4/9/2016 Feverofunknownorigininchildren:Evaluation

OfficialreprintfromUpToDate
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Feverofunknownorigininchildren:Evaluation

Author SectionEditors DeputyEditor

DebraLPalazzi,MD,MEd SheldonLKaplan,MD MaryMTorchia,MD
RobertSundel,MD
JanEDrutz,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2016.|Thistopiclastupdated:Apr29,2015.
INTRODUCTIONFeverisacommonpresentingcomplaintinchildren,accountingfornearlyonethirdofpediatric
outpatientvisitsintheUnitedStates[1].Thespecificentityof"feverofunknownorigin"(FUO),asopposedto"fever
withoutasource"(FWS),hasoccupiedaspecialplacewithininfectiousdiseasessincethefirstdefinitionofandseries
aboutFUObyPetersdorfandBeesonin1961[2].Althoughtheoriginaldefinitionhasbeenmodified,theassessmentof
broadcategoriesofillness(includinginfections,connectivetissuedisease,andmalignancy)asacauseofFUOremains
useful.

AnapproachtoFUOinchildrenwillbereviewedhere.EtiologiesofpediatricFUO,FWS,andfeverinuniquehostgroups
(eg,newborns,neutropenicchildren,orthosewithhumanimmunodeficiencyvirus[HIV]infection)arediscussed
separately.(See"Feverofunknownorigininchildren:Etiology"and"Feverwithoutasourceinchildren3to36monthsof
age".)

DEFINITIONSThetermfeverofunknownorigin(FUO)initiallywasreservedforadultswithfever>38.4C(101.2F)on
atleastseveralmeasurementsoverthreeormoreweekswithoutanestablishedcauseafteratleastoneweekof
investigationinthehospital.Thisexactingdefinitionprobablywasneverrigorouslyappliedinpediatrics.

WeapplythefollowingdefinitionsforFUOandfeverwithoutasource(FWS):

FUOChildrenwithfever>38.3C(101F)ofatleasteightdays'duration,inwhomnodiagnosisisapparentafter
initialoutpatientorhospitalevaluationthatincludesacarefulhistoryandphysicalexaminationandinitiallaboratory
assessment.

FWSChildrenwithfeverlastingforoneweekorlesswithoutadequateexplanationafteracarefulhistoryand
thoroughphysicalexamination.(See"Febrileinfants(youngerthan90daysofage):Outpatientevaluation"and
"Feverwithoutasourceinchildren3to36monthsofage".)

TheabovedefinitionofFUOisareasonableworkingdefinitionforclinicalpurposes.However,anagreedupondefinition
hasnotbeenusedinpublishedstudiesofFUOinchildren[311].Therequireddurationoffeverforinclusioninvarious
caseserieshasrangedfromfivetosevendaystothreeweeks[311].Someseriesuseddifferentdurationsdepending
uponthesetting(inpatientversusoutpatient)[4,5].SeveralmadeadistinctionbetweenFUOand"prolongedfever"[10,11].

FUOshouldbedistinguishedfromFWSforthreeimportantreasons:

Thedifferentialdiagnosesandmostfrequentcausesofeachentityaredistinct
ChildrenwithFWSusuallyrequireimmediatetestingandevaluation,whereasthosewithFUOgenerallydonotneed
anemergencyassessment
ExpectantantibiotictherapyisnottypicallyindicatedinchildrenwithFUO,whereastreatmentgenerallyis
recommendedinaselectgroupofinfantswithFWS

(See"Febrileinfants(youngerthan90daysofage):Outpatientevaluation"and"Feverwithoutasourceinchildren3to36
monthsofage".)

ETIOLOGYThenumberofinfectiousandnoninfectiousetiologiesoffeverofunknownorigin(FUO)inchildrenis
extensive(table1).FUOisusuallycausedbycommondisorders,oftenwithanunusualpresentation.Thishasbeen
illustratedinseveralseriesofFUOinchildren,inwhichraredisorders(eg,Behetsyndrome,ichthyosis)areexceedingly
uncommon[414].(See"Feverofunknownorigininchildren:Etiology".)

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InfectiousdiseasesandconnectivetissuediseasesarethemostcommonetiologiccategoriesofFUOinchildren
neoplasticdisordersarelesscommonandusuallyhavemanifestationsotherthanfever[414].

Inmanycases,adefinitivediagnosisisneverestablishedandfeverresolves.Inmorerecentseries,therehasbeena
trendtowardanincreasingproportionofundiagnosedcases[10,13,14].ManyoftheclassicFUOcaseseriesinchildren
werepublishedbeforetheroutineavailabilityofsophisticateddiagnostictestingmethodsthatarecurrentlyavailable[3
6,12].Withadvancesindiagnostictesting,childrenwithdiseasespreviouslycommoninFUOseriesarenowdiagnosed
earlierintheircourseofillness,leavingincreasingnumbersofchildrenwithdifficulttodiagnoseconditionsinFUOseries
[1315].

DIAGNOSTICAPPROACHUnlessthechildappearsacutelyill,theevaluationoffeverofunknownorigin(FUO)
usuallybeginsasanoutpatient.Ifoutpatientinvestigationfailstodiscloseacauseforthefever,admissiontothehospital
providesanopportunitytoreviewthedetailedhistory,physicalexamination,andavailablelaboratorydata,andtoobserve
thechildinacontrolledsetting.

Performingadetailedandthoroughhistoryandphysicalexaminationisthefirstandmostimportantcomponentofthe
diagnosticevaluationofthechildwithFUO.Incompletehistories,ignoredphysicalfindings,andfailuretocorrectly
interpretexistinglaboratorydatadelayedaccuratediagnosesinanumberofseriesofpediatricFUOcases[46].

Theclinicianmustbepreparedtorepeattheclinicalassessmentonmultipleoccasionstoreassesshistoricalfeaturesor
clinicalfindingsthatmighthavebeenmissedpreviously.Apatientorparenteventuallymayrecallinformationthatwas
omitted,forgotten,ordeemedunimportantwhentheinitialhistorywasobtained.Newphysicalfindingscanappear,and
subtleabnormalitiesnotoriginallyappreciatedcanbecomeapparent.InoneofthepediatricFUOseries,significant
physicalfindingsthatwerenotpresentatthetimeofadmissiondevelopedinmorethan25percentofchildrenduring
hospitalization[4].

WesuggestthatsomebasictestsbeperformedintheinitialevaluationofallchildrenwithFUO.Subsequentdiagnostic
testingisguidedby"potentialdiagnosticclues"fromtheserialclinicalassessmentsandinitiallaboratoryandradiographic
evaluation[16,17].(See'Diagnostictesting'below.)

HISTORYFeverofunknownorigin(FUO)isusuallycausedbycommondisorders,oftenwithanunusualpresentation.
Althoughitisimportanttoaskquestionsrelatedtouncommondiseases,anuncommonpresentationofacommonentity
alwaysshouldbeentertained.

FeverItisessentialtoobtainasmuchdetailaboutthefeveraspossible.Importantaspectsinclude:

Theduration,height,andpatternparentscanmistakenormalvariationsinbodytemperature(eg,temperature
elevationsafterexerciseorlateintheafternoon)forfebrileepisodes.

Howwasthefeverassessed(eg,bytouch,foreheadstrip,ormeasuredwithathermometerifmeasuredwitha
thermometer,whichtypewasused)?Rectaltemperatureismostaccuratehowever,inanolderchild,temperature
recordedwithanoralthermometerisusuallyadequate.

Wasthefeverconfirmedbysomeoneotherthanthecaregiver?

Aretherespecificcircumstancesthatprecedethetemperatureelevation?

Doesthechildappearillordevelopanysignsorsymptomsduringthefebrileepisode?Absenceofmalaiseorother
generalizedsignsinachildwithahistoryofhighfeverscansignalfactitiousfever.

Whetherandhowquicklythefeverrespondstoantipyreticdrugsandwhetherotherconstitutionalsymptoms(eg,
myalgias,headache,malaise,etc.)persistwhenthefeverabatesthepersistenceofconstitutionalsymptomsis
moreworrisome.Lackofresponsetononsteroidalantiinflammatoryantipyreticsmayindicateanoninflammatory
conditionasthecauseofFUO(eg,dysautonomia,ectodermaldysplasia,thalamicdysfunction,diabetesinsipidus)
[18].

Isthereassociatedsweating?Patientswithfever,sweating,andheatintolerancemayhavehyperthyroidism,
whereasthosewithfever,heatintolerance,andabsenceofsweatingmayhaveectodermaldysplasia.(See"Clinical
manifestationsanddiagnosisofhyperthyroidisminchildrenandadolescents"and"Thegenodermatoses",sectionon
'Ectodermaldysplasias'.)

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FeverpatternThepatternanddurationoffevergenerallyarenotusefulinmakingaspecificdiagnosisinchildren
withFUO[4,6].However,thefeverpattern,suchasthatobservedincasesofmalaria,occasionallycanbeilluminating.It
isbestdocumentedbyaskingthefamilytokeepafeverdiary.

IntermittentIntermittentfeverswithahighspikeandrapiddefervescence(oftentermedahecticorspikingfever)
suggestpyogenicinfectionbutalsocanoccurinpatientswithtuberculosis,lymphoma,andjuvenileidiopathic
arthritis(JIA,formerlyjuvenilerheumatoidarthritis,orJRA).(See"Tuberculosisdiseaseinchildren"and"Overview
ofHodgkinlymphomainchildrenandadolescents"and"Systemicjuvenileidiopathicarthritis:Clinicalmanifestations
anddiagnosis".)

RemittentRemittentfeversarecharacterizedbyfluctuatingpeaksandabaselinethatdoesnotreturntonormal
theycanappeartobeintermittentifantipyreticagentsareadministered.Remittentfeversareseenmostcommonly
withviralinfectionsbutalsomayoccurwithbacterialinfections(especiallyendocarditis),sarcoid,lymphoma,and
atrialmyxoma.

SustainedSustainedfeverspersistwithlittleornofluctuationbutcanappeartobeintermittentifantipyreticagents
areadministered.Typhoidfever,typhus,brucellosis,andmanyotherinfectionscharacteristicallyfollowthispattern.
(See"Epidemiology,microbiology,clinicalmanifestations,anddiagnosisoftyphoidfever"and"Clinical
manifestations,diagnosis,andtreatmentofbrucellosis".)

RelapsingRelapsingfeverswithperiodsduringwhichpatientsareafebrileforoneormoredaysbetweenfebrile
episodesmaybeseenwithmalaria,ratbitefever,Borreliainfection,andlymphoma.(See"Clinicalmanifestationsof
malariainnonpregnantadultsandchildren"and"Ratbitefever"and"Clinicalfeatures,diagnosis,andmanagement
ofrelapsingfever"and"OverviewofHodgkinlymphomainchildrenandadolescents".)

RecurrentRecurrentepisodesoffeveroverperiodsofmorethansixmonths'durationsuggestmetabolicdefects,
centralnervoussystem(CNS)dysregulationoftemperaturecontrol,periodicdisorders(suchascyclicneutropenia,
hyperimmunoglobulinDsyndrome,anddeficienciesofselectedinterleukinreceptorsites),andimmunodeficiency
states.(See"Feverofunknownorigininchildren:Etiology",sectionon'Othercauses'.)

AssociatedcomplaintsItisimportanttoask,andaskagain,aboutpastorcurrentabnormalitiesorcomplaints.As
examples:

RedeyesthatresolvedspontaneouslymaysuggestKawasakidisease(see"Kawasakidisease:Clinicalfeatures
anddiagnosis")

Nasaldischargemaysuggestsinusitis(see"Acutebacterialrhinosinusitisinchildren:Clinicalfeaturesand
diagnosis",sectionon'Acutebacterialrhinosinusitis')

Recurrentpharyngitiswithulcerationsmaysuggesttheperiodicfeverwithaphthousstomatitis,pharyngitis,and
adenitissyndrome(PFAPA)(see"Periodicfeverwithaphthousstomatitis,pharyngitisandadenitis(PFAPA
syndrome)")

GastrointestinalcomplaintsmaysuggestSalmonellosis,anintraabdominalabscess,hepatospleniccatscratch,or
inflammatoryboweldisease

Limborbonepainmaysuggestleukemia,osteomyelitis,orinfantilecorticalhyperostosis(see"Overviewofthe
presentationanddiagnosisofacutelymphoblasticleukemiainchildrenandadolescents"and"Differentialdiagnosis
oftheorthopedicmanifestationsofchildabuse",sectionon'Infantilecorticalhyperostosis(Caffeydisease)'and
"Hematogenousosteomyelitisinchildren:Clinicalfeaturesandcomplications",sectionon'Clinicalfeatures')

ExposuresItisimportanttoaskspecificallyaboutthefollowingexposures:

Contactwithinfectedorotherwiseillpersons.

Exposuretoanimals,includinghouseholdpets,domesticanimalsinthecommunity,andwildanimals(table2).(See
"Zoonosesfromcats"and"Zoonosesfromdogs"and"Zoonosesfrompetsotherthandogsandcats"and
"Microbiology,epidemiology,clinicalmanifestations,anddiagnosisofcatscratchdisease".)

Travelhistory(includingplaceofresidence),extendingbacktobirth.Anumberofdiseasesacquiredinendemic
areascanreemergeyearsafterdeparture(eg,histoplasmosis,coccidioidomycosis,blastomycosis,malaria).The
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travelhistoryshouldinclude:

Thesite(s)oftravel

Prophylacticmedicationsandimmunizationsbeforetravel

Measurestakentopreventexposuretocontaminatedfoodandwater

Whetherartifacts,rocks,orsoilfromothergeographicareaswerebroughtintothehome

Exposuretootherpersonswitharecenthistoryoftravel

TickbitescanbeacluetoRockyMountainspottedfever,ehrlichiosis,tularemia,tickbornerelapsingfever,orLyme
disease.NorthAmericanmosquitoesandsometickscarryavarietyofarboviruses.(Seeappropriatetopicreviews).

Consumptionofgamemeat,rawmeat,orrawshellfishmaybeacluetobrucellosis,toxoplasmosis,tularemia,or
hepatitis.

Ahistoryofpica,specificallyeatingdirt,maybeassociatedwithdiseasessuchasviscerallarvamigransand
toxoplasmosis.

Exposuretomedications(includingprescription,topical,andnonprescriptiondrugs)andnutritionalsupplements.(See
"Drugfever".)

Historyofsurgicalprocedurespatientswithahistoryofabdominalsurgeryhaveanincreasedriskofdevelopingan
intraabdominalabscess.

EthnicorgeneticbackgroundCertainconditionsassociatedwithfevertendtooccuramongmembersofcertain
ethnicgroups.Asexamples:

NephrogenicdiabetesinsipidusinUlsterScots[19](see"Diagnosisofpolyuriaanddiabetesinsipidus")

FamilialMediterraneanfeverinthoseofSephardicJewish,Armenian,Turkish,andArabdescent(see"Clinical
manifestationsanddiagnosisoffamilialMediterraneanfever")

FamilialdysautonomiainthoseofAshkenaziJewishdescent(see"Hereditarysensoryandautonomicneuropathies",
sectionon'HSAN3(Familialdysautonomia)')

EXAMINATION

GeneralassessmentThepatientwithfeverofunknownorigin(FUO)shouldbeevaluatedwhilefebrile.Thisis
necessarytoassesshowillthepatientappears,todeterminetheeffectoffeveronsweatingandtheheartandrespiratory
rates,andtodocumentanyaccompanyingsymptoms(eg,malaiseormyalgias)orsigns.Therashofjuvenileidiopathic
arthritis(JIA)ischaracteristicallyevanescentandmaybepresentonlyduringfever(picture1).

Thephysicalexaminationshouldbeginwithageneralassessmentofthepatient'sappearance,activity,vitalsigns,and
growthparameters.Althoughitisimportanttoevaluatethepatientforweightloss,thisisanonspecificfinding.Certain
chronicdiseases,suchasinflammatoryboweldisease(IBD),orendocrineabnormalities,suchaspituitarygland
impairmentrelatedtoanintracraniallesion,characteristicallyresultindisproportionatedecelerationoflineargrowthorshort
stature.(See"Causesofshortstature",sectionon'Systemicdisorderswithsecondaryeffectsongrowth'.)

Certainfindingsonphysicalexaminationhelptosignalavarietyofconditions,asthosedescribedbelow.

SkinandscalpSkinlesions,abnormalities,andrashesareacomponentofanumberofconditionsthatmaycause
FUOifskinfindingsarenotpresentinitially,theskinshouldbeexaminedrepeatedly.Examplesinclude:

Theabsenceofsweatduringfevermaysuggestdehydrationrelatedtodiabetesinsipidus,ectodermaldysplasia,or
familialdysautonomia

Petechiaeininfectiousendocarditis(IE),bacteremia,andviralandrickettsialinfections

TherashofRockyMountainspottedfever,whichtypicallybeginsontheanklesandwristsandspreadstothepalms
andsolesandcentrally(picture2)

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Papularlesionsincatscratchdisease(picture3)

Escharintularemia(picture4)

Erythemamigransorerythemamigranslikerashesintickbornediseases:Lymedisease(picture5AB)andsouthern
tickassociatedrashillness(picture6)

ThemacularsalmonpinkrashofJIA(picture1)

Malarerythemainsystemiclupuserythematosus(SLE)(picture7AB)

Palpablepurpuriclesionsinvasculitis(eg,polyarteritisnodosa)(picture8)

Urticarialand/orserpiginousmacularrashandbandoferythemaatthelateralaspectsofthehandsandfeet(picture
9)inserumsickness

Erythemanodosum(picture10)maybepresentinchildrenwithinfection,JIA,SLE,malignancy,andinflammatory
boweldisease(see"Erythemanodosum")

Aseborrheicrashcanindicatehistiocytosis(see"Clinicalmanifestations,pathologicfeatures,anddiagnosisof
Langerhanscellhistiocytosis",sectionon'Skinandoralmucosa')

Sparsehair,particularlyoftheeyebrowsandeyelashes,andhypohidrosismaysuggestanhidroticectodermal
dysplasia(see"Thegenodermatoses",sectionon'Ectodermaldysplasias')

Patientswithfamilialdysautonomiamayhaveblotchyskinandmultipleareasofskintrauma(see"Hereditary
sensoryandautonomicneuropathies",sectionon'HSAN3(Familialdysautonomia)')

EyesTheeyeexaminationmayprovideanumberofpotentialdiagnosticclues,including:

Palpebralconjunctivitis:Infectiousmononucleosis,Newcastledisease(aviralinfectionassociatedwithexposureto
chickensorotherbirds)

Bulbarconjunctivitis:Leptospirosis,Kawasakidisease(picture11)

Phlyctenularconjunctivitis(withsmall,white,elevatedlesions):Tuberculosis(TB)

Ischemicretinopathywithhemorrhagesandretinaldetachment,ischemicopticneuropathy:Polyarteritisnodosa
[20,21]

Absenceofthepupillaryconstrictorresponse:Hypothalamicorautonomicdysfunction

Absenttearsandcornealreflexes:Familialdysautonomia(RileyDaysyndrome)

Abnormalfunduscopicexamination:MiliaryTB(choroidtubercles)(image1),toxoplasmosis(raisedyellowwhite,
cottonylesionsinanonvasculardistribution)(picture12),vasculitis(picture13)

SinusesThesinusesshouldbepalpatedinpatientswithpurulentorpersistentnasaldischargetendernessmay
suggestadiagnosisofsinusitis.

OropharynxAbnormalitiesofdentitionandotherlesionsintheoropharynxmayprovideimportantcluestothe
underlyingcauseoffever.Asexamples:

Pharyngealhyperemiawithoutexudateoccasionallycanbetheonlysignofinfectiousmononucleosiscausedby
EpsteinBarrvirus(EBV)orcytomegalovirus(CMV),toxoplasmosis,tularemia,orleptospirosis.

Dentalabscessandotheroralorfacialinfectionscancausepersistentfever[2225].Oralinfectionsalsocanbe
associatedwithotherinfections(eg,sinusitis,brainabscess,mediastinalabscess).

Anomalousdentition(hypodontia,adontia,orconical"pegteeth")isacharacteristicofanhidroticectodermal
dysplasia.(See"Thegenodermatoses",sectionon'Ectodermaldysplasias'.)

Asmoothtonguethatlacksfungiformpapillaeorexcessivesalivationmaysuggestfamilialdysautonomia.(See
"Hereditarysensoryandautonomicneuropathies",sectionon'HSAN3(Familialdysautonomia)'.)

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PatientswithleukemiaorLangerhanscellhistiocytosiscanhavegingivalhypertrophyorinflammationandloosening
orlossofteeth.(See"Overviewofthepresentationanddiagnosisofacutelymphoblasticleukemiainchildrenand
adolescents"and"Clinicalmanifestations,pathologicfeatures,anddiagnosisofLangerhanscellhistiocytosis",
sectionon'Skinandoralmucosa'.)

LymphnodesMaybeenlargedandtendertopalpationinanumberofconditions,includingKikuchiFujimotodisease.
(See"Peripherallymphadenopathyinchildren:Etiology",sectionon'Overview'.)

ChestExaminationofthechestmayrevealfindingsconsistentwithpneumonia.Thepresenceofacardiacmurmur,
especiallyoneofnewonset,maysuggestinfectiveendocarditis.(See"Communityacquiredpneumoniainchildren:
Clinicalfeaturesanddiagnosis",sectionon'Examination'and"Infectiveendocarditisinchildren".)

Forpatients13yearswithtemperature38.9C(102F),failureofthepulsetoincreaseasexpectedwithfever
(approximately10beatsperminuteforeach0.6C[1F]),maybeacluetospecificinfectiousdiseases,including
Legionella,psittacosis,Qfever,typhoidfever,typhus,babesiosis,malaria,leptospirosis,yellowfever,Denguefever,viral
hemorrhagicfever,andRockyMountainspottedfever[26].

AbdomenHepaticorsplenicenlargementiscommonininfectionsofthereticuloendothelialsystem(salmonellosis,
brucellosis,etc),catscratchdisease,infectiveendocarditis,malaria,andmanyothers.Tendernessonpalpationofthe
liveredgemaybenotedinpatientswithliverabscessorcatscratchdisease[27].

MusculoskeletalThebonesandmusclesshouldbepalpatedfortenderness.

Tendernessoverabonecanindicatethepresenceofosteomyelitis,malignantinvasionofthebonemarrow,or
infantilecorticalhyperostosis(see"Overviewofthepresentationanddiagnosisofacutelymphoblasticleukemiain
childrenandadolescents"and"Differentialdiagnosisoftheorthopedicmanifestationsofchildabuse",sectionon
'Infantilecorticalhyperostosis(Caffeydisease)'and"Hematogenousosteomyelitisinchildren:Clinicalfeaturesand
complications",sectionon'Clinicalfeatures')

Muscletendernesscanbefoundintrichinellosis,variousarboviralinfections,dermatomyositis,orpolyarteritis.
Tendernessoverthetrapeziusmusclemayindicatesubdiaphragmaticabscess[12](see"Trichinellosis"and
"Juveniledermatomyositisandpolymyositis:Epidemiology,pathogenesis,andclinicalmanifestations"and"Clinical
manifestationsanddiagnosisofpolyarteritisnodosainadults")

Hyperactivedeeptendonreflexesmaysuggesthyperthyroidism(see"Clinicalmanifestationsanddiagnosisof
hyperthyroidisminchildrenandadolescents")

Hypoactivedeeptendonreflexesmaysuggestfamilialdysautonomia(see"Hereditarysensoryandautonomic
neuropathies",sectionon'HSAN3(Familialdysautonomia)')

GenitourinaryPatientswithFUOshouldhaveacarefulrectal,externalgenitalia,andpelvicexamination(forsexually
activefemaleadolescents).Therectalexaminationisperformedtoevaluatethepatientforperirectaltendernessora
mass,whichcanindicateapelvicabscessortumor.Stoolshouldbeexaminedforoccultblood.

DIAGNOSTICTESTINGThelaboratoryandimagingevaluationsforfeverofunknownorigin(FUO)shouldbedirected
towardthelikelycausesoffeverbaseduponthepatient'sage,durationoffever,andfindingsfromthehistoryandphysical
examination.Inareviewof40childrenwithFUOreferredtoapediatricrheumatologyclinic(presumablyafterthemore
commoncausesofFUOhadbeenruledout),resultsoflaboratory,radiologic,andpathologicstudieswereoccasionally
abnormal,butnoneofthetestsresultedinaspecificdiagnosis[28].

Thetempooftheevaluationisdictatedbytheappearanceofthepatient.Thepaceshouldberapidifthechildappears
severelyill.Itcanbemoredeliberateifthechildislessillappearing.Sometimesthefeverresolveswithoutexplanation
beforeinvasivediagnostictestingisundertaken.

InitialtestsWerecommendthefollowingtestsforallchildrenwithFUO:

Completebloodcount(CBC)andcarefulexaminationoftheperipheralsmear
Erythrocytesedimentationrate(ESR)andCreactiveprotein(CRP)
Aerobicandanaerobicbloodcultures(anaerobicbloodculturesmaybehelpfulinisolatingfastidiousorganismssuch
asStreptobacillusmoniliformisaswellasfacultativeaerobes)
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Urinalysisandurineculture
Chestradiograph
Tuberculinskintesting
Serumelectrolytes,bloodureanitrogen(BUN),creatinine,andhepaticenzymes
HIVserology

Additionaltestsmaybeindicateddependinguponthepresenceofcluesfromthehistory,examination,orinitialtests.(See
'Additionaltests'below.)

CBC,differential,andsmearTheCBCandsmeararetoevaluatethechildforanemiaandthrombocytosisor
thrombocytopenia.Anemiamaybeacluetomalaria,infectiveendocarditis,IBD,SLE,ortuberculosis[29].
Thrombocytosisisanonspecificacutephasereactant,butitcanbeacluetoKawasakidisease.(See"Kawasaki
disease:Clinicalfeaturesanddiagnosis".)

Thetotalwhitebloodcellcount(WBC)andthedifferentialgenerallyarelesshelpful,althoughchildrenwith>10,000
polymorphonuclearleukocytes(PMN)or500nonsegmentedneutrophils/mm3hadagreaterriskofseverebacterial
infectioninsomeseries[30,31].Ifatypicallymphocytesarepresent,aviralinfectionislikelybizarreorimmature
formsshouldpromptfurtherevaluationforleukemia.(See"Overviewofthepresentationanddiagnosisofacute
lymphoblasticleukemiainchildrenandadolescents".)

Eosinophiliamaybeacluetoparasitic,fungal,neoplastic,allergic,orimmunodeficiencydisorders.(See"Approach
tothepatientwithunexplainedeosinophilia"and"Drugfever".)

ESRandCRPTheESRandCRParenonspecificacutephasereactantsbutserveasgeneralindicatorsof
inflammation.AnelevatedESRorCRPmakesfactitiousfeverlesslikely.FollowingthecourseofanelevatedESR
orCRPassistsinmonitoringdiseaseprogress.AnormalESRorCRPcanslowthepaceofmoreinvasive
investigation.However,ESRorCRPmaybenormalinnoninflammatoryconditionsassociatedwithFUO(eg,
dysautonomia,ectodermaldysplasia,thalamicdysfunction,diabetesinsipidus,drugfever)[18].TheESRalsomay
beloweredartifactuallyinconditionsinvolvingconsumptionoffibrinogen(suchasdisseminatedintravascular
coagulopathy),andmayberaisedinnoninflammatorydisorderscharacterizedbyhypergammaglobulinemia.

BloodculturesRoutinebloodculturesshouldbeobtainedfromallpatients.Severalsetsofbloodculturesshouldbe
obtainedover24hoursinpatientsinwhominfectiveendocarditisisbeingconsidered.(See"Infectiveendocarditisin
children".)

Theuseofspecialmediaorenvironmentalconditionsorholdingbloodculturesinthelaboratoryforalongerthan
normalperiodofincubationisvaluableinselectcases.Thesetechniquescanfacilitatetheisolationofanaerobes,
Brucella,Leptospira,andSpirillum.

UrinalysisandurinecultureUrinalysisandurinecultureareimportantdiagnostictestsurinarytractinfection(UTI)
isamongthemostfrequentcausesofFUOinchildren[8,10,11].Inoneseries,thetwomostfrequentlaboratory
errorswerefailuretoperformaurinalysisandfailuretoadequatelypursuethefindingofpyuria[5].Sterilepyuriacan
beacluetoKawasakidisease,adjacentintraabdominalinfection,orgenitourinarytuberculosis.(See"Kawasaki
disease:Clinicalfeaturesanddiagnosis"and"Renaldiseaseintuberculosis".)

ChestradiographPatientswithFUOshouldhaveachestradiographtoevaluateforinfiltratesand
lymphadenopathy.

PPDAllpatientsshouldhaveanintradermalintermediatestrengthpurifiedproteinderivative(PPD)tuberculinskin
test.ControlskintestingisoflimitedvalueandisnotrecommendedbymostexpertssincepatientswithTBmay
haveapositivecontrolandnegativePPD[3235].

Serumelectrolytes,bloodureanitrogen(BUN),creatinine,andhepaticenzymesSerumelectrolytes,bloodurea
nitrogen(BUN),creatinine,andhepaticenzymesareobtainedtoevaluaterenaland/orhepaticinvolvement.
Hypernatremiamaysuggestdiabetesinsipiduselevatedhepaticenzymesmaybeacluetoaviralinfectionwithout
distinctivefeatures(eg,EpsteinBarrvirus,cytomegalovirus),orbrucellosis.

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HIVserologyHIVserologyissuggestedsincethemanifestationsofprimaryHIVinfectioncanbehighlyvariable.

AdditionaltestsAnumberofothertestsmaybeindicatedinpatientswithcluesfromthehistoryorphysical,or
abnormalitiesongeneraltestsdescribedabove.

Laboratorytests

StoolstudiesStoolculturesorexaminationforovaandparasitesmaybewarrantedinpatientswithloosestoolsor
recenttravel.

BonemarrowBonemarrowexaminationinchildrenismostusefulindiagnosingcancer(especiallyleukemia),
histiocyticdisorders,andhemophagocyticdisease[36].Itisnotgenerallyhelpfulinidentifyinginfection.

Inonereviewof414bonemarrowexaminationsfortheevaluationofFUOinchildren,anorganism(Salmonellagroup
D)wasrecoveredfromthebonemarrowbutnoothersiteinonlyonecase[37].Bycontrast,bonemarrowresults
establishednoninfectiousdiagnosesin8percentofcases,includingmalignancy(6.7percent),hemophagocytic
syndromes(0.7percent),histiocytosis(0.5percent),andhypoplasticanemia(0.2percent).Mostofthesedisorders
weresuspectedfromclinicalcluesbeforethebonemarrowexaminationwasperformed.

SerologiesWesuggestatargetedapproachtoserologicstudiesinchildrenwithFUO.Asdiscussedabove,we
recommendHIVserologyforallchildrenwithFUOsinceprimaryHIVhasmanymanifestations.Serologictestingfor
syphilisshouldbeperformedinneonates,younginfants,andadolescentswithFUO.Otherserologiesthatmaybe
warranted,dependinguponthecase,includebrucellosis,tularemia,EBV,CMV,toxoplasmosis,bartonellosis,and
certainfungalinfections.

Serologiesalsocanbeusefulforsomeparasiticinfectionssuchasextraintestinalamebiasisorstrongyloidiasisand
inotherviralinfections,suchaslymphocyticchoriomeningitisvirus.Serologycannotbeappliedtomost
enterovirusessincetherearetoomanydifferentserotypesforgeneralscreening.

SerumantinuclearantibodySerumantinuclearantibodyshouldbeobtainedforchildrenolderthanfiveyearsofage
withastrongfamilyhistoryofrheumatologicdisease.Apositiveantinuclearantibodytestsuggeststhepresenceof
anunderlyingconnectivetissuedisorder,particularlysystemiclupuserythematosus[38].(See"Measurementand
clinicalsignificanceofantinuclearantibodies".)

ImmunoglobulinsSerumconcentrationsofIgG,IgA,andIgMshouldbemeasuredinchildrenwithevidenceof
recurrentorpersistentinfectionandinthosewithpersistentfeverandanegativeinitialevaluation[12].Low
concentrationsmayindicateanimmunodeficiency.Elevatedlevelsalsocanbeaclue,suggestingdeficiencyin
anotherarmoftheimmunesystem,chronicinfection,oranautoimmunedisorder.(See"Approachtothechildwith
recurrentinfections"and"Primaryhumoralimmunodeficiencies:Anoverview",sectionon'HyperimmunoglobulinM
syndromes'.)

IgElevelsareunlikelytobehelpfulunlessthereisevidenceofallergyorinfection,suggestingthe
hyperimmunoglobinEsyndrome(eg,eosinophilia).(See"AutosomaldominanthyperimmunoglobulinEsyndrome".)

SerumIgDlevelsshouldbeobtainedinpatientswithperiodicorintermittentfever.Specificmoleculargenetictests
forotherperiodicdisordersareavailablebutshouldprobablybeobtainedonlyafterconsultationwithanexpertin
theseconditions.(See"HyperimmunoglobulinDsyndrome:Clinicalmanifestationsanddiagnosis"and"Periodic
feversyndromesandotherautoinflammatorydiseases:Anoverview".)

MoleculartestingIncertaincases,moleculartesting(eg,polymerasechainreaction)canbeuseful.Examples
includeEBV,CMV,parvovirus,andBartonella.(Seeappropriatetopicreviews).

ImagingOneofthemostdifficultdecisionsiswhentopursueadditionalimaginginpatientswithFUO.Diagnostic
imagingofthenasalsinuses,mastoids,andgastrointestinal(GI)tractshouldbeperformedinitiallyonlyforspecific
indications,butmaybewarrantedinchildreninwhomFUOpersistswithoutexplanationforalongperiod.

AbdominalimagingChildrenwithpersistentfever,elevatedESRorCRP,anorexia,andweightlossshouldhave
studiestoexcludeinflammatoryboweldisease,particularlyiftheyalsohaveabdominalcomplaintswithorwithout

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anemia.However,imagingoftheGItractalsoshouldbepursuedeventuallyinchildrenwhosefeverspersistwithout
otherexplanationandmaybecausedbyconditionssuchaspsoasabscessorcatscratchdisease.Ultrasonography,
computedtomographic(CT)scanning,andmagneticresonanceimaging(MRI)canbeusefulinevaluatingthe
abdomen[39].Thesetestscandetectabscesses,tumors,andlymphadenopathy.

CNSimagingImagingoftheCNSwithorwithoutanelectroencephalogramgenerallyisnothelpfulintheevaluation
ofchildrenwithFUO.

WBCscansGalliumandindium111labeledWBCscanningcanhighlightinflammatorylesionsandtumorsand
providenoninvasivescreeningoftheentirebody[40].However,thesetestsarenotdiagnostic,andfollowupwith
otherimagingstudiesisrequired.Onegroupfoundthatradionuclidescansseldomrevealedanunsuspected
diagnosisinchildrenwithFUO[38].Anotherfoundthatgalliumscanningcanbehelpfulwhenthereissuspicionof
localizedinfectionbutisunlikelytobehelpfulinthosewithonlysystemicsigns[41].

OtherimagingtechniquesAnumberofotherimagingtechniques,includingradiographicbonesurvey,technetium
bonescan,andliverspleenscancanbeemployedinselectedcaseswhenathoroughevaluationhasfailedtoreveal
thecauseofFUOandsuspicionforasourcethatcouldberevealedbythesetestsexists.

PETscansPositronemissiontomography(PET)scanningisanothertechniquethatmaybehelpfulinpatientswith
persistentFUOwhoremainwithoutadiagnosisafterinitialevaluation.Inareviewofprospectivestudies,(18)FFDG
PETcontributedtothediagnosisin25to69percentofcasesofFUO[42].(18)FFDGPETwasmoresensitivethan
GacitrateSPECTindetectingtumors,infection,andinflammation.

StudiesofPETscansintheevaluationofFUOinchildrenarelimited.OnegroupstudiedPETin11childrenwith
FUOawaitinglivertransplant[43].Thescanswerepositiveinfive,allofwhomhadpositivebacterialculturesand/or
histologicevidenceofinfectionintheexcisedliverotherscanningproceduresinthesechildrenhadbeennegative.
PETscanswerenegativeintheothersixchildren,noneofwhomhadevidenceofinfectionintheliveratthetimeof
transplant.

ImmunoscintigraphyImmunoscintigraphyisanothertechniquethatmaybehelpfulincertainpatientswith
persistentFUOwhoremainwithoutadiagnosisafterinitialevaluation.In30neonatesandinfantswithFUO,
immunoscintigraphywithlabeledantigranulocyteantibodyhadasensitivityandspecificityof72and95percent,
respectively,fordetectionofinfection(asverifiedbyconventionalradiography,MRI,CT,biopsy,bloodculture,and
clinicalfollowup)[44].

WholebodyMRIWholebodyMRIisusedtoevaluatetheextentofmultisystemicdiseaseinpediatriconcology
patients.Inaretrospectivestudy,wholebodyMRIwasfoundtoinfluencethedecisionalprocessandclinical
managementin42childrenwithinflammatorydisorderssuchaschronicrecurrentmultifocalosteomyelitis,juvenile
idiopathicarthritis,chronicgranulomatousdisorder,andLangerhanscellhistiocytosis[45].Theutilityofwholebody
MRIintheroutineevaluationofchildrenwithpersistentFUOwhoremainwithoutadiagnosisafterinitialevaluation
hasnotbeenestablished.

Otherevaluations

Electrocardiographyandechocardiographyshouldbeobtainedinpatientswithpositivebloodculturesandsuspicion
forinfectiveendocarditis[46](see"Infectiveendocarditisinchildren")

OphthalmologicexaminationbyslitlampisusefulinsomepatientswithFUOtoevaluatethepresenceofuveitisor
leukemicinfiltration

Biopsy(eg,oflymphnodesorliver)shouldbereservedforchildrenwithevidenceofinvolvementofspecificorgans

Sophisticatedabdominalimagingprocedureslargelyhaveeliminatedtheneedforexploratorylaparoscopyor
laparotomyintheevaluationofchildrenwithFUO

EMPIRICALTREATMENTEmpiricaltreatmentwithantiinflammatorymedicationsorantibioticsgenerallyshouldbe
avoidedasdiagnosticmeasuresinchildrenwithfeverofunknownorigin(FUO).Exceptionsincludenonsteroidalagentsin
childrenwithpresumedjuvenileidiopathicarthritis(JIA)andantituberculousdrugsincriticallyillchildrenwithpossible
disseminatedtuberculosis(TB).

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Antiinflammatorydrugsdonothelptodistinguishfeversofinfectionsfromthoseofnoninfectiouscauses.Empiricaltrials
ofbroadspectrumantibioticscanmaskordelaythediagnosisofimportantinfections,suchasmeningitis,parameningeal
infection,infectiousendocarditis,orosteomyelitis.Useofempiricalantibioticsalsocanhampertheabilitytoisolatean
organismfromthebloodoraspecificsiteiffurtherculturingiswarrantedastheevaluationproceeds.

OUTCOMEIncontrasttoadults,mostchildrenwithfeverofunknownorigin(FUO)havetreatableorselflimited
diseases.Thefeverresolvesovertimeinmostcases,andaspecificdiagnosiseventuallycanbemadeinothers
[8,9,12,47].

Despitethisfact,theoverallprognosisisfarfrombenign.Intwoseriesfromthe1970s,mortalitywas9percentinone
groupof100childrenwithFUOand6percentinanothergroupof54children[4,6].Inmorerecentseries,mortalityisless
frequent[8,9].

Curiously,theprognosismaybebetterwhenadiagnosiscannotbeestablishedafterextensiveevaluation[5,28,47].Of
thosewithoutadefinitivediagnosis,manyappeartodowell,althoughepisodesoffevermayrecur[5,47].

Inlongtermfollowup(median3.5years,range1.2to5.3years)of19childrenwithFUOforatleasttwoweeksandin
whomnodiagnosiswasestablished,16of19(82percent)wereafebrileandcompletelywell[47].Twopatientswere
subsequentlydiagnosedwithjuvenileidiopathicarthritis(JIA),oneshortlyafterdischargeandone1.5yearslater.One
child,whohadpresentedwithabdominalpainandfever,hadtwoepisodesofintussusception(8and14monthsafter
discharge),andtheauthorsspeculatethatherinitialepisodemighthavebeenintussusceptionthatspontaneouslyreduced.

Among40childrenwhowerereferredforpediatricrheumatologyevaluationwithFUOofatleastonemonth'sdurationand
inwhomnodiagnosiswasestablished,37wereavailableforfollowupatameanof60.5months[28].Twochildren
developedinflammatoryboweldisease(IBD)(one7monthsandone3.5yearsafterinitialevaluation)inbothcases,fever
resolvedafterinitiationofappropriatetherapyforIBD.

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyond
theBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,and
theyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestfor
patientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducation
piecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevel
andarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicsto
yourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingonpatientinfoandthe
keyword(s)ofinterest.)

Basicstopics(see"Patienteducation:Feverinchildren(TheBasics)")

BeyondtheBasicstopics(see"Patienteducation:Feverinchildren(BeyondtheBasics)")

SUMMARYANDRECOMMENDATIONS

Thediagnosisoffeverofunknownorigin(FUO)shouldbereservedforchildrenwithfeverofatleasteightdays'
durationinwhomnodiagnosisisapparentafterinitialevaluationeitherinthehospitalorasanoutpatient.(See
'Definitions'above.)

InfectionsarethemostcommoncausesofFUOinchildren,followedbyconnectivetissuedisordersandneoplasms.
However,inmanycases,adefinitivediagnosisisneverestablishedandfeverresolves.(See'Etiology'above.)

Adetailedhistoryandphysicalexaminationareessentialforallpatients.Theseshouldberepeatedonseveral
occasions.(See'Diagnosticapproach'above.)

Thehistoryshouldincludedetailsaboutthefever,associatedcomplaints,andexposures(eg,toillcontacts,
animals,insects,travel,drugs).(See'History'above.)

Thepatientshouldbeexaminedwhilefebrile.Importantaspectsoftheexaminationincludevitalsigns,theskin,
scalp,eyes,sinuses,oropharynx,chest,abdominal,andmusculoskeletalandgenitourinarysystems.(See
'Examination'above.)

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Wesuggestthefollowingtestsaspartoftheinitialevaluation(see'Initialtests'above):

Completebloodcount(CBC)andperipheralsmear
Erythrocytesedimentationrate(ESR)andCreactiveprotein(CRP)
Bloodcultures
Urinalysisandurineculture
Chestradiograph
Tuberculinskintesting
Serumelectrolytes,bloodureanitrogen(BUN),creatinine,andhepaticenzymes
HIVserology

Additionaltestsandimagingstudiesshouldbebaseduponthefindingsofthehistory,examination,andinitialtests.
Diagnosticimagingofthenasalsinuses,mastoids,andgastrointestinaltractmaybewarrantedeventuallyinchildren
inwhomFUOpersistswithoutexplanation.(See'Additionaltests'aboveand'Otherevaluations'above.)

Empirictreatmentwithantiinflammatorymedicationsorantibioticsgenerallyshouldbeavoidedasdiagnostic
measuresinchildrenwithFUO.(See'Empiricaltreatment'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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