Clinical manifestations and treatment of EpsteinBarr virus infectionWord格式.docx

Clinical manifestations and treatment of EpsteinBarr virus infectionWord格式.docx

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SheldonLKaplan,MD

DeputyEditor

JenniferMitty,MD,MPH

Disclosures

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.

Literaturereviewcurrentthrough:

Feb2014.|Thistopiclastupdated:

三月18,2013.

INTRODUCTION 

— 

Epstein-Barrvirus（EBV）isawidelydisseminatedherpesvirusthatisspreadbyintimatecontactbetweensusceptiblepersonsandasymptomaticEBVshedders.EBVistheprimaryagentofinfectiousmononucleosis（IM）,persistsasymptomaticallyforlifeinnearlyalladults,andisassociatedwiththedevelopmentofBcelllymphomas,Tcelllymphomas,Hodgkinlymphomaandnasopharyngealcarcinomasincertainpatients.ReactivationdiseaseisnotaprominentissuewithEBV,incontrasttoothercommonherpesviruses,butithasbeenassociatedwithanaggressivelymphoproliferativedisorderintransplantrecipients[1].（See"

Treatmentandpreventionofpost-transplantlymphoproliferativedisorders"

.）

TheclinicalmanifestationsandtreatmentofEBVinfectionswillbereviewedhere.ThediagnosisofEBVaspertainstoinfectiousmononucleosisisdiscussedseparately.（See"

Infectiousmononucleosisinadultsandadolescents"

EPIDEMIOLOGY 

ThemajorityofprimaryEBVinfectionsthroughouttheworldaresubclinicalandinapparent.AntibodiestoEBVhavebeendemonstratedinallpopulationgroupswithaworldwidedistribution;

approximately90to95percentofadultsareEBV-seropositive.ThehostrangeofEBVisrestrictedtohumansandcertainsubhumanprimatesincludingsquirrelmonkeysandcottontopmarmosets[2].

VIROLOGY 

Likeothermembersoftheherpesvirusfamily,EBVhasalatencyphase.ThehostcellsfortheorganisminhumansarelimitedtoBlymphocytes,Tlymphocytes,epithelialcellsandmyocytes.Unlikeherpessimplex（HSV）orcytomegalovirus（CMV）,EBViscapableoftransformingBcellsbutdoesnotroutinelydisplayacytopathiceffect.AdetaileddiscussionofthevirologyofEBVisfoundelsewhere.（See"

VirologyofEpstein-Barrvirus"

PRIMARYINFECTION 

EBVcancauseanumberofprimaryinfections,canleadtocomplications,andcaninduceavarietyofmalignancies.

Acuteinfectiousmononucleosis 

Infectiousmononucleosis（IM）isthebestknownacuteclinicalmanifestationofEBV.IMoftenbeginswithmalaise,headache,andlow-gradefeverbeforedevelopmentofthemorespecificsignsoftonsillitisand/orpharyngitis,cervicallymphnodeenlargementandtenderness,andmoderatetohighfever[3].Affectedpatientsusuallyhaveperipheralbloodlymphocytosis,composedinlargemeasureofatypicallymphocytes（picture1）.（See"

Thelymphadenopathycharacteristicallyissymmetricandinvolvestheposteriorcervicalchainmorethantheanteriorchain.Tonsillarexudateisafrequentcomponentofthepharyngitis;

theexudatecanhaveawhite,gray-green,ornecroticappearance.

Severefatiguemaybeprominent,whileotherlesscommonfindingsincludepalatalpetechiae,periorbitalorpalpebraledema,andmaculopapularormorbilliformrashes.Nausea,vomiting,andanorexiaarefrequentinpatientswithIM,probablyreflectingthemildhepatitisencounteredinabout90percentofinfectedindividuals.Splenomegalyoccursinasmanyas50percentofpatients,butjaundiceandhepatomegalyareuncommon.

MostpatientswithIMcausedbyEBVhaveprominentpharyngealsymptoms[4].Thereare,however,severalotherformsoftheillness.SomeindividualswithIMpresentwiththeso-called“glandular”formofthediseaseinwhichlymphnodeenlargementisoutofproportiontothepharyngealsymptoms;

othersdevelopasystemicformoftheinfectioninwhichfeverandfatiguepredominate,whilelymphadenopathyandpharyngitisaremildorabsent.SomepatientshavehepatitisintheabsenceofothertypicalfeaturesofIM.

MostindividualswithprimaryEBVinfectionrecoveruneventfullyanddevelopahighdegreeofdurableimmunity.Acutesymptomsresolveinonetotwoweeks,butfatigueoftenpersistsformonths.

PrimaryEBVinfectionininfantsandchildren 

PrimaryEBVinfectionsinyounginfantsandchildrenarecommonandfrequentlyasymptomatic.Whensymptomsdooccur,avarietyofmanifestationshavebeenobserved,includingotitismedia,diarrhea,abdominalcomplaints,upperrespiratoryinfection,andIM[5].Asanexample,oneseriesreported32childrenyoungerthan4yearsofagewithIM,selectedfromapopulationof200childrenbyreviewofbloodsmears（morethan50percentmononuclearcellsandmorethan10percentatypicallymphocytes）[6].ThemajorityofthesechildrenhadclinicalevidencecompatiblewithIM（significantcervicaladenopathyandtonsillarpharyngitis）;

respiratorysymptomswerefrequentlyprominent,especiallyinyounginfants.

ChildrencanhavesymptomaticprimaryEBVinfectionwithouttheproductionofheterophileantibodies;

asaresult,EBV-specificserologicstudiesarerequiredtoestablishthediagnosis.Intheaboveseriesof32children,interpretationoftheresultsofserologywasmostproblematicinchildrenbelowtheageoftwoyears[6].

▪Theheterophiletestwasparticularlyinsensitive（25percentpositiveforages10to24monthsversus75percentforages24to28months）.

▪Anti-viralcapsidantigen（VCA）IgMwaslessfrequentlypositiveininfants（60percentcomparedwith100percentinolderchildrenandyoungadults）;

inaddition,peaktitersofVCAantibodywerelower,andthedevelopmentofantibodiestoearlyantigenwaslesscommonininfants.

Despitethereductioninantibodyproduction,younginfantscanmountanEBV-specificcytotoxicTlymphocyteresponseduringacuteEBVinfectionandthatthelatentproteinsrecognizedareidenticaltothoserecognizedbyyoungadults[7].

Congenitalandperinatalinfections 

IntrauterineinfectionwithEBVisrarebecausefewerthan5percentofpregnantwomenaresusceptibletothevirus.Inaddition,prospectivestudiesofsusceptible（ie,seronegative）womenhavenotfoundevidenceofcongenitalabnormalitiesamonginfantsofwomenwhodiddevelopprimaryEBVinfectionduringpregnancy[8].WhileisolatedcasesofinfantswithsomeevidenceforEBVinfectionandcongenitalanomalies（biliaryatresia,congenitalheartdisease,hypotonia,micrognathia,cataractsandthrombocytopenia）havebeenreported[9],theevidencearguesagainstEBVasasignificantcauseofcongenitalinfection.Specifically,noevidenceofEBVinfectionhasbeendemonstratedinlargestudiesofchildrenwithcongenitalanomaliesorincordbloodsamples[10].

Othermanifestations 

EBVcanaffectvirtuallyanyorgansystemandhasbeenassociatedwithsuchdiversediseasemanifestationsaspneumonia,myocarditis,pancreatitis,mesentericadenitis,myositis,glomerulonephritis,andgenitalulceration[11].AlargenumberofothermanifestationshavebeenassociatedwithprimaryEBVinfection:

▪NeurologicsyndromescanincludeGuillain-Barré

syndrome,facialnervepalsy,meningoencephalitis,asepticmeningitis,transversemyelitis,peripheralneuritis,andopticneuritis[12].

▪Hematologicabnormalitiescanincludehemolyticanemia,thrombocytopenia,aplasticanemia,thromboticthrombocytopenicpurpura/hemolytic-uremicsyndrome,anddisseminatedintravascularcoagulation.

ChronicEBVinfection 

ChronicEBVinfectionisararedisordercharacterizedbyongoingsymptomsofaninfectiousmononucleosissyndromewithactiveviremia.Thisentityisdiscussedelsewhere.（See"

COMPLICATIONS 

EBVinfectionisassociatedwithanumberofacutecomplicationsand,incertainhosts,moredelayedeffects.

Rash 

OneofthemorecommoncomplicationsofIMisamorbilliformrashfollowingtheadministrationofampicillin,andtoalesserextent,penicillin.Theincidenceinitiallywasreportedtobeashighas70to90percentbutisprobablylower[13].Themechanismresponsibleforthisrashisnotunderstoodbuthasbeenthoughttoinvolvecirculatingantibodiestoampicillin.DevelopmentofthisrashduringIMdoesnotappeartopresageanampicillinallergy;

patientshavesubsequentlytoleratedampicillinwithoutanadversereaction.

Oralhairyleukoplakia 

AnotherEBV-mediatedmucocutaneousmanifestationisoralhairyleukoplakia（OHL）,whichisanunusualdiseaseofthelingualsquamousepithelium[14].OHLgenerallyaffectsthelateralportionsofthetongue,althoughthefloorofthemouth,thepalate,orthebuccalmucosamayalsobeinvolved.Thelesionsaredescribedaswhitecorrugatedpainlessplaquesthat,unlikecandida,cannotbescrapedfromthesurfacetowhichtheyadhere（picture2）.Theyarenotgenerallyassociatedwithfever.

TheOHLlesionsappeartoberelativelyspecificforHIVinfection,sincetheyareonlyrarelyobservedinpatientswithotherimmunodeficiencies[14,15].TheuseofhighlyactiveantiretroviraltherapyappearstohavereducedtheincidenceofOHL[16,17].

OHLisassociatedwithintenseEBVreplicationandtheactionofEBV-encodedproteinssuchaslatentmembraneprotein-1[14].Inaddition,studiesinwhichEBVreplicationhasbeensuppressedbyvalacyclovirhavedemonstratedpersistent,nonproductiveEBVinfectionandcontinuedEBVentryfromthebloodintothetongue[18].Theseobservationssuggestaroleforentry,persistence,andreactivationoforalepithelialEBVinthepathogenesisofOHL.

OHLisnotconsideredapremalignantlesion,beingunlikelytoprogresstosquamouscellcarcinoma[14].Treatmentwithzidovudine,acyclovir,ganciclovir,foscarnet,andtopicalpodophyllin