The outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a review of the current global status

ContentslistsavailableatScienceDirect

Journal

of

Infection

and

Public

Health

j o u r n al ho me p ag e :h t t p : / / w w w . e l s e v i e r . c o m / l oc a t e / j i p h

Review

Article

The

outbreak

of

the

novel

severe

acute

respiratory

syndrome

coronavirus

2

(SARS-CoV-2):

A

review

of

the

current

global

status

Mbarka

Bchetnia

_,

_Catherine

_Girard

_,

_Caroline

_Duchaine

_,

_Catherine

_Laprise

a_{UniversitéduQuébecàChicoutimi(UQAC),Départementdessciencesfondamentales,Centreintersectorielensantédurable,Saguenay,Canada} b_{Centrederecherche,InstitutuniversitairedecardiologieetdepneumologiedeQuébec,UniversitéLaval(IUCPQ-UL),Québec,Canada} c_{Départementdebiochimie,demicrobiologieetdebioinformatique,UniversitéLaval,Québec,Canada}

a

r

t

i

c

l

e

i

n

f

o

Received10May2020

Receivedinrevisedform13July2020 Accepted21July2020 Keywords: SARS-CoV-2 COVID-19 Emergence Transmission Prevention Treatment

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Thereiscurrentlyanongoingworldwidepandemicofanovelvirusbelongingtothefamilyof

Coro-naviruses(CoVs)whicharelarge,enveloped,plus-strandedRNAviruses.Coronavirusesbelongtothe

orderofNidovirales,familyofCoronavirinaeandaredividedintofourgenera:alphacoronavirus,

beta-coronavirus,gammacoronavirusanddeltacoronavirus.CoVscausediseasesinawidevarietyofbirdsand

mammalsandhavebeenfoundinhumanssince1960.Todate,sevenhumanCoVswereidentified

includ-ingthealpha-CoVsHCoVs-NL63andHCoVs-229Eandthebeta-CoVsHCoVs-OC43,HCoVs-HKU1,the

severeacuterespiratorysyndrome-CoV(SARS-CoV),theMiddleEastrespiratorysyndrome-CoV

(MERS-CoV)andthenovelvirusthatfirstappearedinDecember2019inWuhan,China,andrapidlyspreadto

213countriesasofthewritingthispaper.Itwasofficiallynamedsevereacuterespiratorysyndrome

coronavirus2(SARS-CoV-2)bytheinternationalcommitteeontaxonomyofviruses(ICTV)andthe

dis-ease’snameisCOVID-19forcoronavirusdisease2019.SARS-CoV-2isverycontagiousandiscapableof

spreadingfromhumantohuman.Infectionroutesincludedropletandcontact,andaerosoltransmission

iscurrentlyunderinvestigation.Itisassociatedwitharespiratoryillnessthatmaycausesevere

pneumo-niaandacuterespiratorydistresssyndrome(ARDS).SARS-CoV-2becameanemergencyofinternational

concern.AsofJuly12,2020,thevirushasbeenresponsiblefor12,698,995confirmedcasesand564,924

deathsworldwideandthenumberisstillincreasing.Upuntilnow,nospecifictreatmenthasyetbeen

proveneffectiveagainstSARS-CoV-2.Sincethebeginningofthisoutbreak,severalinterestingpaperson

SARS-CoV-2andCOVID-19havebeenpublishedtoreportonthephylogeneticevolution,epidemiology,

pathogenesis,transmissionaswellasclinicalcharacteristicsofCOVID-19andpossibletreatmentsagents.

ThispaperisasystematicreviewoftheavailableliteratureonSARS-CoV-2.Itwasperformedin

accor-dancewithPRISMA(PreferredReportingItemsforSystematicReviewsandMeta-Analyses)andaims

tohelpreadersaccessthelatestknowledgesurroundingthisnewinfectiousdiseaseandtoprovidea

referenceforfuturestudies.

ﾩ2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofKingSaudBinAbdulazizUniversityfor

HealthSciences.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.

org/licenses/by-nc-nd/4.0/).

Contents

Introduction...1602

Methods...1602

Searchstrategy...1602

Inclusionandexclusioncriteria...1602

Dataextractionandsynthesis...1602

Results...1602

SARS-CoV-2emergence...1602

Clinicalfeaturesandpathogenesis...1605

∗ Correspondingauthor.

E-mailaddress:catherine.laprise@uqac.ca(C.Laprise). https://doi.org/10.1016/j.jiph.2020.07.011

1876-0341/ﾩ2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofKingSaudBinAbdulazizUniversityforHealthSciences.Thisisanopenaccessarticleunderthe CCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Convalescentplasmatransfusion(CP)...1607

GlobalSARS-CoV-2preventionmeasures ... 1607

Conclusion ... 1608 Funding...1608 Competinginterests ... 1608 Ethicalapproval...1608 Authorcontributions...1608 Acknowledgements...1608 References ... 1608 Introduction

Coronaviruses(CoV)arethelargestknownRNAviruses.Their sizevariesfrom65to125nmindiameterandtheirnucleicacid genomeissingle-strandedRNA,sizerangingfrom26to32kbin length[1].Since1960,sixcoronaviruseshavebeenfoundtocause diseasesinhumans;SARS-CoV-2istheseventhone,afterSARS-CoV andMERS-CoV[2].WhileHKU1,NL63,OC43and229Eare associ-atedwithmildsymptomsinhumans,SARS-CoV,MERS-CoV,and SARS-CoV-2,belongingtothebetacoronavirusgenus,causesevere todeadlypneumoniainhumans[3].Fever,drycough,difficulty breathingandfatigueusuallyaccompanythispneumonia[4,5].The fatalityrates ofSARS-CoV,MERS-CoVand SARS-CoV-2are9.5%, 34.4%,and 2.3%respectively[6].COVID-19showssome particu-larpathogenic,epidemiologicalandclinicalfeatures whichhave arenotcompletelyunderstoodtodateaswellasitswideandhigh transmissioninthecommunityversusnosocomialspreadofSARS andMERSanditsmilderinfectionandlowmortalitycomparedto theseverephenotypeandhighermortalitycausedbythetwo oth-ersviruses[7].Todate,notherapeuticorvaccineswereapproved againstanyoftheknownhumancoronavirusesandonly protec-tivemeasureswereputinplace.Basedonthecurrentpublished literature,wesummarizeinthispapertheoriginofthisnovelvirus anditslifecycle,theclinicalcharacteristicsofthedisease,the possi-bletransmissionroutes,thepathogenesis,thepreventionmeasures and the undergoing treatments of this emerging infectious disease.

Methods

Searchstrategy

The present study was conducted following the PRISMA guidelines[8]. Weperformeda systematicsearchfor accessible peer-reviewedandfullarticlespublishedfromDecember2019to May2020.TheliteraturesearchwasupdatedinJuly2020while reviewingthepaperpriortoitsresubmission.Articlesforreview wereselectedfromthefollowingdatabasesMEDLINE(PubMed), WebofScienceandGoogleScholar.Thesearchtermsincluded com-binationsof“COVID-19,SARS-CoV-2,newcoronavirus,emergence, symptoms,multiplicationcycle,transmission,diagnosistests, pre-vention,andtreatment”.Full-textversionsoftheincludedpapers wereretrieved. Thereferencelistsofrelevant studieswerealso assessed.

Inclusionandexclusioncriteria

Inclusion and exclusion criteria were recorded following PRISMAguidelinespresentedintheformofa PRISMAflow dia-gram(Fig.1).Briefly, theretrievedliteraturewasimportedinto Endnotesoftware(v.× 9.0)and screenedforexclusion criteria. First,duplicateliteraturewasremovedbyEndnote,andthen obvi-ouslyinappropriateoneswereeliminatedbasedonthetitleand abstract.Finally,remaininginappropriateentrieswereeliminated byreadingthefullarticles.Theexclusioncriteriaforarticleswere non-Englishstudies,entrieswithonlyanabstract,thosewithno relevanttopic,andstudiescontainingnousefulorduplicateddata frompreviouslypublishedstudies.Theinclusioncriteriaare arti-clesreportingconfirmedSARS-CoV-2positivepatients,andstudies presentingoriginaldataaswellasclearandpreciseend-point out-comes.

Dataextractionandsynthesis

The authors independently extracted important information fromeacharticlefulfillingtheinclusioncriteriaandreviewedeach papertoverifytheaccuracyandcoherenceofcollecteddata. Argu-mentsordisagreementswereresolvedfollowingdiscussions.The consensusextracteddataweresynthesizedinthepresentpaper. Ethicalapprovalwasnotrequiredforthisreviewofexisting peer-reviewedpapers.

Results

We identified 170papers through PubMed, Web of science and GoogleScholar databasesand 20 papers throughreference cross-checkand internetresearchof conferenceabstracts. After duplicateremoval,atotalof130paperswerescreenedfor rele-vance.Abstractsandtitlesscreeningidentified32studiesthatmet theinclusioncriteria.Afterthefull-textanalyses,12ofthese stud-ieswereexcluded.Hence,twentystudieswereeligibleaccording toourcriteriaandwereincludedinthisreview(Fig.1).

SARS-CoV-2emergence

Coronaviruseshavebeendescribedascausingseveralsystemic infections in theirselected animal host [9]. However, some of themcanadaptdramaticallyandjumpthespeciesbarrierby nat-uralrecombinationcausingepidemicsorpandemics.Infectionin humanoftenleadstosevereclinicalsymptomsandhigh mortal-ity(https://www.who.int/emergencies/mers-cov/en/).Wepresent

Fig.1.PRISMAflowchartofliteraturesearchstrategy.

Fig.2. Emergenceofhumancoronaviruses:AsofJuly12,2020,sevenCoVsareknowntobehumanpathogensincludingthealpha-CoVsHCoVs-NL63(1200-1500)and HCoVs-229E(1700-1800)andthebeta-CoVsHCoVs-OC43(1890),HCoVs-HKU1(1950),severeacuterespiratorysyndrome-CoV(SARS-CoV)(2002),MiddleEastrespiratory syndrome-CoV(MERS-CoV)(2012)andthenovelSARS-CoV-2(2019).

Fig.3.SARS-CoV-2situationupdateworldwide:AsofJuly12,2020,12,698,995casesofCOVID-19havebeenreportedintheworldincluding564,924deaths.Themost affectedcontinentistheAmericawith6,685,097confirmedcasesand286,796deathsonthisday(https://www.ecdc.europa.eu/).

Table1

ComparativeanalysisofSARS-CoV,MERS-CoV,andSARS-CoV-2.

Coronavirus SARS-CoV MERS-CoV SARS-CoV-2

Emergencyyear 2002 2013 2019

Emergencyarea Guangdongprovince,China Arabianpeninsula Wuhan,China

Numberofinfectedcountries 29 27 213

Animalreservoir Bat Bat Bat

Intermediatehost Palmcivets Camels Unknown

incubationtimeinhumans(days) 2–7 2–14 2–14

Causeddisease Severeacuterespiratorysyndrome

(SARS)

MiddleEastrespiratorysyndrome (MERS)

Coronavirusdisease2019 (COVID-19)

Clinicalsymptoms Malaise,diarrhea,cough,feverand

shortnessofbreath

Pneumonia,acuterespiratory distresssyndrome,renalfailure

Cough,feverandshortnessof breath

Numberofinfectedpatients 8098 2494 3,646,304

Numberofdeaths 776 858 252,425

Entryreceptorinhumancells Angiotensin-convertingenzyme2

(ACE2)

Dipeptidylpeptidase4(DPP4) Angiotensin-convertingenzyme2

(ACE2)

Usedtherapy Supportivecare Supportivecare Supportivecare

inFig.2theappearanceofthesevenhumancoronavirusesover thetime(Fig.2).In 2002,inGuangdong(China),theSARS-CoV virusemerged and spreadtothefivecontinentsinfecting8098 peopleand causing 774deaths(9.5%of cases).In 2012, MERS-CoVemerged intheArabianPeninsulainfecting2494peoplein 27countriesandcausing858deaths(34.4%ofcases)[10].Inlate December2019,SARS-CoV-2emergedinaseafoodmarket(where severalwildlifespeciesaresoldincludingbats,rabbits,snakes,birds andfrogs)inWuhanCity,Hubeiprovince,China[11].AsofJuly 12,2020,thisvirushasbeenresponsiblefor12,698,995confirmed casesand564,924deathsworldwide(2.3%).SARS-CoV-2spread rapidlyto213countries(atthetimeofrevision), andthemost affectedcontinentsaretheAmerica andEuropewith6,685,097 and 2,572,406confirmed cases respectively since 31 December

2019andasofJuly12,2020.InAmerica,286,796personswere diedand196,096onesinEuropeuntilthisday(https://www.ecdc. europa.eu/)(Fig.3).OnJanuary30,2020,theWorldHealth Orga-nization (WHO) declared theSARS-CoV-2 epidemic asa public healthemergencyofinternationalconcern[12].OnMarch11,2020, theWHOissued anannouncementof thechangeinCOVID-19’s statusfroman epidemictopandemicdisease.It wassuggested thatMERS-CoV,SARS-CoVandSARS-CoV-2originatedfrombats [13].Phylogenetic analysesshowedthat SARS-CoV-2,SARS-CoV andSARS-likecoronavirusesisolatedinbatsbelongtoadifferent cladethanMERS-CoV,withacompletegenomenucleotide iden-titybetween SARS-CoV-2 and SARS-CoVof 79.5% and between SARS-CoV-2andbatSARScoronavirus(SARSr-CoV-RaTG13)of96% [13,14].Palmcivetsandracoondogswereidentifiedasthelikely

reservoirhostfuellingspillovertohumansforSARS-CoV[15,16], whileMERS-CoV’sintermediatehostisunequivocallydromedary camels[17,18].ForSARS-CoV-2,pangolinsandsnakesarethought tobepotentialintermediatehostsbutthisrequiresfurther con-firmation[19].Moreevidenceisneededtoconfirmtheoriginof thisnovelvirusanditstransmissiontohumans,tounderstandthe bestwaytopreventandslowdownitstransmissionandto bet-tercontroloffuturezoonoticevents.InTable1,wesummarizethe principalcharacteristicsofSARS-CoV,MERS-CoVandSARS-CoV-2. Briefly,batsseemtobethecommonnaturaloriginofSARS-CoV-2, SARS-CoVandMERS-CoV.Theclinicalfeaturesofthethreeviruses arequitesimilar.However,unlikeSARS-CoVandMERS-CoV, SARS-CoV-2ismorecontagiousandspreadsrapidly,currentlyaffecting morethan213countries(https://www.who.int).SARS-CoV-2uses theSARS-CoVreceptorangiotensin-convertingenzyme2(ACE2) onhosttargetcells;however,MERS-CoVbindstothedipeptidyl peptidase4receptor(DDP4)[20].Accordingtothelateststudies, SARS-CoV-2hasthehighestnumberofcasualtiesbutits mortal-ityrateis lower(2.3%) comparedtoSARS-CoV(9.5%)andMERS (34.4%)[6].Therefore,SARS-CoV-2resemblesbothSARS-CoVand MERS-CoV,butappearsuniqueinitshightransmissionrates.

Clinicalfeaturesandpathogenesis

COVID-19isahighlycontagiousdisease.Itsclinical manifesta-tionsrangefrommildtoseverebutmostinfectedcasespresent amildformofthediseaseandthereforehavenosevereclinical features[21].Basedoncurrentdata,81%ofthecasesexhibitmild symptomsand1.2%areasymptomatic(http://weekly.chinacdc.cn). SARS-CoV-2 canspread rapidly in thecommunity contrarilyto SARSCoVandMERS-CoVthathaveahighermortalityratebuta strongernosocomialthancommunitytransmissibility.Thisislikely duetothefactthattheycauseamoresevereclinicalphenotype thanCOVID-19[6].ItwasreportedthatCOVID-19average incuba-tionperiodis5.2days(95%confidenceinterval(CI),4.1–7.0)with the95thpercentileat12.5days[22].Anotherstudyestimatedit at6.4 days(95%CI,5.6–7.7) [23].The medianageofCOVID-19 casesrangesfrom49to57 years[6] andmediantimefromthe firstsymptomtodeathis14days[24].Whileadetailedclinical landscapecontinuestobeestablished,themostcommonclinical symptomsofSARS-CoV-2observedinpatientswerefever(87.9%), cough(67.7%) and fatigue(38.1%), whereasdiarrhea (3.7%) and vomiting(5.0%)wereoccasional [24,25]. Allpatientshad pneu-moniaandabouthalfhaddyspnea[26].SomeCOVID-19patients showedarrhythmia,acuteheart injury,impaired renalfunction andabnormalliverfunction(50.7%)atadmission[27,28].In addi-tion,thereisevidenceofocularsurfaceinfectioninpatientswith COVID-19asSARS-CoV-2RNAwasdetectedineyesecretionsof patients[29,30]. Aretrospectivecase seriesstudyconductedon 214infectedpatientsfromWuhanshowedthat78(36.4%)patients displayedneurologicmanifestations[31].Furthermore,diminished ability tosmellor tasteobserved insomepatients[32,33]was foundtoresultfromaneurotropicorneurovirulentviralinfection oftheolfactorysystem[34].Theolderpopulationandindividuals withunderlyinghealthcomplicationsascardiovasculardiseases anddiabeteswerereportedtopresenttheseverediseasesymptoms [35].Childrenwerefoundlessvulnerablethantheelderpopulation [36,37].PregnantwomenmaybemorevulnerabletoSARS-CoV-2 asthis virusmayalter theimmuneresponses atthe maternal-fetalinterface,andaffectthewell-beingofmothersand infants [38].Aretrospectivestudybasedonninepregnantwomeninfected byCOVID-19showednoevidenceofintrauterinevertical trans-missionbetweenmothersandinfantsinthelatepregnancy[39]. ToavoidSARS-CoV-2newbornsinfectionsafterbirth,immediate preventioninstructionsshouldbeimplementedforthesewomen and theirneonates, including a 14-day isolation for newborns

and avoiding breast feedingduringthis period [40].Laboratory findingsshowedtypicalCTresultsincludingbilateralpulmonary parenchymalgroundglassandconsolidatedpulmonaryopacities sometimeswitharoundedmorphologyandperipherallung distri-bution[41].Ground-glass-likelungimagesareprobablyduetothe severeinflammationoflungcellsbecomingunabletoexchange car-bondioxideandoxygenafterSARS-CoV-2infection[42].Arecent studyshowedthatthatSARS-CoV-2couldinfectTcellsexplaining thelymphocytopeniacommonlyfoundinCOVID-19patients[43]. Itwasalsoobservedthatmostcriticallyillpatientsinfectedwith SARS-CoV-2hadelevatedlevelsof inflammatorycytokines(IL-6 andIL-10)[44],indicatingpotentialbacterialco-infectioncaused by dysregulated immunesystem [45]. Moreover, Nguyenteam, byusinginsilicoanalysis,showedthatgeneticvariabilityacross thethreemajorhistocompatibilitycomplex(MHC)classIgenes (humanleukocyteantigen[HLA]A,B,andC)mayaffect suscepti-bilitytoandseverityofCOVID-19whichneedfurtherexperimental investigation[46].

SARS-CoV-2transmission

UnderstandingtransmissionpathwaysofSARS-CoV-2has sig-nificant implications for intervention and prevention. It was initiallysuggestedthatChinesepatientsinfectedwith SARS-CoV-2 may havevisited theseafood market in WuhanCity or may haveconsumedinfectedanimals.However,furtherinvestigation revealed that some individuals contracted the COVID-19 with-outvisitingthemarket.Indeed,anepidemiologicalstudyinearly casesinthiscityshowedthatonly22%ofpatientsweredirectly exposed tothemarketplace,32% ofcaseswereinclosecontact withthesuspectedcasesand51%hadnocontactwitheithersource [47].Thissuggestsahuman-to-humantransmissionofthevirus and anabilitytopropagate,resultingin diseaseclustersfroma singleindexpatient [48,49].The WHOestimatedthe reproduc-tive number (R0) of SARS-CoV-2 to range between 2 and 2.5, which is higher than SARS (1.7–1.9) and MERS (<1). This sug-geststhat SARS-CoV-2hasa higherpandemicpotential[50,51]. Three transmission ways of SARS-CoV-2 in humans were pro-posedwithincubationtimesof2–14days:1)contactwithliquid dropletsproducedbyinfectedpatientsand/or2)closecontactwith infectedindividualsand3)contactwithsurfacesandmaterial con-taminated with SARS-CoV-2 (https://www.cdc.gov/coronavirus/ 2019ncov/about/transmission).Inexperimentalsetups,infectious virusescouldbedetectedupto24honcardboard,upto2–3days onplastic and stainlesssteel and upto3 hpostaerosolization (vanDoremalenetal.2020).Certainscientistsrecentlyhighlighted another possible transmission route, the airbornetransmission through dropletnuclei (oraerosols), meaningthe possibilityof thediseasespreadinginmuchsmallerparticlesfromexhaledair, knownasaerosols.Theyaresuggestingthataerosolsarealsomore likelythandropletstobeproducedbytalkingandbreathingand mightposeahigherprobabilityoftransmissionthancoughingand sneezing[52].Inlabexperiments,infectiousSARS-CoV-2particles weredetectedinaerosolsfor3h[53].LiuandcolleaguesatWuhan Universitycollectedsamplesofaerosolsinandaroundhospitals treatingCOVID-19patientsandfoundviralRNAfrom SARS-CoV-2 onprotective apparel andfloor surface and theirsubsequent resuspension.Inthisstudy,viralRNAconcentrationinaerosol sam-pleswaslow(0–42genomes/cubicmetreofair)[54].AnAmerican teamstudiedthepresenceofSARS-CoV-2inairsamplesand sur-facesfrom11isolationroomsofCOVID-19patientsandshowed thatmany(63%)ofairsampleshadevidenceofviral contamina-tion,withhigherairbornevirusconcentration(2860 copiesper cubicmetreofair)[55].Itisnoteworthytomentionthatinfectious viruseshavenotbeenrecoveredfromaerosolsinanystudy.Ina recentlypublishedpaper,tenairsamplesofpatientroomswith

spaces[57].

SARS-CoV-2structureandcellsinfection

SARS-CoV-2RNAgenomeis29.9kb[58].Itcontains14open readingframes (ORFs),encoding 27proteins. Atthe5’-terminal regionofthegenome,theORF1andORF2encode15non-structural proteinsimportantforvirusmultiplication.The3’-terminalregion ofthegenomeencodesfunctionalstructuralproteins,namelyspike (S),envelopeprotein(E),membraneprotein(M)andnucleocapsid (N),plus8accessoryproteins[58,59]. Phylogeneticand compu-tational genomic analyses suggest that to enter in host’s cells, SARS-CoV-2sharesthesamehumancellreceptorwithSARS-CoV (ACE2), while MERS-CoVuses another(DPP4) [20]. ACE2 is an ectoenzyme anchored tothe plasma membrane of thecells of severaltissues,particularlyinthelowerrespiratorytract,heart, kidneysand gastrointestinaltract[60]. Astructure model anal-ysis shows that SARS-CoV-2 binds ACE2 with above 10 folds greateraffinitythanSARS-CoV,andmuchhigherthanthethreshold requiredforviralinfection[61].TheSpike(S)protein(ofabout150 kDa)isthemajorantigenpresentedonthesurfaceofSARS-CoV-2. TheSproteinformsatransmembranehomotrimerprotrudingfrom theviralsurfacetoattachtothehostcellularreceptorACE2.S com-prisestwofunctionalsubunits:subunitS1responsibleforbinding tothecellsurfacereceptorACE2andsubunitS2responsibleviral fusiontothecellmembrane[62].

SARS-CoV-2hijackshostcells(suchaslungcells)byendocytosis [63,64].First,SproteinbindstothecellularreceptorACE2[65].This attachmentisfollowedbyactivationoftheSprotein,which initi-atesfusionoftheviralmembranewiththemembraneofthehost cell[10].Thisfusionallowsthevirustoenterthecells[66]. SARS-CoV-2releasesitsgeneticmaterialintothecellcytoplasmwhere itistranslatedintotheviralreplicasepolyproteinspp1aand1ab. Pp1aandp1abarethencleavedbyviralproteinasestoform func-tionalnon-structuralproteins(NSPs)suchasahelicase(Hel)and theRNA-dependentRNApolymerase(RdRp)whichisresponsible forreplicationofstructuralproteinRNA[67].Theplus-stranded RNAgenomeofSARS-CoV-2willservetosynthetizesubgenomic negative-strandtemplatesthatserveastemplatesformRNA syn-thesis.StructuralproteinsS1,S2,E,andMarethentranslatedby ribosomesthatareboundtotheendoplasmicreticulum(ER)[68]. Viralnucleocapsids(N)areassembledfromgenomicRNA,followed bybuddingintothelumenoftheendoplasmicreticulum(ER)–Golgi intermediatecompartment(ERGIC)[69].Thenucleocapsidsfuse withthevirionprecursor.Formedvirionswillthenbetransported fromtheERthroughtheGolgiapparatustothecellsurfaceviasmall vesiclesandreleasedfromthecellthroughexocytosis[70](Fig.4).

SARS-CoV-2diagnosistests

Diagnostictestsweredevelopedrapidlyafterthestartofthe SARS-CoV-2 outbreak allowing earlyrecognition and detection of this novel virus. Nasopharyngeal swabs are the recom-mended specimen for molecular analysis. As of 19 March 2020, the CDC made oropharyngeal, mid-turbinate, and nasal swabs acceptable specimen types if nasopharyngeal swabs are not available (https://www.cdc.gov/coronavirus/2019-nCoV/lab/ guidelines-clinical-specimens.html). Samples are collectedfrom theupperrespiratory tract(oropharyngealandnasopharyngeal)

(ELISA) kits for detection of IgM and IgG antibodies against N and other SARS-CoV-2 proteins have also recently been made available.Severalotherdiagnostictestsaredeveloped todetect otherregionsoftheSARS-CoV-2genomeortargetingRdRp,Hel, S,EandN genes[72]. Anothereasy-to-implementand accurate CRISPR–Cas12-basedlateralflowassayfordetectionofSARS-CoV-2 fromrespiratoryswabRNAextractsinjust30minisunder develop-ment[73].Currentlythereare628SARS-CoV-2testscommercially availableorindevelopmentforthediagnosisofCOVID-19https:// www.finddx.org/covid-19/pipeline/.

SARS-CoV-2treatment

Todate,novaccinesortherapieshavebeenapprovedtotreat anyoftheknownhumancoronaviruses.Therapidglobalspreadof COVID-19hasemphasizedtheneedforthedevelopmentofnew coronavirusvaccines andtherapeuticsforthisfamilyof viruses. Treatmentwillreducetheeconomicimpactontheworldas SARS-CoVhadahistoryoftaxingtheglobaleconomy30US$to100US $billion[74].SincethebeginningoftheCOVID-19outbreak,the WHOhasencouragedresearchersallovertheworldtodevelopa cureforthisdisease.Herewepresentsomeoftheseinitiativesthat arestillinearlystagesofdevelopment.

Antiviralagents

Randomizedcontrolledtrialswereinitiatedandarebeing con-ductedformanyantiviralagents.Lopinavir(LPV)wasshownto inhibittheproteaseactivityofcoronavirusinvitroandinanimal modelsandalreadyusedforSARSandMERSincombinationwith ritonavir,anotherantiviraldrug[75,76].However,arecent trial showedlopinavir-ritonavirhasnotreatmentbenefitforseverely infectedpatientsbySARS-CoV-2[77].Ribavirinisaguanosine ana-logue,usedtotreatseveralviralinfectionsincludingthosecaused bythehepatitisCandrespiratorysyncytialvirusesbytargettingthe RdRpcomplex[78].MessengerRNA(mRNA)vaccinetechnologyis alsounderdevelopment(inphase1clinicaltrialbytheUSNational InstituteofAllergyandInfectiousDiseases)[79].

Remdesivir, a nucleotide analogantiviral inhibitor that may competeforRdRp,wasdesignedfortheEbolavirusandwaswith efficientagainstMERSandSARS[80].Remdesivirhasbeenreported toinhibitinvitroSARS-CoV-2proliferationandthereforehas clin-icaltherapeuticpotential[81].Recently,Remdesivirwasusedina clinicaltrialincluding53COVID-19patients.Resultsshowed clini-calimprovementin36ofthe53patients(68%).However,thisdrug needstobeusedespeciallyforpatientsnotreceivinginvasive ven-tilationasthemortalityratewas18%whenreceivingventilation, comparedto5%whennotreceiving[82].

Chloroquineandhydroxychloroquine

Chloroquineis antimalarialandautoimmunediseasedrug.It blocksviralinfectionbyincreasingendosomalpHlimitingvirusto cellfusionaswellasinterferingwiththeglycosylationofcellular receptorACE2[83]. Hydroxychloroquineisananalogof chloro-quine.Bothdrugshaveimmunomodulatoryeffectandcansupress theimmuneresponseofIL-6andIL-10thathavebeenreported tobeincreasedinresponsetoSARS-CoV-2[84].Clinicalcontrolled trialshaveshownthatchloroquinewasprovedtobeeffectivein

Fig.4.SARS-CoV-2lifecycleininfectedcellsandinhibitiontargets:SARS-CoV-2beginsitslifecyclebybindingoftheSproteinpresentedonthesurfaceofthevirusto thecellularreceptorACE2onthetargetcell.Afterreceptorbinding,theSproteinchangesconformation,facilitatingviralenvelopefusionwiththeinfectedcellmembrane throughendocytosis.SARS-CoV-2thenreleasesitsgeneticmaterialintothehostcell.GenomicRNAistranslatedintoviralreplicasepolyproteinspp1aand1ab,whichare thencleavedintosmallproductsbyviralproteinases.Bydiscontinuoustranscription,thepolymeraseproducesaseriesofsubgenomicmRNAsthataretranslatedintoviral proteins.Thepositive-sensegenomicRNAisthenpackagedintoaribonucleocapsidandisassembledintoviralparticlesintheERandGolgiapparatuswheretheyundergo maturation.Virionsarefinallytransportedviasmallvesiclesandreleasedoutofthecellthroughexocytosis.Inhibitiontargetsarepresentedinred.

thetreatmentofCOVID-19byreducingpneumoniaexacerbation andwasincludedintherecommendationsforthepreventionand treatmentsofSARS-CoV-2[85].

Corticosteroids

Corticosteroidscouldsupresslunginflammationbuttheiruse for thetreatmentof COVID-19lung injury is not supportedby clinical evidence as the clearance of viral infection is delayed andalsoduetotheoccurrenceofsidecomplications[86,87].The WHOadvisesagainsttheuseofcorticosteroidsunlessindicatedfor anotherreason[72].

Antibodies

ThespikeproteinSis theprincipal targetofantibodies.The SARS-CoVmonoclonalantibodyCR3022,aneutralizingantibody previouslyisolatedfromaconvalescentSARSpatient,was identi-fiedtobindpotentlywiththisprotein[88].Thisantibodymaybea potentialtherapeuticcandidate.

Convalescentplasmatransfusion(CP)

Convalescentplasmatransfusion(CP)therapywassuccessfully usedinthetreatmentofSARS,MERSandduringthe2009H1N1

pandemicwithacceptableefficacyandsafety[89–91].Itconsistsof collectingconvalescentplasmafrompatients2weeksafter recov-ery,toensureneutralisationandahighantibodiestiterfollowed byitsadministrationtoinfectedpatients.Duanandhiscolleagues (2020) performed a pilotstudy in three participating hospitals in Chinatoexplore thefeasibilityof CPtreatmentin 10severe COVID-19patients.Theyshowedthatclinicalsymptoms signifi-cantlyimprovedwiththeincreaseofoxyhemoglobin saturation within 3 days, accompanied by rapid neutralizationof viremia [92].Anotherstudyperformedonanuncontrolledcaseseriesof fivecriticallyinfectedpatients,showedimprovementintheir clin-icalsymptoms[93].DespiteCPbeinganeffectivewaytoimprove survivalrateofseverelyinfectedpatients,itdoesnotpermitthe patienttoacquireaSARS-CoV-2immuneprotectionandthesafety ofplasmaglobulinproductsspecifictoSARS-CoV-2deserves fur-therconsideration[94].

GlobalSARS-CoV-2preventionmeasures

Given the lack of available effective vaccine or treatments, it is primordial to control the source of infection and cut off the transmission routeof SARS-CoV-2 by implementing robust preventativemeasuresagainstthisvirus.Weknowthatclose

con-ofrespiratoryillnessinordertodecreasetheriskofspreadingby breakingthetransmissionchain.Thus,manycountriessuspended alltypes(cultural,social,religious,scientific,sporting,andpolitical) ofmassgatheringsandoptedforvideoconferences,and telecom-muting.TheWHOalsorecommendedtomaintainpersonalhygiene especially regular hand washing with soap and water or hand sanitizercontainingatleast60% alcohol,a healthylifestyle and adequatenutritionalintake[95].Outside,peopleneedtorespect minimum2msocialdistancinganditispreferredtowear protec-tivemasks.Tolimitaerosoltransmission,itisimportanttokeep regularroomventilationandeffectivesanitization[24].

In the face of this pandemic, some countries showed good COVID-19curvecontrolbecausetheyrapidlydeployedintensecase findingmeasurestostopvirustransmission.Forexample,South Koreadramaticallyslowedtheepidemicbyperformingmorethan 300000diagnostictests(5,828.6testspermillion)inthe9weeks afterthefirst case wasdescribed. Individualswho tested posi-tivewereidentifiedandisolated[96].Singaporeusedabroadcase definition,aggressivecontacttracing,andisolationbytestingall patientswithpneumoniaandinfluenza-likeillnessesinprimary caresettingsandhospitals,severelysickpatientsinintensivecare, anddeathswithapossibleinfectiousdisease[97].TaiwanandHong Kongusedsimilarstrategies[98].

Conclusion

TheinternationalalertabouttheCOVID-19infectionhashelped inthecontainmentofSARS-CoV-2.Atthedateofwriting, COVID-19showedpromisingsignsofending.Manycountriesseemtobe efficientlycontrollingthisSARS-CoV-2pandemicwaveandhave considerablylimitedthemortalityratethankstoknowledge gar-neredinthepastfromSARSandMERSepidemics,allowingforthe rapidinstitutionofmoreefficientpreventivemeasures.However, SARS-CoV-2isfarfrombeingeradicatedandmanyresearchers pre-dictnovelwavesin thefuture. Thatiswhy researcheffortson SARS-CoV-2andCOVID-19needtoberedoubledtodiscover effi-cienttreatmentsassoonaspossible.Severalpromisingcompetitive therapeuticoptionsarecurrentlyunderdevelopmentalloverthe worldbut requiretime tofor validationandcommercialization. ThereisstillmuchtolearnaboutCOVID-19anditcriticalthat sci-entistaroundtheworldcollaborateandshareinformationinorder tofacethis newglobalthreatand todevelop asuitablecureto benefitallofhumanity.

Funding Nofundingsources. Competinginterests Nonedeclared. Ethicalapproval Notrequired. tion. Acknowledgements

CatherineLaprise(C.L)isthedirectoroftheCentre intersecto-rielensantédurabledel’UQACandthechairholderoftheCanada ResearchChairtier1(CRC1)intheEnvironmentandGeneticsof RespiratoryDisordersandAllergies(www.chairs.gc.ca).Catherine LapriseisoneoftheprincipalresearchersoftheBiobanque Québé-coisedelaCOVID-19(bqc19.ca).CarolineDuchaineisholderofthe Tier-1CanadaResearchChaironBioaerosols.MbarkaBchetniais professorundergrantintheLapriselaboratorywiththesupportof CRC1.

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