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Feverofunknownorigininchildren:Etiology
Author
DebraLPalazzi,MD,MEd

SectionEditors
MorvenSEdwards,MD
RobertSundel,MD
JanEDrutz,MD

Deputy
Editor
MaryM
Torchia,

MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Feb2016.|Thistopiclastupdated:Jan28,2016.
INTRODUCTIONFeverisacommonpresentingcomplaintinchildren,accountingfornearly
onethirdofpediatricoutpatientvisitsintheUnitedStates[1].Thespecificentityof"feverof
unknownorigin"(FUO),asopposedtoa"feverwithoutasource"(FWS),hasoccupiedaspecialplace
withininfectiousdiseasessincethefirstdefinitionofandseriesaboutFUObyPetersdorfandBeeson
in1961[2].Althoughtheoriginaldefinitionhasbeenmodified,theassessmentofbroadcategoriesof
illness(includinginfections,connectivetissuedisease,andmalignancy)asacauseofFUOremains
useful.
CommonetiologiesofFUOinchildrenwillbediscussedbelow.TheapproachtothechildwithFUO,
FWS,andfeverinuniquehostgroups(eg,newborns,neutropenicchildren,orthosewithhuman
immunodeficiencyvirus[HIV]infection)arediscussedseparately.(See"Feverofunknownoriginin
children:Evaluation"and"Feverwithoutasourceinchildren3to36monthsofage".)
DEFINITIONWeapplythetermfeverofunknownorigin(FUO)tochildrenwithfever>101F
(38.3C)ofatleasteightdays'duration,inwhomnodiagnosisisapparentafterinitialoutpatientor
hospitalevaluationthatincludesacarefulhistoryandphysicalexaminationandinitiallaboratory
assessment.(See"Feverofunknownorigininchildren:Evaluation",sectionon'Definitions'.)
OVERVIEWThenumberofinfectiousandnoninfectiousetiologiesoffeverofunknownorigin
(FUO)inchildrenisextensive(table1).FUOisusuallycausedbycommondisorders,oftenwithan
unusualpresentation[313].
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ThethreemostcommonetiologicalcategoriesofFUOinchildreninorderoffrequencyareinfectious
diseases,connectivetissuediseases,andneoplasms[314].Inaddition,therearecausesofFUO,such
asdrugfever,factitiousfever,centralnervoussystemdysfunction,andothers,thatdonotfitintothe
abovecategories.Inmanycases,adefinitivediagnosisisneverestablishedandfeverresolves.
Ineachcategorybelow,theconditionsarediscussedinalphabeticalorder,ratherthanbythe
frequencyofdiagnosis.
GENERALIZEDINFECTIONSGeneralizedinfectionsthatcausefeverofunknownorigin
(FUO)typicallyhavenonspecificpresentingfeatures.Obtainingadetailedhistoryofexposurescanbe
criticaltomakingthediagnosisoftheseinfections.(See"Feverofunknownorigininchildren:
Evaluation",sectionon'Exposures'.)
BrucellosisBrucellosisfrequentlyisconsideredinthedifferentialdiagnosisofFUObecausethe
infectionisindolent,causesnonspecificsymptomsandsigns,andpersistsifuntreated.Itisalsooften
excludedasadiagnosticpossibility,particularlyamongclinicianswhopracticeinurbanareasand
mayforgettoconsiderthedisease.Clinicalmanifestationsmayincludepersistentfeverandlethargy,
osteoarticularcomplaintsandepididymoorchitis,hepatosplenomegaly,andmildelevationofliver
enzymes.
Whenconsideringthepossibilityofbrucellosis,itisimportanttoaskaboutexposuretoanimalsor
animalproducts,especiallyconsumptionofunpasteurizedcheeseand/orimportedcheese
(pasteurizationisnotrequiredforcertificationofimportedcheeses).(See"Microbiology,
epidemiology,andpathogenesisofBrucella"and"Clinicalmanifestations,diagnosis,andtreatmentof
brucellosis".)
CatscratchdiseaseCatscratchdisease(CSD,Bartonellahenselaeinfection)isoneofthemost
commoncausesofFUOinchildren[10,15].WhileCSDfrequentlypresentswithisolatedlymphnode
involvement,hepatosplenicinvolvementisthehallmarkofCSDassociatedwithFUO.Inoneseries
fromasingleinstitution,B.henselaeinfectionaccountedfor5percentofallpediatriccasesofFUO
and11percentoftheFUOcasesultimatelydeterminedtobecausedbyinfection[10].High
resolutionabdominalultrasonographyrevealingthemultiplehepaticorsplenicfillingdefectsthatare
characteristicofgranulomatacanprovideaprovisionaldiagnosis.Serologyorbiopsyoflesionsin
lymphnodes,liver,orbonemarrowcanleadtoadefinitivediagnosisofB.henselaeinfection.(See
"Microbiology,epidemiology,clinicalmanifestations,anddiagnosisofcatscratchdisease".)
LeptospirosisLeptospirosisisacommonzoonoticinfectionwithworldwidedistributionhumans
areincidentalhosts,andmostinfectionoccursintropicalclimates[16,17].Theclinicalmanifestations
arenonspecificandmayincludefever,rigors,myalgias,headache,cough,andgastrointestinal
complaints.Leptospirosistypicallyoccursafterexposuretoenvironmentalsources,suchasanimal
urine,contaminatedsoilorwater(particularlyduringswimming),orinfectedanimaltissue.Portalsof
entryincludecutsorabradedskin,mucousmembranes,orconjunctiva.Theinfectionisrarely
acquiredbyingestionoffoodcontaminatedwithurineorviaaerosols.(See"Epidemiology,
microbiology,clinicalmanifestations,anddiagnosisofleptospirosis"and"Treatmentandprevention
ofleptospirosis".)
MalariaMalariaisanimportantconsiderationinachildwithFUO.Splenomegalyusually
accompaniesfever.Althoughthepatientfrequentlyhasahistoryoftraveltoareaswheremalariais
endemic,thisisnotuniversalrarecaseshavebeenreportedinindividualswhohavenottraveled
outsideoftheUnitedStates[18,19].Malariainfectioncanbedelayedformonthsaftertravelandcan
ariseinthosewhohavetakenmalariaprophylaxis.Thediagnosisismadebyexaminingappropriately
stainedthinorthicksmearsofblood.(See"Clinicalmanifestationsofmalaria"and"Diagnosisof
malaria".)
MycobacterialTuberculosis(TB)isanotherimportantcauseofFUOinchildren.Extrapulmonary
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TB(disseminatedTB,orTBoftheliver,peritoneum,pericardium,orgenitourinarytract),ismore
likelytocauseFUOthanpulmonaryTB,whichisusuallyevidentonchestradiography.Active
disseminatedTBcanoccurinchildrenwithnegativechestradiographyandtuberculinskintests
[20,21].Ahighindexofsuspicionforthediseasemustbemaintained,andacarefulhistoryof
possiblecontactsobtained.ThediagnosisofTBcanbemadebyculturingtheorganismfromsputum,
gastricaspirates,liver,orbonemarrow.Funduscopicexaminationoccasionallycanrevealchoroid
tubercles.(See"Latenttuberculosisinfectioninchildren"and"Tuberculosisdiseaseinchildren"and
"Clinicalmanifestations,diagnosis,andtreatmentofextrapulmonaryandmiliarytuberculosis".)
NontuberculousmycobacterialinfectionalsocancausedisseminatedinfectionandFUO,althoughthis
ismorecommoninchildreninfectedwiththehumanimmunodeficiencyvirus(HIV).(See"Overview
ofnontuberculousmycobacterialinfectionsinHIVnegativepatients"and"Mycobacteriumavium
complex(MAC)infectionsinHIVinfectedpatients"and"Overviewofnontuberculousmycobacteria
(excludingMAC)inHIVinfectedpatients".)
SalmonellosisSalmonellaspeciescontaminateanumberoffoodproducts,especiallypoultryand
eggs,andcanbetransmittedthroughcontactwithanimalfeces.Salmonellaspeciescancause
typhoidalaswellaslocalizedgastrointestinal(GI)illness.Patientswithtyphoidfrequentlyhave
normalpulsesorevenbradycardiainassociationwithhighfevers.Thediagnosiscanbemadewith
bloodandstoolcultures,whichshouldberepeatedifinitiallynegativeandfeverspersist.Serologic
testingisnotrecommended.(See"Epidemiology,microbiology,clinicalmanifestations,anddiagnosis
oftyphoidfever"and"NontyphoidalSalmonella:Microbiologyandepidemiology".)
ToxoplasmosisToxoplasmosisisanotherinfectionthatcancauseFUOinchildren.Itshouldbe
consideredinchildrenwithexposuretosoilcontaminatedwithfelinefeces,orconsumptionofgame
meat.Feversaremostoftenaccompaniedbycervicalorsupraclavicularlymphadenopathy,butfever
mayoccasionallybethesolemanifestation.Ariseinantibodytitercanestablishthediagnosis
however,asinglehighantibodytiterisnotsufficienttomakeadiagnosisofacuteinfectionsinceIgG
antibodiestoToxoplasmagondiiareprevalent,andIgMantibodiescanpersistformonths.(See
"Toxoplasmosisinimmunocompetenthosts".)
TularemiaFUOresultingfromtularemiaismorecommonwiththepneumonicortyphoidalforms
oftheinfectionthanwiththeglandularforms.Theorganismcanbecarriedbyavarietyofanimals
andinsects(ticks,mosquitoes,lice,fleas,flies),andcanbeacquiredbyabite,ingestion,orinhalation
(table2).Tularemiashouldbeconsideredinchildrenwithahistoryofcontactwithanimals,exposure
todeadwildcarcasses(eg,rabbits)oringestionofrabbitorsquirrelmeat.(See"Clinical
manifestations,diagnosis,andtreatmentoftularemia".)
ViralinfectionsMostvirusescauseselflimitedinfectionsofbriefduration.However,
cytomegalovirus(CMV),EpsteinBarrvirus(EBV),adenovirus,hepatitisviruses,enteroviruses,and
certainarbovirusescancauseFUO.Symptomsandsignsoftheseinfectionscanbenonspecificand
variable.Liverenzymesmaybeelevated.Viralcultures,serologicstudies,andmoleculartechniques
suchaspolymerasechainreaction(PCR)canbeusedtofacilitatethediagnosis.(Seeappropriatetopic
reviews).
LOCALIZEDINFECTIONSWhencommonlocalizedinfectionscausefeverofunknownorigin
(FUO),theymayhaveanunusualpresentation.Carefulandrepeatedhistoryandphysical
examination,andcarefulreviewandinterpretationoflaboratorytests,canhelptodiagnosethese
infections.Allfindings,eventhosethatmayseemtrivial,mustbetakenseriously.(See"Feverof
unknownorigininchildren:Evaluation",sectionon'Diagnosticapproach'.)
BoneandjointInfectionsinvolvingthebonesandjointsusuallypresentwithrecognizable
symptoms.However,occasionallyFUOcanbetheonlymanifestation,especiallyinyoungchildren
whocannotvocalizetheirsymptoms.Thisoccursmorecommonlywithosteomyelitisthanwithseptic
arthritis.WhenFUOisthepresentingcomplaint,thepelvicbones,smallbones,andflatbonesare
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morefrequentlyinvolvedthanlongbones.
Thediagnosisofosteomyelitisorsepticarthritiscanbesuggestedbyimagingstudies,including
computedtomography(CT),magneticresonance(MR)imaging,andradioisotopicbonescanning.All
ofthesemodalitiesaremoresensitivethanplainboneradiography.(See"Bacterialarthritis:Clinical
featuresanddiagnosisininfantsandchildren",sectionon'Imaging'and"Hematogenousosteomyelitis
inchildren:Evaluationanddiagnosis",sectionon'Advancedimaging'.)
InfectiveendocarditisInfectiveendocarditis(IE)isaninfrequentbutimportantcauseofFUOin
children.IEisrareinnormal,terminfantsbutincreasesinfrequencyaschildrenageandusually
occursinthesettingofapreexistingcardiaclesion.Acutebacterialendocarditisgenerallyisfulminant
inonset,whereassubacuteinfectionismoreindolent.(See"Infectiveendocarditisinchildren".)
ThediagnosisofIEcanbedifficulttoestablishsincepatientsdonotalwayshavepositiveblood
culturesoracardiacmurmur,especiallyiftheinfectionisconfinedtotherightsideoftheheart.
Associatednonspecificlaboratoryfindingscanincludeanemia,leukocytosis,andanelevated
erythrocytesedimentationrate(ESR).
Viridansstreptococci,enterococci,andstaphylococci(includingS.aureusandcoagulasenegative
staphylococci)aretheorganismsmostcommonlyisolated.Bloodculturesmaybenegativeifpatients
havereceivedatrialofempiricalantibiotics,haverightsidedcardiacinvolvement,orhaveinfection
causedbyunusualorfastidiousorganisms(eg,Brucella,Coxiellaburnetii,Bartonellaspp.,
anaerobes,fungi).
ChildrenwithsuspectedIEasthecauseofFUOshouldhaveseveralbloodcultures(aerobicand
anaerobic)drawnovera24hourperiodbeforeinitiationofantimicrobialtherapy.Echocardiography
isfrequentlyperformedtoassessdamagetotheheartvalvesandlookforvalvularvegetations.
However,theabsenceofthesefindingsdoesnotexcludethediagnosisofIE.
IntraabdominalabscessIntraabdominalabscesses,includingliver,subphrenic,perinephric,and
pelvicabscesses,cancauseFUO.Patientsmaynothaveabdominalcomplaintsatpresentation.
However,theindexofsuspicionforanabscessshouldincreaseifthepatienthasahistoryofprior
intraabdominaldisease,abdominalsurgery,orvagueabdominalpain.
Pyogenicliverabscessestypicallyoccurinimmunocompromisedchildren,butcanariseinan
immunocompetentchild[22].Manychildrenwithliverabscesshavehepatomegalyandrightupper
quadranttenderness,butsomeonlyhavefever.Liverenzymesareusuallynormalinthesepatients,
anddetectablebacteremiaisuncommon.
Dependinguponthesourceoftheabscess,commonpathogensincludeS.aureus,streptococci,
Escherichiacoli,andanaerobes.Imagingoftheabdomen,typicallywithultrasonographyorCT,
generallydemonstratesthecollection.Ifimagingisnegative,butclinicalsuspicionofintraabdominal
abscessinhigh,radioisotopeorgalliumscanningmaybewarranted.
HepaticinfectionGranulomatoushepatitis,whichcanbecausedbyanumberoforganisms,is
anothercauseofFUOinchildren.Itoccursmorecommonlyinadults,butcaseshavebeenreportedin
children[23],especiallyinassociationwithBartonella.Thediagnosisofgranulomatoushepatitiscan
besuggestedbyultrasonographyorotherdiagnosticimaging.However,confirmationrequiresa
biopsy.(See"Hepaticgranulomas".)
BacterialcholangitiscanoccasionallycauseFUOintheabsenceofjaundiceandotherliverfunction
abnormalities[24,25].(See"Acutecholangitis".)
UpperrespiratorytractinfectionItissurprisinghowfrequentlyupperrespiratorytractinfections
(URI)andinfectionsofrelatedorgans,suchasmastoidsorsinuses,presentasFUOinchildren[35].
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Mastoiditis,sinusitis,chronicorrecurrentotitismedia,chronicorrecurrentpharyngitis,tonsillitis,
peritonsillarabscess,andnonspecificURIhavebeenreportedascausesofFUOinchildren.One
wouldexpecttheseinfectionstobeassociatedwithlocalizedsymptoms,butitappearsthatcomplaints
maybeignoredastrivial.
UrinarytractinfectionUrinarytractinfectionisamongthemostcommoncausesofFUOin
children[810].Inoneseries,thetwomostfrequentlaboratoryerrorswerefailuretoperforma
urinalysisandfailuretoadequatelypursuethefindingofpyuria[4].(See"Urinarytractinfectionsin
infantsandchildrenolderthanonemonth:Clinicalfeaturesanddiagnosis",sectionon'Clinical
presentation'.)
CONNECTIVETISSUEDISEASESConnectivetissuediseaseisthesecondmostcommon
etiologiccategoryoffeverofunknownorigin(FUO)inchildren.Apositiveantinuclearantibodytest
cansuggestthepresenceofanunderlyingconnectivetissuedisorder,particularlysystemiclupus
erythematosus[26].(See"Measurementandclinicalsignificanceofantinuclearantibodies",section
on'ThesignificanceofapositivetestforANAintheasyetundiagnosedpatientwithmusculoskeletal
symptoms'.)
JuvenileidiopathicarthritisJuvenileidiopathicarthritis(JIA,formerlyjuvenilerheumatoid
arthritis,JRA)isachronicinflammatorydisorderwiththreedistinctforms:
Asystemicpresentationwithhigh,spikingfevers,evanescentrash,andlymphadenopathy

Polyarticularinvolvement

Monoarticularinvolvement,thesocalledoligoarticularform
Fevercanbeobservedwithallofthethreepresentationsbutisnearlyuniversalinthesystemicform,
whichisthetypeofJIAmostlikelytopresentasFUO[27].Arthritismayfollowthedevelopmentof
feversbymonthstoyears.Serologictestsareusuallynegative,andthus,JIAinitiallymaybea
diagnosisofexclusion.(See"Systemicjuvenileidiopathicarthritis:Clinicalmanifestationsand
diagnosis"and"Polyarticularjuvenileidiopathicarthritis:Clinicalmanifestations,diagnosis,and
complications"and"Oligoarticularjuvenileidiopathicarthritis".)
OthersOthercollagenconnectivetissuediseasestoconsiderintheevaluationofFUOinclude
polyarteritisnodosaandsystemiclupuserythematosus.(See"Systemiclupuserythematosus(SLE)in
children:Clinicalmanifestationsanddiagnosis"and"Clinicalmanifestationsanddiagnosisof
polyarteritisnodosainadults".)
NEOPLASMSLeukemiaandlymphomaarethemostcommonmalignanciesthatcausefeverof
unknownorigin(FUO)inchildren.Other,lesscommontumorsincludeneuroblastoma,hepatoma,
sarcoma,andatrialmyxoma.(See"Overviewofthepresentationanddiagnosisofacutelymphoblastic
leukemiainchildrenandadolescents"and"OverviewofHodgkinlymphomainchildrenand
adolescents"and"Clinicalpresentation,diagnosis,andstagingevaluationofneuroblastoma"and
"Clinicalassessmentofthechildwithsuspectedcancer".)
OTHERCAUSESTheothernoninfectiouscausesoffeverofunknownorigin(FUO)arevaried,
butcanbesummarizedbythecategoriesandexamplesbelow.
CNSdysfunctionChildrenwithseverebraindamageorothercentralnervoussystem(CNS)
dysfunctioncanhavealteredthermoregulationandpresentwithintermittentorrecurrentelevated
bodytemperatures[28,29].Onecasewasreportedofanadolescentwithepisodesoffeverwho
respondedtophenytointherapy,suggestingthataformofepilepsywasresponsibleforthefevers
[30].Epilepsyinducedfeveralsohasbeendescribedinadults[3134].Inanotherreport,an
adolescenthadcyclicepisodesoffeveraccompaniedbynausea,vomiting,andemotionaldisturbance,
resultingfromaCNSlesion[35].
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DiabetesinsipidusFUOininfantsandyoungchildrencanbeduetoeithercentralornephrogenic
diabetesinsipidus(DI).Sincepolyuriaandpolydipsiacanbedifficulttoappreciateduringinfancy,
dehydrationorhypernatremiamaybeunrecognizeduntilhyperthermia,weightloss,anddecreased
peripheralperfusionensue.ThediagnosisofDIcanbeestablishedbyevaluatingelectrolytesand
osmolalitysimultaneouslyinserumandurineforperiodsofnormalhydrationandcarefulwater
restriction.Serumlevelsofantidiuretichormone(ADH)canalsobedeterminedby
radioimmunoassay.(See"Diagnosisofpolyuriaanddiabetesinsipidus",sectionon'Infantsand
children'.)
DrugfeverFeverisacommonallergicreactiontodrugs,andvirtuallyanydrugcancauseadrug
fever.Whentakingamedicationhistory,itisimportanttoincludeprescription,overthecounter,and
illicitdrugs,aswellascomplementaryandalternativetherapies.Topicalpreparations,suchas
atropine,canalsocausefever.Thedurationofusedoesnothelpindeterminingwhethertheagentis
responsiblefortheFUO.
Inaddition,somedrugsimpairthermoregulationorthermoregulatorycontrolmechanismsandcause
feveronthisbasisratherthanasanallergicphenomenon.Examplesinclude:phenothiazines,
anticholinergicdrugs,andepinephrineandrelatedcompounds.
Neithertheheightofthefeversnortheirpatternishelpfulinjudgingwhetherdrugsarethecause.
Drugscancauselowgradeorhighandspikingfeversthepatterncanbecontinuousorintermittent.
Feversresultingfrommedicationstypicallydisappearwithin48to72hoursofdiscontinuationofthe
drug,butcantakeaslongasfivetosevendaystoresolveand,occasionally,fevercanpersistfor
weeks.
FactitiousfeverFactitiousfever,whetherafalsereportbyaparentorpatientorrelatedto
manipulationofbodytemperaturebyrinsingthemouthwithordippingthethermometerbulbintohot
liquid,canbedifficulttoestablishastheetiologyofFUO.However,anumberofcluesshouldraise
thepossibilityoffactitiousfever.Theseinclude:

Absenceoftachycardiaandnonspecificsymptoms,suchasmalaiseordiscomfort,inapatientwith
ahighfever

Rapiddefervescencewithoutdiaphoresis

Failureofthetemperaturecurvetoshownormaldiurnalvariation(see"Feverininfantsand
children:Pathophysiologyandmanagement",sectionon'Normalbodytemperature')

Extremehyperpyrexia

Discrepanciesbetweentemperaturesrecordedbythepatientorbyprovidersnotinattendanceand
thoseobtainedrectallyorwhensomeoneisobservingintheroom
Measuringthetemperatureofafreshlyvoidedurinespecimen,whichreflectscorebodytemperature,
isonewaytoverifyorexcludethepresenceoffever.Thetemperatureoffreshlyvoidedurineclosely
parallelsthetemperatureobtainedorally.Electronicoronetimeusethermometersthatmeasure
temperaturerapidlyreducethelikelihoodthatarecordedfeverisfactitioussinceaproviderisusually
inattendancetomakethesemeasurements.
AmoreunusualcauseoffactitiousfeverisMunchausensyndromeorMunchausensyndromeby
proxy(caregiverfabricatedillness)inwhichoneperson,usuallyaparent,fabricatessymptomsand
signsofillnessonbehalfofthechild.Insomeofthesecases,feversareactuallyinducedbythe
injectionofinfectiveorforeignmaterials,eitherbytheusuallyolderpatientorbyaparent.(See
"Medicalchildabuse(Munchausensyndromebyproxy)"and"Factitiousdisorderimposedonself
(Munchausensyndrome)".)
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FamilialdysautonomiaFamilialdysautonomia(alsocalledtheRileyDaysyndromeand
hereditarysensoryautonomicneuropathytype3(HSAN3)),isanautosomalrecessivedisorderin
whichautonomicandperipheralsensorynervedysfunctionresultsindefectivetemperatureregulation.
Hyperthermiaorhypothermiamaybeobserved[36].Themajorityofaffectedchildrenareof
AshkenaziJewishparentage.
Anumberoffeaturesinthehistoryandphysicalexaminationcansuggestfamilialdysautonomia,
includingahistoryofrecurrentaspirationorvomitingbecauseofpoorcoordinationofswallowing,
excessivesalivation,diminishedtearing,excessiveordiminishedsweating,labilebloodpressure,and
erythemaorblotchinessoftheskin.Fungiformpapillaeofthetonguemaybesparseorabsent,andthe
senseoftasteisdiminished[37].Absenceofperipheralpainsensationcanleadtomultiplesitesof
skintrauma.Deeptendonreflexesandcornealreflexesusuallyareimpaired,anddysarthriais
common.Patientswiththissyndromealsodemonstratementaldeficienciesandemotionallability.
(See"Hereditarysensoryandautonomicneuropathies",sectionon'HSAN3(Familialdysautonomia)'.)
HemophagocyticlymphohistiocytosisHemophagocyticlymphohistiocytosis(HLH)isanon
malignantbutlifethreateningdisorderinwhichuncontrolledproliferationofactivatedlymphocytes
andhistiocytesleadstohemophagocytosisanddysregulationandhypersecretionofinflammatory
cytokines.HLHencompassesbothfamilialandreactivediseasetriggeredbyinfection,immunologic
disorder,malignancy,ordrugs.TypicalmanifestationsofHLHareprolongedfever,
hepatosplenomegaly,hyperferritinemia,andcytopenias[38,39].Othercommonfindingsincludeliver
dysfunction,coagulopathy,hypertriglyceridemiaorhypofibrinogenemia.Clinicalpresentationsof
patientswithprimary(familial)andsecondary(reactive)HLHareindistinguishable[40,41].
ThediagnosisofHLHisbasedonapatientfulfillingatleastfiveofeightcriteria(fever,
splenomegaly,bicytopenia,hypertriglyceridemiaand/orhypofibrinogenemia,hemophagocytosis,
low/absentNKcellactivity,hyperferritinemia,andhighsolubleinterleukin2receptorlevels)[42].
HLHcanmanifestinitiallyasFUObutcanrapidlyprogresstoresembleoverwhelmingsepsisand
resultindeaththerefore,ahighindexofsuspicionisrequiredtoestablishthediagnosis.Therapy
includestreatingtheunderlyinginfectionortrigger,ifpossible,andaggressiveimmunemodulation
therapies.Evenwithpromptandappropriatechemotherapy,mortalityduetoHLHishigh[39,42,43].
(See"Treatmentandprognosisofhemophagocyticlymphohistiocytosis".)
ImmunodeficiencyFUOalsocanbecausedbyanumberofcongenitalandacquired
immunodeficiencystates(eg,HIV).Somechildrenwithimmunoglobulindeficiencies(eg,Bruton
agammaglobulinemia)haveahistoryofrecurrentfeverswithorwithoutfocalinfections.Otherswith
lymphocytefunctionabnormalitiesaremorelikelytohavepersistentviralorparasiticinfectionsin
associationwithprolongedfevers.(See"Primaryhumoralimmunodeficiencies:Anoverview".)(See
appropriatetopicreviews.)
InfantilecorticalhyperostosisInfantilecorticalhyperostosis(Caffeydisease)isaninherited
diseasecharacterizedbypersistentfevers,sometimesashighas40C(104F),subperiostealbone
hyperplasia,andswellingofoverlyingtissues.Patientswiththisdiseasecanexhibitirritabilityand
tendernessovertheaffectedregionsinadditiontofever.LeukocytosisandanelevatedESRare
commonlaboratoryfindings.Theseclinicalfeatures,inconjunctionwithradiologicdemonstrationof
periostealinvolvement,establishthediagnosis.(See"Differentialdiagnosisoftheorthopedic
manifestationsofchildabuse",sectionon'Infantilecorticalhyperostosis(Caffeydisease)'.)
InflammatoryboweldiseaseFeverisaprominentcomponentofinflammatoryboweldisease
(IBD)inmanychildren[4446]andmaybemorecommonthanabdominalsymptoms,especiallyin
childrenwithCrohn'sdisease.UlcerativecolitisisalesscommoncauseofFUOinchildrenthan
Crohn'sdiseasepatientswithulcerativecolitistypicallyhaveaccompanyingGIsymptoms.(See
"ClinicalmanifestationsofCrohndiseaseinchildrenandadolescents"and"Managementofmildto
moderateulcerativecolitisinchildrenandadolescents".)
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AbdominalCTcanbesuggestiveofIBDinchildrenwithprolongedFUO,evenintheabsenceofGI
symptoms,butcontraststudiesofthebowelwithspecialattentiontotheterminalileumshouldbe
performed,especiallyinpatientswithanelevatedESRaccompaniedbyanemia,weightloss,failure
oflineargrowth,oroccultbloodinthestool.(See"Clinicalpresentationanddiagnosisof
inflammatoryboweldiseaseininfants,children,andadolescents".)
KawasakidiseaseKawasakidiseaseisamultisystemvasculitisofunknown,butpossible
infectious,etiology.Itisanimportantcauseofprolongedfeverinchildhood.Thediagnosisis
establishedprimarilyonthebasisoftheclinicalfindings(table3):bulbarconjunctivitis(picture1),
oralchanges(picture2andpicture3),rash,changesinthehandsandfeet(picture4andpicture5),
andcervicaladenopathy.Thesemanifestationsmaynotappearuntilthesecondweekoffeverormay
haveoccurredandresolvedbythetimethepatientisexamined.(See"Kawasakidisease:Clinical
featuresanddiagnosis".)
KikuchisdiseaseKikuchisdisease(alsoknownasKikuchiFujimotodisease,Kikuchis
histiocyticnecrotizinglymphadenitis)isabenign,unusualdisordercharacterizedbyfeverand
cervicallymphadenopathythatmaylastforonetofourmonths[47,48].Fatigue,hepatosplenomegaly,
nausea,vomiting,diarrhea,jointpain,arthritis,andrashalsomayoccur.Kikuchisdiseaseismore
commoninfemalesandpatientsyoungerthan40yearsofage.Thepathogenesisisunknownbut
thoughttoberelatedtoaTcellandhistiocyticresponsetoaninfectiousagent.Lymphnodebiopsy
demonstratingparacorticalfociwithnecrosisandhistiocyticcellularinfiltrateconfirmsthediagnosis.
Treatmentissupportive.Kikuchisdiseasemayprecedeoroccurinassociationwithanautoimmune
condition.(See"Kikuchidisease".)
PeriodicfeversSeveraldifferentperiodicfeverdisordershavebeendescribed.Somehavebeen
classifiedasautoinflammatory,referringtoepisodesof"unprovoked"inflammatoryevents,andare
often,butnotalways,accompaniedbyfever.Atleasteightsuchhereditarydisordershavebeen
reported[49,50].(See"Periodicfeversyndromesandotherautoinflammatorydiseases:An
overview".)
ThetwomostcommonheritableperiodicfeverdisordersinchildrenarefamilialMediterraneanfever
(FMF)andhyperimmunoglobulinDsyndrome(hyperIgDsyndromeorHIDS).Thefebrileepisodes
inthesedisordersusuallyrecuratirregularintervals.Specificdefectivegeneshavebeenidentifiedfor
bothFMFandHIDS.

FMFisanautosomalrecessivediseasefoundinindividualsofMediterraneandescent.Itis
characterizedbyepisodicfeverandserosalinflammation[51].(See"Clinicalmanifestationsand
diagnosisoffamilialMediterraneanfever"and"FamilialMediterraneanfever:Epidemiologyand
pathogenesis".)

HIDSisalsoanautosomalrecessivedisease.Clinicalmanifestationsincludeepisodesoffever,skin
eruptions,abdominalcomplaints,andjointinvolvement[5254].TheelevatedserumIgDis
probablyasecondaryeffect,andsomepatientsalsohavehadelevatedserumlevelsofIgA[55].
(See"HyperimmunoglobulinDsyndrome:Clinicalmanifestationsanddiagnosis".)
Cyclicneutropenia,alsoknownascyclichematopoiesis,isanotherheritablecauseofrecurrentfevers.
Childrenwiththisdisorderarepronetofeverduringperiodsofsevereneutropenia.Neutropenic
cyclesusuallyoccuratregularintervalsof15to35days,with21daysbeingthemostfrequentpattern
[56].(See"Cyclicneutropenia".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,
TheBasicsandBeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplain
language,atthe5thto6thgradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatient
mighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverview
andwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesarelonger,
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moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevel
andarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedical
jargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintore
mailthesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyof
subjectsbysearchingonpatientinfoandthekeyword(s)ofinterest.)

Basicstopic(see"Patientinformation:Feverinchildren(TheBasics)")

BeyondtheBasicstopic(see"Patientinformation:Feverinchildren(BeyondtheBasics)")
SUMMARY

Feverofunknownorigin(FUO)hasanumberofinfectiousandnoninfectiouscauses(table1).
FUOisusuallycausedbycommondisorders,oftenwithanunusualpresentation.(See'Overview'
above.)

ThethreemostcommonetiologicalcategoriesofFUOinchildreninorderoffrequencyare
infectiousdiseases,connectivetissuediseases,andneoplasms.Inmanycases,adefinitivediagnosis
isneverestablishedandfeverresolves.(See'Overview'above.)

GeneralizedinfectionsthatcauseFUOtypicallyhavenonspecificpresentingfeatures.Obtaininga
detailedhistoryofexposurescanbecriticaltomakingthediagnosisofthesedisorders.(See"Fever
ofunknownorigininchildren:Evaluation",sectionon'Exposures'and'Generalizedinfections'
above.)

WhencommonlocalizedinfectionscauseFUO,theymayhaveanunusualpresentation.Careful
andrepeatedhistoryandphysicalexamination,andcarefulreviewandinterpretationoflaboratory
tests,canhelptodiagnosetheseinfections.Allfindings,eventhosethatmayseemtrivial,mustbe
takenseriously.(See'Localizedinfections'aboveand"Feverofunknownorigininchildren:
Evaluation",sectionon'Diagnosticapproach'.)

NoninfectiouscausesofFUOincludecollagenvasculardiseases(eg,juvenileidiopathicarthritis),
neoplasms,centralnervoussystemdysfunction,diabetesinsipidus,Kawasakidisease,drugfever,
factitiousfever,inflammatoryboweldisease,infantilecorticalhyperostosis,andperiodicfevers.
(See'Othercauses'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic5996Version15.0Allrights
reserved.2016UpToDate,Inc.

Disclosures
Disclosures:DebraLPalazzi,MD,MEdGrant/Research/ClinicalTrialSupport:Astellas
[AntifungalsafetyandPK(Micafungin)]Merck[Invasivefungalinfections(Caspofungin,
posaconazole)]Durata[AntibioticsafetyandPK(Dalbavancin)]Cempra[Antibioticsaftey
andPK(Solithromycin)].Consultant/Advisoryboards:Pfizer[Antifungaltrialdatasafety
monitoringboard(Voriconazole,Anidulafungin)].OtherFinancialInterest:JAMAPeds
AssociateEditor[pediatrics(journalarticles)].MorvenSEdwards,MD
Grant/Research/ClinicalTrialSupport:PfizerInc.[GroupBStreptococcus].
Consultant/AdvisoryBoards:NovartisVaccines[GroupBStreptococcus].RobertSundel,
MDNothingtodisclose.JanEDrutz,MDNothingtodisclose.MaryMTorchia,MDNothing
todisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.When
found,theseareaddressedbyvettingthroughamultilevelreviewprocess,andthrough
requirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
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