








key: cord-340119-af8i359n
authors: Wang, Shi-xin; Wang, Yan; Lu, Yu-bao; Li, Jie-yun; Song, Yu-jun; Nyamgerelt, Munkhtuya; Wang, Xue-xi
title: Diagnosis and treatment of novel coronavirus pneumonia based on the theory of traditional Chinese medicine
date: 2020-04-15
journal: J Integr Med
DOI: 10.1016/j.joim.2020.04.001
sha: 
doc_id: 340119
cord_uid: af8i359n

Since the outbreak of novel coronavirus pneumonia (coronavirus disease 2019, COVID-19) in December 2019, it has rapidly spread to 187 countries, causing serious harm to the health of people and a huge social burden. However, currently, drugs specifically approved for clinical use are not available, except for vaccines against COVID-19 that are being evaluated. Traditional Chinese medicine (TCM) is capable of performing syndrome differentiation and treatment according to the clinical manifestations of patients, and has a better ability of epidemic prevention and control. The authors comprehensively analyzed the etiology and pathogenesis of COVID-19 based on the theory of TCM, and discussed its syndrome differentiation, treatment and prevention measures so as to provide strategies and reference for the prevention and treatment with TCM.

Since December 2019, the novel coronavirus pneumonia (coronavirus disease 2019, outbreak in Wuhan, Hubei Province, China has rapidly spread across the world and has now infected a total of 348678 people in 187 countries (March 21, 2020) [1] . China has listed COVID-19 as a class B infectious disease and has undertaken preventive and control measures according to class A infectious diseases [2] . With the spread of the epidemic, presently, patients infected with the novel coronavirus, as well as those with asymptomatic infection, are the main sources of infection; thus, COVID-19 is an infectious disease with a medium to slightly high contagious capacity [3] . The incubation period of the disease is generally 7 days, and the longest is 14 days; however, some cases have reported an incubation period of 24 days as well [4] . Common clinical manifestations include fever, dry cough and fatigue.

Computerized tomography of the chest can show multiple ground glass shadows of the pulmonary lobes, indicative of conditions such as respiratory distress syndrome, shock and sepsis, which can even lead to death [5] . Thus far, although China has announced six trials and strategies for the diagnosis and treatment of the disease, the focus remains mainly on symptomatic treatment, new drugs specifically approved for the infection are not available. Clinical trials for new drugs such as remdesivir and coolidge are underway; however, the clinical promotion and short-term use of these drugs is unlikely. Therefore, given the particularities of this disease, it is of critical clinical value to formulate a set of treatment plans using integrated traditional Chinese medicine (TCM) and Western medicine, based on the concept of prevention and treatment. To utilize the advantages of integrated traditional Chinese and Western medicine in the prevention and treatment of COVID-19, this paper discussed the etiology and pathogenesis of COVID-19 from the viewpoint of integrated TCM and Western medicine, the treatment measures for different susceptible groups, and the effect along with matters needing attention, so as to provide a reference for the prevention and treatment of COVID-19.

Coronavirus is a type of a ribonucleic acid virus with an envelope structure, characterized by rod-like protuberances on the surface and can infect multiple host species, causing a variety of diseases [6] . The COVID-19 pathogen is a novel coronavirus (2019-nCoV), which can infect humans and is significantly clustered with the bat-like severe acute respiratory syndrome coronavirus (SARS-CoV) sequence isolated in 2015, with a nucleotide similarity of 88%. Based on these results, it can be concluded that 2019-nCoV is similar to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) [7] . It is a zoonotic pathogen that can cause severe respiratory diseases in humans and can be transmitted from person to person [8] . Therefore, the International Committee on Taxonomy of Viruses announced that the official classification of the novel coronavirus is SARS-CoV-2.

There is no virus theory in TCM, and according to the clinical characteristics of COVID-19, the disease belongs to the category of "plague" [9] . As the General Treatise on the Etiology and Symptomology says [10] , "if a person feels grumpy and gets sick, he will be easily infected by evil Qi, which may even exterminate the family, and extend to outsiders." The common symptoms in the early stage of COVID-19 in mildly infected patients include fever, fatigue and dry cough, which could be easily confused with other common exogenous diseases. However, according to Wu You-ke's The Treatise on Epidemic Febrile Diseases [11] , which mentions "the febrile disease is non-wind, non-cold, non-heat and non-damp; it is a different feeling between heaven and earth," the cause of this disease is very clear, differing from the other six exotic evils, and presenting characteristics of a strong and contagious epidemic virus.

Wuhan, the center of the outbreak pathogen, is located in the east of Jianghan Plain of China. The vertical and horizontal water areas of the city's rivers account for one-fourth of the total city area, demonstrating the natural environmental basis of "damp evil" [12] . At the initial stage of this epidemic, most patients presented symptoms of fever; however, there were also patients with no fever or low fever, and some patients presented gastrointestinal symptoms, such as indigestion and loose stool, as well as chest tightness and fatigue, coinciding with the characteristics of "damp evil" in TCM. Hence, this disease is an epidemic, with the primary nature of "damp" and "toxic," and thus can be termed "damp toxin disease." Furthermore, in 2019, Wuhan experienced a warm winter climate, with incoming heat instead of cold.

From the perspective of TCM, this kind of climate change is prone to generate damp-heat in the human body, which persists and is difficult to eliminate from Sanjiao (one of the six fu-organs in TCM theory). Some patients have a recurrent fever, bitter mouth, insomnia, upset, chest tightness and shortness of breath, fatigue, yellow or greasy tongue coating, and slippery pulse, which are manifestations of the evil underlying Shaoyang meridian according to the six-meridian syndrome differentiation theory [13] . Notably, the most severe cases developed dyspnea one week later, which even progressed to acute respiratory distress syndrome, septic shock, intractable metabolic acidosis, and coagulation dysfunction, leading to death [14] . According to TCM, the toxins from these patients not only hurt the Qi but also injure the nutrient blood and result in blood stasis; the pericardium transmission channel is also reversed, resulting in mental changes. Dampness stagnates for a prolonged period and turns into heat; heat toxin accumulates for a long time, resulting in stasis; stasis and heat combine mutually and then generate syncope, which consumes Qi and Yin and leads to a deficiency. According to the principle of "three factors and measures," there exist various etiological characteristics in different regions, as well as climatic factors. Fan et al. [15] observed and analyzed the TCM pathological characteristics of "dryness" in Hunan cases, and concluded that dryness and dampness are mainly due to "child disease to mother" in the course of the disease. In the theory of TCM, dryness evil can easily injure the lung. Lung and spleen belong to "gold" and "soil" in the five-element theory of TCM. Dryness turns into dampness. Dampness easily traps spleen. Wet soil is the mother of dryness "gold." Furthermore, excessive lung dryness injures the spleen "soil"; hence, both lung dryness and spleen dampness are significant. In contrast, Yu et al. [16] summed up the data and concluded that the diseases in Guangdong Province and Gansu Province were caused by warm-heat toxin or epidemic toxin, which was closely related to their regional environment. Guangdong Province is hot and humid all year round, and the epidemic Qi can easily mix with evils of damp and heat to attack the lung; however, the overall 2019 winter temperature in Gansu Province was higher than that experienced in previous years.

Additionally, Gansu is located in the northwest region of China, which is mostly dry and warm, and susceptible to the evil of dryness that can cause lung disease. TCM runs through the whole idea of disease differentiation all the time, and the unified relationship between man and nature has been called "correspondence between man and nature" in ancient books, which presents considerable advantage in the treatment of COVID-19 in different populations and regions.

Compared with other diseases, the evil Qi of the "damp toxin epidemic" is relatively fixed, and hence, the etiology and pathogenesis are relatively fixed, with obvious stages of disease progression in clinical settings. Understanding the consistency of the stages also allows for clinical diagnosis and evidence-based treatment. After careful assessment of the four pieces of diagnostic evidence available regarding the confirmed cases, it was observed that this epidemic is mainly caused by a dampness pathogen, with the disease location of mainly Sangjiao, and the core pathogenesis is "dampness, heat, poison, blood stasis and deficiency," which runs through the whole process of dampness and intoxication and closure of the lung. The Treatise on Epidemic Febrile Diseases [11] ascertains that typhoid fever does not infect people, but epidemic diseases can infect people. The evil of typhoid fever enters from the orifices, while the evil of epidemic disease enters only from the mouth and nose; it has been observed that during an epidemic, the evil comes from the mouth and nose, remains in the membrane, and unconsciously lurks in the human body [17] .

COVID-19 is located in the lung, where evil Qi first invades the body from the mouth and nose, repressing the lung Qi. In turn, the lung fails to disperse and descend, with symptoms of dry cough. The "damp evil" is heavy and viscous, blocking the Qi mechanism and causing chest tightness, body heat, and muscle soreness. "Damp evil" traps the spleen, easily injuring Yang Qi. The spleen dominates and transports water and food through the body. When the Qi fails to rise, the spleen cannot be nourished, and symptoms begin to appear, including fatigue, gastric congestion and loose stool.

The spleen and stomach act as the exterior and interior of each other; hence, the spleen's dysfunction affects the stomach's absorption. The dampness accompanying the epidemic toxin into heat is manifested as high fever, occasional yellow phlegm, obvious asthma due to the dampness toxin, and sticky stool due to the stagnation of dampness. Wang Qingren stated in Correcting Mistakes in Medicine that "the plague toxin burns its blood inside, and if the blood is burned and refined, the blood will coagulate [18] ." During this period, the heat toxin burns the body fluid, and dampness suppresses the Qi mechanism, resulting in the stasis of blood, manifested in the form of increased dyspnea and additional mental problems occurring during the reverse transmission of the pericardium. In the later stage, the body is damaged by fluid consumption, and is deficient in both Qi and Yin. During this period of treatment, attention should be paid to whether there is any residual evil in the body.

Given the differences in etiology and pathogenesis attributed to climatic factors in different regions, Fan et al. [19] observed and stated that owing to climatic factors, dryness has been present in the lung for a prolonged period. On encountering the epidemic toxin, dampness and cold will collide with each other, and obstruct the lung and chest, injuring vital Qi, leading to the stagnation of the Qi mechanism and abnormal rise and fall of evil Qi, finally leading to a deficiency of vital energy.

Although there exist differing opinions, combined with the clinical manifestations of the published and confirmed cases, the main etiology and pathogenesis can be attributed to "dampness, heat, toxin, blood stasis and deficiency." Furthermore, the pathogenesis may differ among individuals. In the case of adults without underlying diseases, because of being in the prime of life, the presence of vital Qi, as well as the balance and coordination of movement and transformation of Qi, blood, Yin and Yang, is sufficient to resist external evil, demonstrating no susceptibility or mild susceptibility, with a short disease course and a good prognosis. In children, for the viscera are not well developed, presenting delicate viscera, unfilled shape and Qi, and immature Yin and Yang, they fall sick easily and quickly [20] . However, in the overall growing phase, they are made up of "pure Yang", are robust, and will recover easily.

Patients with underlying diseases, such as diabetes, hypertension, heart disease, chronic tracheitis, tumors, or other diseases, usually suffer from a deficiency of vital Qi; if they experience the external evil, the disease is often characterized by severe illness, rapid progression, and rapid transmission, resulting in critical illness and even death. Pregnant women have a special physiological state, with a relative deficiency of Yin-blood and relative hyperactivity of Yang Qi. The growth of the fetus blocks the rise and fall mechanism of the Qi in pregnant women, which may lead to poor operation of Qi and blood. Therefore, the elderly, the infirm, children and pregnant women require close monitoring.

Currently, there are no drugs specifically approved for COVID-19. In the treatment plan announced by the National Health Commission of the People's Republic of China [21] , Western medicine offers mainly symptomatic treatment support, including early oxygen therapy and the use of corticosteroids. The treatment plan comprises antiviral therapies, including interferon-α, lopinavir, ritonavir and ribavirin; however, the curative effect remains unsatisfactory.

Chinese medicine is now fully involved in the treatment of COVID-19 patients [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] , utilizing the advantages of TCM syndrome differentiation and treatment, improving the cure rate, and reducing mortality (Table 1) . Fever is the main symptom of the disease, with most hiding fever not accompanied by a cold. Other symptoms include sleepiness and discomfort, dry cough and less phlegm, thirst without the desire to drink, chest tightness and palpitation, occasional muscle aches, nasal congestion and runny nose, and loose stools. No sweat, no sthenic heat or irritable heat sensation, and no sore throat. The tongue is dark red, or its edge is red, the moss is thin and white, and the pulse has no fixed point. 

Currently, according to published data, COVID-19 clinically manifests as different stages of disease progression. TCM treatment requires syndrome differentiation and treatment based on the stages, which are defined as initial stage (mild), progressive stage (severe), extreme stage (extremely severe) and recovery stage (convalescent stage). The medicines' sources, medicines' names in Latin and English are presented in Table 2 . 

The damp toxin in the Shangjiao membrane should be treated for "damp-heat clearance to cure the lung," including separating and dissipating the damp-heat, paying critical attention to the smooth release of lung Qi. Furthermore, it is crucial to closely monitor the potential of the toxin to enter the blood in order to resolve the dampness, eliminate the filth, promote the Qi mechanism, resolve blood stasis, and relieve the blood vessel networks, thereby following the principles of the Huopu Xialing Decoction and Sanren Decoction [14] . The combination prescription includes Guanghuoxiang, Peilan, Banxia and Doukou for aromatizing, drying and regulating Qi; Xingren for promoting lung Qi; Fuling, Zexie, Huashi, Tongcao, Danzhuye and Yiyiren for relieving and removing dampness or allowing the removal of dampness;

and Mudanpi and Chishao for resolving blood stasis. The combination of these herbs can smoothen the Sanjiao Qi mechanism, dissipate and dissolve the dampness, resolve blood stasis, and dredge collaterals.

Toxins causing dampness can increase the heat in the body; this dampness and heat can lead to infection of the lung and negatively affect the functioning of the lung. 

During the progressive stage, if the disease is not properly treated, the heat and dampness cause the lung to close, with the possibility of internal closure and external prolapse appearing. It is necessary to discuss treatment from the point of Qi 

This period is dominated by asthenia, with many changes necessitating individual syndrome differentiation and treatment. Some studies have emphasized that Xue's Wuye Lugen Decoction can be used as reference to clear the residual evil and promote lung circulation, activate the spleen, and strengthen healthy Qi [14] . The five leaves in the formula float and bring the evil to the surface. Among them, Huoxiang leaf, Bohe, fresh lotus leaf and Peilan leaf are all fragrant and good at invigorating the spleen. Lugen and Dongguazi can be used for infiltration. The formula is light and nimble and can be used for dispersing, purging, and infiltration.

Additionally, it is necessary to pay attention to the following points. (1) Focus on removing dampness. The process of dampness removal is considered during diagnosis and treatment of the disease. Although the epidemic toxin is mainly characterized by toxic heat, dampness and turbidity, it is difficult to separate the heat and dampness characteristics from the initial stages of the infection to the end. It is also difficult to only get rid of heat without removal of dampness as well. Dampness is Yin evil, and it is unsuitable to use cold and cool drugs during the early stage; warm and tonic herbs in the later stage should also be used cautiously. Furthermore, it is permissible to use a combination of drugs to resolve dampness, dry dampness, and drain dampness during different stages.

(2) Promoting blood circulation and resolving blood stasis. The patients should be treated with drugs for promoting blood circulation and resolving blood stasis immediately after the appearance of lung shadow. During COVID-19, the patients present high fever, sputum mixed with blood, dark purple-colored tongue, and consolidation or ground glass shadows in early lung images. Pathological reports indicated diffuse alveolar damage, hyperemia, hemorrhage, edema, and pulmonary interstitial inflammation, which are all manifestations of blood stasis. Therefore, during the different stages of treatment, it is necessary to combine products promoting blood circulation and eliminating blood stasis, dredging blood vessels, removing blood stasis, reducing alveolar damage, preventing pulmonary interstitial fibrosis, and reducing sequelae, which is conducive to the comprehensive rehabilitation of patients.

Additionally, there are no specific Chinese medicine prescriptions for the elderly, pregnant women, children, and patients with underlying diseases. Hence, it is essential to study the signs and symptoms of COVID-19 cases to provide effective treatment.

TCM focuses on the idea of "prevention of disease," advocating prevention before the disease occurs and prevention of change after disease. Therefore, those who have a history of exposure or have been in close contact with epidemic areas should be prioritized with the treatment principles, including stabilizing Qi and strengthening the exterior, removing heat, and detoxifying the body according to the composition of the prescription and climatic factors in different regions, to practice prevention before disease occurrence. In the cases of patients with chronic illness or those susceptible to infection, emphasis should be given to strengthening the vital energy, improving immunity, and using Yupingfeng Powder to invigorate Qi and solidify the exterior [26] . Individuals with underlying diseases can be treated regionally according to their diseases. According to TCM, after conception, the whole body's Yin-blood is gathered in Chong Meridian, Ren Meridian, and the uterus, placing the pregnant women in a special physiological state of a relative deficiency of Yin-blood and relative hyperactivity of Yang Qi. The growing fetus will block the rise and fall of Qi and blood, resulting in poor operation of Qi and blood. "It should be cool before pregnancy and warm after birth" is the general principle of regulation and stabilization in TCM before and after pregnancy. This can be adjusted and treated in advance to prevent the occurrence of disease, and the method of nourishing Yin and clearing heat, regulating the Qi mechanism, and calming the fetus is adopted. Young children are not full of Qi; their Yin and Yang are immature, and their viscera are delicate, especially, the lung, spleen and kidney [26] . Hence, it is recommended to protect the Qi of the spleen and stomach in advance to nourish other organs, strengthen their physique, and resist the evil of epidemic disease, utilizing Sijunzi Decoction or Yupingfeng Powder to invigorate the Qi for consolidating superficies [26] . According to TCM, different people have different physical characteristics, and hence, different treatment principles and medication plans should be generated based on their physical characteristics (Table 3) . Based on the existing treatment schemes, the prescription composition and dosage recommended for prevention and treatment of COVID-19 during different stages are introduced in Table 4 . Renshen 9 g, Baizhu 9 g, Fuling 9 g, Gancao 6 g Shengmai Drink Renshen 9 g, Maidong 9 g, Wuweizi 6 g, Danshen 6 g Guizhi Decoction Guizhi 9 g, Shengjiang 9 g, Dazao 9 g, honey-fried Gancao 6 g Shenzhu Powder

Cangzhu 1000 g, Chenpi 1000 g, Houpo 1000 g, honey-fried Gancao 360 g, Guanghuoxiang 250 g, Sharen 120 g Huangqi Guizhi Wuwu Decoction Huangqi 15 g, Guizhi 12 g, Baishao 12 g, Shengjiang 25 g, Dazao 4 g

Huopu Xialing Decoction and Sanren Decoction Guanghuoxiang 6 g, Peilan 6 g, Banxia 9 g, Doukou 6g, Xingren 9g, Fuling 9 g, Zexie 6 g, Huashi 18 g, Tongcao 6 g, Danzhuye 6 g, Yiyiren 12 g, Mudanpi 6 g, Chishao 6 g Progressive stage Lei's aromatic turbid-resolving method Guanghuoxiang 3 g, Peilan 3 g, Chenpi 6 g, Banxia 6 g, Dafupi 3 g, Houpo 3 g, Heye 9 g Jiedu Huoxue Decoction combined with Shengjiang Powder Lianqiao 6 g, Gegen 6 g, Chaihu 9g, Danggui 6g, Shengdihuang 15g, Chishao 9g, Taoren 24g, Honghua 15 g, Zhiqiao 3 g, Gancao 6 g, Jiangcan (wine fried) 6 g, Chantui 3 g, Jianghuang 9 g, Dahuang (raw) 12 g Extreme stage Shenfu Sini Decoction Honey-fried Gancao 12 g, Fuzi 10 g, Ganjiang 6 g, Renshen Shigao 1500 g, Hanshuishi 1500 g, Huashi 1500g, Shuiniujiao 500 g, Lingyangjiao crumbs 500 g, Muxiang 500 g, Chenxiang 500 g, Xuanshen 500 g, Shengma 500 g, Gancao 240 g, Mangxiao 5000 g, Xiaoshi 930 g, Shexiang 38 g, Zhusha 90 g, Jinbo 3000 g, Dingxiang 30 g Suhe Xiang Pill

Suhexiang 60 g, Baizhu 60 g, Muxiang 60 g, Shuiniujiao 60 g, Xiangfu 60 g, Zhusha 60 g, Hezi 60 g, Tanxiang 60 g, Anxixiang 60 g, Chenxiang 60 g, Shexiang 60 g, Dingxiang 60 g, Bibo 60 g, Longnao 60 g, Ruxiang 60 g Recovery stage Xue's Wuye Lugen Decoction Huoxiang leaf 6 g, Bohe leaf 1.8 g, fresh lotus leaf 3 g, Pipaye 15 g, Peilan leaf 4.5 g, Lugen 30 g, Dongguazi 15 g

According to the description of discharge criteria in the Diagnosis and Treatment Protocol for COVID-19 (Trial Version 7) [40] , the evaluation of COVID-19 should be based on body temperature (more than 3 days after returning to normal), obvious improvement of respiratory symptoms, and pulmonary imaging (obvious alleviation of inflammation). If the above symptoms and signs are relieved and the respiratory pathogen nucleic acid test is negative for two consecutive times (the sampling interval is at least 24 hours), patient can be considered to be cured.

However, we believe that the quantification of lung imaging related to the above efficacy evaluation index is insufficient. Hence, we suggest that the lung imaging of patients with COVID-19 should be comprehensively evaluated, based on the definition of the lung segment and the density criteria of high, medium and low grades, to better evaluate the treatment efficacy.

The use of TCM adopts the holistic concept, combined with symptoms, signs and other corresponding manifestations, to examine the syndromes and seek the causes, to support the selection of drugs based on syndrome differentiation. Syndrome differentiation and treatment, as one of the characteristics and advantages of TCM, is very important in diagnosis and treatment. For example, in the treatment of COVID-19, the syndrome types differ among individuals in different regions, under different climatic conditions, and for relatively different physiques. Syndrome differentiation should be clearly defined in combination with different factors and clinical syndrome characteristics. Prescriptions are mainly used to improve immunity, balance human Qi, blood, Yin and Yang, and recover organ function. According to the study of COVID-19 treatment herbs [41, 42] , Chinese herbal medicines with a higher probability to directly inhibit SARS-CoV-2 have been selected, including Lianqiao, Gancao, Sangbaipi, Jinyinhua, Sangye, Pipaye, and other herbs, commonly used to treat viral pneumonia. Drugs should be selected and utilized according to the corresponding syndrome types. Furthermore, with disease development, the drugs should be given the flexibility to deal with different syndrome types, and the whole process should be adjusted according to the principle of "three factors and measures," undertaking multi-target treatment. TCM also plays a leading role during the recovery period and post-discharge convalescence. Currently, although some patients present a negative nucleic acid test accompanied by alleviated pneumonia and recovered body temperature, they may still demonstrate symptoms, including fatigue, shortness of breath, loss of appetite, and anxiety. Some patients may present pulmonary fibrosis due to poor absorption of pulmonary inflammation, which may affect the quality of life; additionally, some patients may suffer adverse reactions during drug therapy. It is crucial to resolve such related issues when TCM is involved. However, we do not advocate taking medicine without incident, and the preventive prescription is only a corresponding choice for people with an imbalance of Qi, blood, and Yin and Yang.

When selecting the prescription, attention should be paid to the syndrome and symptoms, especially in special groups, such as children, pregnant women, and the elderly. Moreover, any special physique should be closely monitored when using Medicine of China on screening effective prescriptions for the prevention and treatment of the novel coronavirus pneumonia [43] . As of February 5, four pilot provinces have used the Qingfei Paidu Decoction to treat 214 confirmed cases, with a treatment course of 3 days, demonstrating a total efficacy rate exceeding 90%, among which over 60% of the patients showed significant improvement in symptoms and imaging manifestations, and 30% patients demonstrated stabilized symptoms without aggravation. Concurrently, Lianhua Qingwen Granule [44] is used in clinical treatment based on the principle of clearing away epidemic toxin, dispersing the lung, and expelling heat. Reportedly, it has been confirmed to significantly improve fever, cough, expectoration, and shortness of breath in confirmed cases of COVID-19.

According to the feedback of clinical data, the efficacy of TCM in the clinical treatment of COVID-19 is great, and it still needs to be adjusted and improved with the clinical accumulation. In brief, the combination of Chinese and Western medicine can complement each other's advantages, which can improve the comprehension of the core of the disease, and cooperate actively and effectively in clinical settings to enhance overall efficacy.

The study was not supported by any funding.

WSX and LYB wrote the article; WY revised part of the article and made grammatical corrections; WXX provided research ideas; LJY reviewed the article and provided guidance; NM and SYJ collated the data.

The authors declare that they have no conflict of interest.

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