Clinical Practice Guidelines of Traditional Chinese Herbal Medicine for Novel Coronavirus (Covid-19): Protocol of a Systematic Review

Background: The World Health Organization declared on 11 March 2020 that thespread of the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) had escalated from epidemic into pandemic. As the initial outbreak area, China has taken multiple active measures to deal with the epidemic. Updated versions of diagnosis and treatment guideline for novel coronavirus (COVID-19)patients have been issued, and traditional Chinese herbal medicine has been recommended as a treatment. Methods: In this systematic review, we will search for guidelines, expert consensuses and policy documents published since December 2019 in electronic databases and on websites of governments or organizations. Eligible documents will be independently selected, and relevant data will be independently extracted by two reviewers. We will also independently evaluate the methodological quality and reporting quality of the included guidelines, using the Appraisal of Guidelines for REsearch& Evaluation (AGREE) II tool and Reporting Items for Practice Guidelines in healthcare (RIGHT) statement, respectively. Any discrepancies will be discussed and resolved through discussion among the reviewers. We will use the extracted information to summarize their recommendationsfor traditional Chinese herbal formulae and Chinese patent medicine for COVID-19 patients, and to summarize the strength and quality of these recommendations with reference to the ndings from the AGREE II and RIGHT tools. Discussion: This review will summarize the recommendations in current clinical practice guidelines andprovide insight into the implementation strategies for traditional Chinese herbal medicine in COVID-19 patients.


Introduction
Novel coronavirus (COVID-19) pneumonia, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identi ed in Wuhan, China in late December 2019 [1]. COVID-19 patients mainly present with u-like symptoms (such as fever, cough and dyspnoea) and some other systemic symptoms (such as malaise, fatigue, and diarrhea) [2,3]. With a range of 1 to 14 days for the estimated incubation periodand various severity of clinical symptoms [4,5], human-to-human transmission of infectious disease has rapidly spread across the globe. The World Health Organization (WHO) declared a pandemic on 11 March 2020 [6]. As of 30 April 2020, COVID-19 patients have been diagnosed in more than 200 countries, areas or territories with more than 2 million con rmed cases [7].
As the initial outbreak area, China has taken multiple active measures to deal with COVID- 19 Since the third version of National COVID-19 Diagnosis and Treatment Guideline, traditional Chinese herbal medicine has beenrecommended as a treatment for COVID-19, based on different stages and syndrome differentiations of disease [8].
Traditional Chinese herbal medicine has played an important role in thousand-of-years' combat between Chinese doctors and pandemic and endemic diseases. During the outbreak of severe acute respiratory syndrome (SARS) coronavirus in the late 2002 in Guangdong, China, traditional Chinese herbal medicine showed bene cial effects such as relief of symptoms, decrease of mortality, and control of infection in patients with SARS [9][10][11][12]. With accumulated experiences of its anti-viral properties for the treatment of SARS and strong encouragement from the Chinese government [13,14], traditional Chinese herbal medicine has also been applied in treating COVID-19. The State Council Information O ce of China reported on 23 March 2020 that 74,187 COVID-19 patients (91.5% of total con rmed COVID-19 cases in China) had been treated with traditional Chinese herbal medicine with promising outcomes [15].
Along with the guideline issued by the National Health Commission of China, provinces, cities, and autonomous regions have also released clinical practice guidelines recommendingtraditional Chinese herbal medicine. The syndrome differentiations, treating principles and recommended formulae may differ acrossthese guidelines, because of the different characteristics of their respective regions and population. The objective of this systematic review is to summarize the recommendations in current clinical practice guidelines about the use oftraditional Chinese herbal medicine for COVID-19 patients. We will also evaluate and report on the methodological and reporting quality of theseguidelines.

Study registration
This systematic review is registered inthe Prospective Register of Systematic Review (PROSPERO) database (CRD42020179205). We formulated this protocol in accordance with the Preferred Reporting Item for Systematic Review and Meta-analysis -Protocol (PRISMA-P) statement [16] (Additional le 1).

Study design
We will include clinical practice guidelines, consensus statements and guidance documents published by any advising body or healthcare organization since December 2019, which provide information on the use of traditional Chinese herbal medicine therapy for COVID-19 patients.

Participants
Recommendations forpatients diagnosed with COVID-19 pneumonia withrecognized diagnostic criteria will be included (such as positive real-time uorescent Reverse Transcription-Polymerase Chain Reaction of respiratory or blood samples for new coronavirus nucleic acid, highly homologous of the respiratory specimen or blood specimen sequenced to novel coronavirus). There will be no restrictions with respect to age, gender or ethnicity.

Intervention
We will include recommendations for Chinese herbal medicine involving extracts from herbs, single or mixture herbal formulas, and Chinese patent medicine, regardless of their forms (e.g. pill, powder, oral liquid etc.).

Exclusioncriteria
We will exclude old versionsof guidelines or consensus statements published by a single advising body or healthcare organization.

Databases and search strategy
We will search for guidelines, expert consensuses and policy documents published since December 2019 in the following electronic databases: PubMed, Embase, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP), and Wanfang database (Wanfang Data). We will also search other sources of guidelines including: The National Guideline Clearinghouse (NGC), Guidelines International Network (GIN), National Institute for Health and Clinical Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN) and WHO. We will use search strategies that combine termsrelating to novel coronavirus, traditional Chinese medicine and guideline. The search strategy for PubMed is described in Additional le 2, and suitably modi ed search strategies will be applied to the other electronic databases. We will also search grey literature via websites of governments or organizations. No language restrictions will be applied.

Study selection
We will upload search results into EndNote X9 reference management software. We will lter and remove duplicate references. Two independent reviewers (YXL and DLZ) will screen titles and abstracts to identify potentially eligible documents, which will be retrieved in full text for nal review. Any disagreements will be discussed and arbitratedby a third reviewer (YGZ).

Data extraction
We will design a data extraction form based on characteristics of included guidelines and consensuses. In order to achieve consistency (at least 80%) in extracted items, we will pilottest the data extraction form with data extractors using a sample of eligible documents. Results of this pilot extraction will be discussed among review authors and extractors before nalizing it. Data extraction will beconducted independently by two reviewers (JL and YZ), and will include the following data: (1) characteristics of guidelines: name, type, source and date; (2) stage of disease; (3) syndrome differentiation; (4) treatment principle; (5) recommended formula; and (6) recommended Chinese patent medicine etc. Disagreements will be resolved by discussion among the review team.

Quality assessment
We will evaluate the methodological quality and reporting quality of the included guidelines using the Appraisal of Guidelines for REsearch& Evaluation (AGREE) II tool and Reporting Items for Practice Guidelines in healthcare (RIGHT) statement, respectively. In order to achieve consistency of at least 80% in the quality assessments, the assessors will pre-assess a sample of eligible documents and discuss their assessment among review authors and assessors. Afterthat, two independent reviewers (YXL and JL) will appraise the quality of included guidelines.Discrepancies will be discussed and resolved among the reviewers.

Data synthesis
With the information extracted from the included guidelines, we will summarize the recommendations made for traditional Chinese herbal formulae and Chinese patent medicine for COVID-19 patients. The recommendations of prescriptions for different stages and syndrome differentiations of COVID-19 will also be summarized. These ndings will be discussed in light of the strength and quality of these recommendations with reference to the results of AGREE II and RIGHT tools.

Discussion
This will be the rst systematic review that we are aware of which will comprehensively gather information from, and appraise the quality of guideline recommendations fortraditional Chinese herbal medicine for COVID-19 patients. Otherreviews have either examined the application of traditional Chinese herbal medicine for COVID-19 patients [17][18][19][20] or investigated current management for COVID-19 patients [21]. Examples of other studies, include Ho and colleagues' work on the case de nition, clinical classi cations, and relevant treatments of COVID-19 patients, in accordance to recommendations of the 7th edition of the National COVID-19 Diagnostic and Treatment Guideline of China [19]. While, Du and colleagues have summarized the theoretical foundation, potential effect of Chinese herbs on COVID-19 patients [17], and Yang and colleagues outlined clinical data forSARS-CoV and compared the evidence of current applications of traditional Chinese herbs in the treatment of COVID-19 patients [18].
In conclusion, given the manyguidelines and consensus statements that are now being regularly updated to advise clinical practices on the use of traditional Chinese herbal medicine for COVID-19 patients, this review will provide an important overall summary of their recommendations and provide insight into relevantimplementation strategies. This will have relevance outside China because, although traditional Chinese herbal medicine is mainly used in China, our preliminary search has found guidelines containing recommendations of Chinese herbs for COVID-19 patients from elsewhere.

Declarations
Ethics approval and consent to participate No ethics approval is required for this systematic review because we will be using information from published documents. Our ndings will be published in a peer-reviewed journal according to the PRISMA guidelines.