Feng-Chan Wang ,Ping Han ,Hong Li ,Hai-Yan Ye ,Pei-Xia Zhou ,Wei Tian ,Yi Xiao,Yi Wei,Kun Wang,Xue-Chao Lu*,Hai-Bo Hu*

1Department of Pulmonary Disease in Qingdao Hospital of Traditional Chinese Medicine,Qingdao 266033,China.2Clinical Laboratory in Qingdao Hospital of Traditional Chinese Medicine,Qingdao 266033,China.3Department of Internal Medicine in Qingdao Technicians College,Qingdao 266229,China.4First Clinical Hospital,Shandong University of Traditional Chinese Medicine,Jinan 250355,China.

Abstract Towards the end of 2019,a novel coronavirus pneumonia (coronavirus disease 19,COVID-19) caused by SARS-CoV-2 infection emerged in Wuhan.The SARS-CoV-2 virus quickly spread across the globe,seriously affecting public health and economic development of countries worldwide.Currently,antiviral drugs developed for COVID-19 lack strong clinical trial support and the high mutation rate of the virus causes difficulties in vaccine development,thus a complex and delayed large scale role out of an efficacious vaccine.Traditional Chinese medicine (TCM) has been used for treating various conditions for thousands of years and has a unique systems theory.It can be individualized into specific therapeutic regimens according to the patients’ physical condition,clinical symptoms,and other distinguishing factors.In addition,TCM often has different effects at different disease stages,thus contributing to disease prevention,treatment,and rehabilitation.Existing evidence shows that TCM has efficacy in the treatment of COVID-19.The active ingredients of TCM have various pharmacological properties,including antiviral,anti-inflammatory,and immunomodulatory activity,with clinical trials showing that these prescriptions reduce symptoms of COVID-19,promote viral clearance,and ultimately improve survival in infected patients.This article discusses the advantages and mechanisms of TCM in the treatment of COVID-19,hoping to provide a reference platform in the fight against the disease.

Keywords: traditional Chinese medicine;COVID-19;SARS-CoV-2;benefits

Highlights

Traditional Chinese medicine has its own advantages in the treatment of coronavirus disease 19.

The active ingredients of traditional Chinese medicine have antiviral,anti-inflammatory and immunomodulatory effects.

Traditional Chinese medicine can alleviate symptoms,promote virus clearance,and improve the survival rate of coronavirus disease 19 patients.

Medical history of objective

In history,the Chinese nation has always used traditional Chinese medicine to fight against the epidemic.The theory of traditional Chinese medicine has been continuously improved and developed in the fight against the epidemic,forming an effective prescription specifically for epidemic diseases and being recorded in the classics of traditional Chinese medicine.Auxiliary of The Theory of Typhoid Fever(Boyun Ke,1706 C.E.),Treatment Cases of Plague(Lantai Zhu,1892 C.E.)recorded he prescriptions with good curative effect on epidemic.There are also monographs on the plague,such asOn Plague Diseases(Youxing Wu,1642 C.E.),Origin of Plague(Yinling Ma,1725 C.E.).

Background

The outbreak and rapid spread of coronavirus disease 19 (COVID-19)at the end of 2019 caused great harm to mankind [1,2].The typical symptoms of COVID-19 include fever,cough,shortness of breath,fatigue,muscle soreness,and diarrhea,with dyspnea occurring in severe cases[3].Many studies have reported that COVID-19 can cause combined damage to multiple organs such as the heart,liver,kidney,and skin [4-9].Studies have shown that the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative virus of COVID-19,is an enveloped single-stranded RNA virus that is zoonotic and highly pathogenic,and like all viruses,can undergo nucleotide mutations over time to form different viral lineages [10,11].

COVID-19 spreads rapidly,is difficult to treat,and has a high virus mutation rate.Currently,no specific antiviral drugs are available.Owing to this,vaccination is cardinal to prevent infection;however,for various reasons,the full popularization of vaccines has not been achieved in recent years [12].Considering the complexity of the disease,there is an urgent need to develop novel,effective,and safe treatment options to stop its spread.

Traditional Chinese medicine (TCM) has been extensively used for epidemic prevention and control.For example,TCM had successful use in the management of SARS.The Department of Traditional Chinese Medicine of the First Affiliated Hospital of Guangzhou Medical College treated 71 cases of SARS,and reported a cure rate of 98.6%.Of these,70 patients were treated with TCM,mainly using the“Xinliang” (clearing away heat) detoxification method,and all recovered fully prior to being discharged from hospital[13,14].In the face of the current COVID-19 epidemic,the national epidemiological survey has reported that TCM has played an important role in the fight against the disease,with the total effective rate of some TCM prescriptions for the treatment of COVID-19 reaching more than 90%[15].

This article reviews and analyzes the benefits and mechanisms of action of TCM in the prevention and control of COVID-19,and the findings are perceived to assist in further understanding of the disease and exploring possible treatment options.

Pathogenic mechanism of SARS-CoV-2 and use of Western medicine in treating COVID-19

SARS-CoV-2 directly damages respiratory cells

SARS-CoV-2 is a single-stranded positive RNA virus of the genus β coronavirus,which is wrapped in an envelope with an average diameter of between 75-150 nm.The SARS-CoV-2 genome is less than 30 kb long.There are 14 open reading frames encoding non-structural proteins used in viral replication and assembly processes.Structural proteins include spike (S),envelope (E),membrane/matrix (M),and nucleocapsid (N),as well as auxiliary proteins [16,17].In addition,S consists of receptor binding (S1) and cell membrane fusion (S2)subunits[18].

SARS-CoV-2 requires a host cell for pathogenicity,which usually involves attachment,entry,replication,assembly,and release.First,the virus binds to the angiotensin-converting enzyme 2 (ACE2)receptor located on the host cell membrane,mainly through the receptor-binding domain of its S protein S1 subunit,promoting host cell invasion [19].In addition to ACE2,alternative receptors/co-receptors and cellular proteases have been implicated in the pathogenesis of SARS-CoV-2,including basic immunoglobulin CD147 [20,21],neuropilin-1 [22],Middle East Respiratory Syndrome-CoV receptor dipeptidyl peptidase 4[23,24],angiotensin II type 2 receptor [25],and alanyl aminopeptidase[26].

Second,similar to other coronaviruses,SARS-CoV-2 requires the protein hydrolysis process of the S protein to activate the endocytic pathway.Host proteases have been shown to be involved in the cleavage of S proteins that activate the entry of SARS-CoV-2,including the transmembrane proteases serine protease 2,histone protease L,and flavoproteinase(furin) [27-29].

Third,upon entry into the host,the virus releases the viral genome(single-stranded positive RNA) and uses the host ribosome to convert it into a viral polyprotein.Viral proteases,3-chymotrypsin-like protease and papain-like protease,cleave viral polyproteins into effector proteins.RNA-dependent RNA polymerase in turn synthesizes a full-length,negative-stranded RNA template for making more viral genomic RNA.The viral genome is then synthesized by genome duplication,producing the four essential viral structural proteins (N,S,M and E) by transcription and translation.N proteins bind to genomic RNA,while S,M,and E proteins integrate into the membrane of the endoplasmic reticulum (ER) to form the ER-Golgi intermediate compartment (also known as the vesicle tube cluster) [30].

Lastly,the viral daughter is transported via the ER-Golgi intermediate compartment to the plasma membrane of the host cell,where it is released as a daughter virus by cytosolic action.

SARS-CoV-2 triggers a cytokine storm

After entering the human body,SARS-CoV-2 can infect mononuclear cells,macrophages,and dendritic cells,causing them to activate and secrete interleukin (IL)-6 and other inflammatory cytokines.IL-6 has pro-inflammatory properties [31] and mainly transmits signals through two main signaling pathways: the cis and trans pathways[32].Activation of cis signaling leads to pleomorphism in the acquired immune system (B cells and T cells) and the innate immune system(neutrophils,macrophages,and natural killer cells),contributing to the development of cytokine release syndrome [33],that is,excessive release of pro-inflammatory cytokines (interferon-α,interferon-γ,IL-1β,IL-6,IL-12,IL-33,TNF-α,TGF-β,etc.) and chemokines (CCL2,CCL3,CCL5,CXCL8,CXCL9,CXCL10,etc.),which is known as the“cytokine storm” [34].This may be an important factor in the development of acute respiratory distress syndrome.These inflammatory factors further damage epithelial cells and enter the blood circulation,causing damage to other organs [35].

SARS-CoV-2 damages multiple systems

COVID-19 is known to cause severe respiratory illness,which is associated with high expression levels of ACE2 in type 2 alveoli.The disease causes extensive lung inflammation,characterized by deep airway and alveolar damage,leading to progressive respiratory failure[36].It also causes direct and indirect damage to the endothelial cells of blood vessels.By attacking these cells,SARS-CoV-2 can cause blood vessels to leak and clot.These changes trigger systemic inflammation and contribute to acute respiratory distress syndrome[37].It can also cause a number of serious complications that are sometimes the only clinical feature of COVID-19,even in mild cases and asymptomatic individuals.

A study that investigated the fate of other organs besides the lungs from autopsy specimens reported the following: SARS-CoV-2 genomic RNA was highest in the lungs;however,the heart,kidney,and liver also showed high amounts,with the virus being detected in heart specimens of 16/22 patients [38].SARS-CoV-2 infection caused apoptosis and cell arrest within 72 h of exposure [39].In addition to directly infecting heart muscle cells,the virus also enters endothelial cells that connect the heart to multiple blood vessel beds.Therefore,it can also lead to cardiac complications,including myocarditis,cell necrosis,heart attack like heart attack,arrhythmia,and acute or delayed heart failure(muscle dysfunction) [40].

Similarly,because ACE2 is highly expressed in differentiated intestinal epithelial cells,the gut may be another target organ for the virus [41].After invading intestinal epithelial cells,SARS-CoV-2 causes digestive tract symptoms,such as malabsorption,intestinal secretion imbalance,and intestinal nervous system activation,leading to diarrhea [42].ACE2 is also expressed in bile duct cells,pancreatic exocrine glands,and islet tissues,thus SARS-CoV-2 infection also causes damage to liver function and islets [43,44].In the urinary system,the accumulation of the SARS-CoV-2 virus coshell protein antigen in renal tubules was detected by immunohistochemistry,and was postulated to be the cause of acute renal tubule injury [45].The nervous system is also damaged following viral infection,and patients with the severe form of the disease may suffer from consciousness disorders or acute cerebrovascular diseases [46].

Western medicine treatment and advances in vaccines for COVID-19

The current treatment for COVID-19 is based on symptomatic and supportive therapy.In antiviral therapy,a variety of drugs are currently available for targeted use,including remdesivir,favipiravir,chloroquine,and hydroxychloroquine [47];however,most antiviral drugs have side effects.In immunotherapy,monoclonal antibodies are the preferred passive regimen [48].Other therapies include interferon-based immunotherapy,cell immunotherapy-chimeric antigen receptor NK cell therapy,SARS-CoV-2-specific T-cell response therapy,suppression of T-cell depletion,macrophages,and other cell immunotherapies [49-53].However,the rapidly mutating SARS-CoV-2 virus has been characterized by targeted evolution with enhanced evasion capabilities.Other therapies include glucocorticoid,antithrombotic,and mesenchymal stem cell treatment[54-56].In addition,researchers are actively exploring novel treatment options such as intravenous immunoglobulin and recovery plasma therapy.For critically ill patients,apart from respiratory and circulatory support,there is also a need to improve caloric intake and nutritional support,which is important for improving the immune function of the patient,shortening the course of the disease,and reducing morbidity and mortality [57].In addition,in the United States,the Food and Drug Administration gave emergency approval to Pfizer’s oral anti-SARS-CoV-2 drug Paxlovid for people over 12 years of age and weighing at least 40 kg on December 22,2021,making it the first oral anti-SARS-CoV-2 drug approved in the United States.A 3CL protease inhibitor specifically designed to combat SARS-CoV-2 is recommended by the World Health Organization for patients with mild or severe COVID-19 with a high risk of hospitalization.However,owing to its high cost,its clinical application has been difficult to popularize.

Regarding SARS-CoV-2 vaccines,many of them have been used in clinical practice,including inactivated vaccines,live attenuated vaccines,viral vector vaccines,subunit (recombinant protein)vaccines,DNA vaccines,and RNA vaccines [58].Each category of vaccine has its own shortcomings.For example,inactivated vaccines need to verify the integrity of antigens and/or genetic epitopes,and because the whole genome is very small,live attenuated vaccines take longer to establish infectious clones for the attenuated coronavirus vaccine seeds.Owing to this,safety issues must be thoroughly monitored.Further,vector immunization with viral vector vaccines may adversely affect vaccine efficacy (mainly based on the vector selected)and subunit(recombinant protein)vaccines that can produce globally available recombinant proteins may be limited and must be tested for antigen and/or gene epitope integrity.Moreover,to achieve robust immunogenicity for DNA vaccines,a different distribution system is required,and safety issues associated with reactogenicity have been identified for RNA vaccines.

Regarding the development of vaccines against strains with immune escape,the French Higher Authority for Health announced the approval of three neo-crown vaccines against Omicron variants on September 20,2022.The European Medicines Agency,the regulators of drugs in the European Union,tweeted on September 27,2022 that it had begun evaluating applications for authorization of the Moderna bivalent vaccine against SARS-CoV-2,which targets the original Omicron strains and the BA.4 and BA.5 variants.

There are uncertainties regarding the duration of vaccine protection and controversy regarding the effectiveness of existing vaccines against existing SARS-CoV-2 variants.Numerous adverse reactions to vaccines have been reported,including allergic reactions,myocarditis,and vaccine-induced immune thrombotic thrombocytopenia [59,60].Therefore,the global population still faces several challenges in terms of safe and efficacious treatment against COVID-19.Details of the main classes of vaccines are summarized in Table 1.

Table 1 Main classes and current situation of COVID-19 vaccines

Possible mechanisms of TCM in the treatment of COVID-19

At present,studies on the mechanisms of TCM in the treatment of COVID-19 mainly rely on bioinformation technologies,such as network pharmacology,which can predict potential bioactive ingredients and mechanisms of action with high probability.TCM is characterized by multiple components,targets,and regulatory modes.By constructing a complex network between drug-target-disease to analyze the mechanism of drug action,the “traditional search for a single target” to a “comprehensive network analysis” can be applied for TCM.

Antiviral effects of active ingredients of TCM

Currently,the treatment of COVID-19 is mainly based on supportive measures.Natural medicines may play a fundamental role in preventive therapy and provide alternative methods for the treatment of patients with COVID-19.With the advancement of research,various flavonoids have been found to inhibit different targets of COVID-19[61],such as blocking the enzyme activity of viral proteases,such as 3-chymotrypsin-like protease,papain-like protease,and helicase,or interfering with spike protein.Further,a few flavonoids have been shown to inhibit ACE activity [62].A large number of network pharmacological studies have found that the LianHuaQingQen capsule,Xuebijing injection,and Tanreqing injection can inhibit virus replication [63-66].

The Maxingshigan decoction was also commonly used as a TCM for managing COVID-19 during the height of the pandemic.Experimental studies have shown that the Maxingshigan decoction can improve the immune function of the body and regulate the expression and secretion of cytokines,thereby reducing lung inflammation and improving the general condition of influenza virus pneumonia.Maxingshigan decoction can also improve the immune system,upregulate the expression and secretion of IL-2 and IL-4 proteins,and downregulate the expression and secretion of TNF protein in the treatment of viral pneumonia[67].

In addition,some active ingredients of TCM have clear antiviral effects.For example,ephedra extract(+)-catechin is one of the active antiviral components that inhibits adenosine acidification and growth of the PR8 influenza virus [68].Further,glycyrrhizic acid,the main bioactive ingredient of licorice,has been shown to interact directly with ACE2,suggesting that glycyrrhizic acid may be a potential anti-SARS-CoV-2 therapeutic agent [69].Honeysuckle has a wide range of antiviral effects against viral infections,including influenza virus,respiratory syncytial virus,avian influenza virus subtype H9,enterovirus EV71,and herpes virus [70].Rhubarb has considerableantiviral activity and is often used to treat respiratory diseases.Anthraquinone compounds extracted from rhubarb can inhibit the infectivity,inhibit the synthesis and replication,and even directly inactivate the virus[71].Natural products such as quercetin,puerarin,porphyrin,quercetin-7-O-β-d-glucoside,and patchouli alcohol have good binding affinity to Mpro and can reduce viral replication.

Wang et al.[72] used real-time fluorescence quantitative PCR,immunofluorescence,qRT-PCR,and other methods to investigate the mechanisms behind TCM activity.Their results showed that at the RNA and protein levels,the Lung Cleansing and Detoxifying decoction can inhibit coronavirus replication in a dose-dependent manner at non-toxic concentrations.Time process analysis revealed that the Lung Cleansing and Detoxifying decoction mainly plays a role in the early stage of coronavirus infection;on the one hand,it can hinder its cell entry process by inhibiting the adsorption of the virus.Further,it has antiviral activity through adjusting the expression of interferon and interferon-stimulated genes.

Active ingredients of TCM have anti-inflammatory properties

Cytokine storm is a serious clinical symptom caused by a systemic hyperinflammatory response.By changing vascular permeability,blocking the airways,and causing edema and hypoxia,cytokine storm can cause serious damage to many organs,including the lungs,and even lead to death [73].Among the various cytokines associated with cytokine storm,IL-1 and IL-6 are considered key cytokines in most patients.These cytokines are representative pro-inflammatory cytokines,which together with TNF-α,play an important role in the acute response to inflammation [74].Rapid clinical deterioration and a high risk of death in patients with severe COVID-19 may be related to cytokine storm [75].

TCM plays a regulatory role in the cause and process of cytokine storm by regulating the release of cytokines,macrophages,monocytes,and neutrophils,as well as the permeability of pulmonary blood vessels and the activity of T cells [76].TheNotice of the Health Commission of the People’s Republic of China and the Administration of Traditional Chinese Medicine of the People’s Republic of Chinaon printing and distributingthe Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia(Trial Sixth Edition) also recommends the use of “Lung Cleansing and Detoxifying decoction” for the clinical treatment of confirmed cases of COVID-19 [77].The Lung Cleansing and Detoxifying decoction was analyzed using network pharmacology and the results showed that the it can play an important role in the pharmacological mechanism of treating COVID-19 through Toll-like signaling pathways.Its active ingredients can directly interfere with Toll-like receptor 4 and regulate downstream signaling pathways,including the NF-κB and MAPK signaling pathways,inhibiting the release of the pro-inflammatory factors TNF-α,IL-1β,and IL-8,thus avoiding a cytokine storm.Interestingly,Lung Cleansing and Detoxifying decoction may also regulate downstream positions other than Toll-like receptor 4,PI3K,AKT,and CASP8 without interfering with Toll-like receptor 2/3.Flavonoid active substances widely found in TCM also play a strong anti-inflammatory role.It has been reported that flavonoids can interfere with the activation of NLRP3 inflammatory bodies,which often occur in coronavirus diseases and have been proven to increase the production of inflammatory cytokines,leading to respiratory distress syndrome.

A large number of clinical observations and randomized controlled trials have shown that the Lianhua Qingwen capsule has a good curative effect when used in patients with COVID-19.In the current COVID-19 pandemic,a randomized controlled trial with 259 participants found that Lianhua Qingwen capsule combined with umifenovir alleviated the clinical symptoms of patients with mild COVID-19,regulated the expression of related inflammatory factors,improved therapeutic efficacy,and reduced the rate of severe conversion.The Lianhua Qingwen capsule consists of 13 TCMs,among whichIsatis indigoticaFort.root has activity against the influenza virus and oxygen free radicals through reducing the synthesis and secretion of inflammatory mediators TNF-α,IL-6,and IL-10,which are considered key indicators of the severity and poor prognosis of COVID-19.In addition,isatis root erucic acid inhibits viral replication by inhibiting the NF-κB and p38 kinase signaling pathways,thus playing a broad-spectrum antiviral role [78,79].It has been reported that some surface proteins on SARS-CoV-2 can bind to the hemoglobin molecule of red blood cells,resulting in the destruction of the heme structure and the release of harmful iron ions into the blood,leading to the development of oxidative stress,causing oxidative damage to tissues and organs.Therefore,we speculate that Lianhua Qingwen capsule may treat COVID-19 by alleviating oxidative stress.In addition,the P38 MAPK signaling pathway is also associated with the death of SARS-CoV-2 infected cells.It has been reported that platelet activation induced by SARS-CoV-2 may be involved in thrombosis and inflammation in patients with COVID-19.The expression of platelet ACE2 receptors were shown to decrease after activation of SARS-CoV-2.Therefore,the MAPK pathway may play an important role in the treatment of COVID-19 when using the Lianhua Qingwen capsule.

Immunomodulatory effects of TCM

Studies have shown that SARS-CoV-2 infection can cause immune imbalance in the body,leading to sepsis.It is difficult for patients to develop a normal immune response when infected as the body is in a state of immunosuppression.Immunosuppression causes low immunity,which makes it difficult for the body to clear the virus.Consequently,this leads to secondary infection,rapid progression to septic shock,multiple organ failure,and even death [80].In addition,some patients discharged from hospital and are in the convalescence stage still present with symptoms such as lack of energy,anxiety,depression,poor sleep,abnormal blood results,and an immune function that has not fully recovered.Owing to this,follow-up rehabilitation is needed to enhance immunity and prevent re-infection[81].

According to research by academician Zhang Boli’s team,COVID-19 is pathologically characterized by damaged organ and immune function.The immune and pulmonary function of patients in the rehabilitation stage will not have been completely repaired,and supplementing Qi and nourishing Yin (a concept based on TCM theory,Qi is like “energy”,Yin is like “substance”) can be used to promote the recovery of these patients with success [82].TCM has multi-component and multi-target functions,and its use in alleviating the immune imbalance caused by SARS-CoV-2 infection has become a hot topic in clinical research.

Many TCMs have immunomodulatory effects.For example,ginseng extract can improve the human body's resistance and immunity to external viruses,and the active components in ginseng can promote lymphangiogenesis and repair,regulate immune imbalance,and play a positive role in both the severe illness and recovery periods [83].Ginseng polysaccharide can reverse the imbalance of CD4+/CD8+T lymphocytes,and assists in maintaining bodily immune homeostasis in the case of inflammation or immune suppression [84],enhancing immune active molecules,thus improving immunosuppression.Ginseng protein can promote the proliferation of lymphocytes and the secretion of immune factors,thus enhancing immunity [85].Cordyceps enhance immune function,promote the differentiation and proliferation of T and B lymphocytes,and affects the production of various cytokines [86].Astragaluspolysaccharide andAstragalussaponin promote the regeneration and differentiation of effector B cells and activate the synthesis of antibodies to enhance acquired immunity[87].

Overall,the use of TCM in treating COVID-19 can play a role in multiple pathogenic stages as is depicted in Figure 1.In addition,Table 2 summarizes possible mechanisms of some TCM constituents used in treating COVID-19.

Table 2 Possible mechanisms of TCM constituents for the treatment of COVID-19

Figure 1 Pathogenic stages of SARS-CoV-2 and the therapeutic effects of TCM.SARS-CoV-2,severe acute respiratory syndrome coronavirus 2;TCM,traditional Chinese medicine;ACE2,angiotensin-converting enzyme 2;IL,interleukin.

Therapeutic benefits of TCM

TCM can relieve COVID-19 symptoms

Currently,TCM therapy is still one of the main treatment strategies for COVID-19 [88].In the latest guidelines,Lianhua Qingwen capsule(Shijiazhuang Yiling Pharmaceutical Co.,LTD.,China)was reported to have anti-inflammatory activity in vitro,inhibiting the replication of SARS-CoV-2 and changing viral morphology.A large number of clinical trials of Lianhua Qingwen capsule have been conducted in China.One such trial involving 284 patients found that the Lianhua Qingwen capsule treatment group had a shortened recovery time from COVID-19 symptoms,with a shortened median duration in clinical symptoms (median duration: 7 days vs.10 days,p＜0.001).In addition,the duration of fever(2 days vs.3 days),fatigue(3 days vs.6 days),and cough (7 days vs.10 days) were all shortened in the treatment group (p＜0.001).Further,the chest CT improvement rate(83.8%vs.64.1%,p＜0.001)and clinical cure rate(78.9%vs.66.2%,p=0.017) were both improved in the treatment group [89].For example,under the guidance of the “harmony method” theory of traditional Chinese medicine,Lu et al.treated COVID-19 (mainly severe and critically ill patients,most of whom had acute lung injury)using integrated traditional and Western medicine for more than 50 days in the Optics Valley Hospital of Wuhan Tongji Hospital in early 2020,and found that the decoction shortened the negative nucleic acid conversion time and fever time in patients.The reduced negative nucleic acid conversion time(23.09 days vs 20.13 days,p=0.03)and fever duration (15.79 days vs 12.36 days,p=0.03) in the experimental group led to an increase in lymphocyte count and improved chest CT features in these patients.In addition,none of the severely ill patients developed critical illnesses and none of all patients died in the ward [90].

TCM promotes viral clearance

Immunoinflammation-related parameters in patients with COVID-19 are closely associated with disease severity.Meta-analysis suggests that an elevated white blood cell count and a high incidence of neutrophil to lymphocyte ratio are associated with disease deterioration in patients with COVID-19 (neutrophil counts are higher while lymphocyte counts tend to be lower in patients with severe COVID-19) [91].Therefore,it is of great significance to study the immune characteristics of peripheral blood to determine the prognosis of these patients [92].A clinical experimental study involving a total of 300 confirmed COVID-19 cases adopted the Qingfei Paidui decoction launched by the National Health Commission of China for clinical intervention in COVID-19 patients.According to the intervention days,Qingfei Paidu decoction administration was varied for the different treatment groups: those with less than 7 days of intervention,8-14 days of intervention,and more than 15 days of intervention.The experimental results showed that when used for early treatment intervention of COVID-19,Qingfei Paidu decoction was effective in improving the white blood cell count and lymphocyte count,with a significantly higher percentage of lymphocytes being observed with earlier intervention.Moreover,early treatment intervention with TCM was found to shorten the time for nucleic acids to turn negative and thus promote virus clearance [93].

TCM therapy improves survival in patients with COVID-19

Given the lack of strong evidence on the effectiveness of antiviral drugs and antibiotics,and the time required for vaccine promotion,TCM use is a viable alternative for the complementary clinical treatment of COVID-19.In particular,TCM has been successfully applied in the treatment of SARS caused by SARS-CoV,a coronavirus homologous to SARS-COV-2,providing valuable information for the application of these herbal products in the prevention and treatment of COVID-19.In theCOVID-19 Diagnosis and Treatment Protocol(the Eighth Trial Edition) issued by the National Health Commission,a variety of TCM prescriptions are recommended,among which “three medicines and three parties” are the general prescriptions for clinical treatment,including Jinhua Qinggan granule,Lianhua Qingwen capsule,Xuebijing injection,Qingfei Paidu decoction,Huashi Baidu decoction,and Xuanfei Baidu decoction.The functions of “three medicines and three parties” which include dispelling evil,clearing heat and dampness,nourishing the spleen,and disinhibiting dampness are suitable for mild,ordinary,and severe COVID-19,as well as critically ill patients based on the clinical characteristics they present[94].In a retrospective cohort study,data of 662 patients with severe/critical COVID-19 admitted to a designated hospital in Wuhan before March 20,2020,were collected,including 484 patients that received TCM.The mortality rates in the TCM and non-TCM groups were 8.3% and 23.1%,respectively.These results indicate that TCM can improve the survival rate of patients with severe COVID-19 as well as those who are critically ill.TCM therapeutics improves Qi,eliminating evil Qi,regulating the internal environment,enhancing immunity,improving antiviral activity,inhibiting inflammation,preventing organ failure,and improving survival [95].

In conclusion,the therapeutic advantages of TCM are shown in Figure 2.

Figure 2 Therapeutic benefits of traditional Chinese medicine

Prospective

During the COVID-19 pandemic and subsequent epidemic,TCM has been widely used in disease prevention and treatment,with its integration with Western medicine showing remarkable therapeutic success.Based on existing clinical data,literature analysis,and network pharmacology,the active ingredients of TCM have been shown to exert anti-inflammatory effects by inhibiting the entry and replication of viruses in vivo through combining Mpro and ACE2 targets,acting on signaling pathways such as TNF,MAPK,Toll,NF-κB,IL-17,and HIF-1,and exhibiting unique characteristics and advantages in preventing multisystem damage[96].

Conclusion

However,there are still some shortcomings with the use of TCM in preventing and treating COVID-19 that need to be addressed,for example,in clinical treatment,attention should be paid to rational drug use especially in patients with liver and kidney dysfunction or related underlying diseases,to reduce the probability of drug accumulation poisoning [97].In terms of clinical research,only a few clinical studies with small sample sizes have been conducted,thus low clinical evidence levels exist.To this end,more clinical practice data and further in-depth pharmacological mechanism research is needed[98].

In summary,TCM has shown the unique advantages of a short treatment duration and good therapeutic efficacy during the COVID-19 pandemic.Its use in early prevention and treatment can reduce mortality,improve symptoms,reduce the occurrence and recurrence of complications,and has broad beneficial prospects.We should focus on evidence-based medicine,combine it with modern science and technology,modernize TCM,establish standardized diagnostic and treatment standards,and ultimately realize economic and social value.Simultaneously,we should further strengthen evidence-based research on Chinese medicine,improve the level of its clinical-based research evidence for the treatment of future novel coronavirus infections as well as other sudden,emerging,and major infectious diseases.The TCM decoction mentioned in the article is shown in Table 3.

Table 3 Scheduled chinese medicine decoctions and prescriptions