Adenovirus Current Epidemiology and Emerging Approaches toPrevention and Treatment(2)

TRANSPLANTANDONCOLOGY(MISON,SECTIONEDITOR)

Adenovirus:CurrentEpidemiologyandEmergingApproachestoPreventionandTreatment

UrielSandkovsky&LucianoVargas&DianaF.Florescu

Published#online:8June2014

SpringerScience+BusinessMediaNewYork2014

AbstractInfectionscausedbyadenovirusesareassociatedwithsignificantmorbidityandmortalityinbothhematopoieticstemcellandsolidorgantransplantrecipients.Theriskseemstobehighestinallogeneichematopoieticstemcelltransplantrecipientsaswellasheart,lungandsmall-boweltransplantrecipients.Managementoftheseinfectionsmaybedifficultandincludesreductionofimmunosuppressionwheneverpos-siblecombinedsometimeswithantiviraltherapy(mainlycidofovir).Thecurrentlyavailableantiviraltherapyislimitedbytheneedforintravenousadministration,potentiallysignif-icantrenalandhematologictoxicities.Newemergingthera-piessuchasbrincidofovirandtransfusionofadenovirus-specificT-lymphocytesmayincreasetheavailablearmamen-tariumforthesepotentiallylife-threateninginfections.KeywordsAdenovirus.Solidorgantransplantation.

Hematopoieticstemcelltransplant.Bonemarrowtransplant

Introduction

Adenoviruses(ADV)arenon-enveloped,lyticdouble-strandedDNAvirusesresponsibleforself-limitedrespi-ratory,gastrointestinalorconjunctivalinfectionsin

ThisarticleispartoftheTopicalCollectiononTransplantandOncologyU.Sandkovsky:D.F.Florescu

DivisionofInfectiousDiseases,TransplantInfectiousDiseasesProgram,UniversityofNebraskaMedicalCenter,Omaha,NE,USAL.Vargas:D.F.Florescu

TransplantSurgeryDivision,UniversityofNebraskaMedicalCenter,Omaha,NE,USA

D.F.Florescu(*)

TransplantInfectiousDiseasesProgram,UniversityofNebraskaMedicalCenter,Omaha,NE68198-5400,USAe-mail:dflorescu@unmc.edu

immunocompetentpatients,withchildren,militaryre-cruitsandcollegestudentsbeingthemostcommonlyaffectedgroups[1].Inhematopoieticstemcelltrans-plant(HSCT)andsolidorgantransplant(SOT)recipi-ents,dependingonthedegreeofimmunosuppression,ADVcancauseaspectrumofdiseasefromasymptom-aticinfectionstosevereorevendisseminatedinfections,sometimesaffectinggraftorpatientsurvival[2,3].TherearesevenrecognizedADVsubgroups(A–G)classifiedbasedonhemagglutinationproperties,DNAhomol-ogyandoncogenicpotentialinrodents[4••].Thesesubgroupscanbefurtherdividedinto57distinctserotypesbasedonneutralizationbyspecificanimalantisera[4••].Differentge-notypescanbedistinguishedwithinthesameserotype[2].ThespecificADVserotypesareimportantforepidemiologicpurposesandtounderstandtheclinicalmanifestationsofthediseasethataremainlydictatedbytheorgantropismasillustratedinTable1[2,4••,5].

The2013guidelinesfromtheAmericanSocietyofTrans-plantation(AST)defineasymptomaticADVinfectionasde-tectionofADVfromstool,blood,urine,orupperairwayspecimensbyviralculture,antigentests,orpolymerasechainreaction(PCR)intheabsenceofsignsandsymptoms[4••].ADVdiseaseisdefinedasthepresenceofattributableorgansignsandsymptomscombinedwithvirusdetectioninbiopsyspecimensonimmunohistochemicalstainingorinbronchoal-veolarlavageandcerebrospinalfluid(culture,antigendetec-tion,orPCR),intheabsenceofanotherdiagnosis[4••].DisseminatedADVdiseaserequiresinvolvementoftwoormoreorgans,notincludingviremia[4••].

TheEuropeanConferenceonInfectionsinLeukemiahasdevelopedguidelinesfordiagnosisandtreatmentofADVinpatientswithleukemiaofHSCT.TheproposeddefinitionsareslightlydifferentthantheproposedASTdefinitionabove.Systemicinfection/viremiaisdefinedasapositiveADVPCR,virusisolation,orantigendetectioninperipheralblood.

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Table1AssociationsbetweenclinicalmanifestationsandADVserotype

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ADVserogroupsandserotypes

SerogroupsB1andB2;serotypes7,11,34and35Serotypes3,4,7,11,14,16,21,34,35and50Serotypes40,41and52Serotypes1,2,3,5and7

Serotypes11,31,33,34,35and40Serotypes2,5and7Serotypes7and21

Serotypes,particularlyfromsubgroupC

Clinicalmanifestation

MainlyassociatedwithhemorrhagiccystitisRespiratorytractdiseaseGastroenteritisHepatitis

DisseminatedADVdisease

MeningoencephalitisMyocarditis

Inducelatentinfection;thelatentviruscanreactivateduringperiodsofimmunesuppression

Adaptedfromreferences[2]and[4••]

LocalinfectionisdefinedasapositiveADVPCR,virusisolation,orantigendetectioninbiopsymaterialorinbodyfluidsotherthanperipheralblood.ProbablediseaserequiresthecriteriaforADVinfectionpluscorrespondingsymptomsandsignswithouthistologicconfirmation.ProvendiseaserequiresADVinfectionplusattributablesymptomsandhisto-logicconfirmationofADVintheappropriatelocation[6••].

Epidemiology,RiskFactorsandClinicalManifestationsBoneMarrowTransplantRecipients

TheincidenceofADVafterautologousHSCTseemstobelowerthanafterallogeneictransplants,between2.5%and14%[7–10].ADVinfectionsinallogeneicHSCTrecipientsaremorecommon,withanincidencerangingfrom5%to47%,withthehighestrateinthefirst100daysaftertrans-plantation[11–28].RiskfactorsforADVinfectioninthispopulationinclude:youngerage,numberofsiteswhereADVisisolated,detectionofADVinbloodandrisingviralloadinblood(whichisalsoapredictorofmortality),treatmentwithT-cell-depletingagents,totalbodyirradiation,allogeneictransplantation,HLAmismatch,lowT-cellcountaftertrans-plantationandgraft-versus-hostdisease(GVHD)[13,25,29–36].Oneparticularriskfactoristheuseofalemtuzumabinconditioningregimens(inbothadultsandchildren)[37,38].ADVinfectionsinthispopulationareassociatedwithmortalityratesupto70%[11–28].ADVviremiaismorecommoninchildren,butinadultpatientsitseemstobeassociatedwithhighermortalitythaninthepediatricpopulation[32].SolidOrganTransplantRecipients

ThetrueincidenceofADVinfectioninSOTislesswelldefinedthaninHSCTrecipients,mainlyduetolackofsys-tematicscreeningforthevirusandreportsthatdonotdiffer-entiateasymptomaticinfectionfromdisease.Mostreports

describetheepidemiologyandclinicalpresentationofADVinfectionswithinthefirstyearaftertransplantation.Theinci-denceisreportedtobehigheramongpediatricSOTrecipients,probablymirroringtheepidemiologyofADVinfectionsinchildren[3,4••,39,40].InaretrospectivestudyofpediatricSOTrecipients,theoverallincidenceofADVinfectionwasfoundtobe6.25%,withthehighestrateinlivertransplantrecipients(57%),followedbyhearttransplantrecipients(32%)andthelowestrateinkidneytransplantrecipients(11%)[41].Thereportedincidenceinpediatriclungandheart–lungtransplantrecipientsisbetween7%and50%,andmostinfectionsarediagnosedmainlyinthefirstfewmonthsaftertransplantation[42–46].OnestudyshowedanADVinfectionrateof22.5%inadultlungtransplantrecipi-ents.Themajorityoftheinfections(78%)wereasymptom-atic,andonlyaminorityofpatientsdevelopedself-limited’flu-likeillness[47].

Theratesofviralinfectionsareusuallyhigheramongheartandheart–lungtransplantrecipientsthanamongliverandkidneytransplantrecipientsastheseallograftsusuallyrequireamoreintenseimmunosuppressiveregimen[48].Inkidneytransplantrecipients,forunclearreasons,ADVinfectionsaremorecommonlyreportedintheadultpopulation,withanincidencerateof4.1%,withamediantimetoinfectionof1.25months(range0.5–75months).Mostinfectionsoccurwithin3monthsoftransplantation[49].ADVinfectionratesafterlivertransplantationareintherange3.5%to38%,withtheinfectionsbeingdiagnosedatamedianof0.85–1monthsaftertransplantation(range0.13–29.6months)[40,50–52].ADVinfectionisreportedatvariablerates(incidence4.3–57.1%)afterintestinalormultivisceraltransplantation,withoccurrenceatamedianof1.6monthsaftertransplantation,andthemajorityofcasesbeingdiagnosedinthefirst6monthsaftertransplantation[52–55].

Insmall-boweltransplantrecipients,graftinvolvementismorecommonthanwithotherallografts,withasignificantproportionofthesepatientsprogressingtodisseminateddis-ease[53,55,56].Althoughstudiesinrenalandhearttrans-plantationhavelinkedADVinfectionstosubsequentgraft

CurrInfectDisRep(2014)16:416rejection,itisunclearwhetherADVinfectionshavethepo-tentialtotriggersmall-bowelrejectionthroughactivationofthecytokinecascadeandstimulationofthecellularimmuneresponse[57–59].Themostcommonmanifestationinkidneytransplantrecipientsishemorrhagiccystitis,whichpresentswithfever,dysuria,frequency,grosshematuriaandhighratesofallograftdysfunction.AllograftdysfunctionseemstobemorecommoninadultsandusuallyrenalfunctionreturnstobaselinewithresolutionofADVdisease[60,61].InkidneytransplantrecipientswithADVviremia,organinvolvementiscommon,andincludesenteritis,orchitisandpneumonitis[49].Pneumoniaisalesscommonmanifestation,buthasahighfatalityrate(upto17%)[2].AlthoughtherelationshipbetweenADVandrejectionisnotwellestablished,itispossiblethatADVmightbeabletotriggerrejectionviaactivationoftheinnateimmunesystem[3]Anotherpossiblemechanismforacuteallograftrejectionisthereductioninimmunosuppression,commonlyusedtoallowclearanceoftheviralinfection.

ADVinfectionsinlungtransplantrecipientscanbeasso-ciatedwithrespiratoryfailureleadingtodeathorgraftloss[42,46].Inonestudy,ADVwasfoundtobepresentin50%ofpediatriclungorheart–lungtransplantrecipientswithbron-chiolitisorgraftloss[42].

TheclinicalpresentationofADVdiseaseinhearttrans-plantrecipientsisusuallysimilartothatinotherSOTrecip-ients,buttheallograftcanbeindirectlyaffected[58,62].TheidentificationofADVinheartbiopsiesiscorrelatedwithacuterejection,decreasedgraftsurvival,ventriculardysfunction,vasculopathy,needforretransplantationandgraftlossduetodeathintworetrospectivestudies[58,62].Themostfrequentclinicalmanifestationsinlivertransplantrecipientsincludejaundice,hepatomegaly,andhepatitis,followedbyenteritis,pneumonitisandhemorrhagiccystitis[39,40,52].Thegraftmaybeinvolved,leadingtograftfailureandneedforretransplantation.Mortalityratescanbeashighas53%[40,51,63].

SeveralriskfactorshavebeenreportedtoincreasetheriskofADVinfectioninSOTrecipients.AgeisanindependentriskfactorforADVinfection;insmallboweltransplantationthereisa19%increaseintheriskofADVinfectionforeveryyeardecreaseinage[53].ThetypeofthetransplantedorgancorrelateswiththeriskofADVinfections.ThehighestratesofADVarereportedinintestinaltransplantation,mostlikelybecauseofthelargeamountofgut-associatedlymphoidtissue(GALT)intheallograft.GALTposesanimmunologicchal-lenge,ahighriskofrejection,requiringintenseimmunosup-pressiveregimens;GALTcouldalsobethesourceofpersis-tentorlatentADVinfections[3,52–56,].Immunosuppres-sionplaysapivotalroleasariskfactor:resolutionofinfectionwithreductioninimmunotherapyalonesupportstheroleofimmunosuppressionasariskfactorforADVinfection[3],andtherateofADVinfectionsishighestinthefirstmonthsafter

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transplantation,correlatingwithexposuretolyticantibodytherapy(OKT3,thymoglobulin)andhigherlevelsofmainte-nanceimmunosuppressiontherapy[40,49,53].TheuseofADVsero-mismatchedorgansisconsideredtobeariskfactorforinfection[2,4••,65],butscreeningofdonorandrecipientisnotcurrentlypartofthestandardpracticeinSOT.Severalriskfactorscanincreasetheriskofprogressionofasymptom-aticinfectiontoADVdisease:isolationofthevirusearlyaftertransplantation,persistentisolationofthevirus,isolationofthevirusfrommorethanonesite,initialhighviralloadinbloodandintensificationofimmunosuppression[49,52,55].InadultSOTrecipients,asymptomaticviremiaiscommon(6.5–22.5%)andtheriskofprogressiontoadenoviraldiseaseappearstobeinfrequent[47,66].Hence,routinescreeningforADVDNAemiaisnotrecommendedinSOTrecipients[65].

Diagnosis

AllADVserotypesgrowwellincultureproducingacharac-teristiccytopathiceffectafter2–28days,butcultureisimpracticalfromtheclinicalviewpointbecauseofitslaborintensiveness,andbecauseofthepossibilityoflongerturn-aroundtimesandpotentialbacterialcontaminationinnonsterilesites[2].Immunofluorescenceassaysarecommer-ciallyavailableforrapiddiagnosisusingrespiratoryspeci-mens,whileenzymeimmunoassays,immunochromatographyandlatexagglutinationtestsareusedforrapiddiagnosisusingstoolsamples[2].Histopathologyremainsthegoldstandardmethodtodiagnoseinvasivedisease.Biopsyspecimensfromaffectedorganscanhelpdifferentiateviralinfection,rejectionorotherconcomitantpathology.ThepresenceofADVinbiopsysamplesissuspectedbytheidentificationof“smudgecells,”whicharecellswithlargebasophilicnucleisurroundedbyathinrimofcytoplasm,andconfirmedthroughimmunoperoxidaseand/orinsituhybridizationstaining[2].Electronmicroscopyshowsthetypicaladenoviralparticlesof70–80nmdiameterwithinthenucleiandcytoplasmoftubularepithelialcells,andtissueinvasioncanbeconfirmedwithimmunoperoxidasestaining[60].

QualitativeandquantitativePCRareprobablythemostcommondiagnosticmethodologiesusedinclinicalpracticefordiagnosisandmanagementofADVinfections.Thesensi-tivityofPCRisveryhigh,usuallydetectingquantitiesaslowas100copies/mL,regardlessoftheADVserotype.Becausetheremaybehome-brewedPCRassays,whichhavenotbeenstandardized,interpretationoftheresultsacrosslaboratoriesisdifficult[2,4••,67].Itisrecommendedthatviremiabemon-itoredwiththesameassay.ResultsofPCRshouldbecom-binedwithclinicalfindingsandhistopathologyinordertodifferentiatediseasefromasymptomaticshedding/viremia

416,Page4of8[4••].SerialquantitativePCRisusedinclinicalpracticetodecideifandwhentostarttherapyandtomonitorresponsetotherapy.Thereisnoclearviralloadcut-offthatdeterminesthelikelihoodofdisseminationorprogressiontodisease.Persis-tentlyhighorrisingviralloads(0.5–1.0logincrease)seemtobeanindicationthatinterventionisneeded,whiledecreasingviralloadscorrelatewithclinicalimprovement[22,49,68].

PreventionandTreatment

Becauseofpotentialtransmissionandoutbreaksinthehealthcaresetting,strictcontactanddropletisolationisrec-ommendedinpatientswithADVinfectionforthedurationoftheillness.Becauseimmunocompromisedhostsusuallyhaveprolongedsheddingofvirus,precautionsrelatingtodurationofcontactanddropletsshouldbeextended[69].

InallogeneicHSCTrecipients,viralmonitoringisnotrecommendedinthosewhoarenotathighriskofdisease.High-riskpatients(thosewhohaveatleastoneriskfactor)shouldhaveADVPCRmonitoredinbloodweeklyuntilimmunereconstitutionoccurs.RoutinemonitoringisnotrecommendedinautologousHSCTrecipients[6••].RoutineADVmonitoringisalsonotrecommendedinSOTrecipients[4••].

Inmostimmunocompromisedpatients,supportivecarecombinedwithadecreaseinimmunosuppressiontherapyisthemostimportantcomponentoftreatment,sincethesealonecanleadtoresolutionoftheinfection[4••,6••,41,49,55,56,].Thisapproachmaynotalwaysbefeasible,especiallywhendiseaseoccursearlyaftertransplantationandtheriskofgraftrejectionisgreatest.Insomesituationsantiviraltherapyisconsidered.

Oftheavailableantiviralagents,cidofovir,ribavirinandganciclovirhaveinvitroactivityagainstADV[70,71].TheconcentrationsofribavirinneededtoreachinhibitoryactivityagainstADVinplasmaorintissueareinthetoxicrange,limitingitsuse.Gancicloviractivityisquestionablebecauseitneedstobephosphorylatedbyviralkinases,whicharenotpresentinADV(contrarytoherpesviruses)andalsorequiresplasmaconcentrationsthataremuchhigherthanthoseachiev-ablewithstandarddosing[71,72].Inmanytransplantcenters,cidofovirisconsideredthestandardtreatment,althoughitsuseisnotsupportedbyprospectiverandomizedclinicaltrials.CidofovirhasnotbeenFDA-approvedforthetreatmentofADVinfections,anditisassociatedwithsignificantnephro-toxicityandbonemarrowtoxicity[73].Aregimenof5mg/kgweeklyor1mg/kgthriceweeklyfortwoconsecutiveweeksfollowedby5mg/kgeveryotherweekisrecommended[4••,74].Theseregimenshavenotbeendirectlycompared,butitispossiblethatadministrationofcidofovir1mg/kgthriceweek-lymightbelessnephrotoxicbutmaycarryanincreasedriskofbreakthroughcytomegalovirus(CMV)andherpessimplex

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virusinfectionandtheemergenceofcidofovirresistance[16].ItisrecommendedthattreatmentbecontinueduntilsymptomscompletelyresolveandthreenegativeADVsam-plescollected1weekapartfromthesitesthatwereoriginallypositivearedocumentednegative[4••,53].Inpatientswithacreatinineclearance<0.3mL/min/kg,thedoseshouldbedecreasedto0.5mg/kgthriceweekly[4••,53].Inpatientsonhemodialysisorhemofiltration,theprocedureshouldbestopped1hourbeforeandatleast4hoursafterdrugadmin-istrationtoallowintracellulardistributionofcidofovir[53].Probenecidat0.5–1.25g/m2shouldbeadministered3hoursbefore,and2–3hoursand8hoursaftertheadministrationofcidofovirincombinationwithpretreatmentandposttreatmenthydration(normalsalinesolutionat5mL/kg/h)topreventnephrotoxicity[4••,22,43,53,75].PlasmaADVPCRmonitoringwouldbeusefultoassessvirologicresponsetocidofovir,anditshouldbecorrelatedwithclinicalchanges[68].

AlthoughprophylactictherapywithantiviraldrugsisnotrecommendedinHSCTrecipients,preemptivecidofovir3–5mg/kgweeklyfor2–3weeksandevery2weeksthereafterisrecommendedinpatientswhopresentwithviremiaandatleastoneriskfactorfordisease.Provenorprobablediseaseshouldbetreatedwithcidofovirat5mg/kgweeklyfor2–3weeksandevery2weeksformaintenance.Renalprotectionwithhydrationandprobenecidshouldalsobeused[6••].

EmergingApproachesforAdenovirus

Hexadecyloxypropyl-cidofovir,alipidconjugateofcidofovir(CMX001,brincidofovir;Chimerix,Durham,NC)hasseveraladvantageswhencomparedtotheunmodifiedparentcom-pound:goodoralbioavailability,rapidtransportacrosstargetcellplasmamembranesleadingtomuchhigherintracellularconcentrations[76],and5to>2,500-foldgreaterpotencyagainstdifferentADVserotypes[77].Brincidofovirisnotassociatedwithmyelosuppressionornephrotoxicity[78,79].Themostcommonsideeffectisdiarrhea,especiallyatdosesof200mgweeklyorbiweekly[79].

Thefirstclinicalexperiencewithbrincidofovircomesfromasmallretrospectivestudy.BrincidofovirwasshowntobeasafeandeffectivesalvagetherapyforADVdiseaseinhighlyimmunocompromisedpatientswithrefractoryADVdiseaseorintoleranttostandardtherapy(cidofovir)[80].Thecohortincluded11patientswithHSCT,1patientwithseverecom-binedimmunodeficiency,and1patientwithsmall-boweltransplant(eightchildrenandfiveadults),andallpatientshadADVviremiaandsixhaddisseminatedADVdisease.Thebrincidofovirdoseswere1,2or3mg/kgperweek;doseswerealsoadjustedtobiweeklybasedondruglevels,virologicresponseandsafetydata.Theresponsetobrincidofovirtreatment(changeinlog10viralload:median−2.71,

CurrInfectDisRep(2014)16:416range−5.63to1.1)wassignificantlybetter(p=0.001)thantheresponsetocidofovirtreatment(median0.08,range−2.14to4.66)withthenumberofweeksoncidofovirmatchedwiththenumberofweeksonbrincidofovir.Almost70%ofthepatientsachievedvirologicresponse(achievementof≥99%decreaseinplasmaviralloadfrombaselineorundetectableviralloadbytheendoftreatmentorfollow-upperiod)after8weeksoftherapy.The8-weeksurvivalrateafterbrincidofovirtreat-mentwashigherinpatientswhorespondedtotreatment(88.9%)thaninthosewhodidnotrespondtotherapy(50%)[80].

Prospectivedataonbrincidofovircomesfromaphase2randomized,blinded,placebo-controlledproof-of-concepttrialusingbrincidofoviraspreemptivetherapyforADVviremiainHSCTrecipients(14patients,CMX001-202)[78],andanopen-labelstudyinpatientswithseriousand/orlife-threateninginfectionscausedbydsDNAviruses(12patients,CMX001-350)[81]whoreceivedbrincidofovirbiweeklybasedonADVviremia.Brincidofovirshowedpromisingantiviralactivityinim-munocompromisedtransplantrecipientsbydecreasingADVviremiatothelowerlimitofdetectionoftheassayin67%ofthepatientswithinthefirstweekoftherapy[82].

AnothertreatmentapproachforADVdiseaseislym-phocytereconstitutionthroughadoptivetransferofADV-specificT-cellimmunity,especiallyafterallogene-icstemcelltransplantation[83,84].DifferentADV-adoptiveimmunotherapyprotocolshavebeendevelopedintheresearchsetting.ApilotstudyhasshownthatadoptiveT-celltransferisassociatedwithreductionorclearanceoftheADVviralloadandclinicalimprove-mentofADVdisease.InvivoexpansionofspecificT-cellswasnoted,probablyexplainingwhytheefficacyoftheadoptiveT-celltransferwasindependentoftheT-celldoseadministered.Theclinicalresponsewasattrib-utedtotheadoptiveimmunotherapysincetheantiviraltherapywasnotchangedduringthestudy.PatientswithnoexpansionofADV-specificT-cellsdiedfromADVinfection.Inthatstudy,onlyonepatienthadacuteGVHDoftheskinwhichwasattributedtopreexistingchronicGVHDoftheskin[83].AdifferentstudyshowedthatcytotoxicT-lymphocyteswithspecificityforbothEpstein-Barrvirus(EBV)andADV,canbesafelyadministeredtopediatricpatientsreceivingpar-tiallyHLA-matchedandhaploidenticalstemcellgraftswithoutinducingGVHD.TheinfusedcellsprovidedprolongedprotectionasnoneofthepatientsdevelopedADVinfectionafterinfusion[84].ArecentmulticentertrialinallogeneicHSCTrecipientswhoreceivedvirus-specificT-cellsforpersistentCMV,ADVorEBVinfec-tionordiseaseshowedpromisingresults[85].The6-

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weekcumulativeresponseratetoADV-specificT-cellinfusionwas77.8%,andhalfoftherespondershadanincreaseinADV-specificT-cells.Alltheinfusionswerewelltoleratedwithoutimmediateadverseeffects.Inthistrialthatincluded50patients,eight(16%)developedGVHD(sixgrade1,onegrade2andonegrade3)within45daysofthefirstinfusion;however,sixoftheeightpatientshadahistoryofGVHD.Eightpatients(16%)developedadverseeventsbutnoneofthesewasdeemedtobedefinitelyrelatedtotheinfusion[85].Therecommendationfortherapywithdonor-derivedADV-specificT-cellsiscurrentlyreservedforpatientswhodonotrespondtostandardantiviraltherapy.Sincethisoptionisnotpartofcurrentpracticeinmostcenters,thistreatmentapproachshouldbecarriedoutincenterswithexperienceaspartofclinicaltrials[6••].

Finally,adifferentapproachtocontrolviremiahasbeenstudiedinvitroinvolvingthedirecttargetingofearly,middleandlateviralgenesinvolvedintherepli-cationofAdV5todecreasethereplicationcapacityofthevirus.Inthisstudy,silencingofearlyandmiddlegeneswasmoreeffectiveininhibitingADVreplicationandimprovingviabilityoftheinfectedculturesthanwassilencingoflategenes.However,combiningtargetingofdifferentadenoviraltranscriptsdidnotseemtofurtherdecreasevirionproduction.Todate,noanimalorhumanstudieshavebeenperformed,butsilencingofcertainearlygenestoinhibitADVmultiplicationseemstobeanattractiveoptionforfuturedrugdevelopment[86].

Conclusions

ADVinfectionisanemergingprobleminbothSOTandHSCTrecipients.DepletionofT-lymphocytesisamajorriskfactor,anddependsontheintensityanddurationofimmunosuppression.Transplantrecipientswhorequiremoreintenseimmunosuppressiveregimenssuchasheart,lung,small-bowelandallogeneicHSCTrecipientsaremorepronetoADVinfection.InHSCTrecipients,vire-miaisdirectlycorrelatedwithseverityofdisease,mor-bidityandmortality,andacriticalaspectinthispopula-tionisthedurationoflymphocytedepletionandthedependenceofsurvivalontherecoveryoflymphocytepopulations.AhighindexofsuspicionisneededinSOTandHSCTpatientswithunexplainedsymptomssothatdiseasecanbediagnosedearlyinordertopreservegraftfunctionanddecreasemorbidityandmortality.DuringthelastseveralyearstherehasbeensignificantefforttooptimizediagnosticmethodsforADV,andthedevelop-mentofEuropean(ECIL)andASTguidelines.Inthelastdecade,effortstodevelopnewtherapeuticoptionsforADVinfectionshaveincreased.

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AcknowledgmentsNofundingwasreceivedforthiswork.CompliancewithEthicsGuidelines

ConflictofInterestDianaFlorescureceivedgrantsfromChimerixInc.andCLSBehring.FlorescuhasservedasaconsultantforChimerixInc.andCLSBehring.UrielSandkovskyreceivedresearchgrantsfromCLSBehring,ViiVHealthcare,GSKandPfizer.SandkovskywasaconsultantforRib-XPharmaceuticals.LucianoVargasdeclaresnoconflictsofinterest.

HumanandAnimalRightsandInformedConsentThisarticledoesnotcontainanystudieswithhumanoranimalsubjectsperformedbytheauthor.

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