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Chinese medicine diagnosis and treatment for COVID-2019: Is China ready for implementing a national guideline?

Highlights • Chinese herbal medicine is included in the national guideline for diagnosis and treatment of COVID-19 in China, but compliance were variable.• Instead of national-recommended approach of individualising Chinese herbal medicine, many organizations developed their own guideline.• These local guidelines suggest the use of standardised herbal formulae or herbal active ingredients on all COVID-19 patients.• It is urgent to revise the national guideline based on preliminary outcome evaluation and consensus to attaining wider recognition.• National research programmes to establish clinical evidence base for Chinese herbal medicine in managing COVID-19 are urgently needed.


Introduction
The World Health Organization characterised the coronavirus disease (COVID-19) as a pandemic on 11 March 2020, after the number of new confirmed cases outside China, the former outbreak epicentre, had increased by 13-folds [1]. Traditional Chinese Medicine (TCM), as a formal part of the Chinese healthcare system, has been playing an important role in combating the disease since it received the highest political endorsement at the beginning of the outbreak [2]. After summarising TCM experts' experiences, the Chinese health authority incorporated a section on Chinese herbal medicine (CHM) treatments into the National COVID-19 Diagnostic and Treatment Guideline published on 22 January 2020 [3]. The guideline recommends the prescription of CHM based on a process called Bian Zheng Lun Zhi (pattern differentiation-guided treatment decision). Pattern differentiation is a traditional diagnostic procedure guided by classical TCM theories [4]. The process requires TCM clinicians to examine patients by observation, listening, questioning, and pulse-taking. Subsequently, complex information is analysed in accordance with TCM theories to allow the formulation of a TCM pattern diagnosis. These form the basis for designing individualised treatment strategies.

Classical pattern differentiation for individualising Chinese herbal medicine prescriptions
When the pattern differentiation result suggests that a patient is Yang deficient, treatment should be directed towards the

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Advances in Integrative Medicine j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / a i m e d nourishment of Yang using CHM. This diagnostic framework for pattern differentiation has been recognised by the eleventh edition of the International Classification of Diseases (ICD-11) [5]. Drawing upon the successful experience of implementing integrative Chinese-Western Medicine in managing COVID-19 [6], the latest national guideline recommends healthcare professionals in China to offer tailored CHM treatments in accordance with disease trajectory [7]. Patients are stratified into mild, moderate, severe, critical, and recovering stages, and for each respective stage individualised CHM formulae are prescribed based on their TCM pattern diagnosis. Two pattern diagnoses are observed in mild, moderate, severe, and recovering cases respectively. Only one pattern diagnosis is commonly seen among critical cases. Details on the TCM pattern diagnoses and relevant clinical features are illustrated in Table 1.
Unexpectedly, this national guideline is not implemented by all hospitals treating patients with COVID-19 and at least 24 other guidelines were developed by various provincial and regional governments across China [8]. There are multitude of reasons for local healthcare professionals to develop de novo guidelines [9]. In the case of COVID-19, these may include uncertainty on quality of national guideline development process; low confidence in the evidence due to lack of clinical research; and finally, possible existence of regional variations in prevalence of different TCM pattern diagnoses [10]. This may also reflect a lack of timely diagnostic research on how pattern differentiation in COVID-19 should be standardised, or stratified, for the country.

Standardised herbal formulae
Evidence on whether the use of pattern-differentiation would improve treatment outcome is yet to be synthesized. Existing trial comparing individualized CHM treatment based on patterndifferentiation, with standardized CHM treatment showed that the individualized approach is favoured for improving longer term outcome among patients with irritable bowel syndrome [11]. However, another trial on acupuncture for postmenopausal hot flushes did not observe clinical benefits of pattern-differentiation [12]. Also, slow progress in pattern differentiation research has eroded confidence in its application [13], and increasingly, CHM is prescribed solely based on conventional diagnosis. Indeed, direct application of CHM therapy without considering pattern differentiation was shown to be effective in the treatment of H1N1 influenza in a rigorously designed randomised trial [14]. This successful experience may have encouraged similar approaches in the current outbreak. For instance, the Guangdong provincial government encourages hospitals to prescribe a standardised CHM formula Pneumonia Prescription 1 to all suspected cases and confirmed cases, regardless of their TCM diagnosis [15]. In Wuhan, TCM clinicians are advised to prescribe three standardised CHM formula to quarantined citizens, suspected cases, and confirmed cases [16]. Consistent with the general trend of low guideline adherence rate among TCM clinicians in China [17], the promulgation of a COVID-19 national guideline backed only by expert opinions has received little recognition, let alone the implementation and adherence at the front line.

Herbal active ingredients
In the modern evaluation framework of pharmaceutical science, establishing evidence base of complex TCM diagnosis and treatment is challenging. Development of new drugs based on active ingredients of CHM has been considered a preferred approach for internationalising TCM [18]. This modernisation approach gained momentum since the 1950s when Mao Zedong advocated the use of biomedical technologies in herbal research [19]. Its popularity soared after the award of the Nobel Prize to Youyou Tu in 2015 for the discovery of the antimalarial artemisinin through her research on Artemisia annua L [20]. In the treatment of patients with COVID-19, the Chinese Academy of Sciences Table 1 Traditional Chinese Medicine Diagnostic Patterns of COVID-19 based on the 7th version of the Chinese National Guideline.

TCM pattern diagnosis Clinical features
Mild cases 1: Cold-dampness obstructing the lung Fever, muscle fatigue, muscle pain, coughing, expectoration of sputum, chest discomfort, shortness of breath, loss of appetite, nausea, vomiting, and ungratifying defecation. Pale tongue with teeth-marked, or pale red tongue. White, thick and curdy tongue fur, or white and slimy tongue fur. Soggy or slippery pulse

Mild cases 2: Dampness-heat in the lung
Mild fever or no fever, slight aversion to cold, muscle fatigue, heaviness in the head and body, muscle pain, dry coughing with small amounts of sputum, sore throat, dry mouth without a desire to drink, chest discomfort, absence of sweating or difficulty in sweating, loss of appetite, nausea, vomiting, and watery stool or ungratifying defecation. Pale red tongue. White, thick and slimy tongue fur, or yellow and thin tongue fur. Slippery and rapid pulse, or soggy pulse. endorsed this active ingredient approach and, wittingly or unwittingly, promoted the use of Shuanghuanglian oral liquid via the state media. [21]. This remedy consists of extracts from three herbs, and preliminary laboratory investigations conducted by the Shanghai Institute of Materia Medica and the Wuhan Institute of Virology have demonstrated its capability in inhibiting the SARS-CoV-2 in vitro [21]. From Chinese government and business perspectives, understanding CHM bioactivities does not only generate new leads for drug development. It is also crucial for potential international exports of CHM products, as the discovery of therapeutic mechanisms is important for satisfying registration requirements from overseas regulatory authorities [22]. For example, the United States Food and Drug Administration botanical drug registration requires proofs of mechanism using clinical relevant bioassays [18]. For TCM clinicians and guideline developers, mechanistic investigations help with clarifying dosage for achieving beneficial outcomes with minimal side effects [23]. However, without clinical research providing effectiveness and safety evidence in vivo, the current trend of investing heavily on in vitro investigation will contribute little for improving quality of TCM practice [24].

Conclusion: research recommendations
Developing a national consensus on what constitutes the best strategy based on current observations and, subsequently, revising the national guideline to attain wider recognition and higher compliance are urgently needed. With such a guideline, national clinical research programmes can be initiated to facilitate in-depth investigations on the three aforementioned approaches, namely classical pattern differentiation for individualising CHM prescriptions, standardised herbal formula, and herbal active ingredients, in a coordinated manner across hospitals. A comparison on the relative strengths and weaknesses of the three approaches is illustrated in Table 2.
For the first approach, standards for operationalising TCM pattern differentiation process for COVID-19 under the ICD-11 framework should be established using innovative diagnostic research methods. [25]. For the second and third approaches, focused investment should be channelled to support the conduct of rigorous phase II or III randomised trials on the most promising CHM treatment strategy, instead of spreading scare resources across numerous different trials [26]. Moreover, complex trials evaluating the effect of ICD-11-based pattern differentiation on patients' response to CHM should subsequently be performed, with all details reported in accordance to the CONSORT (CONsolidated Standards of Reporting Trials) reporting guideline for CHM trials [27]. The results of such trial will reveal how different ICD-11 based TCM diagnosis across different regions may impact treatment outcomes [25]. With such evidence, regional guideline could be developed based on how individualised treatment may yield different outcomes among different types of patients, with different TCM pattern diagnoses. Without serious investment in building clinical research capacity, CHM will remain a "pseudoscience" among sceptics [28]. It is now prime time for policymakers to work towards the World Health Organization's goal of promoting evidence-informed decision-making in traditional medicine [29].

Funding
The writing of this commentary is supported by the National Natural Science Foundation of China (No. 81973709) and the Hunan Natural Science Foundation (No. 2019JJ40348)

Declaration of Competing Interest
Dr Vincent CH Chung is a member of the editorial board for Advances in Integrative Medicine. The remaining authors declare that there are no conflicts of interest regarding the publication of this paper.

Strengths
Adherence to the wealth of clinical experience in TCM. Practice style taught in the national syllabus among TCM universities [30] CHM could be prescribed more widely by clinicians without training in TCM and pattern differentiation.
Clear understanding on the in vitro therapeutic mechanism of CHM.

Limitation
Evidence supporting the comparative advantage of pattern differentiation, versus the absence of it, for guiding CHM prescription, is yet to be established.
In vitro discovery of herbal active ingredient may not translate to clinically effective CHM medications [31] Facilitators to adopt this approach Addition of diagnostic framework for pattern differentiation in ICD-11, allowing the incorporation of pattern differentiation process in randomized trials [32] Majority of current clinical evidence on CHM is generated using this approach, making their clinical application straightforward [33] Opportunities for promoting overseas registration and trade of CHM products [34] Barriers to adopt this approach Lack of diagnostic research results which would guide the reliable use of ICD-11 pattern differentiation codes [35] In certain jurisdictions, the use of classical theories and pattern differentiation in daily practice is required by regulatory bodies [36] Substantial upfront investment on time and resources for in vitro and in vivo research prior to clinical application.

Example of success
Individualized CHM is superior to standardized CHM for reducing longer term symptoms among irritable bowel syndrome patients [11] Maxingshigan-Yinqiaosan is effective for reducing time to fever resolution among patients with H1N1 influenza [14] Discovery of the antimalarial artemisinin [20] Chinese herbal medicine (CHM); Traditional Chinese medicine (TCM).