2019 Focus on Middle East respiratory syndrome coronavirus (MERS-CoV)

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Médecineetmaladiesinfectieusesxxx(2019)xxx–xxx

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Review
Focus on Middle East respiratory syndrome coronavirus (MERS-CoV)

A.Bleibtreua,M.Bertineb,C.Bertina,N.Houhou-Fidouhb,B.Visseauxb,∗

aServicedesmaladiesinfectieusesettropicales,hôpitauxuniversitairesPitié-SalpêtrièreCharlesFoix,AP–HP,Paris,France
bInserm, Lab oratoired eVirologie, IA ME,UMR1 137,Hôpi talBichat,Sor bonneParisCité, Univers itéPa risDide rot,AP –HP,Paris,France

a r t i c l e i n f o a b s t r a c t

Articlehistory: SincethefirstcaseofhumaninfectionbytheMiddleEastrespiratorysyndromecoronavirus(MERS-CoV)
Receiv ed16September2018 inSau diA rab iain Ju ne2012 ,moreth an 226 0cases ofc onfirmedM ERS-CoVi nfectionand 803related
AReccceepivteedd i8n Or ecvtoisbeedr f2o0r1m 9 22 October 2018 de aths h ave bee n repor ted sin ce the 16th of O ctober 20 18. The va st majority of these c ases (71% ) were
reportedinSaudiArabiabuttheepidemichasnowspreadto27countriesandhasnotceased6years

later,unlikeSARS-CoVthatdisappearedalittlelessthan2yearsafteremerging.Duetothehighfatality
Keywords: rateo bserve dinMERS -CoV infectedpa tie nts( 36% ),mu ch effor thas beenput into un ders tand ingthe
Emergingdisease
originandpathophysiologyofthisnovelcoronavirustopreventitfrombecomingendemicinhumans.
MERS-CoV
Thisreviewfocusesinparticularontheorigin,epidemiologyandclinicalmanifestationsofMERS-CoV,
Coronavirus
aswellasthediagnosisandtreatmentofinfectedpatients.Theexperiencegainedoverrecentyearson
Pneumonia
howtomanagethedifferentrisksrelatedtothiskindofepidemicwillbekeytobeingpreparedforfuture

outbreaksofcommunicabledisease.
©2019ElsevierMassonSAS.Allrightsreserved.

r é s u m é

Motsclés: Depuislepremiercasd’infectionliéeauMiddleEastRespiratorySyndrome–Coronavirus(MERS-CoV),

Maladiesémergentes détectéenArabieSaouditeenjuin2012,leMERS-CoVadonnélieu,au16octobre2018,àplusde2260cas
MERS-Co V d’infect ion sconfi rméeset à 803 décès. L agrandem a jorité desc as (71 %)ont étéd éc laré se nAra bie
Coronavirus Saouditema isl’épidémie a de puis touché 27 payset n’esttoujo urs pas enra yée 6an sap rèssoné me rgence,
Pneumonie contraire ment auSRAS-C oV quiad isparu un peum o insd edeuxan sap rèssapr em ièr edéte ctio n.Enraison

dutauximportantdedécèsobservéparmilespatientsinfectésparleMERS-CoV(36%),beaucoupd’efforts

ontétédéployéspourcomprendrel’origineetlaphysiopathologiedecenouveaucoronavirusainsique

pourluttercontreuneéventuelleinstallationendémiquedecevirusauseindelapopulationhumaine.

Cetterevues’attacheplusparticulièrementàretracerl’origineetl’épidémiologieduMERS-CoVàdécrire

lacliniqueobservéechezlespatientsainsiquelapriseenchargediagnostiqueetthérapeutiquedes

patientsinfectés.L’expérienceacquiseaucoursdesdernièresannéesdanslagestiondesdifférentsrisques

liésàcetyped’épidémieestimportantepourpouvoirfairefaceàlaprochaineémergenced’infection

transmissible.
©2019ElsevierMassonSAS.Tousdroitsre´serve´s.

1. Introduction firmedcasesofinfectionwithMERS-CoVhadbeendocumentedin

27countriesbytheWorldHealthOrganization(WHO)andwere

ThefirstcaseofinfectionattributedtoMiddleEastrespiratory associatedwith803deaths[2].Thevastmajorityofthecases(73%)

syndromecoronavirus(MERS-CoV)wasdetectedinSaudiArabia werereportedinSaudiArabiaandonlyonewidespreadoutbreak

in June 2012 [1]. MERS-CoV then spread to several neighboring wasobservedoutsideoftheArabianpeninsulainSouthKoreain

countries,mainlyJordanandQatar(seeFig.2),andimportedcases 2015 [3] (Figs. 1 and 2). Due to the disease’s high fatality rate

ofthediseasewerereportedthroughouttheworldinAsia,Africa, (36%)[2],muchefforthasbeenputintounderstandingtheorigin

EuropeandtheAmericas[2].Bythe16thofOctober2018,2260con- andpathophysiologyofthisnovelcoronavirustopreventitfrom

becomingendemicinhumans.

Thisreviewfocusesinparticularontrackingdowntheoriginof

∗ MERS-CoV,itsepidemiologyandclinicalmanifestations,aswellas
Correspondingauthor.
thediagnosisandtreatmentofinfectedpatients.
E-mail address: [email protected] (B. Visseaux).
https://doi.org/10.1016/j.medmal.2019.10.004
0399-077X/©2019ElsevierMassonSAS.Allrightsreserved.

Pleasecitethisarticleinpressas:BleibtreuA,etal.FocusonMiddleEastrespiratorysyndromecoronavirus(MERS-CoV).MedMalInfect

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2 A.Bleibtreuetal./Médecineetmaladiesinfectieusesxxx(2019)xxx–xxx

Fig.1. GeographicaldistributionofconfirmedcasesofMERS-CoVinfection.WorldHealthOrganization(WHO)dataonSeptember10th,2018.

Fig.2. DistributionovertimeofconfirmedcasesofMERS-CoVinfectionworldwide.WorldHealthOrganization(WHO)dataonSeptember10th,2018.

2. Originandemergenceofthevirus toryinfectionsofmoderateseriousnesslikethecoronaviruses229E

andOC43.Greatefforthasbeenmadetoidentifycoronavirusesin

2.1. Humancoronaviruses animal populations, both before and after the SARS outbreak, in

ordertobetterunderstandandcontroltheriskofanimal-to-human

Thefirsttwocoronavirusesdemonstratedtocauserespiratory transmission. This resulted in the discovery of coronaviruses in

infectionsinhumans,thecoronaviruses229EandOC43,wereiden- numerousanimalspecies,withafewexceptionssuchassheepand

tified in the 1960s. They were held responsible for respiratory goats,fishandnon-humanprimates[5].

infectionsofmoderateseverityinhumans.Despitetheseviruses

beingidentifiedinseveralreportsascausinglowerrespiratorytract
2.2. EmergenceoftheMERSepidemic
infections, it was generally accepted that coronaviruses were of

lowpathogenicityuntiltheemergenceofSARS-CoV(SevereAcute
The first case of MERS-CoV infection was reported in Jeddah,
RespiratorySyndromeCoronavirus)in2002,aviruswithafatal-
SaudiArabia,inJune2012[1].Thepatient,a60-year-oldman,died
ityrateestimatedat10%.TheSARSoutbreakthatresultedinmore
fromlungandkidneyfailure11daysafterbeingadmittedtohos-
than8400caseswasfinallycontainedtwoyearslater,in2004,and
pital.Veryshortlyafterwards,inSeptember2012,asecondpatient
thevirushasnotbeendetectedagainsince[4].Therewasrenewed
wasadmittedtohospitalintheUnitedKingdomforsevererespira-
interestincoronavirusresearchfollowingtheSARSepidemic,and
toryinfectionrelatedtoanovelcoronavirusfollowingtraveltothe
twonovelendemichumancoronaviruseswereidentified,NL63and
MiddleEast.Thenewviruswasfoundtoreplicateinatissuecul-
HKU1respectivelyin2004and2005,butcouldnotbereplicatedin
turemodelandwasrapidlyisolatedandidentifiedforbothcases
cellculture.Bothofthesenewviruseswereresponsibleforrespira-
[6,7].Retrospectively,othercasesofthediseasewerefoundtohave

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Fig.3. StructureandgenomicorganizationofMERS-CoV.

occurredbeforethe2aforementionedcases:inApril2012,anout- > 80%) in the East African countries (Somalia, Sudan and Egypt).

breakatZarqahospitalinJordanaffectedthestaffoftheintensive ThesecountriesexportdromedarycamelstoArabiancountries,but

careunit,withtwofatalcases.Therespiratorysamplescollected alsoinKenya,Nigeria,Tunisia,Ethiopia,BurkinaFasoandMorocco

werelaterconfirmedtobepositiveforMERS-CoV[8]. [12–14].Phylogeneticanalysisrevealed5distinctcoronaviruslin-

These initial cases were rapidly followed by a series of out- eagesindromedarycamels,includingonerecombinantlineagethat

breaksinallSaudiArabianprovincesthatwerecharacterizedby ledtotheMERS-CoVepidemicinhumans[15].

the infection of health professionals in direct contact with the

patients.Othersimilaroutbreakswereobservedinseveralneigh- 3. Virusstructureandcycle
boringco untrie s:Qatar ,Bahrain,K uwait ,Jordanan d Tunisia. Health

authoritiesreactedquicklytothereportsoftheseepidemicsand MERS-CoVisabetacoronavirusbelongingtolineageC.Itisan
thestrongr esembla ncewith ob serv edclini cal featur esofSARS- CoV envelopedviru s w ithapositive-sen sesingle-st ran dedRN Ag en om e
infe ctions. Indeed,altho ugh afewpat ientsd eveloped m ildinfec- of about 3 0kb. Unde r electron micro scopy, virions a re g enerally
tions,thefa talityra teforpati en tsin fectedw ithMERS-C oVwa sover sp herical wi ths urface projectio ns(spikes)f ormedb yth esurface
30%[2 ]. proteinS creati nganim agereminis centofa crowno rs olar corona.

Thepositive-sensesingle-strandedRNAgenomeactsasmessenger
2.3. NaturalreservoirofMERS-CoV RNA (mRNA) with a 5(cid:3) cap and a 3(cid:3) po lyadeny lated ta il. It plays

threerolesduringthehostcellcycle:(i)itactsastheinitialRNA

FollowingtheidentificationofMERS-CoV,greateffortwasput moleculefortheinfectioncycle;(ii)itisthetemplateforreplication

intofindingwhichanimalspeciesitoriginatedfrominordertostop andtranscription;(iii)itisthesubstratethatispackagedintothe

thefurtherspreadofthediseasetohumans.MERS-CoVwasvery newlyassembledviralparticles[16].

rapidlydeterminedtobegenotypicallycloselyrelatedtothebeta- The MERS-CoV genome is organized in the same way as

coronaviruslineageCvirusesidentifiedinbats[9].Basedonthese other coronavirus species. The first two thirds of the MERS-

findings, and the major role of bats in the genetic diversity and CoVgenomecontaintwooverlappingreadingframes(ORF1aand

spreadofcoronaviruses,muchoftheinitialworkaimingatfind- ORF1b) that translate into the replication-transcription complex

ingthenaturalreservoirofMERS-CoVfocusedonbats.However, including 16 non-structural proteins. The remaining third of the

no conclusive evidence demonstrating that bats were the natu- genomeencodesthefourstructuralproteins,thespike(S),envelop

ral reservoir of MERS-CoV in the Arabian peninsula were found, (E), membrane (M) and nucleocapsid (N) proteins, as well as

despitetheidentificationofcloselyrelatedvirusesinbatsinSub- five accessory proteins (ORF3, ORF4a, ORF4b, ORF5 and ORF8b)

Saharan Africa [10], far from the existing outbreaks. Very strong that are not required for genome replication but are probably

epidemiological links were identified between the human cases involved in virulence. The flanking sequences, on both ends of
andcamelsand result edin theisolatio nincam elso fviruse sthat thegeno me ,containu ntran slated5(cid:3) and3(cid:3)regio ns (UTR) (Fig. 3)

were directly related to MERS-CoV and that could replicate in [17].

culturedhumancells[11].Theinvestigationofdromedarycamel Theviralparticlecanenterthecellintwoways,whichprobably

serumcollections,someofwhichcollectedasearlyas1983,demon- contributetothebroadtissuetropismofthisvirusthatreplicates

stratedthattheviruswasalreadywidespread(seropositivityrate mainlyinrespiratoryepithelialcellsbutcanalsoinfectmanyother

Pleasecitethisarticleinpressas:BleibtreuA,etal.FocusonMiddleEastrespiratorysyndromecoronavirus(MERS-CoV).MedMalInfect

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4 A.Bleibtreuetal./Médecineetmaladiesinfectieusesxxx(2019)xxx–xxx

celltypes.Viatheendosomalpathway,theS1domainoftheMERS- Allotherpreventivemeasuresaimatpreventingbothanimal-

CoV spike protein (S) binds its receptor, dipeptidyl peptidase 4 to-human transmission and human-to-human transmission. It is

(DPP4)[18],inducesendocytosisoftheviralparticleandachange thereforerecommendedtoavoidanycontactwithdomesticani-

in the conformation of the S2 subunit of the S protein that then mals (firstly dromedary camels), their secretions, raw milk and

mediatesvirus-hostmembranefusionanduncoatingofvirusRNA. insufficientlycookedmeat.Itisalsoadvisedtoavoideatingfruitand

MERS-CoV can also enter host cells via a non-endosomal mech- vegetablesthatmighthavebeenincontactwithanimalsecretions

anism by direct fusion of the virus with the plasma membrane ifnotwashedandpeeledbyoneself.

followingSproteincleavagebyhumanproteases[19]. Toavoidhuman-to-humantransmission,theusualrecommen-

Followingentryintothecytoplasmanduncoatingofthevirus dationsforpreventingthespreadofanyrespiratoryvirusshould

nucleocapsid,theviralgenomicRNAistranslatedtoproducetwo beapplied:handwashingwithsoapywateroranalcohol-based

polypeptides,pp1aandpp1b,thatformthereplicase-transcriptase solution,coveringone’snoseandmouthwhensneezing,refraining

complex. This initial replicase-transcriptase complex uses the fromshakinghandsandtouchingone’smouthandnosewithone’s

genomicRNAtoproduce16non-structuralproteinsthatassemble hands,avoidingcontactwithpeoplewithrespiratorysymptoms.

intothereplicationcomplex.Thereplicationcomplexthenrepli- Finally,alastseriesofrecommendationsfocusonhowtobehave

catesthegenomicRNAandproducesothersubgenomicRNAsthat in case of suspicious symptoms: (i) consult a doctor as soon as

ensurethetranslationofthestructuralproteins. symptomsoccurduringtravelanddelaythereturnuntilsymptoms

Virionsareassembledattheendoplasmicreticulummembrane disappear;(ii)ifsymptomsoccurwith14daysofreturninghome,

asviralproteinsandgenomicRNAaregroupedtogetherandthen consultadoctorandtellhim/herabouttherecenttravel[24].

budintothelumenoftheendoplasmicreticulum.Thevirionsare

thenexportedviathesecretorypathwayoftheendoplasmicreti-
5. Diagnosticlaboratorytesting
culumintotheGolgiintermediatecompartmentandthenintothe

extracellularenvironment.TheMproteindrivesthepackagingpro-
PCR-baseddetectionmethodsarecurrentlythepreferredoption
cessbyselectingandorganizingtheviralenvelopcomponentsat
fordetectingthevirusinrespiratorysamplesandmakingadiagno-
theassemblysitesandinteractingwiththenucleocapsidtoallow
sisofMERS-CoVinfection.Serologytestscanalsobeperformedand
budding[20].
areoftenusedforsecond-linediagnosticinvestigationinpatients

withahighsuspicionofMERS-CoVbutnegativeresultsbydirect

4. Transmissionmechanismsandpreventivemeasures PCRtesting.

4.1. Transmissionmechanisms 5.1. DirectPCRdetection

Several large serology studies suggest that cases of asymp- Various respiratory matrices can be used: nasopharyngeal
tomatic or mild MERS-Co V infec tion occ ur re gularly , a lthough swabs, nas opharyngea l or trach eal asp irates, bronchoalveolar
infreque ntl y. The importanc e of such cases is difficult to assess lavage (BAL),andevenin som ecases,i nducedspu tum.Thedeepest
[10].Itisther efor edifficultto de termi newh eth erthese ca sesare sample s,trac heal aspir at esand BALs, showth egreates tsen sitivity
duet oo r takeparti nhuman -to -humantra nsmissio n.Sev eralst ud- andsigni ficantlyh ighervir allo ads[2 5].
ies s ug ge st th at le ss than 50% of infe cted patients transm it the T he genome a mplific ation and detection methods used (PCR)
viru stoindi vidu alsth eyco mein to contactw ith,even atthebe gin- werein itiallym ostlydevelope din situandpe rformed inbio safety
ning of an outbrea k [10 ]. The dise ase the refore seem s to spread level 3 (BSL-3 ) refer ence facilit ies . Th e tim e to resul ts is gener-
due to freq uent anim al-t o-hu man tra nsmission , from cam els to ally r el atively l ong, 24–4 8h, due t o the usu al t ime req ui red for
hum an s,withlim itedsubsequenthu man-to-huma ntran smissio ns conv entionalP CRte stingto w hich m ust bead dedth eadditio nal
[21]. The re ar e unfor tunately exc eptions to this ob servation and preparationa ndsa mplen eu tralizat iontim e needed top rotectthe
local outbr eaks caused by hu man-to-hu ma n tr ansmission h ave laboratorys taffa gainstt hisvirus.TheP CRm ethods us edareg en-
been observed on a re gula r basis, mostly in hospitals. To date, erally sem i-qua ntitativ e an d som e st udie s suggest a co rrela tion
them ostpoign ant ex ampleis theo utbreak tha toccurred in South betwe en the amount of viru s dete cted an d the se ve rity of the
Kor eainw hichthe indexca se cau sed185se con darycase s,a mong symptom s[2 6].Never the less,n oconsen sush asb eenreach ed yet
whom 30 were care provi ders, leading to2 4fatalities [3].Th isout- regarding a thr eshold level t hat could actu ally pred icts clin ical
breakw as chara cter izedbythe keyrole o faf ew“supe rsp read ers”, severity. T ar geting the enve lop g ene u pE is rec ommend ed with
delaye ddi agnosis,high doc tor sho ppin gb e havi orand theimpor- confirma tory testin g fo r ORF 1A or 1 B or th e N gene. If re sults
tanceof confinedsp aces (waitin groom,ho spitalroo m,a mbu lance). diverge, sequ encing is so met ime s r equ ired to ob tain c on clusive
Inthis ex ample,th eresem blance withS ARS-CoV ’sspre adingmech- results[ 27].Today,a n increasingn umberof co mmerci altestsare
an isms is strikin g, despite lowe r deg rees of tran smission t o care becomi ng a vailable (A ltona Diag nostics, Fa st Track Dia gnost ics,
provide rs for MER S-CoV [ 22]. Th ese regu la r cases of im por ted- Primerdes ingLtd.)s omeeve nwithatim eto results oflessthan
MERS, the mo st recent w as re ported in Engl and in Au gust 2018 1hour(BioFir e–bio Mérie ux).S omeo ft hese tes tsarep oin t-of- care,
[23],re pre senta realthr eato flocalepi de micsouts ide SaudiA rabia or can beperformedinBSL3f aciliti es oras tanda rdl aboratoryfol-
ands pecialscr ee ning andi so lation procedure sneed tobe imple- low ing sa mpleneutr ali zation inaBSL 3f a cility.The secommer cial
men tedinu nitslikely tor eceivepa tientssuspe ctedo fM ER S-CoV testsm ustalwa ysbevalidated b ef oreus etoche ckthe irsensitivity
infection s. andc ompa retheir pe rformanc ewith refe ren ceme thod s.

4.2. Preventivemeasuresfortravelers 5.2. Indirectserologicaltesting

Whenpossible,thefirstmeasuretobetakenistodelaydepar- Aswithanyotheracuteviralinfection,antibodiescanonlygen-

ture,inparticularforindividualsover65orwithchronicdisease, erallybedetectedabout10daysaftertheonsetofsymptoms.In

andforpregnantwomenorchildren.Suchmeasuresareneverthe- some patients, especially those with severe infections, the time

lesschallengingtomaintaintodayasthatthevirusisstillpresent intervaltoantibodydetectionmaybeevenlonger[28].Serolog-

6yearsafteritsapparition. ical testing is therefore of little help for the initial diagnosis of

Pleasecitethisarticleinpressas:BleibtreuA,etal.FocusonMiddleEastrespiratorysyndromecoronavirus(MERS-CoV).MedMalInfect

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symptomaticpatients,butcanbeusefulforepidemiologicalinves- Themediantimetorespiratoryfailureis12daysaftertheonset

tigations. of symptoms. Depending on studies, 53 to 89% of hospitalized

ThehighlyimmunogenicSandNviralproteinsarewidelyused patientsareadmittedtoanintensivecareunit(ICU)[43,52].

targets for serological tests and are found on all coronaviruses.

Various approaches have been developed: serum neutralization 6.3. Fatalityrate

assays[29],microarrays[30],ormorerecentlyELISAconfirmedby

amicroneutralizationtest[31].Allmethodsaretechnicallycom- Since the first MERS outbreak, WHO had documented, in

plexandrequireahighlevelofexpertisethatrestricttheirusetoa October2018,2260casesofMERS-CoVinfectionconfirmedbylab-

fewhighlyspecializedfacilities. oratorytestingand803relateddeathsin27differentcountries.

The retrospective fatality rate varies between outbreaks, ran-

gingfrom36.5to60%[33,35,37,38,42].Themortalityrateof20.4%
6. Clinicalpresentation
observedfortheKoreanoutbreakisprobablythemostreliableepi-

demiologicallyduetothecomprehensiveinvestigationscarriedout
The first cases of infection with MERS-CoV were reported
[34].ThedeathrateishighestamongpatientsadmittedtoanICU,
in 2012 [1]. Hospital-acquired MERS-CoV infections have been
ranging from 58% to 90% [49,53]. In the only cohort study per-
describedworldwideandrepresentedathirdofallcasesreported
formed in Saudi Arabia, the fatality rate for MERS-CoV patients
inSaudiArabiaintheearlystagesoftheepidemic[1,32,33].Clus-
wasofonly10%(8/80).However,thepatientsofthiscohortwere
teredhospital-acquiredinfectionswerefrequentlyobservedduring
younger,hadlesssymptoms,showedlessradiologicalfeaturesand
thefirstoutbreaksandprobablycontributedtospreadingthedis-
only17%wereadmittedtoanICU[37].Thefindingsofthelatter
easefromtheprimarysiteofvirusinfectiontothewholeArabian
studydivergethereforewiththesituationsobservedinotherhospi-
peninsula,themoststrikingexampleofhospital-acquiredoutbreak
tals,butareperhapsabetterreflectionoftheinfectionprofileinthe
beingtheKoreanoutbreakin2015[34].Careprovidersareoften
generalpopulationinwhichyoungersubjectsarelesssymptomatic
affectedandrepresent15–22%ofcases[33–39].
andthereforelessfrequentlyadmittedtohospital.
MostofthecasesaredescribedinMiddleEastcountries,inpar-
The time interval between the onset of symptoms and death
ticularSaudiArabia(73%),withapredominanceofmalepatients
rangesfrom11.5to27days[34,44,54].
(66–69%invariousstudies)andameanpatientagerangingfrom
Finally,co-infectionwithotherrespiratoryviruses,inparticular
40to55years[34,38,40].
influenza, has been described although the impact of such com-
Comorbiditiesarefoundin46–68.6%ofpatients,inparticular
bined infections have not been evaluated [44,55]. Co-infections
diabetesandhighbloodpressure,followedbyotherheartcondi-
withbacteriahavealsobeenreportedinthepatientsdeveloping
tionsandfinallyobesity[34,37,38,41].
themostseveredisease[49,51].
Themeanincubationtimeis5to6.5days.Thegenerationinter-

val(timebetweentheonsetofsymptomsofthefirstcaseandthose
6.4. Laboratoryfindings
ofthesecondcase)is7.6days,whichisidenticaltothatoftherespi-

ratorysyncytialvirus(RSV)butthreefoldmorethantheinfluenza
TherearenospecificlaboratoryfindingsrelatedtoMERS-CoV
virus[36,42–44].
infection.Neverthelessinpatientswithacuterespiratoryinfection

in MERS-endemic areas, MERS-CoV infections have been associ-
6.1. Clinicalsymptoms
atedwithnormalleukocyteand/orpolymorphonuclearneutrophil

countsbutelevatedtransaminases[37,45].
The main challenge of MERS-CoV infection is the absence of
Moreover, hyperleukocytosis, lymphocytopenia, thrombocy-
specificclinicalfeaturesfordifferentialdiagnosiswithotherviral
topenia, hypoalbuminemia, elevated serum creatinine, LDH and
respiratorydiseases[37,45].Thisdifficulty,combinedwithprecau-
CRPlevels,andhypoxemia(PaO2/FiO2<300)havebeenrepeated
tionary action taken to avoid potential secondary contamination
reported in MERS-CoV infected patients and are associated with
withMERS-CoV[46],canresultinmedicalconfusionandinappro-
severityanddeath[34,45].
priatepatientmanagementduetoprolonged,difficultisolationthat
Imaging (chest X-ray and sometimes chest CT) has revealed
makesitimpossibletoperformthenecessarycomplementarytests
infection-relatedfeaturesin51–75%ofcases.Thelesionsobserved
whilewaitingforPCRresults[47].
are uni- or multi-focal ground glass opacifications, of subpleural
TheclinicalfeaturesofMERS-CoVinfectionareextremelyvari-
andlowerlobepredominance,withsometimesbilateralbi-basal
able,rangingfromanabsenceofsymptoms(14–80%ofcases)toa
involvementorfeaturesoforganizingpneumonia[34,37,42,45].
flu-likesyndrome,pneumoniaandacuterespiratorydistresssyn-

drome(ARDS)[37,48].
6.5. Riskfactorsformortality
The three most frequent symptoms are: fever (77% [IQR:

59–82]),cough(90%[52–69]),anddyspnea(68%[22–69]).
Mortalityishighestinelderly,malepatientswithcomorbidi-
Manyothersecondarysymptomshavebeenreported,suchas
ties,especiallydiabetes[38,45,56].PatientsfromSaudiArabiaand
sputum production (40%), odynophagia (39%), digestive system
theMiddleEasthaveanincreasedmortalityratecomparedwith
signs(20%),hemoptysis(4.3%),myalgia(43%)andheadache(20%)
patientsfromKoreaorothercountries[38,40].Incontrast,being
[34,37,41,42].
a medical professional significantly reduces the risk of mortality
Diarrheaissignificantlymorefrequentinpatientsinfectedwith
[38,45].
MERS-CoVthaninpatientswithanotheracute,febrilerespiratory
Other factors associated with a higher mortality risk have
conditions[45].
beendescribedinvariousstudies:digestivesymptoms,prolonged

delaybetweentheonsetofsymptomsandadmissiontohospital,

6.2. SevereMERS smoking,lowbloodpressure,impairedgasexchange,leukopenia,

anemia,disturbanceofliverorkidneyfunction,useofmechanical

Severe MERS is characterized predominantly by ARDS, acute ventilationandprolongedstayintheICU[42,57].

kidney failure, and in the most severe cases, by multiple organ For the Korean outbreak in 2015, the independent risk fac-

failurethatcanbefatal[49,50].Onethirdofpatientsdeveloppneu- torsformortalitywere:age>55years,dyspnea,diabetes,chronic

moniaand20%developARDS[51]. lung disease, systolic blood pressure at admission<90mmHg,

Pleasecitethisarticleinpressas:BleibtreuA,etal.FocusonMiddleEastrespiratorysyndromecoronavirus(MERS-CoV).MedMalInfect

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6 A.Bleibtreuetal./Médecineetmaladiesinfectieusesxxx(2019)xxx–xxx

Fig.4. ViralcycleofMERS-CoVandtargetsoftheantiviraldrugsavailableorunderdevelopment.

hyperleukocytosis at admission (>10,000/mm3) and the use of 7. TreatmentofMERS

mechanicalventilation[34].

Severaltherapeuticoptionstargetingvariousviralelementsare

currentlyavailableorunderdevelopment(Fig.4)[62].Thedifferent

classesofavailabletreatmentare(i)immunotherapywithspecific

6.6. RiskfactorsforsevereMERS anti-MERS-CoV antibodies, (ii) molecules with antiviral activity,

(iii)symptomatictreatment.Fewmoleculeshaveshownrealcura-

PositivePCRresultsforMERS-CoVinbloodatdiagnosisareasso- tive action and the reports in the literature generally describe

ciatedwithanincreasedriskofrequiringmechanicalventilation, isolatedcasesorsmallseriesofcases.Morestudieshavefocusedon

extracorporealmembraneoxygenation(ECMO)ortoleadtodeath associatedtreatmentandsupportivecare.Atthistime,preventive

[58,59]. therapiesarestillinpreclinicalstages.

The lack or delayed detection of MERS antibodies (ELISA IgG

andIgA,orPRNT)inthebloodorairwaysisapoorprognosticfac- 7.1. Immunotherapy

tor[54,60].Itshouldhoweverbenotedthatnoseroconversionis

observedinasymptomaticMERS-infectedpatients[54].Finally,the 7.1.1. Convalescentplasma

MERS-CoVviralloadsindistallungsampleswerehigheramong The efficacy and safety of plasma from convalescent patients

deceasedpatients[60]. havenotbeenassessed.Threeseparatereportsconcludedthatsuch

Inastudyincluding45patientsinatertiaryreferralhospitalin therapeuticapproacheswereinappropriate[63].Onetrialislisted

SouthKorea: onwww.clinicaltrials.gov.

7.1.2. Intravenousimmunoglobulins(IgGs)

• the predictive factors for pneumonia in MERS-CoV patients Two cases of therapy with intravenous polyclonal IgGs have
wer e: age>45 years, bod y temperat ure >37.5◦C on day 3, been reported. In one of them, the IgGs originated from donors in
platele tcou n ts< 150,00 0/mm 3,lymphocyto p enia(< 1000 /mm 3), regions negative for MERS specific antibodies.
CRP≥20 mg/La n dhighviralloa ds(Ctvalue<28.5 ); Several monoclonal antibodies were tested and seemed to
• thep r edi ctive facto rsfo rresp irato ryf ailure w eremalesex,high show anti-MERS-CoV activity in vitro [64]. No clinical trials are
currentlyunderway.Recently,aphaseIplacebo-controlled,dose
bloodpressure,thrombocytopenia,lymphocytopenia,hypoalbu-
minem ia<35g/ LandCRP≥40mg/L . escalation study evaluated the efficacy of polyclonal IgGs pro-
ducedbytranschromosomalcattlewithhumanimmunoglobulin

genesimmunizedwiththeMERS-CoVspike(S)protein[65].The

primaryoutcomeoftolerancetoasingledosewasreached.Thesec-
Thepatientswithatleasttwo,oneandnoneofthepredictive ondaryp harmaco dy namicend po i nt(ser umn eutr alization activ ity)
pneum oniafact orsde ve loped pne umo niai n100 %, 50% and0%of showed efficacywithados eof50m g/kg.No phaseIItrials arecur-
cases,respe ctively [61]. rentlyu nderway .Aph a seIs tu dy hasbee nre gister ed toas sess the

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immunogenicityandtoleranceofacombinationoftwomonoclonal This blocks helicase activity and inhibits protein translation. A

anti-MERS-CoVantibodies.Thestudyhasnotyetstartedrecruiting recentinvitrostudydemonstratedthatsilvestrolhasanti-MERS-

patients. CoVactivity[73].Noclinicaldataorstudiessupportitsuseinvivo

atthepresenttime.

7.2. Antivirals

7.2.9. Corticosteroids
7.2.1. Interferons(IFN) Co rticosteroid therapy is currently the most widely studied
In fection wit h MERS-CoV reduces the host’s interferon therapeuticoptio n.Inare tro spectivest udy ,Arabi etal.[6 7]com-
response.M ERS-Co Vis100tim esmores ensit ivetoIF N-(cid:2).Treat- pared the o utcome o f 309 patients with c onfirm e d M ERS -CoV
ment wit h IFN-(cid:2) has b een report ed for many cl ini cal cas es and infecti onm anagedin an ICU settingan dtrea tedwith(15 1)orwith-
sever alretr ospect ivec ohort studiesh ave beenp erforme d,inc om- out(159) corticost ero id ther apy.Th eov erallfa tality ratew a s67%.
bination withribaviri n,lopin avirorm ycop heno latemofetil (M MF). Uni variat eanalysisshow edthat mor talityin theIC U,d uring the
None of these studies have dem on strated increas ed over all sur- hospitalsta yorat9 0daysw ash igherinth ec orti coste roidgro up.
vival. On estud yreport edinc reasedsurviva latD14bu tnotat D30 Then,fo llowi ng ad jus tmen tusi ngam arg ina lstructuralmo delfor
forcr itical lyillin tubated andventil atedpat ien ts[6 6].A IFN /M MF causa linference ,corticoster oidthe r apywass hownnott obeas so-
com bination tr ialiscurre ntly underway (seebelo w). ciated withmort ality,butdelay edvirus clea rance. Thes e find ings,

togetherwiththeabsenceofanydescriptionoftheadverseeffects
7.2.2. Ribavirin causedb ycort icos teroidtr ea tme nt,argueag ain stt heuseo fcorti-
Hi ghdosesofribavirinhaveshownanti-MERS-CoVactivityin costero ids .

vitro.RibavirinhasbeenusedtotreatpatientsinSaudiArabiaas

wellasinFranceforthemostseverecasesmanagedinICUs[67].
7.3. Extracorporealmembraneoxygenation(ECMO)
Nosignificanteffectsweredemonstratedeitheronthemortality

rateorthetimespentintheICU.
AretrospectivestudywasrecentlycarriedoutinSaudiArabia

inMERS-CoVpatientswithrefractoryrespiratoryfailure[74].The
7.2.3. Proteaseinhibitors
patientswereincludedinthestudyfrom2014to2015infiveICUs.
Ritonavir-boostedlopinavirhasshownefficacyagainstMERS-
Thestudyconsistedoftwopatientgroups:ECMOversusconven-
CoVinvitro.Asaresult,theFDAhasextendedtheindicationsof
tionaltreatment.Theprimaryendpointwasinhospitalmortality.
lopinavirtopatientsinfectedwithMERS-CoV.Twocasereports(in
SecondaryendpointsincludedthelengthofstayintheICUandin
GreeceandKorea)havedescribedimprovementinpatientstreated
hospital.Thirty-fivepatientswereincluded:17weretreatedwith
withlopinavir,type1interferonandribavirin[68].AphaseII-III
ECMOand18receivedconventionalcare.Bothgroupshadsimi-
clinicaltrialisregisteredonclinicaltrials.gov.Theaimofthisstudy
larbaselinecharacteristics.Inhospitalmortalitywaslowerinthe
istoevaluatethefeasibility,efficacyandsafetyofthecombination
lo pin avir/rito nav ir/recombin antIFN (cid:3)-1b vs.a pla ceb oinpatients ECMO group (65 vs. 100%; P = 0.02) although they stayed longer in
theICU(medianstayof25daysvs.8days;P<0.01).Theoverall
withconfirmedMERSreceivingoptimalsymptomaticcare.
timeinhospitalwassimilarinbothgroups(medianstayof41vs.

31days;P=0.421).Inaddition,patientsintheECMOgroupshowed
7.2.4. Chloroquine
improvedPaO2/FiO2valuesat7and14daysafteradmissioninto
ChloroquineisamongthemoleculesapprovedbytheFDAfol-
theICU(124vs.63,and138vs.36,respectively;P<0.05),andlower
lowinginvitrostudies.Noclinicaldataorstudiessupportitsuse
levelsofvasoactiveaminesatD1andD14(29vs.80%,and36vs.
invivoatthepresenttime.
93%,respectively;P<0.05).Theresultsofthisstudysupporttheuse

ofECMOassalvagetreatmentforMERSpatientswithrespiratory
7.2.5. Nitazoxamide
failure,asisthecaseforotherrespiratoryinfections.
In vitro, anti-MERS-CoV activity has been demonstrated for

dosesofnitazoxamidethatcouldbereachedwithtwodailyoral
doses . N o clinical data or s tudies su pport its use in v ivo at the 8. Vaccinedevelopment

presenttime[69].
Two trials with candidate vaccines are currently registered

7.2.6. Mycophenolatemofetil(MMF) at https://clinicaltrials.gov/ct2/home. A phase-I clinical trial on
In vitro, anti-MER S-CoV activity has been demonstrated for he althyvolunteerswassetuptoevalu ate thesafe tyandi mmu no-
doses ofMM Fthatareaccep tablefor use inhu mans.MMFsee ms genicity ofaplasmi dDN Av acc in e(GLS-53 00) thate xpre ssestheS
to sho w a syn ergis tic effect with IFN -(cid:3)1 b i n vitro [7 0]. Bu t in a protein of M ERS-CoV .This trialw asplanned tola stoneyea ran d
no nhum a nprimatec ommo nmar mosetsm od el,an imal stre ate d started in 2016.Nores ults area vaila bleyet.A se cond ph ase-I trial
with MMFd eveloped moresev erelesionsa ndshow edahigh ercase wassta rte dbyO xfo rdUni vers ityinJan uary 2 018.Itu sesach im-
fatali tyrat ecompared with untrea tedanim als [70].Inc o ntrastw ith panz eeaden ov irusvec torcontain ing theMER S-CoV S prot ei ngene
animal mod el,thecom bina tionIFN-(cid:3) 1b/MMF was ad minister edto [75].Pa tientinclusi oniscu rrentlyund erw ay.Manyo th ercand idate
8patien tsinS aud iArabia.Allt hepatientssur vive dbuthadlow er vacci nesusin gvarious d ifferentte chnologies areat aless advanced
A PACHEII sc oresth atothe rpa tien tgroups [71]. stageofd evelo pment.

7.2.7. Alisporivir 9. Conclusions

Alisporivir has been shown to provide additive in vitro anti-

MERS-CoVactivitywhenusedincombinationwithribavirin.No TheMERSepidemicstartedin2012.IncontrastwithSARS-CoV

clinicaldataorstudiessupportitsuseinvivoatthepresenttime that disappeared 2 years after it first appeared, MERS-CoV con-

[72]. tinues to persist in the Middle East 6 years later. Although the

diseasehasnotbecomepandemic,outbreakshaveoccurredworld-

7.2.8. Silvestrol wide. Today, it is impossible to predict with certainty whether

Silvestrolisamoleculeoftheflavaglinefamilyfoundinplants. MERS-CoV will disappear or continue to remain a threat for

It binds to eIF4A and enhances the affinity of eIF4A for mRNA. human populations. Efficient vaccine development for host ani-

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8 A.Bleibtreuetal./Médecineetmaladiesinfectieusesxxx(2019)xxx–xxx

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(2019),https://doi.org/10.1016/j.medmal.2019.10.004