined with western medicine treatment regimen reduced adverse events and other complications induced by glucocorticoid, antibiotic and antiviral treatments. [20,21] After the pneumonia outbreak of the 2019-nCoV, the State Administration of Traditional Chinese Medicine in China led an expert team to formulate a TCM treatment Program. On 24 January 2020, the first case of a cured patient in Beijing being discharged from hospital after treatment of TCM with symptomatic therapy was reported. [22] Later, another cured 4 patient was reported following TCM therapy, prompting the wider application of TCM for Although TCM treatment is being applied for 2019-nCoV pneumonia, uncertainty remains about its effectiveness. Therefore, we intend to systematically review studies of TCM application in NCIP patients in order to examine the empirical evidence of the effects of TCM for 2019-nCoV pneumonia. We aim to provide a robust evidence for improvement of clinical practice in treating 2019-nCoV pneumonia.

Study registration
This systematic review was registered on PROSPERO (CRD42020168004) on 5 February 2020. We have prepared this protocol in accordance with the Preferred Reporting Item for Systematic Review and Meta-analysis (PRISMA-P) statement (Additional file 1). [25] Inclusion criteria

Type of studies
Randomized trials and quasi-randomized or prospective controlled clinical trials that have tested TCM with or without western medicine for NCIP will be included. There will be no restrictions for blinding, follow-up or publication status. Publications in English and Chinese will be included.

Type of participant
Patients diagnosed with pneumonia caused by 2019-nCoV without immediately life-5 threatening co-morbidities will be included. There will be no restrictions with respect to gender, age or ethnicity.

Type of interventions
Traditional Chinese herbal medicine involving extracts from herbs, single or mixture herbal formulas regardless of their compositions or forms. TCM combined with one or more other pharmacological intervention will also be included. There will be no restrictions with respect to dosage, frequency or duration of treatment.

Type of comparators
There will be no restrictions with respect to the type of comparator. The comparators are likely to include western medical therapies, supportive care and other therapeutic methods.

Type of outcome measurements
Our primary outcomes will be survival at the end of treatment and at the end of follow-up, and time and rate of the patient becoming negative for the coronavirus. We will also assess the following outcomes at the end of treatment and at the end of follow up: days to absence of fever; symptom score (based on fever, fatigue, cough, difficulty in breathing, poor appetite, etc.); duration of each symptom; pulmonary function; inflammation index; results of chest CT; length of stay in hospital; use (including dosage and duration) of corticosteroid; quality of life; and adverse events. If other outcomes are reported in the eligible studies, these will be extracted and reported but we will give particular attention to the possibility of selective reporting bias when using any such outcomes in our review.

Exclusion criteria
(1) Suspected or misdiagnosed NCIP patients; (2) Patients with severe basic diseases that are likely to lead to death within the trial follow-up period; (3) Duplicated data or data that cannot be extracted; (4) Full text cannot be obtained.

Databases and search strategy
We will search electronic databases including PubMed, Embase, the Cochrane Central Reference lists of relevant trials and reviews will be searched. We will manually search grey literature such as conference proceedings and academic degree dissertations, and trial registries (both through the WHO International Clinical Trials Registry Platform (ICRP) and on the websites of national registries).

Study selection
After removing duplicates, the retrieved records will be checked independently by two reviewers (XL and DZ), who will apply the eligibility criteria based on the title and abstract. Where a study is potentially eligible, the full-text will be obtained and checked independently by two reviewers (XL and DZ) to identify the eligible studies. Any disagreements will be discussed and resolved in discussion with a third reviewer (JL).

Data extraction
Two independent reviewers (YL and LG) will extract data with a predefined extraction template, which includes the following items: (1) General information: first author, title, outcomes, main conclusions, adverse events, etc. The original authors will be contacted to request missing data where necessary. Extracted information will be cross checked. Any disagreements will be discussed and resolved in discussion with a third reviewer (YZ).

Assessment of risk of bias
Two independent reviewers (YL and DZ) will assess the risk of bias of the included studies.
We will follow the guidance in the latest version of Cochrane Handbook for systematic reviews of interventions when choosing and using tools to assessing risk of bias for randomized and on-randomized trials. Any disagreements will be discussed and resolved in discussion with a third reviewer (RJ).

Data analysis
Statistical analyses will be conducted using RevMan software (version 5.3.5) and R software (version 3.6.1). If possible, analyses for all outcomes will be done by intentionto-treat. We will perform analyses to provide effect estimates for dichotomous data and continuous data, with 95% confidence intervals. We will use risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data. If subsets of included studies are sufficiently homogeneous, we will perform meta-analysis for all outcomes.
Heterogeneity will be detected by using a standard Chi-square test with a significance level of P < 0.10. The I 2 statistic will be applied to quantify inconsistency across studies and to assess the impact of heterogeneity on the meta-analyses. Fixed-effects model will be used if there is small statistical heterogeneity among studies (I 2 < 50%, P > 0.10).
Otherwise, random-effects model will be used.

Subgroup analysis
If an adequate number of studies are identified, we will perform subgroup analysis for the following variables: age; patients with or without other diseases; and NCIP stage at which the TCM was given.
We will also consider analyses for other subgroups as reported in the included studies, but we will give particular attention to the possibility of selective reporting bias when using any such subgroups in our review.

Sensitivity analysis
To check the robustness of pooled outcome results, we will carry out sensitivity analysis to explore the influence of studies with high risk of bias.

Publication bias
We will test for publication bias using the funnel plot or other corrective analytical methods, depending on the number of clinical trials included in our review.

Quality of evidence
Two independent reviewers (DLZ and JL) will assess the quality of evidence for each outcome with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. [26] Each outcome will be assessed for each of the five aspects: limitations, inconsistency, indirectness, imprecision, and publication bias. They will be rated as high, moderate, low, or very low level quality. This is the first systematic review to examine empirical evidence of the application of TCM for 2019-nCoV pneumonia. It will provide an overview of the application of TCM in treating NCIP patients and assess the strengths and limitations of available evidence. Furthermore, we will conduct our study based on PRISMA statement and AMSTAR2 checklist to achieve as high a level of quality as possible in reporting and methodology. This review will help explore the potential role for TCM in the treatment or prevention of viral infections affecting the respiratory tract.

Ethics approval and consent to participate
No ethics approval is required for this systematic review and meta-analysis because we will be using information from published studies. Our findings will be published in a peerreviewed journal according to the PRISMA guidelines.