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Clinicalmanifestations,diagnosis,andtreatmentofextrapulmonaryandmiliarytuberculosis
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Clinicalmanifestations,diagnosis,andtreatmentofextrapulmonaryandmiliarytuberculosis
Author
JohnBernardo,MD

SectionEditor
CFordhamvonReyn,MD

DeputyEditor
ElinorLBaron,MD,DTMH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2016.|Thistopiclastupdated:Sep11,2015.
INTRODUCTIONMiliarytuberculosis(TB)referstoclinicaldiseaseresultingfromthehematogenousdissemination
ofMycobacteriumtuberculosis.Thetermmiliarywascoinedin1700byJohnJacobusManget,wholikenedthe
appearanceoftheinvolvedlung,withitssurfacecoveredwithfirmsmallwhitenodules,tomilletseeds(picture1).
Originallyapathologicandthenaradiographicdescription,thetermmiliaryTBisnowusedtodenoteallformsof
progressive,widelydisseminatedhematogenousTB.MiliaryTBcanariseasaresultofprogressiveprimaryinfectionor
viareactivationofalatentfocuswithsubsequentspread.
Theclinicalmanifestations,diagnosis,treatment,andpreventionofmiliaryTB,aswellasextrapulmonaryTB,willbe
reviewedhere.ThepathogenesisandepidemiologyofmiliaryTBarediscussedseparately.(See"Epidemiologyand
pathologyofmiliaryandextrapulmonarytuberculosis".)
CLINICALMANIFESTATIONSSeverallargeretrospectiveseriesprovidemuchofthedataontheclinicalfeaturesof
miliarytuberculosis(TB)(table1)[16].Whilethesestudiesincludearelativelylargenumberofpatients,theydiffer
markedlybyyear,inclusioncriteria,country,andtypeofmedicalcenter,sodirectcomparisonisdifficult.
TheclinicalpresentationofmiliaryTBishighlyvariablemanifestationscanbeacutebutaremorelikelytobesubacute
orchronic.Inhighlyendemicareas,miliaryTBmaybeassociatedwithreinfection.DevelopmentofmiliaryTBduring
primaryinfectioncanpresentwithrelativelyacuteonsetandrapidclinicalcourse.Acutediseasemaybefulminant,
includingmultiorgansystemfailure[7],asyndromeofsepticshock[8],andacuterespiratorydistresssyndrome(ARDS)
[9,10].
ThesubacuteorchronicpresentationsofmiliaryTBaremorecommonthanacutedisease.Thesepatientsmaypresent
withfailuretothrive[5],feverofunknownorigin[2],ordysfunctionofoneormoreorgansystems[11].Themost
commonextrapulmonarysitesofdiseaseincludethelymphaticsystem,bonesandjoints,andtheliver.Nightsweats
arefrequent.Rigorsareunusualbuthavebeendescribed[12,13].Inoneseriesincluding38patients,themedian
durationofillnesswastwomonths[2].SymptomsandsignsofmiliaryTBaredescribedintheTables(table2andtable
3).
ThediagnosisofmiliaryTBisoftenmissedduetothenonspecificnatureofthepresentation.Inonereview,
approximately20percentofmiliaryTBcasesintheUnitedStateswerediagnosedpostmortem[14].AmongHIV
infectedpatientsinAfrica,previouslyunrecognizeddisseminatedtuberculosishasbeenidentifiedatautopsyinasmany
as40percentofhospitaldeaths[15].
PulmonarydiseasePulmonarydiseaseisnotedinover50percentofpatientswithmiliaryTBinmostseries.
Patientsreporteddyspneaorcoughandhadralesorrhonchionphysicalexamination.Hypoxemiawascommon.
Pleuriticchestpainwithaccompanyingpleuralruborothersignsofapleuraleffusionhavealsobeenwelldescribed.
Asnotedabove,miliaryTBisararecauseofacuterespiratoryfailureandARDS[9,10,1618].Inoneseriesfroma
regionendemicforTBinSouthAfrica,itwasestimatedthat2percentofcasesofARDSwereassociatedwith
disseminatedTB[19].AnotherstudysuggestedthatthediagnosisofTBismorelikelytobedelayedormissedentirely
inpatientspresentingwithacuterespiratoryfailureasopposedtomoretypicalsymptomsofpulmonaryorpleuralTB
[20].(See"Clinicalmanifestationsandcomplicationsofpulmonarytuberculosis".)
LymphaticdiseasePatientswithlymphaticTBusuallypresentwithsignsandsymptomsreferabletothesiteof
disease,althoughconstitutionalsymptomsmaybethesolecomplaint.Cervicallymphnodeenlargement,withor
withoutothersymptoms,isafrequentpresentationofcervicaltuberculousadenitis.

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Withinthechest,hilar(usuallyunilateral)andmediastinallymphnodeenlargementmayreflecteitherprimaryTBor
reactivationdisease.Enlargedintrathoracicnodesmaycauseextrinsicairwaycompressionleadingtofocalwheezingor
airwayobstruction,especiallyinchildren.(See"Tuberculouslymphadenitis".)
BoneandjointdiseaseInadults,boneorjointTBshouldbesuspectedinindividualsatriskforTBwhopresent
withboneorjointpain(includingbackpain)withorwithoutfocalswellingorfever[1,6,21].Thecourseusuallyis
indolentandpainusuallyisthefirstpresentingsymptom.SpinalTB(Pottsdisease)maypresentinchildrenasscoliosis
oralimp[22].Thediagnosisoftenisdelayedandmaybedifficulttoestablish.Radiographicfindingscanbe
nonspecificearlyfeaturesmayincludesofttissueswelling(especiallyoftheanteriorportionsofthevertebralbody)with
bonedemineralizationandpreservationofjointsurfaces.Withchronicdisease,completedestructionofbonewithlocal
sclerosismaybeseen,accompaniedbylossofstructuralsupportandspinaldeformity.Diseaseismostcommoninthe
lowerthoracicandlumbarvertebrae.Extensionoftheinfectiousprocesstosurroundingsofttissuemaycreatecold
abscesses[23].InvolvementofmultiplevertebraeischaracteristicofPottsdisease.Computedtomography(CT)and
magneticresonanceimaging(MRI)canidentifyearlylesionsnotseenonplainradiographs.Confirmationofadiagnosis
ofTBrequiresaspirationorbiopsyandcultureoftheaffectedtissue.(See"Skeletaltuberculosis".)
GastrointestinaldiseaseFormsofgastrointestinalinvolvementincludehepaticdisease,tuberculousenteritis,and
tuberculousperitonitis.MiliaryTBmayalsopresentaspancreatitis[24]orcholecystitis[25].
TheliverisfrequentlyinvolvedindisseminatedTB.Signsandsymptomsincludediffuseabdominalpainorpain
localizingtotherightupperquadrant,nausea,vomiting,anddiarrhea[26].Histopathologicsectionsofinvolvedliver
demonstratescatteredgranulomatouslesionsthatongrossexaminationhavetheappearanceofmilletseeds(picture
2)[27].Liverfunctiontestabnormalitiesarecommon,includingelevatedalkalinephosphataseandtransaminasesin83
and42percentofpatients,respectively,inoneseries[1].CholestaticjaundiceisalsowelldocumentedinmiliaryTB.
Rarely,fulminanthepaticfailurecanoccur[28].Thediagnosisisestablishedbyidentifyingtheorganismobtainedfrom
abiopsysampleinculture.
Tuberculousenteritisconsistsofrelativelyvague,nonspecificsymptomsandsigns.Apresumptivediagnosiscanbe
madeinthepresenceofknownactivepulmonaryTB.However,chestimagingistypicallypositive(foractiveorhealed
TB)inlessthanhalfofcases.(See"Tuberculousenteritis".)
Tuberculousperitonitisusuallydevelopsfollowingspreadofinfectionfromadjacentorgans.Itshouldbesuspectedin
patientsatriskforTBwhopresentwithascites.Symptomsoffever,fatigue,andabdominalpainarecommon.Ascites
fluidusuallydemonstrateslymphocytosis,elevatedprotein,andelevatedinflammatorymarkers.Cultureofascitesfluid
orofperitonealtissueisrequiredtoconfirmthediagnosis.Thesurfaceoftheperitoneummaydemonstratemiliary
lesionsonvisualexaminationbiopsyoftheselesionsdemonstratescaseatinggranulomas,withorwithoutacidfast
stainingorganisms.(See"Tuberculousperitonitis".)
CentralnervoussystemdiseaseCentralnervoussystem(CNS)disease,suchasmeningitisortuberculoma,was
observedin15to20percentofpatientswithTBintwolargeseries[1,3].Amongpatientswithtuberculousmeningitis,
aboutonethirdtoonehalfhadmiliaryTBinoneseries,meningealinvolvementwasevidentpostmortemin54percent
ofcasesofmiliaryTB[29].
Ahighindexofsuspicionisnecessarytomakeatimelydiagnosis,sincepresentingsymptomsandfindingson
examinationoftenarenonspecific.Inadults,CNSTBtypicallypresentsindolently,withheadache,lowgradefever,
and/orfocalneurologicalfindings.Inchildrenorimmunocompromisedhosts,thediseasemaypresentasacute
meningitis.
CTwithcontrastorMRIwithgadoliniumofthebrainmaydemonstratehydrocephalus,parenchymallesions,or
leptomeningealandbasalcisternenhancement.Cerebrospinalfluid(CSF)pressureusuallyiselevatedthefluidusually
demonstrateshighprotein,verylowglucose,andlymphocytosis,althoughpolymorphonuclearleukocytesmaybeseen
earlyinthedisease.IsolationofM.tuberculosisbycultureconfirmsthediagnosis(althoughsensitivityis50to60
percent),andnucleicamplificationtestingoftheCSFmaysupportthediagnosis[3032].Nucleicacidamplificationby
polymerasechainreaction(PCR)forMTbDNAintheCSFisnotapprovedbytheUSFoodandDrugAdministration
(FDA),althoughmanylaboratoriesofferinternallyvalidatedPCRtesting.However,treatmentshouldbeinitiatedas
soonasTBissuspectedinordertominimizetheriskoflongtermneurologicsequelaeordeath.(See"Centralnervous
systemtuberculosis".)
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GenitourinaryandadrenaldiseaseTBoftheurinarytractmaypresentwithhematuria,proteinuria,and"sterile"
pyuria.Inthekidney,thediseasefrequentlylocalizestotherenalpapillae,andcharacteristicdistortionofthecollecting
systemtractmaybeseenradiographically(image1).Flankpain,hydronephrosis,andcystitisindicatemoresevere
disease,andspreadtothegenitaliamayoccur.Diagnosisisestablishedbycultureoftheorganismfromtheurineacid
fastmicroscopygenerallyisnotperformedonurinesamplesbecauseofthenormalpresenceofnonpathogenic,
nontuberculousmycobacteriainmanyindividuals.Focalscarringofthekidneysandthecollectingsystemmayoccur
evenaftersuccessfultreatment.(See"Renaldiseaseintuberculosis".)
TBofthefemalegenitaltractmayoccurinthesettingofprimaryorreactivationdisease.Menstrualabnormalitiesinthe
settingofknownTBinfectionshouldpromptconsiderationoffemalegenitaltractinvolvement.Ultrasonographyorother
radiographicstudiesmaybehelpfulinlocalizinglesions.Thediagnosisisestablishedwithopenbiopsy,dilationand
curettage,and/orcolposcopy,withhistologicexaminationandcultureofbiopsymaterials[33,34].
Scrotalpain,swelling,and/orepididymalorprostatetendernessinthesettingofknownTBinfectionshouldprompt
considerationofmalegenitaltractinvolvement[35].Urinecultureand/orbiopsyofaffectedtissueforcultureare
necessaryfordiagnosis.
AdrenalinsufficiencyhasbeenassociatedwithmiliaryTBandinvolvementoftheadrenalsmaybefoundinasmanyas
42percentofautopsies[4,36].Overtadrenalinsufficiencyislesscommon,occurringin1percentofreportedcasesof
miliaryTB[1,36].Inaprospectivestudyincluding30patientswithmiliaryTB,adrenalfunctionwasabnormalin1of30
patients[37].Among55patientswithTBinvolvementoftheadrenalglandinoneseries,12percentpresentedwith
clinicalmanifestationsofAddison'sdisease[36].
CardiovasculardiseaseCardiovasculardiseaseisunusualinmiliaryTB.Autopsyseriesreportanincidenceofless
than10percent,almostalwaysclinicallysilent[29,38].ThemostcommonsingleformofcardiovascularTBis
pericarditis[1,2].Myocardialdiseaseismuchlessfrequentonepatientwithsuddencardiacdeathduetomyocardial
disseminationhasbeenreported[39].Tuberculousendocarditisisalsoveryrare[40].
Tuberculouspericarditisgenerallyisalatediagnosis.Thechestradiographusuallydemonstratesanenlargedcardiac
silhouette,andechocardiographymayshowsignsofconstriction[41].Apositivetuberculinskintestisobservedinmore
than85percentofpatients,althoughthisnumberislowerintheimmunocompromised[4245].Pericardialfluidand
biopsycanbeobtainedformycobacterialsmearandculture,buttheyieldfromthesespecimensisnotashighasfor
pleuralfluidortissue.Thus,presumptivetherapyoftenisadministeredtopatientswithevidenceofconstrictive
pericardialdiseaseandapositivetuberculinskintest.(See"Tuberculouspericarditis".)
DisseminatedTBcanbeassociatedwithmycoticaneurysmsoftheascendingordescendingaorta[46].Potential
mechanismsincludespreadfromalymphnodeorfromvertebralosteomyelitistotheaorta,followedbyhematogenous
dissemination.Embolizationtotheaorticwallvasavasorumduringhematogenousspreadfromanotherfocuscanalso
occur.Aneurysmruptureaftertheinitiationofantituberculouschemotherapyhasbeendescribed[46].
CutaneousdiseaseCutaneousdiseaseisrareinmiliaryTB.ThemostcommonpresentationisTBcutismiliaris
disseminata,whichconsistsof5to10mmmaculesandpapules[47].Ageneralizedrashwhichresemblesalichenoid
tuberculidresponsehasalsobeendescribed[13].AdvancedHIVmayalsopredisposetoskinmanifestationsof
disseminatedTB[48].(See"Cutaneousmanifestationsoftuberculosis".)
BreastdiseaseTBofthebreastisrare[49].Clinicalpresentationisusuallyofasolitary,illdefined,unilateralhard
lump[50].TBcanalsopresentwithnippledischarge,skinthickening,ordischargingsinusesinthebreastoraxilla.
BreastTBcanmimicbreastcarcinomaorbreastabscess,clinicallyandradiographically[49,50].Mammographic
imagingmayshowadensetractconnectinganilldefinedbreastmasstoanareaofskinthickeningandaskinbulge.
Ultrasoundmaydemonstrateacomplex,predominantlycysticmass.
OtherorganinvolvementAutopsyseriesofmiliaryTBdescribeseedingofeveryorganinthebody[29].Laryngitis
[51]andotitismedia[52]havebeenreportedasclinicalpresentationsofmiliaryTB.Involvementofthethyroidgland
withclinicalhyperthyroidismorhypothyroidismhasalsobeendescribed[53].
Onelargeautopsyserieswhichincludedeyeexaminationsfoundtuberclesin50percentofeyes[29],suggestingthata
gooddilatedexaminationmightbehelpfulinthediagnosisofhematogenousspreadofTB.Choroidaltuberclesaresaid
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tobespecificformiliaryTB,althoughtheywererarelyfoundinthelargeclinicalserieswheredilatedexaminationswere
notroutinelyperformed.(See"Tuberculosisandtheeye".)
LABORATORYFINDINGSManylaboratoryabnormalitiesmaybeobservedinmiliarytuberculosis(TB)(table4).
Hematologicabnormalitiesareprominent.Normocytic,normochromicanemiaisseeninapproximatelyonehalfofthe
patientsinmostseries.Mostpatientshaveanormalwhitebloodcellcount,butleukopeniaandleukocytosisoccurina
minorityofpatientswithroughlyequalfrequency.MiliaryTBshouldbeconsideredinthedifferentialdiagnosisof
patientswithaleukocytosisorleftshiftwheninitialevaluationdoesnotrevealatypicalbacterialetiology,especially
whenaccompaniedbyanemia.Leukemoidreactionsarealsodescribedandhaveevenledtoamisdiagnosisof
leukemia[54,55].Monocytosisoccursbutislesscommon.Thrombocytopeniaandthrombocytosisarealsoreported.
Pancytopeniaisanotherhematologicmanifestation,whichshouldraiseconcernformiliaryTBthismaybedueto
marrowinfiltrationaloneormaybeamanifestationofanunderlyinghematologicdisorder[56].Casesofthehistiocytic
hemophagocyticsyndromeassociatedwithmiliaryTBhavealsobeendescribed[57].Somecaseshaveresolvedwith
antituberculouschemotherapyalone,althoughassociatedconditions,suchasviralinfections,werenotalwaysexcluded
andresponsetosteroidsmayhavebeennonspecific.
Overtdisseminatedintravascularcoagulationisrareithasbeendescribedinacute,fulminantdisease.Milder
coagulationabnormalitieshavebeendescribedmorefrequently[1].Theerythrocytesedimentationrateandotheracute
phasereactantsareelevatedinthemajorityofpatientswithmiliaryTB.Polyclonalgammaglobulinemiaisalsocommon
[2].
HyponatremiaisthemostcommonelectrolyteabnormalityobservedinmiliaryTB.Itispresumedtobeduetothesame
problemswithregulationofantidiuretichormoneseeninotherpulmonaryprocesses,sincenotallseriesnotea
correlationwithcentralnervoussystemdisease[2].HypercalcemiaisrarebutmaybeseeninmiliaryTB[58].(See
"Pathophysiologyandetiologyofthesyndromeofinappropriateantidiuretichormonesecretion(SIADH)".)
Sterilepyuriawasfoundin32percentofpatientswithmiliaryTBinoneseries[2],withoutpositivemycobacterial
culturesfromtheurinarytract.UrineculturesmayalsobepositiveforM.tuberculosisinmiliaryTB,intheabsenceofan
abnormalurinesediment.
RADIOGRAPHICIMAGINGTwoseriesofcasesofmiliarytuberculosis(TB)providethebestoverviewofpulmonary
findings,sinceamiliarypatternonchestradiographwasnotrequiredforstudyinclusion[1,2].Morethantwothirdsof
patientswiththediagnosisofdisseminatedTBhadachestradiographwithamiliarypattern.
ChestradiographyTheclassicappearanceisafaint,reticulonodularinfiltratedistributedfairlyuniformlythroughout
thelungs(image2).Thismiliarypatternmayonlybecomeapparentdaysorweeksafterpresentation[1,3,6].This
findingisthoughttoreflectnodularinterstitialspreadwithoutsignificantalveolarinvolvement,althoughithasbeen
demonstratedthat,bythetimethemiliarynodulesarelargeenoughtobeappreciatedonaplainchestradiograph,they
typicallyinvolvetheadjacentalveoli[59].
Conversely,pathologicconditionsthatinitiallyinvolvealveoli,suchasalveolarhemorrhage,pulmonaryedema,or
inhalationaldiseases,canappearasearlysmallnodules.Thesesocalled"acinarnodules"aredescribedaslarger(5to
10mm)andmoreheterogeneousthanclassicmiliaryTB,butoverlapoccurs,makingtheappearanceofmanyofthese
conditionsindistinguishable[60].Thedifferentialdiagnosisofamiliarychestradiographypatternissummarizedinthe
Table(table5).
Otherchestradiographabnormalitiesincludepleuralreactions,hilarormediastinaladenopathy,andotherevidenceof
activeorhealedparenchymalTB(interstitialoralveolarinfiltratesorcavities).Amiliarypatterncanbeseeninaddition
tononmiliarydisease.NormalchestradiographsmaybeobservedinuptoonehalfofpatientswithdisseminatedTB
[61].Insomecases,abnormalitiesmaybesubtleandappreciatedonlyafterreviewwithanexperiencedchest
radiologist.
ComputedtomographyHighresolutioncomputedtomography(HRCT)ofthechestismoresensitiveformiliaryTB
thanplainchestradiographyandhasimprovedantemortemdiagnosis[62].Numerous2to3mmnodulescanbe
visualizeddistributedthroughoutthelung(image3).Septalthickeningusuallyaccompaniesthesenodules.These
findingsaresensitivebutnotnecessarilyspecific.InseriescorrelatingclinicalandpathologicfindingswithHRCT,
disseminatednoduleswerefoundinmanyotherinfections(Haemophilusinfluenzae,Mycoplasmapneumoniae,
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Candidaalbicans)andnoninfectiousdiseases(sarcoidosis,metastaticadenocarcinoma,lymphoma,amyloidosis,
hypersensitivitypneumonitis,andpneumoconiosis)[63,64].
OthernonspecificfindingsonchestCTcanbeobservedinmiliaryTB.Asanexample,inonestudy,groundglass
opacitiescovering>50percentofthelungfieldwereseenin20percentofpatientswithmiliaryTB[65].
OtherimagingGalliumscanscanshowdiffusepulmonaryandextrapulmonaryuptakeinmiliaryTB[66].However,
sensitivityandspecificityarelimitedpatientswithmiliaryTBandevidenceofmiliarypatternsonchestimagingmay
havenegativegalliumscans.
AbdominalimagingmayalsoshowfindingsconsistentwithmiliaryTB[67].Contrastenhancedabdominalcomputed
tomographymaydemonstratemultiplefocioflowattenuation,typicallywithoutenhancementafterintravenouscontrast
administration.Ultrasoundmayrevealmultipleechogeniclesionswithsurroundinghypoechoichalos.
DIAGNOSISEstablishingadiagnosisofmiliarytuberculosis(TB)requiressufficientclinicalsuspicionthediagnosis
canbechallengingduetononspecificclinicalsymptomsandsigns[68].Carefuldiagnosticevaluationofextrapulmonary
findingsiswarrantedwhethersystemicdiseaseissuspectedinthesettingofknownpulmonaryTBorwhether
extrapulmonarydiseaseistheinitialpresentingfactorpromptingclinicalattention.Thisisimportantbecausethenature
andscopeofextrapulmonaryfindingsobservedondiagnosticevaluationmayinfluencetheapproachtotreatment.
ClinicalapproachClinicalevaluationbeginswithathoroughhistoryandphysicalexamination(includingadilated
funduscopicexamination,whichcanbehelpfulinthediagnosisofhematogenousspreadofTB).Ingeneral,an
evaluationforpulmonarydiseaseiswarrantedinallpatientsinwhomdisseminatedTBissuspected(table6),including
chestradiography(followedbycomputedtomography,ifwarranted),sputumforacidfastsmearandculture,and
tuberculinskintest.Ifsputumcannotbeobtained,evaluationofbronchoscopyorgastricsecretionsmaybewarranted.
Inaddition,mycobacterialbloodcultureshouldbeperformedusingalysiscentrifugationorautomatedbrothsystem
designedformycobacterialculture[6971].Inregionswhereavailable,moleculartestscanbeusefulrapiddiagnostic
tools.(See'Tuberculinskintest'belowand'Acidfastsmearandculture'belowand'Moleculartests'belowand
"DiagnosisofpulmonarytuberculosisinHIVuninfectedpatients".)
Thesubsequentdiagnosticapproachshouldbetailoredtolocalizingsignsorsymptomsofdiseaseinvolvement:
Patientswithneurologicsignsorsymptomsshouldundergoneuroimagingandlumbarpuncture(iffeasible).The
mostcommonradiographicfindingsintuberculousmeningitisarebasalmeningealenhancementand/or
hydrocephalus.Cerebrospinalfluid(CSF)shouldbeanalyzedforcellcount,protein,andglucoseconcentrations,
aswellasacidfaststainingandcultureforbacterialandmycobacterialorganisms.(See"Centralnervoussystem
tuberculosis".)
Inthesettingofpleuraleffusion,pericardialeffusionorascites,fluidshouldbeobtainedforevaluationofcell
count,protein,glucose,andLDHconcentrations,aswellasacidfaststainingandcultureforbacterialand
mycobacterialorganisms.PleuralbiopsyiswarrantedinthesettingofmoderatetohighsuspicionforTBwhen
pleuralfluidevaluationisnotdiagnostic.(See"TuberculouspleuraleffusionsinHIVuninfectedpatients"and
"Tuberculouspericarditis"and"Tuberculousperitonitis".)
Patientswithsymptomsreferabletothegastrointestinalorgenitourinarytractshouldundergoradiographic
imagingoftheinvolvedsite(s).Gastrointestinaldiseasemaywarrantfurtherendoscopicand/orsurgical
evaluation.Suspectedgenitourinarydiseaseshouldprompturineacidfastbacillus(AFB)culture(urineAFB
smearsarelessusefulsincetheycanbeconfoundedbyother,nontuberculousmycobacteria).(See"Renal
diseaseintuberculosis".)
Patientswithsymptomslocalizingtootherextrapulmonarysites(lymphnodes,bones/joints,skin,andothersites)
shouldundergoevaluationaswarranteddependingontheinvolvedorgansystem.Radiographicimagingmaybe
warranted.Tissuebiopsymayberequiredtoestablishadefinitivediagnosis.(See"Tuberculouslymphadenitis"
and"Skeletaltuberculosis"and"Cutaneousmanifestationsoftuberculosis".)
Biopsyspecimensfromthelung,bonemarrow,pericardium,lymphnodes,bones,joints,bowel,liver,brain,orother
tissuesallowforbothhistopathologicexaminationandculture.Liverbiopsiesaregenerallyassociatedwiththehighest
yieldfordiagnosisofextrapulmonaryTB.Intwoseries,granulomasweredemonstratedmorefrequentlyinliverbiopsies
(91to100percent)thanbonemarrowbiopsies(31to82percent)ortransbronchialbiopsies(72and63percent)[1,2].
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Lymphnodesandserosalbiopsiesalsohadhighyieldsinpatientsintheseseries.Thebiopsyyieldislikelytobe
increasedinthesettingofassociatedclinicalorlaboratoryabnormalities.Biopsyspecimensshouldbecollectedwith
andwithoutfixativeculturerequiresspecimenswithoutfixative.(See'Histopathology'below.)
ThereisnoroleforserologictestingindiagnosisofTBsuchtestshaveverylowspecificity[7275].Whilelarge
numbersofindividualsworldwidehaveTBantibodies,onlyabout10percentofthemgoontodevelopactivedisease.
Diagnostictools
TuberculinskintestThetuberculinskintestcanbeasupportivediagnostictoolifpositive,butanegativeskin
testdoesnotexcludethediagnosisanergyisobservedmorefrequentlyamongpatientswithmiliaryTBthanthosewith
pulmonaryorisolatedextrapulmonaryinvolvementandmaybeashighas68percent[76].(See"Diagnosisoflatent
tuberculosisinfection(tuberculosisscreening)inHIVuninfectedadults",sectionon'Tuberculinskintest'.)
AcidfastsmearandcultureAcidfastcultureoftissue,fluid,ordrainagefromaninfectedlocusisthestandard
toolforestablishingthediagnosisofTB.AcidfastmicroscopymaysupportadiagnosisofTB,especiallyiforganismsor
caseatinggranulomasareseen.ThefrequencyofpositivesmearsorculturesissummarizedintheTable(table7)[1,2].
Thesedatamakeseveralimportantpoints:
Smearsforacidfastbacilliwerepositiveinaminorityofpatientswhenonlyasinglesitewassampledthe
probabilityofapositivesmearincreasedwiththenumberofsitessampled.Thus,whenpossible,samplesof
multiplesites(sputum,gastricaspirate,pleuralfluid,ascites,urine)shouldbeexaminedforthepresenceofacid
fastbacilli.
Gastricaspiratecultureswerefrequentlypositiveintheseseries.However,itwasnotclearhowoftentheywere
positivewhensputumsmearswerenegative.Itisreasonabletoobtaingastricaspiratesifsputumsmearsarenot
availableornegative.
Bronchoscopymaybewarrantedifacidfastbacilliarenotdetectedatmultiplesites(sputum,gastricaspirate,
pleuralfluid,ascites,urine)ingeneral,bronchoscopyismostusefulwhenthereisevidenceofpulmonary
involvementonchestradiography[77,78].Inthesettingofsubacuteorchronicpresentationwithnegativesputum
smears,itisreasonabletodelaybronchoscopyuntilculturesarenegativeforonetotwoweeks,particularlyifa
rapiddiagnosticassayisavailable.Inthesettingofacutepresentationorintheabsenceofrapiddiagnostictools,
promptbronchoscopyiswarranted.(See'Moleculartests'below.)
Smearsshouldbestainedwiththeacidfastfluorochromedye,auramineO,whichismoresensitivethanthe
conventionalZiehlNielsenstain[79].Rapidprobescanbeappliedtosmearpositivesputumspecimenstoconfirmthe
diagnosisofM.tuberculosis(inareaswhereavailable)[80].Specimensshouldthenbeinoculatedintoacommercial
automatedradiometricdetectionsystem(BACTEC,BectonDickson),whichisfasterandmoresensitivethanstandard
techniquesusingsolidmediumfortheisolationofM.tuberculosis[81].M.tuberculosiscanbedifferentiatedfrom
commonlyisolatednontuberculousmycobacteriabyhybridizationusingnucleicacidprobesontheliquidmedium.
Mycobacterialbloodcultures(preferablyusinglysiscentrifugationtechniques)shouldbeperformedinallpatientsin
whomhematogenousdisseminationissuspected[69].PositivebloodculturesindisseminatedTBarerelativelyrare
thoughmaybeobservedinimmunocompromisedpatients,includingthosewithHIVinfection[71,82].
HistopathologyHistopathologyoftissuebiopsyspecimensinthesettingofTBtypicallydemonstrates
granulomatousinflammation.GranulomasofTBcharacteristicallycontainepithelioidmacrophages,Langhansgiant
cells,andlymphocytes.Thecentersoftuberculousgranulomasoftenhavecharacteristiccaseation("cheeselike")
necrosisorganismsmayormaynotbeseenwithacidfaststaining.Thedemonstrationofcharacteristiccaseating
granulomasonatissuesectionintheappropriateclinicalandepidemiologiccircumstancesstronglysupportsa
diagnosisofactiveTB,butitisnotpathognomoniccultureisrequiredtoestablishalaboratorydiagnosis[83].
MoleculartestsInregionswhereavailable,moleculartestscanbeusefulrapiddiagnostictools.
NucleicacidamplificationNucleicacidamplificationassays(NAA)areusedtoamplifythequantityofM.
tuberculosisDNAindiagnosticspecimenswhereorganismsmaybepresentinamountstoosmalltobeseenbyroutine
stainingtechniques.ThesetechniquesaresensitiveforrapiddetectionofM.tuberculosisinavarietyofspecimens,
includingblood,sputum,andurine[8490].
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TwoNAAtestswereapprovedbytheUSFoodandDrugAdministration(FDA)asof2012butonlyforusewithsputum
orrespiratorysecretionsobtainedbybronchoscopy.Ofthesetests,theAmplifiedMTDtest(GenProbe)isapprovedfor
AFBsmearpositiveorsmearnegativespecimensAmplicor(Roche)isapprovedonlyforsmearpositivesamples.
Sensitivityofthesetestsisbetterinsmearpositivesamples,andapositivetestintheappropriateclinicalsettinglikely
representspulmonaryTB[91,92].
Theprimaryadvantageofthesetestsisthatapositiveresulttoestablishadiagnosismaybeavailablewithin24hours.
TheUnitedStatesCentersforDiseaseControlandPrevention(CDC)haspublishedrecommendationsfortheuseof
thesetestsinthediagnosisofTB[93].(See"DiagnosisofpulmonarytuberculosisinHIVuninfectedpatients",section
on'Nucleicacidamplification'.)
XpertMTB/RIFassayTheXpertMTB/RIFassayisanautomatednucleicacidamplificationtestthatcan
simultaneouslyidentifyM.tuberculosisandrifampinresistance.TheXpertMTB/RIFassayisapprovedbytheUnited
StatesFoodandDrugAdministrationonlyfortestingsputuminadults,althoughitmaybeappliedinanonapproved
indicationtononsputumsamplesfollowingavalidationprocessforthatindicationbythelaboratoryperformingthetest.
(See"DiagnosisofpulmonarytuberculosisinHIVuninfectedpatients",sectionon'XpertMTB/RIFassay'.)
TheXpertMTB/RIFassayisusefulfordetectionofextrapulmonaryTBinlymphnodesandcerebrospinalfluid,butthe
sensitivityinpleuralfluidislow[9496].Inasystemicreviewandmetaanalysisincluding18studies,thesensitivityand
specificityfortheXpertMTB/RIFassay(comparedwithculture)inlymphnodeswere83and94percent,respectively,in
cerebrospinalfluidwere81and98percent,respectively,andinpleuralfluidwere46and99percent,respectively[96].
OthermoleculartestsManyhospitalandclinicallaboratoriesoffernucleicacidamplificationtestingforM.
tuberculosiscomplexusingmolecularmethods(eg,polymerasechainreaction[PCR])notapprovedbytheFDAbut
validatedinternallywithinthetestinglaboratoryaccordingtoawrittenprotocol.These"inhouse"testsgenerallyoffer
highspecificityand,ifpositive,maybeusefulinsupportingaclinicaldiagnosisofTB.
DIFFERENTIALDIAGNOSISThedifferentialdiagnosisofmiliarytuberculosisisbroadanddependsonthedegree
ofdisseminationandtheinvolvementofspecifictissuesandorgans.Theanatomicdistributionofgranulomatouslesions
withinthelungonhighresolutioncomputedtomography(CT)scanningcanbehelpfulfordistinguishing
hematogenouslydisseminatedprocesseslikemiliarytuberculosis(whichexhibitsarandomdistributionoflesions)from
airwaycentereddisorders(suchasinhalationaldiseases)andlymphaticcenteredprocesses(suchassarcoidosis)[97].
Amiliarypatternonchestimagingmaybeduetomanyconditions,including(table5):
HistoplasmosisClinicalmanifestationsofhistoplasmosisincludefever,fatigue,hepatosplenomegaly,and
pancytopenia.Pulmonarymanifestationsmayincludepneumonia,adenopathy,lungmass,lungnodule(s),and/or
cavitarylungdisease.Thediagnosisisestablishedviahistopathology,culture,antigendetection,orserology.(See
"Diagnosisandtreatmentofpulmonaryhistoplasmosis".)
SarcoidosisClinicalmanifestationsofsarcoidosisincludecough,dyspnea,chestpain,eyelesions,and/orskin
lesions.Bilateralhilaradenopathyisaclassicchestradiographfindingitmaybeabsentand/oroccurin
combinationwithparenchymalopacities.Thediagnosisisbasedoncompatibleclinicalandradiographic
manifestationsandhistopathologicdetectionofnoncaseatinggranulomas.(See"Clinicalmanifestationsand
diagnosisofpulmonarysarcoidosis".)
HypersensitivitypneumoniaSubacuteorchronichypersensitivitypneumonitisischaracterizedbyproductive
cough,dyspnea,fatigue,anorexia,andweightloss.Thediagnosisisbaseduponexposurehistory,clinical
assessment,radiographicandphysiologicfindings,andtheresponsetoavoidanceofthesuspectedetiologic
agent.(See"Classificationandclinicalmanifestationsofhypersensitivitypneumonitis(extrinsicallergic
alveolitis)".)
TalcgranulomatosisClinicalmanifestationsoftalcgranulomatosisareusuallynonspecificsuchasdyspnea,
cough,oranincreaseinsputumproduction.Somepatientsareasymptomaticnightsweats,weightloss,and
hemoptysisoccurlesscommonly.Clinicalhistoryandradiographicfindingsareoftenhighlysuggestivewhenthe
diagnosisisunclearflexiblebronchoscopywithbronchoalveolarlavageiswarranted.(See"Foreignbody
granulomatosis".)

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PulmonaryhemosiderosisTheclinicalpresentationofpulmonaryhemosiderosisvariesfromanacuteonset
illnesswithhemoptysisanddyspneatoaninsidiousprocesscharacterizedbyfatigue,anemia,andslowly
progressiveexertionaldyspnea.Radiographydemonstratesbilateralgroundglassalveolaropacities.
Hemosiderinladenalveolarmacrophagesmaybeidentifiedinsputum,bronchoalveolarlavagefluid,andlung
biopsy.(See"Idiopathicpulmonaryhemosiderosis".)
PrimarybronchoalveolarcarcinomaRadiographicfindingsofbronchioloalveolarcarcinomamaybevariableand
rangefromasolitaryorlimitednumberofnodulestomoreextensivemiliarydiseaseordiffuseparenchymal
infiltrates.Thediagnosisisestablishedviahistopathology.(See"Bronchioloalveolarcarcinoma,including
adenocarcinomainsitu".)
TumormetastasesMetastaticdiseasefromprimaryneoplasmssuchasthyroidorkidneymaypresentwith
radiographicnodulesoramiliaryappearance.Thediagnosisisestablishedviahistopathology.(See"Differential
diagnosisandevaluationofmultiplepulmonarynodules".)
SpreadofpyogenicinfectionfromaremotesiteBacterialinfectionmayreachthelungviahematogenousspread
and/orviasepticembolization.Thediagnosisisestablishedviabacterialculture.(See"Complicationsand
outcomeofinfectiveendocarditis",sectionon'Septicembolization'.)
TREATMENTIngeneral,theapproachtoantimicrobialtherapyfortreatmentofmiliarytuberculosis(TB)isthesame
asforpulmonaryTB[98].Thisapproachisbaseduponretrospectivereviewofarelativelysmallnumberofpatientswith
extrapulmonaryTB,sinceextrapulmonaryTBismuchlesscommonthanpulmonaryTB.Whilethedatasuggestthat
thisapproachissuccessful,individualizationofregimensmaybewarranted.(See"Treatmentofpulmonarytuberculosis
inHIVuninfectedadults"and"TreatmentofpulmonarytuberculosisinHIVinfectedadults".)
ModificationstothestandarddrugregimenmaybewarrantedinthesettingofdrugresistantTB.Inaddition,longer
durationoftherapymaybewarrantedforchildren,immunocompromisedhosts,patientswithalargeorganismburden,
andpatientswithaslowmicrobiologicorclinicalresponse.Longerdurationoftherapyisalsowarrantedforpatientswith
diseaseinvolvingthecentralnervoussystem(CNS),somepatientswithboneorjointdisease,andsomecasesof
lymphadenitis(asiteofearlyrelapseinanecdotalreports)[99].Dependingonthesite(s)andscopeofdisease,surgical
interventionmaybeneededfordiagnosticand/ortherapeuticmanagement.
DataontheroleofcorticosteroidsinpatientswithmiliaryTBarelimitedresultsofcasereportsandsmallclinicalseries
usingcorticosteroidsinmiliaryTBareconflicting[27].Insomecircumstances,corticosteroidsarewarrantedfor
treatmentofTBinvolvingtheCNS[100]orpericardium[101].(See"Centralnervoussystemtuberculosis",sectionon
'Glucocorticoids'.)
OUTCOMETheclinicalcourseandoutcomesofmiliarytuberculosis(TB)haveimprovedmarkedlybetweenthepre
antibioticandpostantibioticeras[29,102].IntheUnitedStatesVeteran'sAdministrationstudyofmiliaryTB(excluding
meningitis),theattributablemortalitydroppedsuccessively(fromnearly100percent)withtheintroductionofeachnew
drug.Mortalitydroppedwiththeintroductionofstreptomycin(to47percent),withstreptomycinplusparaaminosalicylic
acid(to18percent),andwithisoniazidbasedcombinationtherapy(to5percent)[102].Subsequently,twolargeseries
notedmortalityofapproximately20percent[1,2].Thesestudiesincludedrelativelydiversepopulationswitharangeof
underlyingdiseasesanddidnotexcludemeningealTB.Sincetheintroductionofisoniazidbasedtherapy,caseseries
havedocumentedshorterdurationoffeverandmorerapidclinicalandradiographicimprovement.Inonestudy,the
mediantimetodefervescencewassevendays(range1to55days)76percentofpatientswereafebrilewithin14days
oftheinitiationoftherapy[1].
ThefactorsthatcontributetosurvivalinmiliaryTBaredifficulttoassess,sincetheliteratureisgenerallylimitedto
retrospectivecaseandincludespatientswithvariableclinicalandlaboratorypresentations.However,centralnervous
systemdiseaseappearstobeanindependentpredictorofmortalityinmoststudies[2,3,102].Pancytopeniaor
lymphopeniawerepoorprognosticindicatorsinsomestudies[1,56].Age,latepresentation,seriousunderlyingdisease,
andanonreactivetuberculinskintestarecitedinotherstudiesaspredictorsofmortality[103].
PREVENTIONMiliarytuberculosis(TB)canbepreventedbytreatmentoflatentTBinfection.Inaddition,childhood
administrationofBacillusCalmetteGurin(BCG)inendemicareasreducestheincidenceofmiliaryTB.Alargemeta
analysisfounda78percentprotectiveeffectofthevaccineagainstmiliaryTB[104].(See"Treatmentoflatent
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tuberculosisinfectioninHIVuninfectedadults"and"TreatmentoflatenttuberculosisinfectioninHIVinfectedadults"
and"BCGvaccination".)
SUMMARY
Miliarytuberculosis(TB)referstoclinicaldiseaseresultingfromthehematogenousdisseminationof
Mycobacteriumtuberculosis.MiliaryTBcanariseasaresultofprogressiveprimaryinfectionorviareactivationof
alatentfocuswithsubsequentspread.TheclinicalpresentationofmiliaryTBishighlyvariablemanifestationscan
beacutebutaremorelikelytobesubacuteorchronic.(See'Introduction'above.)
Acutediseasemaybefulminant,includingmultiorgansystemfailure,asyndromeofsepticshockandacute
respiratorydistresssyndrome(ARDS).Patientswithsubacuteorchronicdiseasemaypresentwithfailureto
thrive,feverofunknownorigin,ordysfunctionofoneormoreorgansystems.Themostcommonextrapulmonary
sitesofdiseaseincludethelymphaticsystem,bonesandjoints,andtheliver.Theclinicalapproachtoevaluation
ofTBatextrapulmonarysitesisdiscussedindetailseparately.(See'Clinicalmanifestations'above.)
Themostcommonlaboratoryabnormalitiesincludeanemiaandotherhematologicfindings.Otherlaboratory
abnormalitiesmayincludeelevatedacutephasereactants,hyponatremia,hypercalcemiaandsterilepyuria.The
classicchestradiographappearanceisafaint,reticulonodularinfiltratedistributedfairlyuniformlythroughoutthe
lungs(image2).Otherchestradiographabnormalitiesincludepleuralreactions,hilarormediastinaladenopathy,
interstitialoralveolarinfiltrates,orcavities.Computedtomographyofthechestismoresensitiveforevaluationof
miliaryTBthanplainchestradiography(See'Laboratoryfindings'aboveand'Radiographicimaging'above.)
Clinicalevaluationbeginswithathoroughhistoryandphysicalexamination.Ingeneral,anevaluationfor
pulmonarydiseaseiswarrantedinallpatientsinwhomdisseminatedTBissuspected.Inaddition,mycobacterial
bloodcultureshouldbeperformed.Inregionswhereavailable,moleculartestscanbeusefulrapiddiagnostic
tools.(See'Clinicalapproach'above.)
Thesubsequentdiagnosticevaluationshouldbetailoredtolocalizingsignsorsymptomsofdiseaseinvolvement.
Patientswithneurologicsignsorsymptomsshouldundergoneuroimagingandlumbarpuncture(iffeasible).Inthe
settingofpleuraleffusion,pericardialeffusion,orascites,fluidshouldbeobtainedforevaluationandabiopsy
stronglyconsidered.Radiographicimagingoftheinvolvedsite(s)maybewarrantedforpatientswithsymptoms
referabletothegastrointestinaltract,genitourinarytract,bones/joints,orlymphnodes.Suspectedgenitourinary
diseaseshouldprompturineacidfastbacillus(AFB)culture.Dependingontheinvolvedsite(s),tissuebiopsymay
berequiredtoestablishadefinitivediagnosis.(See'Clinicalapproach'above.)
Biopsyspecimensallowforbothhistopathologicexaminationandacidfastculture.Biopsysiteswithrelatively
goodyieldincludethepleura,liver,bonemarrow,lymphnodes,andtransbronchialbiopsiestheyieldislikelyto
beincreasedinthesettingofassociatedclinicalorlaboratoryabnormalities.Histopathologytypicallydemonstrates
granulomatousinflammation.Tuberculousgranulomascharacteristicallycontainepithelioidmacrophages,
Langhansgiantcells,andlymphocytes,andthecentersoftenhavecharacteristiccaseation("cheeselike")
necrosis.(See'Histopathology'above.)
Ingeneral,theapproachtoantimicrobialtherapyfortreatmentofmiliaryTBisthesameasforpulmonaryTB,
althoughmodificationsmaybewarrantedinthesettingofdrugresistantTB.Inaddition,longerdurationoftherapy
maybewarrantedforchildren,immunocompromisedhosts,patientswithalargeorganismburden,andpatients
withaslowmicrobiologicorclinicalresponse.Longerdurationoftherapyisalsowarrantedforpatientswith
diseaseinvolvingthecentralnervoussystem,somepatientswithboneorjointdisease,andsomecasesof
lymphadenitis.Surgicalinterventionmaybeneededfordiagnosticand/ortherapeuticmanagementinsomecases.
(See'Treatment'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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prospectivecohortstudy.ClinInfectDis201255:242.
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medlib.med.utah.edu/WebPath/TUTORIAL/MTB/MTB.html(AccessedonMarch23,2006).
84.ShinnickTM,JonasV.Molecularapproachestothediagnosisoftuberculosis.In:Tuberculosis:pathogenesis,
protectionandcontrol,BloomBR(Ed),AmericanSocietyofMicrobiologyPress,WashingtonDC1994.p.517.
85.ClarridgeJE3rd,ShawarRM,ShinnickTM,PlikaytisBB.Largescaleuseofpolymerasechainreactionfor
detectionofMycobacteriumtuberculosisinaroutinemycobacteriologylaboratory.JClinMicrobiol199331:2049.
86.KanekoK,OnoderaO,MiyatakeT,TsujiS.Rapiddiagnosisoftuberculousmeningitisbypolymerasechain
reaction(PCR).Neurology199040:1617.
87.AkcanY,TuncerS,HayranM,etal.PCRondisseminatedtuberculosisinbonemarrowandliverbiopsy
specimens:correlationtohistopathologicalandclinicaldiagnosis.ScandJInfectDis199729:271.
88.FolgueiraL,DelgadoR,PalenqueE,etal.RapiddiagnosisofMycobacteriumtuberculosisbacteremiabyPCR.J
ClinMicrobiol199634:512.
89.SchlugerNW,RomWN.Thepolymerasechainreactioninthediagnosisandevaluationofpulmonaryinfections.
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90.AcetiA,ZanettiS,MuraMS,etal.IdentificationofHIVpatientswithactivepulmonarytuberculosisusingurine
basedpolymerasechainreactionassay.Thorax199954:145.
91.PanelonOpportunisticInfectionsinHIVInfectedAdultsandAdolescents.Guidelinesforthepreventionand
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forDiseaseControlandPrevention,theNationalInstitutesofHealth,andtheHIVMedicineAssociationofthe
InfectiousDiseasesSocietyofAmerica.http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf(Accessedon
April20,2015).
92.HavlirDV,BarnesPF.Tuberculosisinpatientswithhumanimmunodeficiencyvirusinfection.NEnglJMed1999
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93.CentersforDiseaseControlandPrevention(CDC).Updatedguidelinesfortheuseofnucleicacidamplification
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95.TortoliE,RussoC,PiersimoniC,etal.ClinicalvalidationofXpertMTB/RIFforthediagnosisofextrapulmonary
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96.DenkingerCM,SchumacherSG,BoehmeCC,etal.XpertMTB/RIFassayforthediagnosisofextrapulmonary
tuberculosis:asystematicreviewandmetaanalysis.EurRespirJ201444:435.
97.DalpiazG,PiolantiM,CancellieriA,BarozziL.Diffusegranulomatouslungdisease:combinedpathologicalHRCT
approach.RadiolMed2014119:54.
98.AmericanThoracicSociety.MedicalSectionoftheAmericanLungAssociation:Treatmentoftuberculosisand
tuberculosisinfectioninadultsandchildren.AmRevRespirDis1986134:355.
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100.DooleyDP,CarpenterJL,RademacherS.Adjunctivecorticosteroidtherapyfortuberculosis:acriticalreappraisal
oftheliterature.ClinInfectDis199725:872.
101.CentersforDiseaseControlandPrevention(CDC),AmericanThoracicSociety.Update:adverseeventdataand
revisedAmericanThoracicSociety/CDCrecommendationsagainsttheuseofrifampinandpyrazinamidefor
treatmentoflatenttuberculosisinfectionUnitedStates,2003.MMWRMorbMortalWklyRep200352:735.
102.FALKA.U.S.VETERANSADMINISTRATIONARMEDFORCESCOOPERATIVESTUDYONTHE
CHEMOTHERAPYOFTUBERCULOSIS.13.TUBERCULOUSMENINGITISINADULTS,WITHSPECIAL
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104.ColditzGA,BrewerTF,BerkeyCS,etal.EfficacyofBCGvaccineinthepreventionoftuberculosis.Metaanalysis
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GRAPHICS
Comparativesizeofmilletseeds

Milletseedsfromwhichthenamemiliarytuberculosisderivescompared
tothesizeofadime(right)andacentimeterscale(left).These
correspondtotheapproximatesizeofmiliarylesionsseenonchest
radiograph.
CourtesyofNesliBasgoz,MD.
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Majorclinicalseriesofmiliarytuberculosis
First
author,
year

Years
included

Maartens,
1990

1978to
1987

Groote
Schuur
Hospital
(community
based
teaching
hospitalin
SouthAfrica)

Kim,1990

1975to
1988

Gelb,
1973

1960to
1970

#of
patients

Percent
male

Race,
percent

Miliarypatternon
CXRplusMTBon
culturefromany
siteorbiopsyor
autopsyevidenceof
miliaryorgan
involvementwithTB

109

51

African,
45,mixed,
49,white,
6

Duke
University
Medical
Centerand
DurhamVA
Hospital
Durham,
North
Carolina

Dischargediagnosis
ofdisseminatedor
miliaryTB

38

50

African
American,
50*

UCLAHospital
LosAngeles,
California

Miliarypatternon
CXRandoneor
more:

109

59

African
American,
81

69

65

African
American,
87

Location

Inclusion
criteria

1.MTBonculture
2.Biopsyorautopsy
showingcaseating
granulomaswithAFB
3.Clinical
presentationand
responseconsistent
withTB
Munt,
1971

1954to
1970

Sanitorium
drawingfrom
easternpart
ofNorth
Carolina

"Acute,diffuse
pulmonaryand
extrapulmonary
disseminationofTB,
usuallyassociated
withamiliary
patternonCXR,with
eitherMTBby
cultureorresponse
toTBtherapy"

Proudfoot,
1969

1954to
1967

Edinburgh,
Scotland

"Adultsdiagnosedin
Edinburghashaving
disseminatedTB"

40

40

Non
British,<1

Biehl,
1957

1951to
1956

Cincinatti
General(city
teaching

Bacteriologicor
pathologicdiagnosis
ofmiliary

68

69

African
American,
23

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hospital
Cincinatti,
Ohio)

tuberculosisor
probablediagnosis
withresponseto
therapy

CXR:chestradiographMTB:MycobacteriumtuberculosisTB:tuberculosisAFB:acidfastbacilli.
*ExcludingVApopulation.
CourtesyofNesliBasgoz,MD.
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Symptomsinpatientswithmiliarytuberculosis
Maartens,
1990

Kim,
1990

Gelb,
1973

Munt,
1971

Proudfoot,
1969

Biehl,
1957

Feverand/ornightsweats

96*

89

85

83

83

35

Anorexia

92

78

87

91

42

Weightloss

92

66

87

85

75

61

Weaknessormalaise

92

92

78

40

Respiratory(cough,dsypnea,
pleuriticchestpain)

72

55

69

78

18

91

Gastrointestinal(abdominal
pain,nausea,vomiting,
diarrhea)

21

12

32

Headacheorcentralnervous
system

25

16

10

27

Musculoskeletal

13

Symptom

*Allofthenumbersrecordedarepercentages.
CourtesyofNesliBasgoz,MD.
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Physicalsignsinpatientswithmiliarytuberculosis
Sign

Maartens,
1990

Kim,
1990

Gelb,
1973

Munt,
1971

Proudfoot,
1969

Fever

96*

90

85

84

82

Pulmonary(rales,rhonchi,
rubs,signsofeffusion)

72

50

51

46

Hepatomegaly

52

16

31

36

20

Splenomegaly

15

13

11

13

10

Neurologic(alteredmentalstatus,
meningismus)

20

32

15

26

10

Ascites

Jaundice

Dermatologic

PositivePPD

42

28

53

PPD:purifiedproteinderivative.
*Allnumbersarepercentages.
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Miliarylesions

Milletseedsaresmallgrains(averagediameter<2mm)thatare
consumedwithouttheirouterlayerbeingremoved.Pearlmillet
(Pennisetumtyphoides,bajra)isshownhere.Thesegrains(inset,upper
right)correspondtotheapproximatesizeofmiliarylesionsonthehigh
resolutioncomputertomographyscanofthechest(inset,lowerleft).
Reproducedfrom:SharmaSK,MohanA,SharmaA,MitraDK.Miliary
tuberculosis:newinsightsintoanolddisease.LancetInfectDis20055:415.
IllustrationusedwiththepermissionofElsevierInc.Allrightsreserved.
Graphic83409Version2.0

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Tuberculousuretericstricture

Intravenousurogramshowingdiseasedleftkidneywith
hydroureteronephrosisbecauseofstrictureoflowerureter.Thebladder
isofsmallcapacity.
From:GoelA,DalelaD.Optionsinthemanagementoftuberculousureteric
stricture.IndianJUrol200824:376.DOI:10.4103/09701591.42621.
ReproducedwithpermissionfromWoltersKluwerMedKnow.Copyright
2008UrologicalSocietyofIndia.Unauthorizedreproductionofthismaterial
isprohibited.
Graphic96429Version1.0

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Laboratoryfindingsinpatientswithmiliarytuberculosis
Maartens,
1990

Laboratoryfinding

Kim,
1990

Munt,
1971

Proudfoot,
1969

Anemia

52*

38

58

12

Leukopenia

15

25

12

Leukocytosisorleftshift

14

61

11

Thrombocytopenia

23

Thrombocytosis

24

Hyponatremia

78

68

29

Elevatedalkaline
phosphatase

83

34

Transaminitis

42

Hyperbilirubinemia

15

24

ElevatedESR>50

68

97

Hypoxemia(pO2<60)

40

Sterilepyuria

32

ESR:erythrocytesedimentationrate.
*Numbersarepercentages.
CourtesyofNesliBasgoz,MD.
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Chestradiographofmiliarytuberculosis

Afullposterioranteriorradiographofthechestshowsdiffuseinvolvement(left).The
rightpanelismagnified,illustratingthereticulonodularpatternofmiliarytuberculosis.
CourtesyofJoAnneShepard,MD,MassachusettsGeneralHospital,Boston.
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Differentialdiagnosisoffebrileillnesswithmiliarychestxrayinfiltrates
InfectiousDiseases
Mycobacterial
Mycobacteriumtuberculosis
Atypicalmycobacteria
Fungal
Endemicfungi(histoplasmosis,coccidioidomycosis,blastomycosis,paracoccidioidomycosis)
Bacterial
Legionellamicdadeiinfection
Nocardiosis
Staphylococcusaureus,Haemophilusinfluenzaeandotherpyogenicbacteria
Psittacosis
Tularemia
Bartonellosis
Brucellosis
Meliodosis
Viral
Varicella
Cytomegalovirus
Influenza
Measles
Parasitic
Toxoplasmosis
Strongyloidiasis
Schistosomiasis

Neoplasticdiseases
Lymphoma
Lymphangiticspreadofcarcinoma
Mesothelioma

Otherdiseases
Sarcoidosis
Amyloidosis
Hypersensitivitypneumonitis
Pneumoconioses
Foreignbodyinducedvasculitisrelatedtoinjectiondruguse
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Highresolutioncomputedtomographyofthechest
inapatientwithmiliarytuberculosis

Numerous2mmnodulesandseptalthickeningareseendiffusely
throughoutthelung.
CourtesyofJoAnneShepard,MD,MassachusettsGeneralHospital,Boston.
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Guidelinesfortheevaluationofpulmonarytuberculosisinadultsinfive
clinicalscenarios
Patientandsetting

Recommendedevaluation

Anypatientwithacoughof2to3weeks'
duration,withatleastoneadditionalsymptom,
includingfever,nightsweats,weightloss,or
hemoptysis

Chestradiograph:IfsuggestiveofTB*,collect
threesputumspecimensforAFBsmearmicroscopy
andculture.Atleastonespecimenshouldalsobe
testedusinganNAAtest.

AnypatientathighriskforTB withan

Chestradiograph:IfsuggestiveofTB*,collect

unexplainedillness,includingrespiratory
symptoms,of2to3weeks'duration

threesputumspecimensforAFBsmearmicroscopy
andculture.Atleastonespecimenshouldalsobe
testedusinganNAAtest.

AnypatientwithHIVinfectionandunexplained
coughandfever

Chestradiograph,andcollectthreesputum
specimensforAFBsmearmicroscopyandculture.
Atleastonespecimenshouldalsobetestedusing
anNAAtest.

AnypatientathighriskforTB withadiagnosisof
communityacquiredpneumoniawhohasnot
improvedaftersevendaysoftreatment

Chestradiograph,andcollectthreesputum
specimensforAFBsmearmicroscopyandculture.
Atleastonespecimenshouldalsobetestedusing
anNAAtest.

AnypatientathighriskforTB withincidental
findingsonchestradiographsuggestiveofTBeven
ifsymptomsareminimalorabsent

Reviewofpreviouschestradiographsifavailable,
threesputumspecimensforAFBsmearmicroscopy
andculture.Atleastonespecimenshouldalsobe
testedusinganNAAtest.

TB:tuberculosisAFB:acidfastbacilliNAA:nucleicacidamplification.
*Infiltrateswithorwithoutcavitationintheupperlobesorthesuperiorsegmentsofthelowerlobes.
Patientswithoneofthefollowingcharacteristics:recentexposuretoapersonwithacaseofinfectiousTB
historyofapositivetestresultforMycobacteriumtuberculosisHIVinfectioninjectionornoninjectiondrug
useforeignbirthandimmigration5yearsfromaregioninwhichincidenceishighresidentsandemployees
ofhighriskcongregatesettingsmembershipinamedicallyunderserved,lowincomepopulationoramedical
riskfactorforTB(includingdiabetesmellitus,conditionsrequiringprolongedcorticosteroidandother
immunosuppressivetherapy,chronicrenalfailure,certainhematologicalmalignanciesandcarcinomas,weight
>10percentbelowidealbodyweight,silicosis,gastrectomy,orjejunoilealbypass).
Chestradiographperformedforanyreason,includingtargetedtestingforlatentTBinfectionandscreening
forTBdisease.
Adaptedfrom:ControllingtuberculosisintheUnitedStates.RecommendationsfromtheAmericanThoracic
Society,CDC,theInfectiousDiseasesSocietyofAmerica.MMWRRecommRep200554(RR12):1.DaleyCL,
GotwayMB,JasmerRM.Radiographicmanifestationsoftuberculosis:aprimerforclinicians.SanFrancisco,
CA:FrancisJCurryNationalTuberculosisCenter2003:130,andUpdatedguidelinesfortheuseofnucleic
acidamplificationtestsinthediagnosisoftuberculosis.MMWRMorbMortalWklyRep200958:7.
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Frequencyofpositivesmearorcultureinpatientswithmiliary
tuberculosis
Site

Maartens,1990

Kim,1990

Sputumsmear

33*

36

Sputumculture

62

76

BALsmear

27

BALculture

55

54

Gastricaspiratesmear

43

Gastricaspirateculture

100

75

Urinesmear

14

Urineculture

33

59

CSFsmear

CSFculture

60

Serosalsmear

Serosalculture

44

14

BAL:bronchoalveolarlavageCSF:cerebrospinalfluid.
*Allnumbersarepercentages.
9ascites,7pleural,2pericardial.
Allpleural.
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ContributorDisclosures
JohnBernardo,MDNothingtodisclose.CFordhamvonReyn,MDNothingtodisclose.ElinorLBaron,MD,DTMH
Nothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby
vettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthe
content.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsof
evidence.
Conflictofinterestpolicy

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