WHO: PANDEMIATILANNE vappuaattona 2020

Uutisia:
https://covid19.who.int/
Maailmassa on varmistettuja  CoV positiivisia tapauksia 3 090 445.
Menehtyneitä 217 769.
Käyristä päätellen  ollaan vielä  pandemian leviämisvaiheessa. Näyttää koko Afrikkakin olevan jo  pandemian  kourissa.  Kiina on  saanut  pandemiapiikin äkkiä alas.

Kertaan proteiinia 3a COVID-19. Sillä on interaktio 8 ihmisproteiiniin.

 https://covid-19.uniprot.org/uniprotkb/P0DTC3

Interaction

subunit

Homotetramer composed of two homodimers linked non covalently. Interacts with M, S and E proteins. Also interacts with the accessory protein 7a

 Tällä proteiinilla on 8 interaktioproteiinia ihmisen proteiineissa:
TRIM59,  E3 ubikitiiniligaasi;
SUN-domeenin sisältävä proteiini2;
 Vps39;
dolikyylifosfaatti-beta-glukosyylitransferaasi;
hemioksygenaasi-1 (HO-1);
 ADP-ribosylaatiotekijän kaltaisen proteiini6:n kanssa interaktion tekevä proteiini 6;
 kloridikanavan CLIC- kaltainen proteiini 1, vakuolaaristen proteiinien lajitteluun liittyvän proteiini; 11:n (vps11) homologi.

Protein-protein interaction databases

IntAct

• P0DTC3

8 interactors

	1	tri59_human	protein	1	EBI-10262539	human (9606)	EBI-10262539	Tripartite motif-containing protein 59
	2	sun2_human	protein	1	EBI-1044964	human (9606)	EBI-1044964	SUN domain-containing protein 2
	3	vps39_human	protein	1	EBI-1050197	human (9606)	EBI-1050197	Vam6/Vps39-like protein
	4	alg5_human	protein	1	EBI-11725055	human (9606)	EBI-11725055	Dolichyl-phosphate beta-glucosyltransferase
	5	orf3a_wcpv	protein	8	EBI-25475894	SARS-CoV-2 (2697049)	EBI-25475894	Protein 3a
	6	hmox1_human	protein	1	EBI-2806151	human (9606)	EBI-2806151	Heme oxygenase 1
	7	ar6p6_human	protein	1	EBI-2808844	human (9606)	EBI-2808844	ADP-ribosylation factor-like protein 6-interacting protein 6
	8	clcc1_human	protein	1	EBI-2836109	human (9606)	EBI-2836109	Chloride channel CLIC-like protein 1
	9	vps11_human	protein	1	EBI-373380	human (9606)	EBI-373380	Vacuolar protein sorting-associated protein 11 homolog

Tavallisista uutislähteistä tietoa pandemiasta

Ruotsi:
Göteborg:  Väki ulkoilee auringossa. Jopa enemmän on lenkkeilijöitä nyt metsätielläkin. kaupungissa näyttää ulkotarjoilupaikat olevan kansoitettuja. Liseberg autiona.

Sydsvenskan antaa statistiikkaa: Vasta jäävuoren huippu näkyy.
Ruotsissa  varmistettuja tapauksia  18 640. Kuolleita 2 194.
Globaalisti  2 844 712 varmistettua tapausta, kuolleita 201 315.
Euroopassa  1 070 956 varmistettua taapusta ja kuolleita  116 417.
Tanskassa  8575 varmistettua taapusta ja 422 kuollutta.
Suomessa THL:n mukaan  4576 varmistettua tapausta ja kuolleita  190. 

Israelista kerrotaan että uusi virus omaa useita kymmeniä variaatioita.
https://www.jpost.com/health-science/coronavirus-has-mutated-into-at-least-30-different-strains-new-study-finds-625333 

Coronavirus has mutated into at least 30 different strains new study finds

The study was carried out by Professor Li Lanjuan and colleagues from Zhejiang University in Hangzhou, China and published in a non-peer reviewed paper released on website medRxiv.org on Sunday.More than 30 different mutations were detected, of which 19 were previously undiscovered.

“Sars-CoV-2 has acquired mutations capable of substantially changing its pathogenicity,” Li wrote in the paper. The team discovered that some of the mutations could lead to functional changes in the virus’ spike protein, the South China Morning Post reported. Spike protein is the protein that the coronavirus uses to attach itself to human cells.Li 's team infected cells with COVID-19 strains carrying different mutations, of which the most aggressive strains were found to generate as much as 270 times as much viral load as the weakest strains. The aggressive strains also killed the human cells the fastest.The results indicated "that the true diversity of the viral strains is still largely underappreciated,” Li wrote.The study could have future implications on the treatment of coronavirus, as several different strains have been found throughout the world. The United States, which has the world's worst death toll at 42,897, and 799,515 overall cases, has been struck by different mutations. New York, which itself had the worst death rate in the US, and the eastern coast show a strain of coronavirus similar to that found in Europe, whereas the western US has shown similarities with strains found in China.Coronavirus has so far been treated in hospitals worldwide as one disease and patients receive the same treatment regardless of the strain. It has been suggested by the team at Zhejiang University that defining mutations in different regions may change the way we approach combating the virus. “Drug and vaccine development, while urgent, need to take the impact of these accumulating mutations into account to avoid potential pitfalls,” the scientists said.

WHO:n tilanne katsaus 24.4. 2020 COVID-19 pandemiasta

https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen

(2010) Picornavirus HRV 3CPro- ja Sars CoV CL3Pro- entsyymien dual inhibiittoria etistty

 https://www.ncbi.nlm.nih.gov/pubmed/20021285

4. Expert opinion

In this review, the inhibitors against 3C^pro are summarized and the structural basis of inhibition specificities of 3C^pro and 3CL^pro by peptidomimetic compounds described. The tripeptide aldehyde and the tripeptides with the α,β-unsaturated group as Michael acceptor (e.g., AG7088) for the active-site Cys are the potent inhibitors of 3C^pro. AG7088 has been shown to be effective in inhibiting many 3C^pro from a broad spectrum of picornavirus, but failed to inhibit SARS-CoV 3CL^pro. The AG7088 analogues with P2 cyclohexyl moiety and additional P3 t-butyl group favor the binding with the 3CL^pro. Crystal structures can be used to elucidate the subtle changes between the active-site structures of 3C^pro and 3CL^pro [73-77]. The separate efforts of developing inhibitors against 3C^pro [78] and 3CL^pro [79-81] may be merged to provide the rationale to design selective potent inhibitors against each type of the proteases, that is, with suitable modifications, the inhibitors of 3CL^pro can be converted into the inhibitors of 3C^pro and vice versa. Moreover, a group of compounds were found to inhibit 3C^pro and 3CL^pro almost equally, providing a possibility of developing dual inhibitors against both proteases. These exciting discoveries will lead to more varieties of inhibitors, which can then be potentially used to treat the diseases caused by picornavirus and CoV.

NORO-virusdesinfektiosta

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141050

COVID-19 ja MMPs : Olisiko tetrasykliineistä stabiloijaa?

https://www.eurotimes.org/tetracyclines-proposed-as-treatment-for-covid-19/

Abstract

Currently there is a race against time to identify prophylactic and therapeutic treatments against COVID‐19. Until these treatments are developed, tested and mass produced, it might be prudent to look into existing therapies that could be effective against this virus. Based on the available evidence we believe that tetracyclines may be effective agents in the treatment of COVID‐19. Tetracyclines (e.g. tetracycline, doxycycline, and minocycline) are highly lipophilic antibiotics that are known to chelate zinc compounds on matrix metalloproteinases (MMPs)¹. Coronaviruses are also known to heavily rely on host MMPs for survival, cell infiltration, cell to cell adhesion, and replication, many of which have zinc as part of their MMP complex^2,3. It is possible that the zinc chelating properties of tetracyclines may also aid in inhibiting COVID‐19 infection in humans limiting their ability to replicate within the host.

   Tetracyclines proposed as treatment for COVID-19
    In a letter to the editor of Pharmacotherapy , Mohit Sodhi, MSc, and Mahyar Etminan, PharmD, from the Department of  Ophthalmology and Visual Sciences at the University of British Columbia,
 Vancouver, Canada outline evidence supporting the therapeutic potential  of tetracyclines as a treatment for patients with COVID-19. The letter  was published online on April 8, 2020.

https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.2395
The rationale for using tetracyclines considers the lipophilic nature of the tetrayclines along with their ability to inhibit matrix  metalloproteinases (MMPs), anti-inflammatory properties and possible
antiviral activity. Furthermore, the authors cite the relative safety of  tetracyclines compared with other agents that are being considered to treat COVID-19, including antimalarial and antiretroviral drugs.
Describing the tetracyclines as a potential treatment for COVID-19  “that is hiding in plain sight”, Sodhi and Etminan urge researchers to  consider investigating the efficacy of this available therapy.
Reviewing the activity of tetracyclines, the authors explain that  they chelate zinc compounds on MMPs. Because coronaviruses depend on those enzymes for survival, cell infiltration, cell-to-cell adhesion,  and replication, Sodhi and Etminan postulated that tetracyclines might
inhibit viral replication within the host.
As further support for the antiviral activity of tetracyclines, they cited reports indicating that tetracyclines might have activity for  inhibiting RNA replication on positive-sense single stranded RNA, like SARS-CoV-2, the COVID-19 viral pathogen. The evidence includes findings
from one in vitro study showing that doxycycline inhibited dengue virus serine protease, viral replication and viral entry into cultured cells and another showing a 70% decrease in retroviral load when a murine retrovirus producing cell line was incubated with
doxycycline.
Anti-inflammatory activity of tetracyclines is well-recognised and  includes the ability to downregulate expression of several inflammatory cytokines that have been shown to be significantly elevated in lung  tissue exposed to the coronavirus causing the infection known as SARS.
In addition, chemically modified tetracyclines have been shown to induce apoptosis of mast cells that release a host of pro-inflammatory mediators. The effect on mast cells may be particularly relevant for treating COVID-19 considering evidence that mast cell proliferation
within respiratory submucosa is induced by coronaviruses.
The lipophilic nature of tetracyclines favors their distribution into lung tissue and is also significant because SARS-CoV-2 has a lipophilic  outer shell. Suggesting that tetracyclines might be useful treatment  for pulmonary complications of COVID-19, the authors cite a preclinical
study in which a chemically-modified tetracycline prevented sepsis induced by acute respiratory distress syndrome.<
   
    We want to hear from you with stories, suggestions or ideas,
national recommendations and guidelines. Please send all your items to
COVID19@escrs.org or use wetransfer.com for larger files




  

Tetracyclines proposed as treatment for COVID-19

In a letter to the editor of Pharmacotherapy , Mohit Sodhi, MSc, and Mahyar Etminan, PharmD, from the Department of Ophthalmology and Visual Sciences at the University of British Columbia, Vancouver, Canada outline evidence supporting the therapeutic potential of tetracyclines as a treatment for patients with COVID-19. The letter was published online on April 8, 2020.
https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.2395
The rationale for using tetracyclines considers the lipophilic nature of the tetrayclines along with their ability to inhibit matrix metalloproteinases (MMPs), anti-inflammatory properties and possible antiviral activity. Furthermore, the authors cite the relative safety of tetracyclines compared with other agents that are being considered to treat COVID-19, including antimalarial and antiretroviral drugs.
Describing the tetracyclines as a potential treatment for COVID-19 “that is hiding in plain sight”, Sodhi and Etminan urge researchers to consider investigating the efficacy of this available therapy.
Reviewing the activity of tetracyclines, the authors explain that they chelate zinc compounds on MMPs. Because coronaviruses depend on those enzymes for survival, cell infiltration, cell-to-cell adhesion, and replication, Sodhi and Etminan postulated that tetracyclines might inhibit viral replication within the host.
As further support for the antiviral activity of tetracyclines, they cited reports indicating that tetracyclines might have activity for inhibiting RNA replication on positive-sense single stranded RNA, like SARS-CoV-2, the COVID-19 viral pathogen. The evidence includes findings from one in vitro study showing that doxycycline inhibited dengue virus serine protease, viral replication and viral entry into cultured cells and another showing a 70% decrease in retroviral load when a murine retrovirus producing cell line was incubated with doxycycline.
Anti-inflammatory activity of tetracyclines is well-recognised and includes the ability to downregulate expression of several inflammatory cytokines that have been shown to be significantly elevated in lung tissue exposed to the coronavirus causing the infection known as SARS. In addition, chemically modified tetracyclines have been shown to induce apoptosis of mast cells that release a host of pro-inflammatory mediators. The effect on mast cells may be particularly relevant for treating COVID-19 considering evidence that mast cell proliferation within respiratory submucosa is induced by coronaviruses.
The lipophilic nature of tetracyclines favors their distribution into lung tissue and is also significant because SARS-CoV-2 has a lipophilic outer shell. Suggesting that tetracyclines might be useful treatment for pulmonary complications of COVID-19, the authors cite a preclinical study in which a chemically-modified tetracycline prevented sepsis induced by acute respiratory distress syndrome.

We want to hear from you with stories, suggestions or ideas, national recommendations and guidelines. Please send all your items to COVID19@escrs.org or use wetransfer.com for larger files

ESCARDIO ohjeita COVID-19 taudissa

https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance

COVID-19 ja sydän

J Card Surg. 2020 Apr 19. doi: 10.1111/jocs.14538. [Epub ahead of print]

Cardiac involvement in COVID-19 patients: Risk factors, predictors, and complications: A review.

Aghagoli G¹, Gallo Marin B¹, Soliman LB¹, Sellke FW^1,2.Abstract BACKGROUND:

Respiratory complications have been well remarked in the novel coronavirus disease (SARS-CoV-2/COVID-19), yet an emerging body of research indicates that cardiac involvement may be implicated in poor outcomes for these patients. AIMS:
This review seeks to gather and distill the existing body of literature that describes the cardiac implications of COVID-19. MATERIALS AND METHODS:
The English literature was reviewed for papers dealing with the cardiac effects of COVID-19.
RESULTS:
Notably, COVID-19 patients with pre-existing cardiovascular disease are counted in greater frequency in intensive care unit settings, and ultimately suffer greater rates of mortality. Other studies have noted cardiac presentations for COVID-19, rather than respiratory, such as acute pericarditis and left ventricular dysfunction. In some patients there has been evidence of acute myocardial injury, with correspondingly increased serum troponin I levels. With regard to surgical interventions, there is a dearth of data describing myocardial protection during cardiac surgery for COVID-19 patients. Although some insights have been garnered in the study of cardiovascular diseases for these patients, these insights remain fragmented and have yet to cement clear guidelines for actionable clinical practice.  CONCLUSION: While some information is available, further studies are imperative for a more cohesive understanding of the cardiac pathophysiology in COVID-19 patients to promote more informed treatment and, ultimately, better clinical outcomes.

© 2020 Wiley Periodicals, Inc.  KEYWORDS:

COVID-19; cardiac surgery; heart; respiratory failure; virus PMID: 32306491DOI: 10.1111/jocs.14538

COVID-19 virusvasta-aineita

https://www.ncbi.nlm.nih.gov/pubmed/32306047/

PubMed Trending Articles 20.4. 2020

Trending Articles

PubMed records with recent increases in activity

• Central nervous system manifestations of COVID-19: A systematic review.J Neurol Sci. 2020.
• SARS CoV-2: Recent Reports on Antiviral Therapies Based on Lopinavir/Ritonavir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and Other Drugs for the Treatment of the New Coronavirus.Curr Med Chem. 2020.  Abstract
  Here we report on the most recent updates on experimental drugs successfully employed in the treatment of the disease caused by SARS CoV-2 coronavirus, also referred to as COVID-19 (COronaVIrus Disease 19). In particular, several cases of recovered patients have been reported after being treated with lopinavir/ritonavir (which is widely used to treat human immunodeficiency virus (HIV) infection) in combination with the anti-flu drug oseltamivir. In addition, remdesivir, which has been previously administered to Ebola virus patients, has also proven effective in the U.S. against coronavirus, while antimalarial chloroquine and hydroxychloroquine, favipiravir and co-administered darunavir and umifenovir (in patient therapies) were also recently recorded as having anti-SARS CoV-2 effects. Since the recoveries/deaths ratio in the last weeks significantly increased, especially in China, it is clear that the experimental antiviral therapy, together with the availability of intensive care unit beds in hospitals and rigorous government control measures, all play an important role in dealing with this virus. This also stresses the urgent need for the scientific community to devote its efforts to find other more specific antiviral strategies.
  

  Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.netKEYWORDS:
  COVID-19; Coronavirus; SARS CoV-2; antiviral drugs; favirapivir; hydroxychloroquine; lopinavir; remdesivir;
• Considerations for obesity, vitamin D, and physical activity amidst the COVID-19 pandemic.Obesity (Silver Spring). 2020.
• Virological and Clinical Cure in Covid-19 Patients Treated with Hydroxychloroquine: A Systematic Review and Meta-Analysis.J Med Virol. 2020.
• COVID-2019: update on epidemiology, disease spread and management.Monaldi Arch Chest Dis. 2020  Abstract
  With each passing day, more cases of Coronavirus disease (COVID-2019) are being detected and unfortunately the fear of novel corona virus 2019 (2019-nCoV) becoming a pandemic disease has come true. Constant efforts at individual, national, and international level are being made in order to understand the genomics, hosts, modes of transmission and epidemiological link of nCoV-2019. As of now, whole genome sequence of the newly discovered coronavirus has already been decoded. Genomic characterization nCoV-2019 have shown close homology with bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21. Structural analysis of the receptor binding site has confirmed that 2019-nCoV binds with the same ACE 2 receptor protein as human SARS virus. Compared to the previous coronavirus outbreaks, the overall mortality rate is relatively low for COVID-2019 (2-3%). Suspected cases must be quarantined till their test comes positive or they clear infection. At present, treatment of COVID-2019 is mostly based on the knowledge gained from the SARS and MERS outbreaks. Remdesivir, originally develop as a treatment for Ebola virus disease and Marburg virus infections, is being studied for it effectiveness against 2019-nCoV infection. Many other antiviral agents and vaccines are being tested but most of them are in phase I or II and hence unlikely to be of any benefit immediately with regards to current outbreak. Hence, the standard infection control techniques and preventive steps for healthy individuals and supportive care for the confirmed cases is the best available strategy to deal with current viral outbreak. .

  PMID:

  32297723

  DOI:

  10.4081/monaldi.2020.1292

See more
 Chimeric Antigen Receptor T Cell Therapy During the COVID-19

COVID-19 ilmentää muutamilla myös neurotrooppisuutta

https://www.jns-journal.com/article/S0022-510X(20)30168-4/pdf 

Contents lists available atScienceDirect 
Journal of the Neurological Sciences
 journal homepage:www.elsevier.com/locate/jns 
Review Article
 Central nervous system manifestations of COVID-19: A systematic review
 Ali A. Asadi-Pooyaa,b ,⁎, Leila SimanicaEpilepsy Research Center, Shiraz University of Medical Sciences, Shiraz, IranbJefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USAcSkull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti Univsersity of Medical Sciences, Tehran, IranARTICLE INFOKeywords:CNSCoronavirusCOVID-19NeurologicalSeizure


 ABSTRACTObjective:In this systematic review, we will discuss the evidence on the occurrence of central nervous system(CNS) involvement and neurological manifestations in patients with COVID-19.
 Methods: MEDLINE (accessed from PubMed) and Scopus from December 01, 2019 to March 26, 2020 were systematically searched for related published articles. In both electronic databases, the following search strategy was implemented and these key words (in the title/abstract) were used: 
“COVID 19” OR “coronavirus” AND “brain” OR“ CNS” OR “neurologic”. 

Results:Through the search strategy, we could identify two articles about neurological involvement by COVID-19. One of these publications was a narrative review and the other one was a viewpoint. However, the authors scanned the reference lists of the included studies and could identify multiple references. One study, specifically investigated the neurological manifestations of COVID-19 and could document CNS manifestations in 25% of the patients. Most of the studies investigated the manifestations of COVID-19 in general.

 Conclusion:While neurological manifestations of COVID-19 have not been studied appropriately, it is highly likely that some of these patients, particularly those who suffer from a severe illness, have CNS involvement and neurological manifestations. Precise and targeted documentation of neurological symptoms, detailed clinical, neurological, and electrophysiological investigations of the patients, attempts to isolate SARS-CoV-2 from cerebrospinal fluid, and autopsies of the COVID-19 victims may clarify the role played by this virus in causing neurological manifestations

Introduction: 
Coronavirus is one of the major viruses that primarily targets the human respiratory system, but it also has neuroinvasive capabilities and can spread from the respiratory tract to the central nervous system (CNS). Previous epidemics or pandemics of coronaviruses include the severe acute respiratory syndrome (SARS) in 2002 and the Middle East respiratory syndrome (MERS) in 2012. The most recent pandemic of coronavirus infection is coronavirus disease (COVID-19) that is caused by SARS-CoV2 [1, 2]. The symptoms of COVID-19 infection usually appear after an incubation period of about five days. 
The most common symptoms of COVID-19 illness are

•  fever, 
• cough, and 
• fatigue; 

other symptoms include

•  headache,
•  hemoptysis, and 
• dyspnea, among others. 

In the most severe cases, patients may develop 

• pneumonia, 
• acute respiratory distress syndrome (ARDS), 
• acute cardiac problems, and
•  multi organ failure  (MOF) [1]. 

The first cases of COVID-19 were reported in December2019 [1]; however, when we searched the MEDLINE (accessed from PubMed), from December 01, 2019 to March 26, 2020, with the keyword “COVID 19”, surprisingly 1655 articles were yielded. This shows that COVID-19 pandemic is of great global public health concern. Coronavirus infections have been associated with neurological manifestations (e.g.,

•  febrile seizures,
•  convulsions,
•  change in mentalstatus, and
•  encephalitis) [2, 3].

Neurotropic and neuroinvasive capabilities of coronaviruses have been described in humans. Upon nasal infection, coronavirus enters the CNS through the olfactory bulb, causing

• (CNS) inflammation and 
• demyelination [3].

 In this systematic review, we will discuss the evidence on the occurrence of 

• CNS involvement and 
•  neurological manifestations

 in patients with COVID-19.

ACE entsyymi prosessoi erästä HIV-1 eptidiä. T-soluantigeeniksi.

J Exp Med. 1992 Jun 1;175(6):1417-22.

Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules.

Kozlowski S¹, Corr M, Takeshita T, Boyd LF, Pendleton CD, Germain RN, Berzofsky JA, Margulies DH.

Abstract

T cell stimulation by the human immunodeficiency virus 1 gp160-derived peptide p18 presented by H-2Dd class I major histocompatibility complex molecules in a cell-free system was found to require proteolytic cleavage. This extracellular processing was mediated by peptidases present in fetal calf serum. In vitro processing of p18 resulted in a distinct reverse phase high performance liquid chromatography profile, from which a biologically active product was isolated and sequenced. This peptide processing can be specifically blocked by the angiotensin-1 converting enzyme (ACE) inhibitor captopril, and can occur by exposing p18 to purified ACE. The ability of naturally occurring extracellular proteases to convert inactive peptides to T cell antigens has important implications for understanding cytotoxic T lymphocyte responses in vivo, and for rational peptide vaccine design.

PMID:

1316930

PMCID:

PMC2119225

DOI:

10.1084/jem.175.6.1417

[Indexed for MEDLINE]

Free PMC Article

• 
  

Sytokiinimyrskyn muodostumisesta ja kohtalokkuudesta kavalassa COVID-19 taudissa

 (page1)Journal Pre-proof
 Cytokine Storm in COVID-19 and Treatment
 Qing Ye MD , Bili Wang MS , Jianhua Mao MDPII:S0163-4453(20)30165-1DOI:https://doi.org/10.1016/j.jinf.2020.03.037
 Reference:YJINF 4511
 To appear in:Journal of Infection
 Accepted date:24 March 2020
 Please cite this article as: Qing Ye MD , Bili Wang MS , Jianhua Mao MD , Cytokine Storm in COVID-19 and Treatment,Journal of Infection(2020), doi: https://doi.org/10.1016/j.jinf.2020.03.037
 This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.©2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved

 (Otan sitaattina sivu sivulta tästä tärkeästä sytokiinimyrskyasiasta saatavaa tietoa 16.4. 2020  lähdeopintoina) 

(page2) 
 Cytokine Storm in COVID-19 and Treatment
 Qing Ye, MD, Bili Wang, MS, JianhuaMao, MD National Clinical Research Center for Child Health, National Children's Regional Medical Center, the Children’s Hospital, Zhejiang University School of Medicine,Hangzhou 310052, China 
Corresponding authorJianhua Mao, MD, PhD, National Clinical Research Center for Child Health, National Children's Regional Medical Center, the Children’s Hospital, Zhejiang University School of Medicine,Hangzhou 310052, ChinaEmail: maojh88@zju.edu.cn13516819071Mailing address: No 3333, binsheng road, Hangzhou, China
 Contributors 
 QY led the writing of the manuscript.
 JHM developed the initial concept and framework for the manuscript and oversaw the drafting of the manuscript. 
All authors contributed to the content, drafting, and critical review of the manuscript.
 Conflict of Interest
 Disclosures 
The authors declare that they have no competing financial interests.FundingThis study was supported by Zhejiang University special scientific research fund for COVID-19 prevention and control.

 (page3) Abstract:
 Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.
 Keywords: 
Coronavirus, 2019-nCoV, SARS-CoV-2, cytokine storm, immunomodulation
(page4)
 Introduction 
Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) emerged for the first time in Wuhan, China, in December 2019. It is a type of highly pathogenic human coronavirus (HCoV) that causes zoonotic diseases and poses a major threat to public health. The vast majority of patients with the coronavirus disease 2019 (COVID-19) have had a good prognosis, but there were still some critical individuals and even deaths (1). Most of these critically ill and dead patients did not develop severe clinical manifestations in the early stages of the disease. Some of the patients only showed mild fever, cough,or muscle soreness.The conditions of these patients deteriorated suddenly in the later stages of the disease or in the process of recovery. 
 Acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) occurred rapidly, resulting in death within a short time (2). Cytokinestorm is considered to be one of the major causes of ARDS and multiple-organ failure (3). It plays an important role in the process of disease aggravation(4). 

 Clinical studies have detected a cytokinestorm in critical patients with COVID-19. Therefore, effectively suppressing the cytokinestorm is an important way to prevent the deterioration of patients with COVID-19 infection and save the patients' lives(5). 

 This article reviews the mechanisms by which HCoV infection induces cytokine storm and the options to inhibit the cytokinestorm, in order to provide a reference for the clinical diagnosis and treatment of COVID-19. 

HCoVs  (Human Coronaviruses)
 Coronaviruses (CoVs) are single-stranded, positive-strand RNA viruses belonging to the Coronaviridae family, Nidovirales order. The International Committee on Taxonomy of Viruses (ICTV) classifies the CoVs into four categories:α, β, γ,and δ. Under the electron microscope, the virus particles display a rough spherical or multi-faceted crystal shape.The surface of the viruses has prominent club-shaped projections composed of its spike (S) protein. Inside the virus particle is the viral genome wrapped in a nucleocapsid. The viral genome contains approximately 26,000 to 32,000 bases. CoVs are the largest known RNA viruses. The positive-strand viral RNA consists
 (page5) of a cap structure at the 5′ end and multiple poly(A) tails at the 3′ end. It serves as messenger RNA (mRNA), allowing the translation of replicase/transcriptase and viral structural proteins. The replicase/transcriptase genes account for approximately 2/3 of the 5′-end RNA sequence and are composed of two overlapping open reading frames (ORFs): ORF1a and ORF1b. These ORFs encode 16 non-structural proteins (nsps). The remaining 1/3 of the RNA sequence encodes four classical viral structural proteins, namely, spike (S) protein, envelope (E) protein, membrane(M)protein, and nucleocapsid (N) protein. In addition, genes encoding some viral accessory proteins are interspersed in the coding regions of the viral structural proteins. The coding sites and number of these accessory protein genes are an important basis for CoV classification. CoVs can infect a variety of host species, including birds, humans and some other vertebrates. These viruses mainly cause respiratory and intestinal infections and induce a variety of clinical manifestations (6, 7).Coronaviruses have long been recognized as important pathogens that infect the respiratory tracts of domestic and companion animalsand are the causes of mild and severe respiratory diseases in humans (7, 8). 
 So far, seven HCoVs that can invade humans have been identified, including 
 the α-type
 HCoV-229E
 and HCoV-NL63; 
the β-type
 HCoV-HKU1,
 SARS-CoV,
 MERS-CoV,and 
 HCoV-OC43; 
and 2019-nCoV, causing the present epidemic. 
 According to their pathogenicity, HCoVs are divided into 
 mildly pathogenic HCoVs including

•  HCoV-229E, 
•  HCoV-OC43,
•  HCoV-NL63, 
• HCoV-HKU) 

 and 
 highly pathogenic CoVs  including

•  severe acute respiratory syndrome CoV (SARS-CoV)
•  Middle East respiratory syndrome coronavirus (MERS-CoV)
•  SARS-CoV-2.  

The mildly pathogenic HCoVs infect the upper respiratory tract (URTI) and cause seasonal, mild to moderate cold-like respiratory diseases in healthy individuals. In contrast, the highly pathogenic HCoVs (hereinafter referred to as pathogenic HCoVsor HCoVs) infect the lower respiratory tract  (LRTI) and cause severe pneumonia, sometimes leading to fatal acute lung injury (ALI) and ARDS. The pathogenic HCoVs  have high morbidity and mortality and pose a major threat to public health(12-14).

 (page 6)
 Mechanism of cytokine storm by pathogenic HCoV infection

 It has long been believed that cytokines play an important role in immunopathology during viral infection. A rapid and well-coordinated innate immune response is the first line of defense against viral infection. However, dysregulated and excessive immune responses may cause immune damage to the human body (15-17). The relevant evidences from severely ill patients with HCoVs suggest that proinflammatory responses play a role in the pathogenesis of HCoVs. In vitro cell experiments show that delayed release of cytokines and chemokines occurs in respiratory epithelial cells, dendritic cells(DCs),and macrophages at the early stage of SARS-CoV infection. Later, the cells secrete low levels of the antiviral factors interferons(IFNs) and high levels of proinflammatory cytokines (interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)) and chemokines (C-Cmotif chemokine ligand (CCL)-2, CCL-3,and CCL-5)(18-20). Like SARS, MERS-CoV infects human airway epithelial cells,THP-1 cells (a monocyte cell line), human peripheral blood monocyte-derived macrophages and DCs, and induces delayed but elevated levels of proinflammatory cytokines and chemokines (21, 22). After MERS-CoV infection, plasmacytoid dendritic cells, but not mononuclear macrophages and DCs (23), are induced to produce a large amount of IFNs. Serum cytokine and chemokine levels are significantly higher in patients with severe MERS than patients with mild to moderate MERS (24, 25). The elevated serum cytokine and chemokine levels in MERS patients are related to the high number of neutrophils and monocytes in the patients’lung tissues and peripheral blood, suggesting that these cells may play a role in lung pathology (24-26). Similar phenomena have been observed in patients with SARS-CoV infection(27-34). The production of IFN-I or IFN-α/β is the key natural immune defense response against viral infections, and IFN-I is the key molecule that plays an antiviral role in the early stages of viral infection(35, 36). 
Delayed release of IFNs in the early stages of SARS-CoV and MERS-CoV infection hinders the body's antiviral response (36). Afterward, the rapidly increased cytokines and chemokines attract many inflammatory cells,such as neutrophils and (page 7)  monocytes, resulting in excessive infiltration of the inflammatory cells into lung tissue and thus lung injury. It appears from these studies that dysregulated and/or exaggerated cytokine and chemokine responses by SARS-CoV-infected or MERS-CoV-infected cells could play an important role in pathogenesis of SARS or MERS.
 Animal models can well elucidate the role of cytokines and chemokines in mediating pulmonary immunopathology after HCoV infection. Despite of similar virus titers in the respiratory tract, SARS-CoV-infected old nonhuman primates are more likely to develop immune dysregulation than the infected young primates, leading to more severe disease manifestations (37). It seems that the excessive inflammatory response rather than the virus titer is more relevant to the death of the old nonhuman primates (37). Similarly, in BALB/c mice infected with SARS-CoV, disease severity in old mice is related to the early and disproportionately strong upregulation of the ARDS-related inflammatory gene signals (38). The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages (15).
 The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. These mononuclear macrophages produce elevated levels of proinflammatory cytokines (TNF, IL-6, IL1-β, and inducible nitric oxide synthase, iNOS), thereby increasing the severity of the disease. Depleting inflammatory monocyte-macrophages or neutralizing the inflammatory cytokine TNF protected mice from the fatal SARS-CoV infection. In addition, IFN-α/β or mononuclear macrophage-derived proinflammatory cytokines induce the apoptosis of T cells, which further hinders viral clearance (15). Another consequence of rapid viral replication and vigorous proinflammatory cytokine/chemokine response is the induction of apoptosis in lung epithelial and endothelial cells. IFN-αβ and IFN-γ induce inflammatory cell infiltration through mechanisms involving Fas–Fas ligand(FasL) or TRAIL–death receptor 5 (DR5)and cause the apoptosis of airway and alveolar epithelial cells(39-41).

(Page8)  Apoptosis of endothelial cells and epithelial cells damages the pulmonary microvascular and alveolar epithelial cell barriers and causes vascular leakage and alveolar edema, eventually leading to hypoxia in the body. Therefore, inflammatory mediators play a key role in the pathogenesis of ARDS. ARDS is the leading cause of death in patients infected with SARS-CoV or MERS-CoV (42, 43).It is now known that several proinflammatory cytokines (IL-6, IL-8, IL-1β, granulocyte-macrophage colony-stimulating factor, and reactive oxygen species) and chemokines (such as CCL2, CCL-5, IFNγ-induced protein 10 (IP-10), and CCL3) all contribute to the occurrence of ARDS (44-46). These results support such points of view that, following SARS-CoV infection, high virus titers and dysregulation of cytokine/chemokine response cause an inflammatory cytokine storm. The inflammatory cytokine storm is accompanied by immunopathological changes in the lungs. 

The relationship between cytokine levels and disease progression in patients

 High levels of expression of IL-1B, IFN-γ, IP-10,and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response (47). Th1 activation is a key event in the activation of specific immunity (48). However, unlike SARS patients, patients with COVID-19 also have elevated levels of Th2 cell-secreted cytokines (such as IL-4 and IL-10), which inhibit the inflammatory response. The serum levels of IL-2R and IL-6 in patients with COVID-19 are positively correlated with the severity of the disease (i.e., critically ill patients > severely ill patients > ordinary patients) (49). Other studies have found that, compared with COVID-19 patients from general wards, patients in the intensive care unit (ICU) display increased serum levels of granulocyte colony-stimulating factor, IP-10, MCP-1, macrophage inflammatory protein-1A, and TNF-α. The above studies suggest that the cytokine storm is positively correlated with disease severity (47). A report on the severe new-type coronavirus-infected pneumonia showed that 37 (page 9)  patients (71.2%) required mechanical ventilation, and 35 patients (67.3%) suffered ARDS. Moreover, the mortality of the elderly patients with ARDS was significantly elevated (50).
 The core pathological change in ARDS is the pulmonary and interstitial tissue damage caused by nonspecific inflammatory cell infiltration (51).Local excessive release of cytokines is the decisive factor that induces this pathological change and clinical manifestation (52). In COVID-19,the inflammatory cytokine storm is closely related to the development and progression of ARDS. The serum levels of cytokines are significantly increased in patients with ARDS, and the degree of increase is positively correlated with mortality rate (53). The cytokine storm is also a key factor in determining the clinical course of extrapulmonary multiple-organ failure (MOF)(54). This partially explains the signs of extrapulmonary organ failure (such as elevated liver enzymes and creatinine) seen in some COVID-19 patients without respiratory failure, suggesting that the inflammatory cytokine storm is the cause of damage to extrapulmonary tissues and organs.

 In summary, the new-type coronavirus infection causes an inflammatory cytokine storm in patients. The cytokine storm leads to ARDS or extrapulmonary multiple-organ failure and is an important factor that causes COVID-19 exacerbation or even death. 

Theoretical treatment strategy with inflammatory cytokine storm

 High virus titer and the subsequent strong inflammatory cytokine and chemokine responses are related to the high morbidity and mortality observed during the pathogenic HCoV infection. The experience from treating SARS and MERS shows that reducing viral load through interventions in the early stages of the disease and controlling inflammatory responses through immunomodulators are effective measures to improve the prognosis of HCoV infection (55-58).

 IFN-λ 
 IFN-λ primarily activates epithelial cells and reduces the mononuclear macrophage-mediated proinflammatory activity of IFN-αβ (59).In addition, IFN-λ inhibits the recruitment of neutrophils to the sites of inflammation (60). SARS-CoV and MERS-CoV mainly infect alveolar epithelial cells (AEC). IFN-λ activates the (page 10)  antiviral genes in epithelial cells, thereby exerting antiviral effects without overstimulating the human immune system. Therefore, IFN-λ may be an ideal treatment. Some studies have applied pegylated and non-pegylated interferons for the treatment of HCoVs, but the efficacy varied significantly due to the application of different treatment regimens. Early administration of interferons has certain benefits in reducing viral load and improves the clinical symptoms of patients to a certain extent. However, it fails to reduce mortality rates (61-63). With the exception of early administration, the use of interferons at other time periods will not bring more benefits than placebo treatment (63). 

 Corticosteroid therapies
 Corticosteroids are a class of steroid hormones that have anti-inflammatory functions. Corticosteroids are commonly used to suppress inflammation. During the 2003 SARS epidemic, corticosteroids were the primary means of immunomodulation. Timely administration of corticosteroids often leads to early improvements such as reducing fever, relieving radiation infiltration of the lung, and improving oxygenation (64-66). A retrospective study of 401 patients with severe SARS revealed that proper administration of glucocorticoids in patients with severe SARS significantly reduced the mortality rate and shortened the hospital stay. Moreover,secondary infections and other complications rarely occurred in these glucocorticoid-treated patients (67). However, there are studies showing that administration of corticosteroid therapy during human SARS-CoV infection led to adverse consequences. Early treatment of SARS patients with corticosteroids increased plasma viral load in non-ICU patients, resulting in the aggravation of the disease (64). In treatment of patients with COVID-19, the use of glucocorticoids has again become a major conundrum for clinicians (68). The timing of administration and the dosage of glucocorticoids are very important to the outcome of the severely ill patients. A too early administration of glucocorticoids inhibits the initiation of the body's immune defense mechanism, thereby increasing the viral load and ultimately leading to adverse consequences. Therefore, glucocorticoids are mainly used in critically ill (page11)  patients suffering inflammatory cytokine storm. Inhibition of excessive inflammation through timely administration of glucocorticoids in the early stage of inflammatory cytokine storm effectively prevents the occurrence of ARDS and protects the functions of the patients’ organs.For patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and excessive inflammatory response, the use of glucocorticoid in the short term (3-5 days) is appropriate, and the recommended dose is no more than equivalent to methylprednisolone 1-2mg/kg/day (69). It should be noted that large doses of glucocorticoid may delay the clearance of coronavirus due to immunosuppression. 

 Intravenous immunoglobulin (IVIG) 
 Chen et al. analyzed the treatment of 99 Wuhan patients with COVID-19 and found that 27% of these patients had received IVIG treatment (70). IVIG therapy has the dual effects of immune substitution and immunomodulation. Its practical application value in treatment of COVID-19 needs confirmation in future studies. 

 IL-1 family antagonists
 During the cytokine storm, the three most important cytokines in the IL-1 family are IL-1β, IL-18,and IL-33 (4). Studies that focus on the inhibition of IL-1β to reduce the cytokine storm have attracted most attention. Anakinra, an antagonist of IL-1β, can be used to treat the cytokine storm caused by infection. It significantly improved the 28-day survival rate of patients with severe sepsis (71). 
There is currently no clinical experience with applying specific IL-1 family blockers to treat COVID-19. Their effects need to be verified through in vivo animal experiments and clinical trials.
 IL-6 antagonists
 Tocilizumab is an IL-6 antagonist that suppresses the function of the immune system. Currently, tocilizumab is mainly applied in autoimmune diseases such as rheumatoid arthritis(72). Tocilizumab itself has a therapeutic effect on the infection-induced cytokinestorm (73). Serum IL-6 level is significantly increased in severely ill patients with COVID-19. Clinical studies from China have shown that Tocilizumab is effective in treating severely ill patients with extensive bilateral lung lesions, who (page12)  have elevated IL-6 levels.The first dose was 4-8mg/kg. The recommended dosage was 400 mg with 0.9% saline diluted to 100 ml. The infusion time was more than 1 hour. For patients with poor efficacy of the first dose, an additional dose can be applied after 12 hours (the dose is the same as before), with a maximum of two cumulative dose. 

TNF blockers 
TNFs are key inflammatory factors that trigger a cytokine storm. They are attractive targets for controlling the cytokine storm. A meta-analysis showed that anti-TNF therapy has significantly improved survival in patients with sepsis (74). Anti-TNF therapy has  also achieved satisfactory outcomes in treatment of noninfectious diseases such as atherosclerosis (75).Studies in animal models have shown that TNFs contribute significantly to acute lung injury and impair theT cell response in SARS-CoV-challenged mice. In mice, neutralization of TNF activity or loss of TNF receptor provides protection against SARS-CoV-induced morbidity and mortality (15, 76).However, it should be noted that, at least in the later stages of infection, TNF has not been detected in the serum of patients with SARS. At present, TNF blockers have not been suggested in the treatment of patients with COVID-19, but the efficacy of TNF blockers in treatment of patients with COVID-19 deserves further exploration.

 IFN-αβ inhibitors
 IFN-αβ limits viral replication by inducing IFN-stimulated gene. However, IFN-αβ also exacerbates diseases through enhancing the recruitment and function of mononuclear macrophages and other innate immune cells. Although an early interferon response has a protective effect on mice infected with SARS-CoV, delayed IFN-αβ signaling causes an imbalance of the anti-SARS-CoV immune responses in humans. This phenomenon indicates that the timing of IFN treatment is crucial to the outcome of diseases. Based on these results, IFN-αβ receptor blockers or antagonists should be administered in the later stages of severe disease to prevent excessive inflammatory responses(16).

(page 13)
Chloroquine
 Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokinestorm in patients infected with COVID-19 (77). Chloroquine phosphate has been used in the treatment of adults aged 18 to 65 in China (78).The recommended dosage by diagnosis and treatment of new coronavirus pneumonia (trial version 7) from china is as follows: If the weight is more than 50 kg, 500 mg each time, 2 times a day, 7 days as a treatment course;If the weight is less than 50kg, 500 mg each time on the first and second days, twice a day, 500 mg each time on the third to seventh days, once a day.

 Ulinastatin
Ulinastatin is a natural anti-inflammatory substance in the body. It protects the vascular endothelium by inhibiting the production and release of inflammatory mediators. Ulinastatin is widely used in clinical practice to treat pancreatitis and acute circulatory failure. Ulinastatin reduces the levels of proinflammatory factors such as TNF-α, IL-6, and IFN-γ, and increases the level of anti-inflammatory factor IL-10 (79). These activities of ulinastatin promote the balance between proinflammatory and anti-inflammatory responses in humans, thus interrupting the cytokine storm induced by the vicious cycle of inflammation. Animal studies show that the anti-inflammatory effect of high-dose ulinastatin is equivalent to that of hormones (80). However, unlike glucocorticoids, ulinastatin does not inhibit immune functions and is unlikely to cause sequelae such as femoral head necrosis. Therefore, ulinastatin has great application prospects in the treatment of COVID-19. 

The inhibitory effect to  oxidized phospholipids (OxPL)
 In a mouse model of influenza A virus (IAV) infection, OxPL increases the production of cytokines/chemokines in lung macrophages through the Toll-like receptor 4 (TLR4)–TIR-domain-containing adapter-inducing interferon-β signaling pathway, thereby promoting the occurrence of ALI (81). 
 Eritoran is a TLR4 antagonist. It does not have direct antiviral activity but has strong immunomodulatory functions. Eritoran effectively lowers the production of OxPL, inflammatory cytokines, and chemokines
(page 14)  in IAV-infected mice, thereby reducing death (82).Pathogenic human coronaviruses also cause a high accumulation of OxPL in patients' lung tissues, resulting in ALI (81). Thus, it seems that eritoran and other OxPL inhibitors may also be able to alleviate HCoV-induced inflammatory responses.

 Sphingosine-1-phosphate(S1P) receptor 1 agonist therapy 
Sphingosine-1-phosphate (S1P) is a signal lysophospholipid (LPL) that promotes cytokine synthesis and secretion (83). The S1P receptor signaling pathways significantly inhibit the pathological damage induced by the host's innate and adaptive immune responses, thereby reducing the cytokine storm caused by influenza virus infection (84, 85). In mouse models of IAV infection,sphingosine-1-phosphate receptor 1 (S1P1) signal transduction in respiratory endothelial cells modulates pathogenic inflammatory responses (85). Agonists targeting S1P1inhibit excessive recruitment of inflammatory cells, inhibit proinflammatory cytokines and chemokines, and reduce the morbidity and mortality of IAV(85, 86).
 SARS-CoV-2 also mainly infects human lung epithelial cells and endothelial cells. Therefore, S1P1agonists may be potential therapeutic drugs for reducing cytokine and chemokine responses in those HCoV patients whose cells generated excessive immune responses. An S1P-receptor modulating drug, siponimod,was approved in 2019 to treat multiple sclerosis. However, clinical trials are needed to further verify whether siponimod is an ideal alternative for the treatment of cytokine storm.

 Stem cell therapy
 As an important member of the stem cell family, mesenchymal stem cells (MSC) not only have the potential of self-renewal and multidirectional differentiation, but also have strong anti-inflammatory and immune regulatory functions. MSC can inhibit the abnormal activation of T lymphocytes and macrophages, and induce their differentiation into regulatory T cell (Treg) subsets and anti-inflammatory macrophages, respectively. It can also inhibit the secretion of pro-inflammatory cytokines,such as,IL-1, TNF-α,IL-6, IL-12,and IFN-γ, thereby reducing the occurrence of cytokine storms (87, 88).At the same time, MSC can secrete IL-10, (page 15) hepatocyte growth factor, keratinocyte growth factor and VEGF to alleviate ARDS, regenerate and repair damaged lung tissues, and resist fibrosis (89).Therefore, many functions of MSC are expected to make it an effective method for the treatment of COVID-19.

 Blood purification treatments
 In addition, the blood purification treatments currently used in clinic practice can remove inflammatory factors to a certain extent.Blood purification system including plasma exchange, adsorption, perfusion, blood/plasma filtration, etc., can remove inflammatory factors, block the "cytokine storm", to reduce the damage of inflammatory response to the body. This therapy can be used for severe and critical patients in the early and middle stages of the disease. 

The artificial liver technology led by Academician Li Lanjuan can eliminate inflammatory factors on a large scale. This technology has also been used to resist the cytokine storm of H7N9, and its application on COVID-19 has also achieved certain efficacy (90).
 Early renal replacement therapy, which is similar to the treatment principle of artificial liver technology, seems to be an effective method to control cytokine storm(91). 

Inhibitors of mononuclear macrophage recruitment and function 
An autopsy report of patients with COVID-19 revealed a large amount of inflammatory cell infiltration in the lungs of the deceased (92).One potentially effective treatment approach is to reduce the recruitment of mononuclear macrophages to the site of inflammation through small interfering RNA(siRNA)-mediated silencing of C-C chemokine receptor type 2 (CCR2), which has been demonstrated by animal experiments to improve the outcome of the disease (93, 94).
 Toll-like receptor 7 (TLR7) agonists stimulate mononuclear macrophages to undergo a strong inflammatory response at the time of infection with single-stranded RNA (ssRNA) viruses such as HCoV. Therefore, TLR7 antagonists may be able to alleviate the storm of inflammatory factors caused by SARS-CoV-2 infection

Strengthens the vascular barrier
 Increased vascular permeability is also a hallmark change that occurs in the process of a cytokine storm. It was found in animal infection models of sepsis and H5N1 virus that activation of the endothelial Slit-Robo4 pathway with drugs improved vascular permeability, thereby reducing the occurrence ofa cytokinestorm during infection (95). 

 Conclusion

 Inflammation is an essential part of an effective immune response. It is difficult to eliminate infections successfully without inflammation. The inflammatory response begins with an initial recognition of pathogens. The pathogens then mediate the recruitment of immune cells, which eliminates the pathogens and ultimately leads to tissue repair and restoration of homeostasis. However, SARS-CoV-2 induces excessive and prolonged cytokine/chemokine responses in some infected individuals, known as the cytokine storm. Cytokine storm causes ARDS or multiple-organ dysfunction, which leads to physiological deterioration and death. Timely control of the cytokine storm in its early stage through such means as

•  immunomodulators and 
•  cytokine antagonists,as well as
•  the reduction of lung inflammatory cell infiltration,

 is the key to improving the treatment success rate and reducing the mortality rate of patients with COVID-19.

 Contributors
 QY led the writing of the manuscript. 
 JHM developed the initial concept and framework for the manuscript and oversaw the drafting of the manuscript. 
All authors contributed to the content, drafting, and critical review of the manuscript.
 Conflict of Interest
 Disclosures 
The authors declare that they have no competing financial interests. 
Funding This study was supported by Zhejiang University special scientific research fund for COVID-19 prevention and control

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