Huang Lian Jie Du decoction in the treatment of COVID-19

Introduction

In December 2019, a pneumonia attributable to a particular pathogen emerged in Wuhan, Hubei Province, China, and shortly speeded world wide. The illness is transmitted primarily by droplets or contact and has the traits of an extended incubation interval, robust infectivity, quick transmission pace and so forth.¹ The particular pathogen was later remoted and recognized as novel coronavirus (extreme acute respiratory syndrome coronavirus 2, SARS-CoV-2; beforehand generally known as 2019-nCoV) by scientists.² As of Nov. 17, 2021, greater than 255,000,000 individuals have been recognized with Coronavirus illness 2019 (COVID-19), and greater than 5,000,000 individuals have died of COVID-19 worldwide. Each the variety of sufferers recognized with COVID-19 and COVID-19-related deaths surpassed these of the 2003 outbreak of extreme acute respiratory syndrome (SARS).³ The widespread susceptibility of individuals to the novel coronavirus is likely one of the main causes of the massive outbreak of COVID-19.⁴ Presently, COVID-19 has turn out to be a severe social downside affecting human well being.⁵

SARS-CoV-2 and SARS-CoV (extreme acute respiratory syndrome coronavirus) and MERS-CoV (center east respiratory syndrome coronavirus) belong to β-coronavirus genus.^6,7 The genomic sequence homology of SARS-CoV-2 and SARS-CoV is 79.5%.⁸ The homology of SARS-COV-2 and BAT-SL-COVZC45 is greater than 85%, the bat stands out as the pure host of SARS-CoV-2.⁸ At current, the mechanism of an infection and invasion of COVID-19 will not be utterly clear. The doable mechanism is that novel coronavirus infects human physique by binding with angiotensin-converting enzyme 2 (ACE2) on cells,^9,10 inflicting physique harm which can be associated to inducing over immune response, resulting in “self-attack” and inflicting multi-organ harm.¹¹

Transmission by respiratory droplets and shut contact is the primary transmission route of SARS-CoV-2.⁸ The medical manifestations of COVID-19 have been fever, fatigue, and dry cough, and chest radiographs confirmed bilateral pulmonary infiltration.¹² Severely in poor health sufferers could develop issues equivalent to acute respiratory misery syndrome (ARDS), septic shock, refractory metabolic acidosis, coagulation dysfunction and a number of organ dysfunction syndrome (MODS).¹³ Scientific remedy is especially symptomatic, however critically in poor health sufferers want mechanical air flow remedy. Most critically in poor health sufferers are over 60 years previous and have a number of issues.^13,14 At current, there isn’t a particular antiviral remedy; as well as, the present principal therapies are all supportive. The Nationwide Well being Fee of China has launched a sequence of prognosis and remedy plans on COVID-19 and really helpful conventional Chinese language medication (TCM) to deal with COVID-19. Chinese language medication stresses syndrome differentiation and remedy. The COVID-19 lesion is within the lung and has the traits of “moist”, “warmth”, “ toxins “ and “stasis”. Chinese language provinces have additionally launched TCM remedy plans on COVID-19 which might be appropriate for native areas together with the native local weather and illness traits. Amongst them is a basic Chinese language medication prescription referred to as Huang Lian Jie Du decoction (HLJDD), which is really helpful to deal with COVID-19 in TCM remedy plans in lots of provinces.

HLJDD, a well-known prescription of TCM, is derived from “Zhou Hou Bei Ji Fang” by Ge Hong and first recorded in “Wai Tai Mi Yao” within the Tang dynasty. HLJDD consists of Phellodendri Chinensis Cortex, Scutellariae Radix, Gardeniae Fructus and Coptidis Rhizoma. HLJDD has the operate of clearing warmth and cleansing, and it has been reported that HLJDD could also be an appropriate remedy for sufferers with a fever of unknown origin.^15,16 Moreover, HLJDD performs an essential function in anti-inflammatory, neuroprotection, anti-atherosclerosis, and blood sugar-lowering actions.^17–19 As talked about above, “warmth” and “toxins” have come to be thought-about traits of COVID-19. Thus, these options appear to counsel that HLJDD can be utilized within the remedy of COVID-19.

Community pharmacology is a brand new self-discipline primarily based on the fusion of huge knowledge relating to pharmacology, molecular biology, pc networks and so forth. Via organic pedigree evaluation, we are able to perceive the potential mechanism between lively elements, goal proteins and pathways associated to the prevalence and growth of illnesses.²⁰ This examine aimed to discover the potential targets and signaling pathways of HLJDD concerned within the remedy of COVID-19 primarily based on community pharmacology and to offer a reference for medical drug remedy in COVID-19. The workflow of the examine is proven in Figure 1.

Determine 1 Workflow of this systematic evaluation primarily based on community pharmacology. Abbreviations: HLJDD, Huang Lian Jie Du decoction; COVID-19, coronavirus illness 2019.

Supplies and Strategies

Compounds and Targets of HLJDD

The Conventional Chinese language Medication Techniques Pharmacology (TCMSP, http://lsp.nwu.edu.cn/tcmsp.php) database is a novel pharmacology database of the Chinese language natural medication system, which incorporates data on Chinese language natural medication, chemical composition, targets, and drug goal networks.^21,22 Chinese language medication prescriptions are sometimes composed of a wide range of Chinese language herbs and comprise 1000’s of compounds, however solely a few of them have good pharmacokinetics and potential organic results. In short, the oral Chinese language medication should overcome the obstacles to absorption, distribution, metabolism and excretion (ADME) course of to be efficient. In ADME course of, oral bioavailability (OB) is outlined as “the speed and extent at which the lively ingredient or lively half is absorbed from the drug product and accessible on the website of motion”, which is likely one of the most important pharmacokinetic parameters.²³ The compounds with OB ≥ 30% have been thought-about to have excessive OB. One other index, drug-likeness (DL), as a qualitative idea, is utilized in drug design to judge the usability of a molecule and can be utilized to shortly display screen lively substances. Within the DrugBank database, the common DL index is 0.18 and compounds with DL ≥ 0.18 have been regarded to have excessive druggability.²⁴ Moreover, drug half-life (HL) has essential implications for dosing routine and peak-to-trough ratio on the regular state, which is considered an essential index for screening efficient molecules and HL ≥ 4 is the really helpful threshold within the TCMSP database.²⁵ Subsequently, the compounds in HLJDD with OB ≥ 30%, DL ≥ 0.18 and HL ≥ 4 have been chosen as lively components on this examine. Subsequent, the Associated Targets operate within the TCMSP database was used to establish the targets of the lively components of every herb in HLJDD. Furthermore, the obtained targets have been additional screened by utilizing UniProt database (https://www.uniprot.org/)²⁶ to match goal data and standardize gene names.

Prediction of Drug Targets for HLJDD within the Remedy of COVID-19

GeneCards database (https://www.genecards.org/) is a complete and authoritative compendium of annotative details about human genes, which offers genomic, transcriptomic, proteomic, genetic, medical and useful data.²⁷ As well as, the On-line Mendelian Inheritance in Man (OMIM, http://www.omim.org/) database is a freely accessed database that can be utilized to display screen disease-related targets.²⁸ On this examine, the GeneCards and OMIM databases have been utilized to establish the COVID-19-related targets with “2019 novel coronavirus an infection”, “2019-nCoV an infection”, “coronavirus disease-19”, “2019-nCoV illness”, “2019 novel coronavirus illness”, “coronavirus illness 2019” or “coronavirus illness” as key phrases, and duplicate targets have been eradicated. The drug targets of HLJDD within the remedy of COVID-19 have been obtained by intersecting the HLJDD-related targets and COVID-19 associated targets.

Goal Community Evaluation

The Search Instrument for the Retrieval of Interacting Genes (STRING, http://string-db.org/) database is a freely accessible database that can be utilized to establish doable protein-protein interplay (PPI).²⁹ The STRING database was utilized to find out the HLJDD goal community and the drug targets community. In STRING database, the species was set as “Homo sapiens” and PPIs with a confidence rating of > 0.9 have been chosen. Cytoscape (https://cytoscape.org/) is software program for graphically displaying, analyzing, and enhancing networks.³⁰ Right here, Cytoscape (model 3.7.2) was used to assemble the herb-compound-target community and the herb-compound-drug goal community.

Purposeful Enrichment Evaluation

The Database for Annotation, Visualization and Built-in Discovery (DAVID) (https://david.ncifcrf.gov/) is a web based bioinformatics database that may extract organic useful annotation data for large-scale genes.³¹ The DAVID database was employed to carry out Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment evaluation of predicted drug targets of HLJDD, with the factors of P-value < 0.01. The GO enrichment evaluation consisted of three phrases, particularly, mobile part (CC), organic course of (BP), and molecular operate (MF).

Outcomes

Screening of Lively Compounds and Goal Genes in HLJDD

All compounds of every Chinese language herb in HLJDD have been recognized by utilizing the TCMSP database with OB ≥ 30%, DL ≥ 0.18, and HL ≥ 4 as standards. In the end, 27 compounds in Huangbai, 32 compounds in Huangqin, 11 compounds in Zhizi, and 10 compounds in Huanglian have been screened (Table S1). After eradicating the repeated compounds, a complete of 67 compounds have been obtained from the 4 sorts of Chinese language herbs in HLJDD. Subsequent, the targets of compounds have been predicted, and 204 goal genes have been present in 4 sorts of Chinese language herbs in HLJDD by way of TCMSP and the UniProt databases. Particularly, there have been 345 targets in Huangbai, 333 targets in Huangqin, 274 targets in Zhizi, and 220 targets in Huanglian (Table S2).

Prediction of Potential Targets of HLJDD in Anti-COVID-19

After looking out the GeneCards and OMIM databases, a complete of 502 targets associated to COVID-19 have been obtained (Table S3). Then, these targets have been in contrast with the 204 goal genes of HLJDD by utilizing R software program (model 3.6.2), and at last 47 overlapping genes have been recognized to be potential drug targets within the remedy of COVID-19 (Figure 2 and Table S3).

Determine 2 Venn diagram presents the overlapping genes between HLJDD and COVID-19-related targets.

Building of PPI Community

As proven in Figure 3A, we noticed that the HLJDD-related targets community contained 175 nodes and 747 edges (common node diploma=7.32, common native clustering coefficient=0.448, and PPI enrichment P-value<1.0e-16). Based mostly on the HLJDD-related targets, the herb-compound- goal community was additionally established. This community revealed the relationships amongst 4 Chinese language herbs, 67 compounds and 204 compound-related targets (Figure 3B).

Determine 3 PPI networks for HLJDD-related targets. (A) HLJDD-related targets community. Node represents the HLJDD-related goal, edge represents the associations between nodes, and the road thickness signifies the energy of information help. (B) Herb-compound-target community. Inexperienced sq. represents goal, yellow triangle represents lively compounds, blue hexagons represents herbs, and crimson diamond represents HLJDD.

As well as, the potential drug goal community was constructed. As proven in Figure 4A, the drug goal community composed of 41 nodes and 146 edges (common node diploma=6.21, common native clustering coefficient=0.5, and PPI enrichment P-value<1.0e-16). Moreover, the herb-compound-drug goal community was established primarily based on the potential drug targets of anti-COVID-19. This community included 4 Chinese language herbs, 67 compounds, and 47 drug targets (Figure 4B).

Determine 4 PPI community for drug targets towards COVID-19. (A) COVID-19 associated drug goal community. Node represents potential drug goal, edge represents protein-protein interactions, and the road thickness signifies the energy of information help. (B) Herb-compound-drug goal community. Inexperienced sq. represents drug goal, yellow triangle represents lively compounds, blue hexagons represents herbs, crimson diamond represents HLJDD, and purple octagon represents COVID-19.

Usually, genes with a excessive depth of affiliation with different genes often play a vital function of hub genes. The higher the diploma worth of a node is, the extra nodes are linked to it and the extra essential it’s within the community. On this evaluation, the diploma worth of all nodes within the drug targets community for COVID-19 is proven in Table S4. R software program (model 3.6.2) was used to display screen out the hub genes by the diploma worth technique in accordance with the HLJDD-COVID-19 goal community. The diploma worth of a node refers back to the variety of edges between nodes in a community and the highest 10 targets are proven in Table 1. As proven in Figure 5, there have been 20 targets, particularly, RELA, IL6, IL1B, MAPK14, CXCL8, MAPK1, IL4, IL10, IL2, MAPK8, CCL2, FOS, IFNG, CXCL2, STAT1, BCL2L1, CASP3, CXCL10, EGFR, and PRKCB, whose diploma worth was higher than the common node diploma worth. These outcomes indicated that these targets may be hub genes efficient within the remedy of COVID-19.

Desk 1 The High 10 Diploma Genes in HLJDD-COVID-19 Goal Community

Determine 5 High 20 drug targets with increased diploma within the drug goal community.

Purposeful Enrichment Evaluation of Drug Targets

To elucidate the molecular mechanism of the 47 drug targets, GO enrichment and KEGG pathway enrichment analyses have been carried out by way of the DAVID database, and the particular enrichment classes are listed in Table S5. The highest 10 vital enriched BP, CC, and MF phrases are displayed in Figure 6A; in the meantime, the highest 30 vital concerned KEGG pathways are confirmed in Figure 6B. In short, a complete of 148 BP phrases have been recognized, equivalent to mobile response to lipopolysaccharide, inflammatory response, immune response, chemotaxis, and regulation of blood strain; a complete of 14 CC phrases have been recognized, together with extracellular house, extracellular area, cytosol, Bcl-2 household protein complicated, exterior facet of plasma membrane, mitochondrial outer membrane, caveola, perinuclear area of cytoplasm, mitochondrion, cytoplasm, nucleoplasm, intracellular, nucleus, and extracellular exosome; furthermore, a complete of 17 MF phrases have been recognized, together with BH3 area binding, cytokine exercise, equivalent protein binding, enzyme binding, protein binding, chemokine exercise, protein homodimerization exercise, transcription issue binding, heme binding, MAP kinase exercise, protein heterodimerization exercise, tumor necrosis issue receptor binding, prostaglandin-endoperoxide synthase exercise, histone kinase exercise (H3-T6 particular), ubiquitin protein ligase binding, nitric-oxide synthase exercise, and progress issue exercise.

Determine 6 Purposeful enrichment evaluation of 47 drug targets towards COVID-19. (A) High 10 phrases for GO enrichment evaluation. (B) High 30 pathways for KEGG enrichment evaluation.

When it comes to the KEGG enrichment evaluation, 77 vital signaling pathways have been recognized, equivalent to Chagas illness (American trypanosomiasis), Leishmaniasis, Pertussis, TNF signaling pathway, Influenza A, NF-κB signaling pathway, HIF-1 signaling pathway, and MAPK signaling pathway.

Dialogue

Beginning in December 2019, a novel coronavirus referred to as SARS-CoV-2 started inflicting a respiratory sickness that’s sweeping the world. The WHO considers the present outbreak of COVID-19 to be a world pandemic. Presently, COVID-19 has turn out to be a severe social downside affecting human well being. Because the newly emerged SARS-CoV-2 is a beforehand unknown pathogen, no particular drug is on the market. Subsequently, there may be an pressing must discover therapeutic medicine and particular vaccines to fight the rising virus. Nevertheless, the event of antiviral medicine takes time and assets, so reusing current medicine to deal with rising viral illnesses are efficient methods. Generally, these drug choices could be roughly divided into virus primarily based and host primarily based remedy.32,33

In China, the mix of TCM remedy and efficient life help has been broadly used within the medical remedy of COVID-19. TCM remedy is efficient in stopping COVID-19, which may help cut back the severity of COVID-19 and promote the restoration of sufferers with COVID-19. TCM emphasizes each evil and constructive remedy. Based mostly on TCM idea, the primary therapeutic ideas are invigorating the lungs to stop dampness, clearing away warmth and cleansing, replenishing qi, and nourishing yin.³⁴ Nevertheless, the molecular mechanism of TCM prescription in treating COVID-19 illness stays not utterly clear. In idea, TCMs have a sure therapeutic impact by means of multiple-molecules, multi-targets and multi-pathways. Within the syndrome differentiation and remedy of syndrome sort by way of TCM, the goal organ location of COVID-19 is the lung and its pathogenic property is damp and toxin plague, so it must be handled with purging the lung and cleansing technique. Notably, HLJDD is the consultant prescription for warmth clearing and cleansing. Within the medical apply of TCM, HLJDD has been broadly used to deal with irritation, hypertension, gastrointestinal illnesses and hepatic and cerebral vascular illnesses.³⁵ Nevertheless, the pharmacological mechanisms of HLJDD within the remedy of COVID-19 haven’t been clearly studied.

Community pharmacology relies on the interplay community relationship of “drug-target-disease”. By analyzing the connection amongst genes, illnesses, medicine and different community libraries, community pharmacology reveals the thriller of “drug-target”, “target-disease” and “drug-disease” interactions and guides correct medical drug use and new drug analysis and growth.³⁶ On this examine, we used community pharmacology method to assemble and analyze a community of targets, conduct enrichment evaluation on these targets, and reveal their doable mechanism of motion to discover the potential targets of HLJDD within the remedy of COVID-19.

Briefly, 67 lively compounds and 204 targets of compounds have been screened. We noticed that a wide range of alkaloids and flavonoids have been searched within the HLJDD, equivalent to quercetin, baicalein, wogonin, berberine, and acacetin, which have been in line with current research.^18,37 Baicalein and wogonin are flavonoids that may inhibit the overactivation of the complement system in vivo and enhance acute lung harm induced by influenza A virus.³⁸ As well as, Tune et al³⁹ explored the therapeutic results of baicalein for the remedy of COVID-19 in vivo and in vitro. They discovered that baicalein might inhibit cell harm induced by SARS-CoV-2; in the meantime, it might additionally enhance the respiratory operate of mice with acute lung harm, inhibit pneumonia cell infiltration in addition to the replication of the virus, and thus cut back lung tissues harm. In the meantime, baicalein had an inhibitory impact on SARS-CoV-2 3C-like protease exercise, and it additionally might inhibit the replication of SARS-CoV-2 in Vero cells.⁴⁰ These research revealed that baicalein could also be a promising drug for the remedy of COVID-19. Berberine has antibacterial and anti inflammatory pharmacological results and might inhibit the replication of respiratory syncytial virus and cytomegalovirus to enhance the signs of viral pneumonia.^41,42 Quercetin has anti-inflammatory, antiviral, and immunomodulatory pharmacological results.⁴³ One other key compound, acacetin, has anti-inflammatory results by decreasing interleukin 6 (IL-6), interleukin 8 (IL-8), and intercellular adhesion molecule-1 (ICAM-1) ranges.^44,45 Taken collectively, we speculate that these lively compounds in HLJDD could enhance lung harm attributable to COVID-19 by means of synergistic anti-inflammatory results.⁴⁶

Extremely pathogenic coronaviruses, equivalent to SARS coronavirus and MERS coronavirus, may cause deadly pneumonia, which is said primarily to speedy viral replication, a considerable amount of inflammatory cell infiltration and an enhanced pro-inflammatory cytokine/chemokine response.⁴⁷ On this evaluation, a number of potential targets of HLJDD towards COVID-19 have been methodically recognized, together with RELA, IL6, IL1B, MAPK14, CXCL8, MAPK1, IL4, IL10, IL2, MAPK8, CCL2, FOS, IFNG, CXCL2, STAT1, BCL2L1, CASP3, CXCL10, EGFR, and PRKCB. Reportedly, majority of them have been concerned in pulmonary irritation. Genes equivalent to interleukin 1β (IL-1B) and IL-6 are concerned within the recruitment of immune cells to the lungs; in the meantime, IL-1B can activate caspases and different associated signaling pathways, induce apoptosis of contaminated cells, and thus inhibit virus replication. MAPK14, MAPK1, and MAPK8 are members of the MAPK household, which might promote the discharge of pro-inflammatory cytokines equivalent to IL-1B and IL-6, and it’s considered a core think about irritation regulation.⁴⁸ Proof has additionally indicated that SARS-CoV-2 an infection can enhance the expression ranges of plasma cytokines and chemokines, equivalent to interleukin 2 (IL2), IL6, interleukin 7 (IL7), interleukin 10 (IL10), C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 3 (CCL3), C-X-C motif chemokine ligand 10 (CXCL10), cytokines interferon γ (IFN-γ), reworking progress issue α (TGF-α), interleukin 1 (IL1), interleukin 12 (IL12), CCL2, C-X-C motif chemokine ligand 9 (CXCL9) and CXCL10, which have been related to pulmonary irritation and lung harm in COVID-19 sufferers.⁴⁹ Moreover, earlier examine revealed that the activation of inflammatory signaling pathways and cytokine storm reserved as essential elements that leaded to ARDS in sufferers with COVID-19, and the extreme secretion of pro-inflammatory cytokines and chemokines resulted in innate immune system issues that ultimately precipitated immune harm.⁵⁰ Subsequently, HLJDD could serve the function of anti-inflammatory, anti-immune apoptosis, and alleviation of pneumonia-induced multi-organ harm by way of regulating the expression of those hub genes, which not directly inhibit the virus-mediated inflammatory response by regulating the immune operate of the physique.

Within the KEGG evaluation of the potential targets towards COVID-19, we recognized a number of signaling pathways related to irritation and viral an infection, together with the tumor necrosis issue (TNF) signaling pathway, nuclear issue κB (NF-κB) signaling pathway, Hypoxia-inducible issue 1 (HIF-1) signaling pathway, Influenza A, Hepatitis B, Herpes simplex an infection, and Prion illnesses. The NF-κB signaling pathway performs a key function within the mobile inflammatory response and immune response, and the regulation of the NF-κB signaling pathway can cut back the harm to the liver, lung and kidney attributable to pneumonia.^51,52 HIF-1 is a transcription issue and can be utilized as the primary regulator of oxygen homeostasis, and the HIF-1 signaling pathway is said to the discharge of inflammatory cytokines in viral pneumonia.⁵³ TNF is a proinflammatory cytokine that performs an essential function in cell proliferation, differentiation and apoptosis.⁵⁴ Extreme pneumonia with sepsis has been reported to be characterised by an inflammatory response dysfunction associated to endotoxin.⁵⁵ Within the early stage of sepsis, Hypoxia-inducible issue 1α (HIF1-α) is activated below hypoxia after which coactivates sign transducer and activator of transcription 3 (STAT3) to take part within the inflammatory course of.⁵⁵

On this examine, community pharmacology was used to discover the feasibility, related molecular targets and signaling pathways of HLJDD within the remedy of COVID-19. It’s value noting that community pharmacology has nice benefits in learning the way in which medicine act. Our analysis has sure limitations. First, the potential targets have been solely obtained by utilizing the community pharmacology technique, and it’s a lack of in vivo experimental verification. Second, due to the problem of information assortment, the database could not embody all recognized or unknown targets and protein-protein interactions. This facet could enhance as further knowledge turn out to be accessible sooner or later. Third, HLJDD is a medication of nice bitterness and chilly, and it will probably simply harm the spleen and abdomen whether it is taken for a very long time or if an excessive amount of is taken, so it must be utilized in accordance with medical apply primarily based on syndrome differentiation. We hope that our outcomes can present some theoretical and scientific foundation for HLJDD within the remedy of COVID-19 and supply a reference for drug growth for SARS-CoV-2 an infection.

Conclusions

On this examine, 47 potential targets towards COVID-19 have been recognized by community pharmacology technique, and the molecular mechanism of HLJDD within the remedy of COVID-19 was additional investigated by means of useful enrichment evaluation. Based mostly on the outcomes of enrichment evaluation, we revealed the traits of multi-target synergistic results and multi-pathway rules and located that HLJDD could enhance COVID-19 by means of the TNF signaling pathway, NF-κB signaling pathway and HIF-1 signaling pathway. Inhibiting the overproduction of inflammatory elements is of nice significance within the prevention and remedy of COVID-19 and the alleviation of multiorgan harm in COVID-19 sufferers. As an essential adjuvant remedy, the mix of HLJDD and different conventional Chinese language medicines with fashionable medical strategies will profit COVID-19 sufferers. The impact of HLJDD within the remedy of COVID-19 requires additional experiments to confirm the particular molecular mechanism.

Knowledge Sharing Assertion

The info used to help the findings of this examine are included throughout the article and the supplementary data file(s).

Ethics Approval and Consent to Take part

The Institutional Overview Board and Ethics Committee of the Second Affiliated Hospital of Guangdong Medical College deemed that this work is a web-based pharmacologic evaluation primarily based on a database of sufferers who’ve obtained moral approval. Customers can obtain related knowledge at no cost to analysis and publish associated articles. This analysis relies on open-source knowledge, so assessment and approval was not required for this analysis by an institutional assessment board or ethics committee and there are not any moral points or different conflicts of curiosity.

Acknowledgments

We respect all of the people who find themselves combating the COVID-19 epidemic world wide. We thank American Journal Specialists (AJE) for English language enhancing. We want to thank Dr. Weinmin Yao and Dr. Guangfeng He from the Division of Respiration, The Second Affiliated Hospital of Guangdong Medical College, for giving us quite a lot of recommendations on this revision, together with the entire work design, knowledge rearrangement, evaluation and interpretation, and so on.

Writer Contributions

All authors made a big contribution to the work reported, whether or not that’s within the conception, examine design, execution, acquisition of information, evaluation and interpretation, or in all these areas; took half in drafting, revising or critically reviewing the article; gave ultimate approval of the model to be printed; have agreed on the journal to which the article has been submitted; and comply with be accountable for all features of the work.

Funding

This examine is funded by 2021 Zhanjiang Science and Expertise Improvement Particular Fund Aggressive Allocation Challenge (Excessive-level Hospital Building Particular Challenge of the Second Affiliated Hospital of Guangdong Medical College) (No. 2021A05107).

Disclosure

The authors declare that they don’t have any conflicts of curiosity.

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