Infectious mononucleosis in adults and adolescentsWord文档格式.docx
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Infectious mononucleosis in adults and adolescentsWord文档格式.docx
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MartinSHirsch,MD
SheldonLKaplan,MD
DeputyEditor
JenniferMitty,MD,MPH
Disclosures
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:
Feb2014.|Thistopiclastupdated:
二月26,2013.
INTRODUCTION
—
Infectiousmononucleosis(IM)ischaracterizedbyatriadoffever,tonsillarpharyngitis,andlymphadenopathy[1].Itwasinitiallydescribedas"
Drusenfieber"
orglandularfeverin1889,buttheterm"
infectiousmononucleosis"
waslaterusedin1920todescribesixcollegestudentswithafebrileillnesscharacterizedbyabsolutelymphocytosisandatypicalmononuclearcellsintheblood[2,3].TherelationshipbetweenEpstein-Barrvirus(EBV)andIMwasestablishedwhenalaboratoryworkerwasinfectedwithEBVanddevelopedIMandanewlypositiveheterophiletest[4].
Infectiousmononucleosisinadultsandadolescentswillbereviewedhere.AcompletedescriptionofEBVandotherclinicalmanifestationsofEBVinfection(includingmalignancy)arediscussedseparately.(See"
ClinicalmanifestationsandtreatmentofEpstein-Barrvirusinfection"
and"
VirologyofEpstein-Barrvirus"
.)
EPIDEMIOLOGY
Epstein-Barrvirus(EBV)isawidelydisseminatedherpesvirusthatisspreadbyintimatecontactbetweensusceptiblepersonsandEBVshedders.Thevirushasnotbeenrecoveredfromenvironmentalsources,suggestingthathumansarethemajorreservoir.
AntibodiestoEBVhavebeendemonstratedinallpopulationgroupswithaworldwidedistribution;
approximately90to95percentofadultsareeventuallyEBV-seropositive.Byagefour,EBVseroprevalenceiscloseto100percentindevelopingcountriesandrangesfrom25to50percentinlowersocioeconomicgroupsintheUnitedStates.Manyattributethisfindingtointensepersonalcontactandpoorpersonalhygieneamongchildren,whichprovideopportunitiesforearlyacquisitionandsubsequentspreadofEBV.
EBVacquiredduringchildhoodyearsisoftensubclinical;
lessthan10percentofchildrendevelopclinicalinfectiondespitethehighratesofexposure.Theincidenceofsymptomaticinfectionbeginstoriseinadolescentthroughadultyears[5].Largestudiesofinfectiousmononucleosisarenowdecadesold,buttraditionallythepeakincidenceofinfectionhasbeendescribedinthe15to24-yearagerange[6].SomedataderivedintheUnitedKingdomsuggestthatinfectiousmononucleosis(IM)casesmaybeoccurringlaterinlifewithincreasingseverity,requiringhospitalization[7].IMisrelativelyuncommoninadults,accountingforlessthantwopercentofpharyngitisinadults[8].Thevastmajorityofadultsarenotsusceptibletoinfectionbecauseofpriorexposure.
ThedifferencesobservedbetweeninfantsandyoungadultswithregardtosymptomaticinfectionmayrelatetothesizeoftheviralinoculumatthetimeofinfectionortotheintensityofcellularimmuneresponsesdrivenbyEBV-infectedBcells.
Theincidenceofclinicalinfectionisapproximately30timeshigherinwhitesthanblacksintheUnitedStates[9].ThismayreflectbothearlierexposurestoEBVamongthelattergroupandthehigherfrequencyofasymptomaticinfectionwhenacquiredbyyoungchildren.
TRANSMISSION
Person-to-person
Followinginfectiousmononucleosis,virusmaybeshedinsalivarysecretionsathighlevelsforaprolongedperiod[10,11].Oralsheddingpersistsforamediandurationofapproximatelysixmonthsafteronsetofillness[11],althoughitshouldbepointedoutthatonceinfectedwithEpstein-Barrvirus(EBV),virusmaybeintermittentlyshedintheoropharynxfordecades[10,12].
AlthoughEBVprimarilyspreadsviapassageofsaliva,itisnotaparticularlycontagiousdisease.Inaclassicstudyconductedamongcollegestudents,susceptibleroommatesofpatientswitheithersymptomsofinfectiousmononucleosis(IM)orasymptomaticviralsheddingwerenomorelikelytoseroconvertordevelopclinicalillnessthanothercollegestudentswithoutevidenceofpreexistingEBVinfection[13].TheviruscanpersistintheoropharynxofpatientswithIMforupto18monthsfollowingclinicalrecovery;
thismayexplaininpartwhyonlyasmallnumberofpatientswithIMrecallpreviouscontactwithaninfectedindividual[13,14].Intrafamilialspreadamongsiblingshasalsobeenreported[15].
Breastfeeding
EBVhasbeenisolatedinbreastmilkfromhealthynursingmothers[16].However,inonestudy,therewasnodifferenceinEBVseropositivitybetweenexclusivelynursedorbottle-fedinfants,suggestingthatbreastfeedingisnotanimportantrouteoftransmission[16,17].
Sexualtransmission
EBVhasalsobeenisolatedinbothcervicalepithelialcellsandinmaleseminalfluid,suggestingthattransmissionmayalsooccursexually[18-20].Inanepidemiologicstudyofmorethan2000universitystudentsinScotland,questionnairesandserumsampleswereanalyzedtoexamineriskfactorsforEBVseropositivity[21].SexualactivitybeforecollegeadmissionwassignificantlyassociatedwithanincreasedriskofEBVseropositivity.Furthermore,theriskofaseropositivestatusincreasedwiththenumberofsexualpartners.
DespitetherecoveryofEBVingenitalsecretions,studieshavebeenunabletodiscriminatewithcertaintywhetherEBVwasacquiredthroughanoralorgenitalroute.InoneprospectivestudythatfollowedEBVantibody-negativeuniversityfreshmen,thetimetoinfectioninindividualsreportingdeepkissingwithoutcoituswassimilartothosewhoreporteddeepkissingpluscoitus[11].BothgroupshadasignificantlyhigherriskofacuteEBVinfectionthansubjectsreportingnokissingorcoitus.
PATHOGENESIS
ContactofEpstein-Barrvirus(EBV)withoropharyngealepithelialcellsallowsreplicationofthevirus,releaseofEBVintotheoropharyngealsecretions,andinfectionofBcellsinthelymphoid-richareasoftheoropharynx[22].EBV-infectedBcellsareresponsibleforthedisseminationofinfectionthroughoutthelymphoreticularsystem.Theincubationperiodpriortothedevelopmentofsymptomsaveragesfourtoeightweeks.
Aprospectivestudywasperformedin20subjectswithserologicallyconfirmedprimaryEBVinfectiontoassessviralkineticsinvariouscompartments,includingwholeblood,peripheralbloodmononuclearcells,andoralwashfluid[23].Themedianhalf-lifeofviraleliminationfromwholebloodin19subjectswasthreedays;
quantityinthiscompartmentcorrelatedwithseverityofsymptoms.Incontrast,viruspersistedatanelevatedlevelfor32weeksintheoropharynxinasymptomaticsubjects,consistentwiththetheorythatEBVistransmittedviasaliva.
PrimaryEBVinfectionofBlymphocytesinducescirculatingantibodiesdirectedagainstviralandunrelatedantigensfoundonsheepandhorseredcells[24].Thelatterantibodies,termedheterophileantibodies,areaheterogeneousgroupofmostlyIgMantibodiesthatdonotcross-reactwithEBVantigens[25,26].Rarely,infectedcellsproduceantineutrophil,antierythrocyte,andantiplateletantibodies,whichareresponsibleforsomeofthelesscommonclinicalmanifestationsassociatedwithinfectiousmononucleosis(IM)(seebelow).AnEBV-specificserologicresponsecanalsobedocumented,althoughthisisnecessaryforlessthan10percentofheterophileantibody-negativeIMcases.
EBV-specificcytotoxicT-lymphocytesareconsideredessentialincontrollingacuteandreactivationinfection.TcellactivationleadstoaThelper1-typeprofilewithproductionofinterleukin-2andinterferon-gammacytokines[27].Theatypicallymphocytes,thatappearintheperipheralbloodofpatientswithacuteIMbetweenoneandthreeweeksaftertheonsetofsymptoms,areprimarilyactivated(HLA-DR+)CD8+T-cellsandalsoincludeCD16+naturalkiller(NK)cells(picture1)[28-32].
Despitetheseimmuneresponses,whichcontroltheinitiallyticinfection,EBVbecomesalifelonginfectionasitestablisheslatencywithperiodicreactivationwithoralsheddingofEBV.Ontheotherhand,insufficientcellularimmuneresponsesmayresultinapoorly-controlledEBVinfectionand/orgenerateanEBV-inducedmalignancy.(See"
sectionon'
Malignancy'
.)Evenwithsufficientimmuneresponses,someepidemiologicalstudieshavelinkedIMtoincreasedrisksofotherconditions,suchasHodgkinlymphoma[33,34].Otherstudieshavelinkedacquisitionofinfectiontoincreasedrisksforautoimmunedisorders,suchasmultiplesclerosisorsystemiclupuserythematosus[35,36].Suchassociationswillrequiresignificantadditionalstudytoprovecausationaswellaswhethertheycouldbearesultofdirectviral,orratherimmunologicalconsequences.Suchconcernshaveheightenedinterestinexploringpotentialpreventativestrategies,suchasanEBVvaccine[37,38].
CLINICALMANIFESTATIONS
ClassicIM
Typicalfeaturesofinfectiousmononucleosis(IM)includefever,pharyngitis,adenopathy,fatigue,andatypicallymphocytosis(table1)[39].Areviewofover500patientsfoundthatlymphadenopathywaspresentinallpatients,feverin98percent,andpharyngitisin85percent[40,41].Thesyndromeisoftenheraldedbymalaise,headache,andlowgradefeverbeforedevelopmentofthesemorespecificsigns[5,42].
Fatiguemaybepersistentandsevere.Inaprospectivestudyof150patients,mostinitialsymptoms(eg,fever,sorethroat)hadresolvedbyonemonthbutfatigueresolvedmoreslowlyandpersistedin13percentofpatientsatsixmonths[41].Fatigueappearstobemorecommonwithamoreprofoundimpactonstudiesandexercis
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