www.jped.com.br
REVIEW
ARTICLE
Atypical
manifestations
of
Epstein---Barr
virus
in
children:
a
diagnostic
challenge
夽
Vasileios
Bolis
∗,
Christos
Karadedos,
Ioannis
Chiotis,
Nikolaos
Chaliasos,
Sophia
Tsabouri
ChildHealthDepartment,UniversityHospitalofIoannina(UHI),Ioannina,Greece
Received11May2015;accepted17June2015 Availableonline20January2016
KEYWORDS
Epstein---Barrvirus; Infectious
mononucleosis; Child;
Complications
Abstract
Objective: Clarifythefrequencyandthepathophysiologicalmechanismsoftherare
manifes-tationsofEpstein---Barrvirusinfection.
Sources: OriginalresearchstudiespublishedinEnglishbetween1985and2015wereselected
throughacomputer-assistedliteraturesearch(PubMedandScopus).Computersearchesused combinationsofkeywordsrelatingto‘‘EBVinfections’’and‘‘atypicalmanifestation.’’
Summaryofthefindings: Epstein---Barrvirusisaherpesvirusresponsibleforalifelonglatent
infectioninalmosteveryadult.Theprimaryinfectionconcernsmostlychildrenandpresents withtheclinicalsyndromeofinfectiousmononucleosis.However,Epstein---Barrvirusinfection mayexhibitnumerousrare,atypicalandthreateningmanifestations.Itmaycausesecondary infectionsandvariouscomplicationsoftherespiratory,cardiovascular,genitourinary, gastroin-testinal,andnervoussystems.Epstein---Barrvirusalsoplaysasignificantroleinpathogenesisof autoimmunediseases,allergies,andneoplasms,withBurkittlymphomaasthemain representa-tiveofthelatter.Themechanismsofthesemanifestationsarestillunresolved.Therefore,the mainsuggestionsaredirectviralinvasionandchronicimmuneresponseduetothereactivation ofthelatentstateofthevirus,orevenvariousDNAmutations.
Conclusions: Physiciansshouldbecautiousaboutuncommonpresentationsoftheviralinfection
andconsiderEBVasacausativeagentwhentheyencountersimilarclinicalpictures.
©2016SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Allrightsreserved.
PALAVRAS-CHAVE
Vírusde Epstein---Barr; Mononucleose infecciosa;
Manifestac¸õesatípicasdovírusdeEpstein---Barremcrianc¸as:umdesafiodiagnóstico
Resumo
Objetivo: Esclarecimentodafrequênciaedosmecanismospatofisiológicosdasmanifestac¸ões
rarasdainfecc¸ãoporvírusdeEpstein---Barr.
夽
Pleasecitethisarticleas:BolisV,KaradedosC,ChiotisI,ChaliasosN,TsabouriS.AtypicalmanifestationsofEpstein---Barrvirusinchildren: adiagnosticchallenge.JPediatr(RioJ).2016;92:113---21.
∗Correspondingauthor.
E-mail:v.bolis7@gmail.com(V.Bolis).
http://dx.doi.org/10.1016/j.jped.2015.06.007
Crianc¸as; Complicac¸ões
Fontes: Estudosdepesquisasoriginaispublicadoseminglêsentre1985e2015foram
seleciona-dospormeiodeumabuscanaliteraturaassistidaporcomputador(PubmedeScopus).Asbuscas nocomputadorutilizaramcombinac¸õesdepalavras-chaverelacionadasa‘‘infecc¸õesporVEB’’ e‘‘manifestac¸ãoatípica’’.
Resumodosachados: OvírusdeEpstein---Barréumherpesvírusresponsávelporumainfecc¸ão
latentevitalíciaemquasetodoadulto.Ainfecc¸ãoprimáriaocorreprincipalmenteemcrianc¸ase seapresentacomosíndromeclínicadamononucleoseinfecciosa.Contudo,ainfecc¸ãoporvírus deEpstein---Barrpodeapresentardiversasmanifestac¸õesraras,atípicasedealtorisco.Elapode causarinfecc¸õessecundáriasediversascomplicac¸õesdossistemasrespiratório,cardiovascular, geniturinário, gastrointestinale nervoso. O vírusde Epstein---Barr também desempenha um papelsignificativonapatogênesededoenc¸as,alergiaseneoplasiasautoimunes,comolinfoma deBurkittsendooprincipalrepresentantedasúltimas.Osmecanismosdessasmanifestac¸ões aindanãoforamresolvidos.Portanto,asprincipaissugestõessãoinvasãoviraldiretaeresposta imunecrônicadevidoàreativac¸ãodoestadolatentedovírusoumesmodiversasmutac¸õesdo DNA.
Conclusões: Osmédicosdevemtomarcuidadosobreapresentac¸õesincomunsdeinfecc¸ãoviral
econsideraroVEBumagentecausadorquandoencontraremsituac¸õesclínicassemelhantes. ©2016SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Todososdireitos reservados.
Introduction
Epstein---Barrvirus(EBV)isacommoninfectiousagent,found in approximately 95% of the world’s population. Primary infectionwithEBVis more frequent duringchildhoodand causes a mild infection, which usually presents with no symptoms.1 However, when primary infection occurs
dur-ingadolescence,it leads toinfectious mononucleosis(IM) in30---70%ofcases,whereupto20%ofBlymphocytesare infectedwithEBV.1,2
EBVisaDNAvirusbelongingtotheherpesfamily,andis alsoknownashumanherpesvirus4.Itiscomposedofa lin-eardsDNAgenomeenclosedbyacapsid,whichissurrounded bythetegumentandahostcellmembrane-derivedenvelope embeddedwithglycoproteins.EBVhasalargegenome, cod-ingfor 87 proteins. The functions of 72 of theseproteins havebeendefinedsofar.1
EBVtransmissionis achievedwithsaliva itandinitially infectsepithelialcellsintheoropharynxandnasopharynx. Afterwards,EBV enters the underlying tissues andinfects B-cells.After a primarylytic infection,EBV is capable of remainingdormantinrestingmemoryB-cells,fromwhichit periodicallyreactivates.The ability ofreactivationmakes EBVaconstantchallengetothehost.1
IM is the main clinical entitycaused by EBV.Diagnosis isbasedonclinicalexamination,revealingtheclassictriad offever,lymphadenopathy,andpharyngitis,3andlaboratory
findings including the presence of atypical lymphocyto-sis and heterophile antibodies.2 The disease is managed
specificallywithsupportive care, sinceit is a self-limited infection.3However,IMhasbeenassociatedwithnumerous
earlyorlatecomplications,witharangeofgraveness. This review focuses on the rare manifestations of IM in children. Original researchstudies publishedin English between1985and2015wereselectedthrougha computer-assistedliteraturesearch (PubMedandScopus).Computer
searchesusedcombinationsofkeywordsrelatingto‘‘EBV infections’’and‘‘atypicalmanifestation.’’Inaddition,the referencelistsoftheretrievedarticleshelpedinthesearch forotherrelevantarticles,whichwerenotfoundduringthe searchingprocedure.Thus,48studieswereselectedand dis-cussedhere(24casereports,14reviews,fivecasecontrol studies,onepopulation-basedstudy,twoletterstoeditor, onecohortstudy,onemeta-analysis).Thepotentialfactors, whichmaybiasthefindingsofthisreview,arerestrictionof articlestoEnglish,togetherwithdatabaseandcitationbias.
Secondary
infections
Acutedacryocystitis
AcutedacryocystitisisararecomplicationofIM,withonly fivereportedcases.Itisdefinedbyapainful,palpablemass inthemedialcanthalarea,usuallyaccompaniedbyfever.4
The etiology is nasal epithelial edema and lymphoid hyperplasia fromIM, which causetemporary nasolacrimal duct obstruction. Colonization of lacrimal saccontents by respiratorypathogensultimatelyleadstoacute dacryocys-titis. This complication is likely to occur in children and youngadultsduetothesmallernasalanatomyandunique epidemiologyofEBV.4
Patients with IM and acute dacryocystitis should be treatedwithantibiotics;drainageofthelacrimalsacabscess mayberequired.4
Respiratory
complications
Upperairwayobstruction
approximately1---3.5%ofcases.Suspicionshouldberaised inthepresenceofodynophagia,cervicallymphadenopathy, andsymptomsofrespiratorydistress.5
IM causes inflammation of Waldeyer’s ring, edema of the pharynx and epiglottis, and pseudomembrane forma-tion in the large airways. Signs of severe upper airway obstruction areoften absentduringthe firststagesof the disease.Patientsshouldbetreatedwithcorticosteroids,and inseverecases,acutetonsillectomy,endotracheal intuba-tion,ortracheotomymaybemandatoryinordertosecure theairway.5
Pneumonia
Pulmonary involvement is found in 5---10% of the IM cases inchildren.ReportsofsevereEBVsymptomaticlung infec-tionarerareandfrequentlydescribedinimmunosuppressed adults.Therehavebeenfivereportedcasesofseverelung involvement in EBV infection in children. Three of these children sufferedfrom respiratorydistressand interstitial pneumonitis, one from bilateral lower lobe consolidation andeffusion complicatedby hemoptysis,andthe lastone frompleuropneumonia.6
Thepathophysiologicalmechanismincludeslymphocytes infectedbyEBV,whichinfiltratethelung duringacuteIM. However,itisquestionablewhetherthispulmonary involve-mentistheresultofdirectviralinvasionoflungorwhether itrepresentsanimmunologicreactiontothevirus.Ithasalso been suggestedthatEBVactsasaco-pathogenorinduces axtemporaryimmunosuppression,causingsusceptibilityto anotherinfection.6
Cardiovascular
complications
Acutemyocarditis
Prevalenceof EBVisestimated tobeless than1%in viral myocarditis,3while thereareseveralanecdotal reportsof
heartcomplicationsfromIMduringthelast60years.7EBV
and CMV are associated with this pathology, particularly afterhearttransplantation.8
Thepathophysiologicalprogressioniscomposedofthree phases. During the first phase, destruction of the car-diomyocytes derives directly from virus-mediated lysis or indirectly from immune response with the expression of proinflammatorycytokines.Duringthesecondphase,T-cells detect the viral antigenand destroy theinfected cardiac cells through cytokine or perforin secretion. In the last phase,thedestroyedmyocytesarereplacedbydiffuse fibro-sis,leadingtodilatedventriclesandcardiacfailure.8
Myocarditis,aswellasotherheartcomplicationsofEBV likepericarditis,mightevenprecedeclinicalIM,hindering thediagnosis.7
Atherosclerosis
The role of EBV in the pathogenesis of atherosclerosis is basedonfindingssuggestingthatEBVDNAiscommonlyfound in atheromatous plaques. However, EBV DNA presence in
atheromarangesfrom12%to80%,thus thesefindings are questionable.9
This complicationregardsonly adults,andthepossible mechanismis basedonEBV-encodedenzymedeoxyuridine triphosphate nucleotidohydrolase (dUTPase).dUTPase has beenshown toinducetheproduction ofpro-inflammatory cytokinessuchas interleukin-6(IL-6) andendothelial cell expression of intercellular adhesion molecule-1 (ICAM-1). Emotional and psychosocial stress is believed to deregu-lateimmunerepressionofthevirus,allowingitsreplication andthe production of dUTPase. This mechanism provides anexplanationfortheconnectionbetweenstress,EBV,and coronaryarteryevents.10 EBV-inducedgene3(Ebi3)isalso
implicatedinatherosclerosis.11
Hematological
complications
Thrombocytopenia
Mildthrombocytopeniaoccursin25---50%ofuncomplicated cases during the acute phase of the disease. An occa-sionalpatientmayhave thrombocytopeniafor 8weeks or more.Incontrast,severethrombocytopenia(plateletcount <20×109/L)israre,with38reportedcases.Twenty-eightof
thesepatientswereyoungerthan21yearsold.Twoofthese patientsdiedofcomplicationsfromthrombocytopeniaand hemorrhage.12 AlthoughsevereEBV-associated
thrombocy-topeniaisrare,itcanhavelife-threateningconsequences. Thiscomplicationshouldbeconsideredinanypatientwith acute EBV infection and evidence of mucosal or dermal bleeding.13
Ithasbeenproposedthatthepathophysiologyof throm-bocytopeniaincludesthepresenceofaplatelet-destroying agglutininproduced in response toa viralagent---platelet bond.Otherpossiblemechanismsincludevasculardamage due to the infectious agents, and hypersplenism or anti-body formation in the spleen and the reticuloendothelial system.12
Aplasticanemia
AplasticanemiafollowingprimaryEBVinfectionorin asso-ciationwithreactivationofEBVinfectionhasbeenreported in24casesintheliterature.Seventeenofthesecaseswere childrenunder18yearsold.However,itislikelythatsome casesofaplasticanemiacharacterizedasidiopathicare,in fact,triggeredbyanEBVinfection,sinceinyoungchildren EBVinfectionpresentswithatypicalsymptoms.14
EBV infected B-cells may provoke oligoclonal expan-sion of suppressor T-cells (CD8+, CD28−), which prevent
autologousmarrowhematopoieticcellsdevelopment. EBV-associated and idiopathic aplastic anemia have similar prognosis.14
Agranulocytosis
ThepathogenesisofagranulocytosisafterIMmayinvolve decreasedproductionormaturationofmyeloidcellsinthe marrow,asaresultofthedirecteffectofEBVor antibody-mediated peripheral destruction of myeloid cells. The hypothesis ofmaturation arrestofmyeloid cellshas been suggested because mature myeloid cells disappear in the patient’s bone marrow. Anti-human neutrophil antigen-1a (anti-HNA-1a)andanti-HNA-1b antibodiesareboth associ-atedwiththepathophysiologyinagranulocytosisafterIM, althoughit isunknown whetheranti-neutrophilantibodies areproducedinEBV-infectedBcells.15
Lymphohistiocytosis
Hemophagocytic syndrome or hemophagocytic lymphohis-tiocytosis(HLH)isarare,life-threateningdiseasecausedby adysfunctionofcytotoxicTcellsandNKcells.16 Incidence
ofHLH is estimated at onecase per 800,000 people,half ofwhich areassociatedwithEBV.EBV-associatedHLHhas beenobservedin infants,children,andadults,but80%of thecasesoccurinchildrenof1---14yearsofage.HPScanbe either primary,i.e., due toan underlying geneticdefect; or secondary, associated with malignancies, autoimmune diseases(macrophage activationsyndrome),or infections. Infectioustriggersaremainlyvirusesof theherpesgroup, withEBVbeingthemostcommon.17
Possible mechanism includes T cell/NK cell deregula-tion,which leads to increasedcytokine release, resulting in activation of histiocytes followed by hemophagocy-tosis. Histiocytic infiltration of the reticuloendothelial system causes hepatomegaly, splenomegaly, lymphadeno-pathy, and pancytopenia, eventually leading to multiple organdysfunctions.16
Genitourinary
system
complications
Renaldysfunction
EBVinfection’srenal involvementvaries frommicroscopic hematuria and mild proteinuria to acute renal failure.18
Renaldysfunctionin IM is infrequent, mostly self-limited, andisrarelyassociatedwithfailureofrenalfunction. Evi-denceofmildrenalinvolvementmaybepresentupto16% inpatientswithIM,butsevererenalfailureisrare.19
Hematuriaorproteinuriacanbefoundin2%and18%of IMcasesrespectively,whereasazotemiahasbeenreported inonly eightcases.Interstitial nephritisis the most com-monhistologicabnormality.EBVisbelieved toplayavital roleinthepathogenesisofIgAnephropathy.Occasionalcase reportsofnephroticsyndrome,hemolyticuremicsyndrome, hepatorenalsyndrome,andrhabdomyolysisinpatientswith IMhavealsoappeared.18 Acuterenalfailure,althoughless
common,hasbeenassociatedprimarilywithrhabdomyolysis andinterstitialnephritis.19
Finally, membranous nephropathy is a result of a prolongedsystemic viralproliferation andpersistent anti-genemiainIMpatientswholackafullycompetentimmune system,thusleadingtoimmunecomplexdepositioninthe kidney.19
ThepossibilityofIMshouldbeconsideredwhenpatients present acute renal failure, particularly if other features
suchasfever, hemolytic anemia,hepatitis,or thrombocy-topeniaarepresent.18
Genitalulcers
Genitalulcerationisanuncommonmanifestationofprimary EBVinfection.IdentifiedbytheAustriandermatologist Lip-schützas an acute diseasewith fever, genital ulceration, andlymphadenomegalyinyoungwomenin1913andcalled Lipschütz’sulcer,todayitis attributedtoEBVinfection.20
Forty-onecaseshavebeenreported,withthevastmajority beingfemales.21---23
Patientsdevelop oneor more largeulcers with diame-terbetween0.3and4cm.24 TheEBV-associatedulcersare
oftenquitedeepandnecrotic,withirregularedges,andmay causepainandurinarysymptoms.Themeanhealingtimeis 18days.20
There have been three hypotheses suggested for the pathogenesis of EBV genital ulcers. The first hypothesis includes typeIIIhypersensitivityreactiontoimmune com-plexes producedin theacutephaseof EBVinfection.EBV genital ulcerscould also resultfrom cytolysis due toEBV replication invulvar keratinocytes,along withthe inflam-matoryresponsetoviralagents.Finally,theseulcersmight representatypeofaphthosis.23
EBVisalsopresentelsewhereinthefemalegenitaltract; however,itspathogenicroleinthecervix,uterus,fallopian tubes,andovariesispoorlyunderstood.22
Gastrointestinal
complications
Hepatitis
Cholestatichepatitis withmild liver dysfunctionhasbeen reported in more than 90% of patients with primary EBV infection,but severe liver dysfunction or gallbladder involvement is rare.25 Primary EBV infection can cause a
mild self-limited hepatitis, which typicallyresolves with-outclinical importance;jaundicecanbeseen in5---10% of cases.Liverfunctionabnormalitiesmostoftenoccurduring thesecondweekofillnessandresolvewithin2---6weeks.25
Acuteacalculouscholecystitis
Eleven cases of acuteacalculous cholecystitis (AAC)have been reportedduringthecourseofprimaryEBVinfection, 10ofwhichwereinchildrenoryoungadults.24
The main cause of AAC is gallbladder stasis and stag-nation of bile. Increased bile viscosity, gallbladder wall ischemia, and proinflammatory mediators like eicosanoid have also been implicated in the pathogenesis. Gallblad-derwallthickeningandsludgeformationmayoccurduring thecourseofviralhepatitis.Hydropsofthegallbladdermay occasionallydevelopduringIM.Whethertheincreased thick-nessofthegallbladderwallresultsfromdirectinvasionof thegallbladder mucosabyEBVor whetherEBV-associated cholestasiscausesthegallbladderwallirritationorboth is notestablished.24
complicateIM, thus avoidingunnecessary invasive surgery andantibiotictherapy.24
Acuteliverfailure
Acute EBVinfection is a rare cause of acute liver failure (ALF)inyoungadults,buttheavailabledataareinsufficient andtherearenotreportsforchildren.Asdemonstratedby an 1887 patient cohort study,EBV is responsible for only 0.21% ofALFcases. Mostcasesoccur post-transplantation orareassociatedwithimmunodeficiencysyndromes.26Since
EBV is a ubiquitous virus and lacks a specific treatment, there is a significant risk for children who areEBV nega-tivebeforelivertransplantationtobeinfectedbyanadult EBVpositive liver. RisingEBVtiters should beapproached withreductionofimmunosuppression.27Itisquestionableif
thepathophysiologyof EBV-related ALFisdue toa gener-alizedhostimmune responsetoEBVantigensor increased viralreplication.26
Splenicrupture
SplenomegalyisacommoncomplicationofIMandofother infectiousconditions.Itis frequentlyself-limited. Sponta-neoussplenicrapture,however,is araremanifestationof IM, estimatedat 0.1---0.5% ofIM cases.28 Mostof reported
splenicrupturesoccurredwithin3weeksafterIMdiagnosis, butruptureappearstooccurevenafter7weeks.17
EBVinfectionisbelievedtodamagethesplenic architec-turebyinvadingthespleenwithlymphocytesandatypical lymphoidcells.Thisinfiltrationweakensthefibroussupport systemofthespleenandthespleniccapsulebecomes thin-ner,promotingtherupture.Therupturemayoccurfollowing aminortraumaorspontaneously.Thespontaneousrupture is hypothesizedtobea resultof eitheran acuteincrease in portalvenous pressurecaused by Valsalvamaneuver or thecompression oftheenlargedspleenbythecontracted diaphragmortheabdominalwall.28
Most cases report full resolution of hematoma from 4 weeksupto1year.Thereis evidencesupportingthat the spleen can retain full function while maintaining a low riskforrepeatruptureevenafterparenchymaldisruption. Thus,non-operativemanagementofsplenicruptureduring IM, in a stable trauma patient, appears to be the treat-ment of choice,when alsoconsidering the risksfollowing asplenectomy.28
Since splenic rupture is more frequent within 3 weeks oftheinfectiononset,itis suggestedthatpatientsshould refrainfromsportsforaminimum3weeksoronceclinical symptomsandfindingsareresolved.17
Neurological
complications
Facialnervepalsy
There have been only 14 cases of EBV-associated facial nervepalsy (FNP).Of these,36% ofthe cases were bilat-eral,althoughbilateralFNPamongFNPpatientsrangesfrom 0.3%to2%.OtomastoiditiscausedbyEBVmaytransmitthe infection to the facial nerve leading to this type of FNP,
sinceitwasrecognizedintwoofthesecases.Another possi-bleexplanationisthedirectviralinvasionorimmunological responsetoEBVbythecentralnervoussystem. Themean ageofthesepatientscomparedtonon-EBV-associatedFNP patientswasmuchlower.Thisisassociatedwithincreased incidenceofEBVinfectionduringchildhood.29
EBVinfectionshouldbesuspectedinpatientswithFNP, especiallywhenitisbilateral,evenwhensystemic manifes-tationsofEBVinfectionareabsent.Thesepatients donot requireanyspecialtreatment.30
Guillain---Barresyndrome
Therehave beenseveralcasereportssince1947reporting EBVinfectiontoprecedeGuillain---Barresyndrome(GBS).It hasalsobeen reported thatEBV isresponsible for 10% of GBScases.However,thecriteriausedinthesereports are questionable,sinceEBVis ubiquitous.31 Theexcess riskof
GBSinthe2monthsfollowingEBVinfectionisbelieved to be20-fold.32
Encephalitis
TheincidenceofEBVencephalitisisless than0.5%,butit maybeincreasedto7.3%amongchildrenwhoare hospital-izedwithIM.33Fatalitiesoccurin0.1---1%ofthesecases.2EBV
encephalitiscommonlypresentswithconfusion,decreased level of consciousness, fever, and epileptic seizures. The manifestationsof EBVencephalitismay existbefore, dur-ing, or even after the symptoms of IM.34 However, most
patientswith EBVencephalitis donot show typical symp-tomsofIM;therefore,EBVshouldbeconsideredapossible causeofacutechildhoodencephalitis,regardlessthe pres-enceofIMsymptoms.33EBVencephalitisprognosismayvary
fromcompleterecoverytodeath.34
EBVencephalitisinvolvesawidediversityoflocationsin centralnervoussystem,withthecerebellum,cerebral hemi-sphere,andbasalgangliaasthemostfrequent.Patientswith isolatedbrain stem involvementare characterizedby the highestmortality,whereaspatientswiththalamic involve-mentwererecognizedwiththemostconsequences.Isolated corticalinvolvement andinvolvement ofspinal cordwere associatedwithexcellentprognosis.34
The pathogenesis of EBV-induced neurologic injury has notbeenelucidated,althoughitissuggestedthat immuno-logic mechanisms are mostly responsible rather than increasedviralreplication.33
AliceinWonderlandsyndrome
Alicein Wonderland syndrome (AIWS) is characterized by metamorphopsia,theself-reportedpresenceof somatosen-soryalteration,suchasdistortionintheperceptionofsize andshapeofapatient’sbodyandillusionsofchangesinthe size,distance,form,evencolorsorspatialrelationshipsof objects.35Theillusionsandhallucinationsaresimilartothe
strangeincidentsthatAliceexperiencedinLewis Carroll’s ‘‘Alice’sAdventuresinWonderland.’’36
associationwithEBVandotherviralinfections.35Fourcases
withAIWSsecondary to IM have been reported, including twoadolescents, a 9½ year-old boy and a 7-year-oldgirl withEBVencephalopathy.36,37
Metamorphopsiamayprecedeonsetorfollowthe resolu-tionofallclinicalsignsandsymptoms.Thedurationofthe visualillusion rangesbetween 2weeksand 7months,but withcompleterecoveryinalldescribedcases.35
AIWSdiagnosismaybecomplicatedifthevisual distur-bancesprecedetheclassicsymptomsofIMorifIMfollows asubclinicalcourse.38Therefore,patientscompatiblewith
AIWSsymptomsshouldbesuspectedforEBVinfection.35
Psychiatric
complications
Psychoticepisodes
Severalstudies suggesta linkbetween early-lifeinfection andadultschizophreniaandincreasedprevalenceofEBVin thelatter.EBVisaknownneurotropicinfectiousagent,since itisamemberoftheHerpesviridaefamily.Thehumanbrain continuestodevelopthroughchildhoodandearlyadulthood, thusinfectionduringthisperiod,especiallywith neurotrop-ingagents,couldpotentiallyincreasetheriskofneurological abnormalities.39
Possiblepathophysiologicalmechanismsinclude inflam-matory cytokinesaffecting the brain after the activation of the innate immune system. Early-life infection harms microglia,distortingneuronalsurvivalandfunctioning.Itis alsobelieved that there is a connection between genetic psychosisbackgroundandvulnerabilitytoinfection.39
Fatigue
IMisaspecificandstrongriskfactorforthedevelopmentof fatigue,subsequently.However,itis possiblethat doctors arebiased,thus overestimatingtheprevalence of post-IM fatigue compared to that of other viral infections. Con-versely,doctorsmaynotrecordfatigueafterIM,considering itasanexpectedsequelofanyviralinfection.Fatigueisa subjectivesymptomandsoisdifficulttocalculateasa fea-ture of theillness. Possible risk markers for fatigueafter IMarefemalesex,premorbidmooddisorder,lackof physi-calfitness,inactivity,andillnessperception.Thesemarkers may be used to target prevention strategies and explore etiologicalmechanisms.40
Depression
The association betweeninfectious agents anddepression hasbeencontroversial. Earlyclinicalstudiessupported an association of raised antibody titers againstHSV and EBV withdepression.However,opposingresultshavealsobeen reported that reveal no significant association between antibodies to HSV, influenza, or neurotropic viruses with depression.Findingssuggestthatsmallersample-sized stud-ies tend to produce negative results, and identifying a significantassociationbetweenEBVinfectionanddepression mayrequireasufficientlylargesamplesize.41
Autoimmunity
The majorenvironmentalriskfactorsforsystemic autoim-mune diseasesareinfections.1 EBVhasbeen suggestedto
beassociatedwithautoimmune diseases,suchas rheuma-toidarthritis(RA),systemiclupuserythematosus,multiple sclerosis (MS), inflammatory bowel diseases, autoimmune thyroiditis, insulin-dependentdiabetes mellitus, Sjögren’s syndrome, autoimmune liver diseases, systemic sclerosis, andmyastheniagravis.42
One of the main mechanisms of how infections may causeautoimmunityismolecularmimicry.Itisbelievedthat sequence or structural similarities between microbial and self-antigenscross-reactwithB-cells,T-cells,and antibod-ies.Suchexamplesareanti-citrullinatedproteinantibodies inRAandautoantibodiesagainst␣B-crystallininMS.42
An additional theory is referred to as bystander acti-vation. In this case, the inflammatory background of an infection promotes activation or expansion of previously activated,autoreactivelymphocytes.Activationand expan-sionofautoreactiveT-cellsareknowntooccurduetothe virus-induced severe local inflammation and intense local cytokineproduction.1EBVproteinsinvolvedinimmune
eva-sionand suppressionof apoptosisoftransformed infected lymphocytes are likely to result in loss of tolerance and developmentofautoimmunity.42
Ithasbeensuggestedthatraisedserumtitersof antibod-iesagainstEBVinautoimmunediseasescouldbetheresult of polyspecificB-cell activation.In responsetopolyclonal stimuli, memory B-cells proliferate and differentiate into plasmacells;thismaydepictanaturalmechanismfor the perpetuationofalifelongserologicalimmunity.42
Anotherhypothesis is the accumulation of T-cells, due to EBV frequent reactivation. EBV specific CD8+ T-cells are enriched in or near the diseased organs of patients with RA and MS, and they also accumulate in synovial fluid frompatients withpsoriatic arthritis, osteoarthritis, and Reiter’ssyndrome. This could reflect a local immune responseagainstEBVinthediseasedorgans.42
Aftermanyyearsofviral,immunological,and epidemio-logicalresearch,itisstilldebatedwhetherEBVisacausative agentoftheseautoimmuneentities.42
Allergies
Hypersensitivitytomosquitobites
ThisdiseasehasappearedmostlyinJapanesechildren.More than 50 casesof hypersensitivity tomosquito bites (HMB) havebeenreportedinJapan,andthereareseveralreports ofcasesinTaiwanandMexico.HMBisidentifiedbyintense localskinsymptoms,whichcomprisebulla,erythema,and ulcerationorscarring,andsystemicsymptomssuchas lym-phadenopathy,highfever,andhepatosplenomegaly.43
increasedexpressionofviraloncogeneLMP1inEBV-infected NK cells, and the mosquito antigen also increases the expressionandinducesNKcellproliferation.LMP1activates varioussignalingpathwaysduringtransformation,including PI3kinase,Rac,NF-kB,andreactiveoxygensignaling.43
Epidemiological observations suggest the possibility of endemicdevelopmentofHMB,asaresultofthepatient’s geneticbackgroundortheimpactofmultipleenvironmental factors.43
Neoplasms
ItisestimatedthateachyearEBVisresponsiblefor84,000 cases of gastric carcinomas, 78,000 cases of nasopharyn-gealcarcinoma,and28,000casesofHodgkinlymphoma.It isnotablethatthe riskofEBV-positiveHodgkin lymphoma culminates at 4 yearsafterIM, while it decreases to nor-mal after 10 years. Each year there are over 6000 cases ofEBVassociatedBurkittlymphoma(BL)inlessdeveloped countries.TheprevalenceofBLincentralAfricais20cases per100,000inchildrenbetweentheagesof5and9years.44
EBV is also associated with malignancies in immuno-compromised patients. EBV lymphoma, for example, is the second most common malignancy developing after organ transplantation, because of the respective immunodeficiency.44
Themostrelevantchildren’sneoplasmderivedfromEBV isBurkittlymphoma.45DenisBurkittobservedaformofBL,
endemic BL, which is most commonly seen in regions of sub-SaharanAfrica.RegionsofendemicBLhaveaveryhigh frequencyofdisease,roughly 5---10casesper100,000 chil-dren.Viralgenomescanbefoundinnearly100%ofendemic BLtumors.46
BL occurs worldwide at a much lower incidence in a formknownassporadicBL,whichisalsoseenprimarilyin children, but has a lower association with EBV infection. SporadicBLvariesfrom15%to85%ofviraltumors.46
The contribution of EBV to the pathogenesis of BL is similarlyenigmatic.EBVleadstothedevelopmentof trans-formedbutnotmalignantlymphoblastoidcelllines(LCLs), byactivatingtheproliferationofBcells.LCLsare respon-siblefor theexpression of numerousEBV-encodedlatency proteins,manyofwhichmodulatekeyregulatorypathways suchasPI3KandNF-kB,which havebeen solidlylinkedto cancer.IntheabsenceoffunctionalTcellsorduring continu-ousantigenpresence,EBV-inducedLCLsgrowunhindered.47
EBValsoinhibitstheapoptosisofpremalignanttumorcells, allowingtransformingeventstooccur.1Thefinalstepsofthe
oncogenicpathwayarethetranslocations inMYCand TCF-3genes.Thesearethemostcommonmutationscausedby EBV,whichleadtotheproductionofoncogenictranscription factorsinBL.47
X-linked
lymphoproliferative
disease
PrimaryEBVinfectioninboyswithX-linked lymphoprolife-rative disease(XLPD)leads tofulminant, oftenevenfatal disease.Inaddition,theconditionpredisposesto consider-ablyelevatedincidenceoflymphomas.48
Mutation or deletion of the SH2D1A gene causes lack of functional signaling lymphocytic activation molecule
(SLAM)-associated protein (SAP), which regulates T-cell apoptosis. The lack of SAP results in uncontrolled pro-liferation of CD8+ T-lymphocytes leading to XLPD. T-cell apoptosis,whichisalsoinefficientintheIMmostlyduetothe Epstein---Barrvirusnuclearantigenanti-apoptoticfunction, enhancestheeffectsofSAPabsence.48
Discussion
EBVinfectsvirtuallyeveryonebyadulthood,andalifelong latencyismaintained.It infectschildrensilently,whereas themajorityofadolescentsdevelopIMwheninfected.17On
rareoccasionsthesymptomsofIMmaypersistinachronicor recurrentform,andfatalIMoccursrarely.Dependingonthe typeanddegreeofimmunedeficiencyandthetimetheEBV infectionoccursinthelifecycle,variousatypicaloutcomes canoccur.1
Thesemanifestationsmaybeacute,suchasgenitalulcers andacutedacryocystitis,4,20ordelayed,suchas
autoimmu-nityandatherosclerosis.10,42Someofthemmayberelatively
benign like fatigue, allergies, and FNP13,30,43 and others
may be life-threatening, like splenic rupture and ALF.17
TheremainingEBVcomplicationsincludemyocarditis,renal dysfunction, hepatitis, and AAC,8,19,24,25 as well as
sev-eralhematological,neurological,andrespiratoryentities.16
Althoughthesemanifestationsarequiterare,physiciansand especiallypediatricians should be aware of such cases in ordertoavoidunnecessarytreatmentandprocedures,since IM wouldbe easily treated only withsupportive care.17,24
When similar signs and symptoms to the aforementioned arepresent, the differentialdiagnosis should includeEBV as a causative agent. The patient’s history is of great importance and may provide the first indications for the appropriatediagnosis.Individualizationandoptimizationof the patient’s follow-up would also aid in preventing and treatingpossiblecomplications.3Inotherwords,knowledge
ofthesescenarioswouldbebeneficialforboththechild’s health and the treatment cost, hence improving medical practice.
It is notable that there are many open questions regardingthe mentioned manifestationsandfurther stud-iesareneededtoelucidatetheroleof theimmunological mechanismofEBVonvarioustargetorgans.42Thefull
under-standingofthesemechanismsandthecorrelationbetween EBVandthepathologicalentitieswillassistinthetreatment andpreventionofseveremorbidity.
Nonetheless, the immune system is criticalin preven-tingtheprogressionofEBVdisease,sincetheimmunological statusofthepatientplaysacrucialroleinthesubsequent developmentof pathologies.1 As lifeexpectancyincreases
and as more manipulations of the immune system are achieved, more unusual manifestations of EBV infection will appear, which will be a diagnostic challenge in the future.
Conflicts
of
interest
References
1.DraborgAH,DuusK,HouenG.Epstein---Barrvirusinsystemic autoimmunediseases.ClinDevImmunol.2013;2013:535738.
2.Carvalho LH. Mononucleose infecciosa. J Pediatr (Rio J). 1999;75:S115---25.
3.ValachisA,KofteridisDP.MononucleosisandEpstein---Barrvirus infection:treatmentandmedication.DovePressJVirusAdapt Treat.2012;4:23---8.
4.GhauriAJ,KeanePA,ScotcherSM,ClarkeJL,MadgeSN.Acute dacryocystitis associated with Epstein---Barr virus infection. Orbit.2011;30:245---8.
5.GlynnFJ,MackleT,KinsellaJ.Upperairwayobstructionin infec-tiousmononucleosis.EurJEmergMed.2007;14:41---2.
6.MironD,MerzelY,LevA,MeirJJ,HorowitzY. Pleuropneumo-niaasthesolemanifestationofEpstein---Barrvirus-associated infectiousmononucleosis.IsrMedAssocJ.2002;4:733---4.
7.SabbataniS,ManfrediR,OrtolaniP,TrapaniFF,VialeP. Myoperi-carditis during a primary Epstein---Barr virus infection in an otherwisehealthyyoungadult.Anunusualandinsidious compli-cation.Casereportanda60-yearliteraturereview.InfezMed. 2012;20:75---81.
8.Andréoletti L, Lévêque N, Boulagnon C,Brasselet C,Fornes P. Viral causes of human myocarditis. Arch Cardiovasc Dis. 2009;102:559---68.
9.KutikhinA,BrusinaE,YuzhalinAE.Virusesandstherosclerosis. NewYork:Springer;2013.
10.BinkleyPF,CookeGE,LesinskiA,TaylorM,ChenM,Laskowski B, et al. Evidence for the role of Epstein---Barr virus infec-tionsinthepathogenesisofacutecoronaryevents.PLOSONE. 2013;8:e54008.
11.Kempe S, Heinz P, Kokai E, Devergne O, Marx N, Wirth T. Epstein---Barr virus-induced gene-3 is expressed in human atheromaplaques.AmJPathol.2009;175:440---7.
12.Walter RB, HongTC, Bachli EB.Life-threatening thrombocy-topeniaassociatedwithacuteEpstein---Barrvirusinfectionin anolderadult.AnnHematol.2002;81:672---5.
13.Pipp ML,Means ND, Sixbey JW, Morris KL, Gue CL,Baddour LM.AcuteEpstein---Barrvirusinfectioncomplicatedbysevere thrombocytopenia.ClinInfectDis.1997;25:1237---9.
14.KhanI,InoueS,MushtaqR,OnwuzurikeN.EBVinfection result-inginaplasticanemia:acasereportand literaturereview.J BloodDisordTransfus.2013;4:141.
15.YokoyamaT, TokuhisaY, TogaA, FujikiT, SakakibaraY,Mase S,etal.Agranulocytosisafterinfectiousmononucleosis.JClin Virol.2013;56:271---3.
16.MaakarounNR,MoannaA,JacobJT,AlbrechtH.Viralinfections associated with haemophagocytic syndrome. Rev Med Virol. 2010;20:93---105.
17.Luzuriaga K, Sullivan JL.Infectious mononucleosis. NEngl J Med.2010;362:1993---2000.
18.ArayaCE,González-PeraltaRP,Skoda-SmithS,DharnidharkaVR. SystemicEpstein---Barrvirusinfectionassociatedwith membra-nousnephropathyinchildren.ClinNephrol.2006;65:160---4.
19.VermaN,ArunabhS,BradyTM,CharytanC.Acuteinterstitial nephritissecondarytoinfectiousmononucleosis.ClinNephrol. 2002;58:151---4.
20.Halvorsen JA,BrevigT,AasT,SkarAG,Slevolden EM,MoiH. Genital ulcers as initial manifestation of Epstein---Barr virus infection:twonewcasesandareviewoftheliterature.Acta DermVenereol.2006;86:439---42.
21.Jerdan K, Aronson I, Hernandez C, Fishman PM, Groth JV. Genital ulcers associated with Epstein---Barr virus. Cutis. 2013;91:273---6.
22.Leigh R, Nyirjesy P. Genitourinary manifestations of Epstein---Barr virus infections. Curr Infect Dis Rep. 2009;11: 449---56.
23.SárdyM,WollenbergA,NiedermeierA,FlaigMJ.Genitalulcers associatedwithEpstein---Barrvirusinfection(ulcusvulvae acu-tum).ActaDermVenereol.2011;91:55---9.
24.CrumNF.Epstein---Barrvirushepatitis:caseseriesandreview. SouthMedJ.2006;99:544---7.
25.Arya SO, Saini A, El-Baba M, Salimnia H, Abdel-Haq N. Epstein---Barrvirus-associatedacuteacalculouscholecystitis:a rareoccurrencebut favorableoutcome.ClinPediatr (Phila). 2010;49:799---804.
26.MellingerJL,RossaroL,NauglerWE,NadigSN,AppelmanH,Lee WM,etal.Epstein---Barrvirus(EBV)relatedacuteliverfailure: acaseseriesfromtheUSAcuteLiverFailureStudyGroup.Dig DisSci.2014;59:1630---7.
27.Kelly D.Liver transplantation inchildren. J Pediatr (Rio J). 2008;84:381---2.
28.StephensonJT,DuBoisJJ.Nonoperativemanagementof sponta-neoussplenicruptureininfectiousmononucleosis:acasereport andreviewoftheliterature.Pediatrics.2007;120:e432---5.
29.TeradaK,NiizumaT, KosakaY,Inoue M,OgitaS, KataokaN. BilateralfacialnervepalsyassociatedwithEpstein---Barrvirus infectionwitha reviewoftheliterature.Scand JInfect Dis. 2004;36:75---7.
30.CoddingtonCT, Isaacs JD, Siddiqui AQ, Andrews TC. Neuro-logical picture. Bilateral facial nerve palsy associated with Epstein---Barr virus infection. J Neurol Neurosurg Psychiatry. 2010;81:1155---6.
31.Yuki N. Infectious origins of, and molecular mimicry in, Guillain---Barré and Fisher syndromes. Lancet Infect Dis. 2001;1:29---37.
32.TamCC,O’BrienSJ,PetersenI,IslamA,HaywardA,Rodrigues LC. Guillain---Barré syndrome and preceding infection with campylobacter,influenzaandEpstein---Barrvirusinthegeneral practiceresearchdatabase.PLoSONE.2007;2:e344.
33.DojaA,BitnunA,FordJonesEL,RichardsonS,TellierR,Petric M,etal.PediatricEpstein---Barrvirus-associatedencephalitis: 10-yearreview.JChildNeurol.2006;21:384---91.
34.Abul-KasimK,PalmL,MalyP,SundgrenPC.Theneuroanatomic localizationofEpstein---Barrvirusencephalitismaybea predic-tivefactorforitsclinicaloutcome:acasereportandreviewof 100casesin28reports.JChildNeurol.2009;24:720---6.
35.Asensio-SánchezVM.AliceinWonderlandsyndrome.ArchSoc EspOftalmol.2014;89:77---8.
36.FineEJ. TheAlice in Wonderland syndrome.ProgBrain Res. 2013;206:143---56.
37.LahatE,EshelG,ArlazoroffA.‘‘AliceinWonderland’’syndrome andinfectiousmononucleosisinchildren.JNeurolNeurosurg Psychiatry.1990;53:1104.
38.CinbisM,AysunS.AliceinWonderlandsyndromeasaninitial manifestationofEpstein---Barrvirusinfection.BrJOphthalmol. 1992;76:316.
39.Khandaker GM, Stochl J, Zammit S, Lewis G, Jones PB. Childhood Epstein---Barr virus infection and subsequent risk of psychotic experiences in adolescence: a population-basedprospectiveserologicalstudy.SchizophrRes.2014;158: 19---24.
40.PetersenI,ThomasJM,HamiltonWT,WhitePD.Riskand pre-dictors of fatigue after infectious mononucleosis in a large primary-carecohort.QJM.2006;99:49---55.
41.WangX,ZhangL,LeiY,LiuX,ZhouX,LiuY,etal.Meta-analysis ofinfectiousagentsanddepression.SciRep.2014;4:4530.
42.Lossius A, Johansen JN, Torkildsen Ø, Vartdal F, Holmøy T. Epstein---Barrvirusinsystemic lupuserythematosus, rheuma-toidarthritisandmultiplesclerosis---associationandcausation. Viruses.2012;4:3701---30.
44.CohenJI,MocarskiES,Raab-TraubN,CoreyL,NabelGJ.The needandchallengesfordevelopmentofanEpstein---Barrvirus vaccine.Vaccine.2013;31:B194---6.
45.McLaughlin-DrubinME,MungerK.Virusesassociatedwithhuman cancer.BiochimBiophysActa.2008;1782:127---50.
46.BiegingKT, Swanson-Mungerson M,Amick AC,Longnecker R. Epstein---BarrvirusinBurkitt’slymphoma:aroleforlatent mem-braneprotein2A.CellCycle.2010;9:901---8.
47.Schmitz R, Ceribelli M, Pittaluga S, Wright G, Staudt LM. OncogenicmechanismsinBurkittlymphoma.ColdSpringHarb PerspectMed.2014;4:a014282.
