Challenges in the diagnosis & treatment of miliary ... · Key words Complications - diagnosis -...

Challengesinthediagnosis&treatmentofmiliarytuberculosis

SurendraK.Sharma,AlladiMohan*&AbhishekSharma**

Department of Medicine, All India Institute of Medical Sciences, New Delhi, *Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, India & **University of Medicine, Pleven, Bulgaria

ReceivedAugust2,2011

Miliary tuberculosis (TB) is a potentially lethal disease if not diagnosed and treated early. Diagnosing miliary TB can be a challenge that can perplex even the most experienced clinicians. Clinical manifestations are nonspecific, typical chest radiograph findings may not be evident till late in the disease, high resolution computed tomography (HRCT) shows randomly distributed miliary nodules and is relatively more sensitive. Ultrasonography, CT and magnetic resonance imaging (MRI) are useful in discerning the extent of organ involvement by lesions of miliary TB in extra-pulmonary locations. Fundus examination for choroid tubercles, histopathological examination of tissue biopsy specimens, conventional and rapid culture methods for isolation of Mycobacterium tuberculosis, drug-susceptibility testing, along with use of molecular biology tools in sputum, body fluids, other body tissues are useful in confirming the diagnosis. Although several prognostic markers have been described which predict mortality, yet untreated miliary TB has a fatal outcome within one year. A high index of clinical suspicion and early diagnosis and timely institution of anti-tuberculosis treatment can be life-saving. Response to first-line anti-tuberculosis drugs is good but drug-induced hepatotoxicity and drug-drug interactions in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients pose significant problems during treatment. However, sparse data are available from randomized controlled trials to define the optimum regimen and duration of treatment in patients with drug-sensitive as well as drug-resistant miliary TB, including those with HIV/AIDS.

Key words Complications-diagnosis-humanimmunodeficiencyvirus-miliarytuberculosis-treatment

703

Review Article

Introduction

In1700,JohnJacobManget1describedaformofdisseminated tuberculosis (TB) and likened the tinytuberclesevidentongrosspathologicalexaminationtothatofinnumerablemilletseedsinsizeandappearance.He coined the term miliary TB (derived from theLatinwordmiliarius,meaningrelated tomilletseed)todenotethisfatalformofdisseminatedTB.Miliary

TB results from a massive lymphohaematogeneousdissemination from a Mycobacterium tuberculosis-ladenfocus2-4(Fig.1).

MiliaryTBstillremainsaperplexingdiseasethatcontinues to elude themost erudite and experiencedcliniciansandisadiagnosticandtherapeuticchallenge.Mortalityfromthisdiseasehasremainedhighdespiteeffectivetherapybeingavailable.Themyriadclinical

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denominatorsused, lackof a“gold standard” for thediagnosisandvariationinthenatureofinvasivemethodsusedforsecuringtissuetoconfirmthediagnosis,sparseautopsydataregardingmiliaryTBinchildrencertainconclusionscanbedrawnregardingtheepidemiologyof miliary TB. Among immunocompetent adults,miliaryTBaccountsforlessthan2percentofallcasesofTB and up to 20 per cent of all extra-pulmonaryTB(EPTB)casesinvariousclinicalstudies5-12.InlateHIV infection,EPTB accounts formore than 50 percent of all cases of TB4. In autopsy studies13-19, thecorresponding figures have been higher; miliary TBaccountsfor0.3 to13.3percentofallautopsiesand11.9 to 40.5 per cent of all cases ofTB. In the pre-antibioticera,miliaryTBwaspredominantlyadiseaseof infants and children20,21. Currently, two peaks areevident- one involving adolescents and young adultsandanotherlaterinlifeamongelderlypersons4,9,11,22-44.MalesseemtobemorefrequentlyaffectedbymiliaryTBinpaediatricaswellasadultseries4,9,11,22-44.Afewrecent adult series on miliary TB9,19,29,33 describe afemale preponderance probably reflecting increasedawarenessandutilizationofhealthservicesbywomen. In USA, a higher incidence ofmiliary TB has beendescribedinAfricanAmericansinsomeoftheearlierpublications though such a trend is not evident fromrecentdata4,24,34.

Predisposing, associated conditions

Severalpredisposingorassociatedconditionshavebeen described in patients with miliary TB. These

Fig. 1.Chestradiograph(postero-anteriorview)(A) andchestCT(lungwindow)(B)showingclassicalmiliarypattern.

manifestations, atypical radiographic findings anddifficulties in establishing TB as the aetiologicaldiagnosis, among others, are challenges in diagnosisandtreatmentofmiliaryTB(TableI).

In this review, we first provide an overviewregarding the epidemiology, current understandingof key pathogenetic mechanisms, molecular basis ofdissemination,predisposingandassociatedconditions,the varied clinical manifestations that have beendocumentedinmiliaryTB,andthenthechallengesinthediagnosisandtreatmentofmiliaryTBareaddressed.

Burden of the problem

Mortality from this disease has remained highdespite effective therapy being available. For along time, miliary TB has been considered to be achildhood disease. However, during the last threedecades, it is increasinglybeing recognized inadultsaswell.Severalreasonsarethoughttoberesponsiblefor this changing epidemiological trend. Theseinclude: human immunodeficiency virus/acquiredimmunodeficiency syndrome (HIV/AIDS), everincreasing list of causes of immunosuppression,such as use of biologicals and immunosuppressivedrugs for treatment of various medical disorders,increasingoccurrenceoforgantransplantation,chronichaemodialysisprogramme,amongothers.

Interpretation of published epidemiological dataonmiliaryTBishamperedbycertainmethodologicalissues.Evenaftergivingallowancefornon-availabilityofcommunitybaseddataontheprevalence,different

includechildhoodinfections,malnutrition,HIV/AIDS,alcoholism,diabetesmellitus,chronickidneydisease,dialysis, post-gastrectomy, organ transplantation,connective tissue disorders, pregnancy, postpartum,presenceofanunderlyingmalignancy,andsilicosis4.However,theirpathogeneticsignificanceisnotclear.

Inadditiontocorticosteroids,immunosuppressiveand cytotoxic drugs are known to predispose to thedevelopmentofmiliaryTB,useofimmunomodulatordrugs(biologicals)hasbeendocumentedtocausefatalTB including miliary TB in rheumatoid arthritis45-48.Theseincludeanti-tumournecrosisfactor(TNF)agentsinfliximab48,etanercept47,andadalimumab46.Inarecentprospective study amongpatientswho received anti-TNF therapy45, EPTB constituted 62 per cent of allcasesofTB;disseminatedandmiliaryTBaccountedfor27.5percentofallTBcases,44percentofextra-pulmonaryTB. The rate of development of TBwashigher for adalimumab and infliximab than foretanercept.ThemediantimetodevelopmentofTBwaslowest for infliximab compared with etanercept andadalimumab (Table II). Patients with non-white

ethnicityhada6-foldhigherriskofTBcomparedwithwhitepatients45.

Several procedures and interventions have beenimplicatedinthecausationofmiliaryTB.Theseincludeureteral catheterization, extracorporeal shockwavelithotripsy, laser lithotripsy, cardiac valve homograftreplacement, intravesical bacille Calmette-Guerin(BCG)therapyforurinarybladdercarcinoma49-53.

Table II. RiskofdevelopingmiliaryTBwiththeuseofanti-TNFagentsinpatientswithrheumatoidarthritisVariable Infliximab Adalimumab Etanercept

RateofdevelopmentofmiliaryTB(events/100,000person-years)

136 144 39

MediantimetodevelopmentofTB(months)

5.5 18.5 13.4

TB,tuberculosis;TNF,tumournecrosisfactorDatafromreference45

Table I.WhymiliaryTBisachallengefordiagnosisandtreatment?Cliniciansmaynotbefamiliarwiththeatypicalpresentation(s),suchas,presentationwithnormalchestradiograph,abnormal•behaviourinTBmeningitis,hyponatraemia,ARDS,andskinmanifestations,etc.Fundusexaminationfollowingmydriaticadministrationmaynotbearoutinepracticeinhealthcarefacilities.•Patientsmaybetoosicktoundergovariousinvestigations.•Patientsgenuinely arenot able toproduce sputum,bodyfluidsmaybe absent,maynothavemeningitis; sometimes, sputum•specimenmaybenegative,bodyfluids,tissuespecimensmaybedifficulttoprocure;stateof-the-artfacilitiesandexpertisemaynotbeavailableexceptintertiarycarecenters.Qualityassured,periodicallyaccreditedlaboratoryinfrastructuremaynotbeavailableforcarryingoutmycoabcterialcultureand•drug-susceptibilitytestingandmoleculardiagnosis.Evenwhenappropriatespecimensaresubmitted,especiallyinHIV-negativemiliaryTB,thesespecimensmayyieldgenuinely•negativeresultsbecauseEPTBisapaucibacillarydisease.Treatment:choosingtherightanti-tuberculosisdrugregimen,additionofsteroids,durationofanti-tuberculosistreatment,lackof•laboratorymonitoringfacilities,difficultiesinthemanagementofcomplications(especiallyinperipheralcentresduetolackofexpertise)arealltherapeuticchallenges.Notassessingtheextentoforgansysteminvolvementinitially(e.g.,TBmeningitis)mayresultinsub-optimaldurationoftherapy.WhiletreatingTB,drugsshouldbegenuinewithgoodbioavailabilitywhichmaynotbethecaseinresource-constrainednations•wherethediseaseismostprevalent.Insomesituations,especiallyinHIVco-infectedpatients,despiteregularanti-tuberculosisdrugintake,adequateplasmalevels•maynotbeachievedduetomalabsorptionproblems.ART andATT: several issues that are still not clear, like adequate staff training for recognition of adverse effects and close•monitoringofco-drugtoxicities,scarcityofqualityassuredlaboratoryfacilitieswherethediseaseiscommon,IRISdiagnosis(adequateeducationofthepatientsforrecognitionofdrugtoxicities,drugadherenceissues).

TB,tuberculosis;HIV,humanimmunodeficiencyvirus;EPTB,extra-pulmonarytuberculosis;ART,anti-retroviraltreatment;ATT,anti-tuberculosistreatment;IRIS,immunereconstitutioninflammatorysyndrome

SHARMAet al:DIAGNOSIS&TREATMENTOFMILIARYTB 705

Immunopathogenesis

The inadequacy of effector T-cell response incontainment of M. tuberculosis is thought to beresponsible for the development of miliary TB54-57.The abundance ofTh1 andTh2 polarized effectorT(Teff) cells in the peripheral blood and local diseasesite(s) among patients with miliary TB suggest thatmiliary TB probably represents the Th2 end of thespectrum56,57. Interleukin-4 (IL-4), with its ability todownregulateinduciblenitricoxidesynthase(iNOS),toll-likereceptor2(TLR2)andmacrophageactivation,mayplayanimportantroleintheeventsthatdeterminewhethertheinfectionbecomeslatentorprogressive4,54,55.M. tuberculosis caneitherfailtoevoketheprotectiveresponseorcandrive theprotectivemechanismsandthendeliberately‘sabotage’themleadingtoprogressivedisease55-57. InmiliaryTB, frequencyof regulatoryT(Treg) cells (CD4+CD25+FoxP3+) andhigher levelsofFoxP3mRNAweresignificantlyincreasedinlocaldisease site specimens57. Further, FoxP3+ Treg cellsobtained from the bronchoalveolar lavage (BAL)fluid of patients with miliary TB predominantlyproduced interleukin-10 (IL-10) and could suppressthe autologousT-cell proliferation in response toM. tuberculosisantigen56.InmiliaryTB,theattemptbythehosttoselectivelyrecruittheTeffcellsatthepathologicsite, however, fails to provide an adequate level ofeffector immunity at the disease site due to efficientandcomparablehomingofTregcells(FoxP3+),whichinhibitthefunctionoftheTeffcellsthathaveinfiltratedthedisease site. Ithasbeenpostulated thatwhen thebalanceofhomingofTregandTeffcellsshiftstowardtheformer,thereisastateoflocalimmunosuppressionleadingtodiseasedissemination4,56,57.

Observationsregardingthecellularcharacteristicsof BAL fluid in patients with miliary TB haveyielded conflicting results58-60.Though the diagnosticsignificance of thesefindings is not clear, thesemayfacilitate the understanding of the pathogenesis ofmiliary TB. The proportion and absolute numberof lymphocytes are substantially increased in BALfluid.A raised CD4+/CD8+ T-lymphocyte ratio andB-lymphocytesaswellasadecrease inCD4+/CD8+T-lymphocyteratiohaveearlierbeenreportedinBALfluid61,62. Polyclonal hypergammaglobulinaemia withincreaseinimmunoglobulin(Ig)G,IgA,andIgMwasobserved in peripheral blood andBALfluid61.Thesefindingsprobablyresultfromincreasedlocalsynthesisby activated B-lymphocytes. Increased BAL fluidfibronectinandserumC3levelsreflectanacutephaseresponse to ongoing inflammation61,62. Lymphocyticalveolitis and increased IgG and IgA levels havepersistedfollowingantituberculosistreatment61.

Molecular basis of dissemination

Several molecular mechanisms have beenimplicated in the development ofmiliaryTB.Theseincludeimpairedexpansionofγ/δT-cells63,failuretogenerateadequatecell-mediatedimmunity64,presenceof HLA-Bw1565, HLA-DRB1*15/16, DRB1*13, andDQB1*060266,absenceofHLA-Cw6,HLA-DRB1*10,andDQB1*050166, impairedMHCclass II restrictedtargetcelllysis,andover-exuberantlysisoftargetcellmacrophages67andLTA+368G/Apolymorphisms68.

Clinical manifestations

TheclinicalmanifestationsofmiliaryTBinadultsareprotean,non-specificandcanbeobscuretilllateinthedisease(Fig.2).

Fig. 2. Median prevalence of symptoms and signs at initial presentation in adult patients with miliary tuberculosis. Datafromreferences9,18,24-27,29,31-34,36,37,39-42,44.


Fig. 3. Clinicalphotographofachildshowingcutaneouslesionsofmiliarytuberculosis(Kind courtesy:DrM.Ramam,DepartmentofDermatology,AllIndiaInstituteofMedicalSciences,NewDelhi,India).

Constitutional symptoms: Patients with miliary TBclassically present with fever with evening rise oftemperature of several weeks duration, anorexia,weight loss, weakness and cough3,4. Occurrence ofdailymorning temperature spikes69 is reported to becharacteristic ofmiliaryTB.However, fevermaybeabsentand thepatientsmaypresentwithprogressivewasting strongly mimicking a metastatic carcinoma(cryptic miliary TB)70. Since its initial description,crypticmiliaryTBisincreasinglybeingreportedintheelderlypopulation20,21.

Chills and rigors, described in patients withmalaria, or, sepsis and bacteraemia, have often beendescribed in adult patients withmiliary TB3,4. Nightsweats are common.A “damp shadow” sign (wheresweat engraved the patient’s silhouette on the bed,closely resembling a body’s shadow) has also beendescribedinmiliaryTB71.

Systemic involvement: SincemiliaryTB can involvemanyorgans,patientspresentwithsymptomsandsignsreferredtovariousorgansystems(Fig.2).Drycoughanddyspnoeaareoftenpresent.Sputummaybescanty.Haemoptysiscanoccurrarely.Cutaneouslesionsmayoffer a valuable clue to the diagnosis ofmiliaryTB(Fig. 3). These include erythematous macules andpapules(tuberculosis miliaria cutis)4.

Choroidaltubercleswhenpresentinanappropriateclinicalsetting,provideavaluablecluetothediagnosisofmiliaryTB.Thepresenceofchoroidaltuberclesisconsidered to be pathognomonic of miliary TB3,4,39.Choroidal tubercles are bilateral, pale, gray-white or

yellowishlesionsusuallylessthanonequarterof thesizeoftheopticdiscandarelocatedwithin2cmoftheopticnerve.Thesearemorecommonlyseeninchildren.Therefore,asystematicophthalmoscopicexaminationisrecommendedaftermydriatricadministrationinallpatientswithsuspectedmiliaryTB(Fig.4).

TB meningitis (TBM) has been describedin 10 to 30 per cent adult patients with miliary TB9,18,22-27,29,30,32-39,41,42; conversely, about one-thirdof patients presenting with TB meningitis haveunderlying miliary TB72. In a recently publishedstudy73, the spectrumof neurological involvement inadultpatientswithmiliaryTBincludedTBmeningitiswithandwithouttuberculoma;andthoracictransversemyelopathy.

Beforetheadventofmodernimagingmodalities,such as CT, MRI and echocardiography, clinicallyevident cardiac or renal involvement was seldomdocumentedinpatientswithmiliaryTB.OvertadrenalinsufficiencymanifestingasAddison’sdiseaseatinitialpresentation,orduringanti-tuberculosistreatmenthasalsobeendescribedinmiliaryTB74,75.

Children

Thereareonlyafewpublishedseriesonchildhoodmiliary TB6-8,22-38. Miliary TB develops less often inchildren who have received the BCG vaccination4.Compared with adults, chills and night sweats,haemoptysis, productive cough are less common;peripherallymphadenopathyandhepatosplenomegalyaremorefrequentinchildrenwithmiliaryTB.Alargerproportion of children with miliary TB (20-40%) suffer from TBM6-8,22-38 compared to adults (15-30%)9,18,22-27,29,31-34,36-42,44.

Miliary tuberculosis in immunosuppressed individuals

The prevalence of miliary TB in persons withearly HIV infection (CD4+ cell counts >200 cells/mm3)issimilartothatobservedinimmunocompetentindividuals.Withprogressionof immunosuppression,in late, advanced stage ofHIV infection (CD4+ cellcounts <200 cells/mm3), miliary TB is seen moreoften4,58,76. Table III shows a comparison of variousaspectsofmiliaryTB in late advanced stageofHIVinfectionand in immunocompetent individuals, earlyHIVinfection4,41,58,76-82.Cutaneousinvolvement,arareclinicalmanifestationinHIV-seronegativepatientswithmiliaryTB,ismorecommonlyseeninlateHIVinfectionwith severe immunosuppression4,58,76-82. The skinmanifestationsincludetinypapulesorvesiculopapules,


(tuberculosis cutis miliaris disseminata, tuberculosis cutis acuta generalisita),anddisseminatedtuberculosisoftheskin(Fig.3).Sometimes,macular,pustular,orpurpuric lesions, indurated ulcerating plaques, andsubcutaneousabscesseshavebeenreported83.

In miliary TB patients co-infected with HIV,especiallyinthosewithprofoundimmunosuppression,intrathoracic lymphadenopathyand tuberculinanergyaremorecommon;sputumsmearsareseldompositive

and blood culture may grow M. tuberculosis4,58,76-82 (TableIII).Theseobservationsseemtobeapplicabletoothercausesofimmunosuppressionaswell84.

Uncommon clinical manifestations and complications Several uncommon clinical manifestations andcomplications have been observed in patients withmiliaryTB(TableIV).Insomepatients,complicationslikeARDS ormyocarditismay in fact be the initial

Fig. 4. Chestradiograph(postero-anteriorview)(A)andchestCT(lungwindow)(B)showingclassicalmiliarypattern,tree-in-bud appearance (B) (arrow).Thepatientalsohadcerebraltuberculomas(arrows)andTBmeningitis(C).Choroidtubercles,locatedintheposteriorpoleoftheorbit (D)(arrows)offeredanearlyvaluablecluetothediagnosis.Thepresentcase illustrates the importanceofdocumenting thepresenceofneurological involvement,particularly,TBmeningitis inpatientswithmiliaryTBandtherebyensuringadequatedurationofanti-tuberculosistreatmentandneedforcorticosteroidtreatment.


Table III. ClinicalpresentationofmiliaryTBinadultpatientswithandwithoutHIVco-infection

Variable MiliaryTBinHIV-seronegativepersons MiliaryTBinlateHIVinfection*

Epidemiology Accountsfor20%ofallEPTBcasesinclinicalstudies

Accountsfor50%ofallEPTBcasesinclinicalstudies

Clinical manifestationsCutaneouslesions Rare MorecommonPeripherallymphadenopathy Maybepresent OftenpresentChoroidtubercles Maybepresent OftenpresentandmaybetheinitialclueAtypicalclinicalpresentation(e.g., CrypticmiliaryTB,ARDS,AKI,etc.,)

Rare CommonARDSmaybedifficulttodifferentiatefromARDSduetoPneumocystis jiroveci andbacterialinfections

Imaging findingsIntrathoracic,intraabdominallymphadenopathy

Rare Common

Extra-thoracicorgan-system involvement

Common Morecommon(hepatic,spleenicandprostaticabscesses,rarelycardiacinvolvementcanoccur)

DiagnosisSputumsmearpositivity Lesscommon CommonDiagnosisofEPTB Difficultduetopaucibacillarystate BacillaemiafrequentandbacilliatEPTB

sitesreadilydemonstrableTuberculinanergy Rare CommonClinicalandlaboratorymonitoringonfollow-up

Relativelyeasy.Mayrequireliverfunctions,serumuricacidandocularmonitoring

Complexandexpensive.Inadditiontoliverfunctions,serumuricacidandocularmonitoring,CD4+T-lymphocytecount,plasmaHIVviralload,drugtoxicities,drug-druginteractionsneedtobemonitored

Treatment Anti-TBtreatment+corticosteroids insomepatients

Anti-tuberculosistreatment+antiretroviraldrugs+co-trimoxazoleprophylaxis

IRIS Rare Common.Mightrequireexpertopinionfordiagnosis.Imagingguidedproceduresmayberequiredfrequentlyfordrainageofabscesses.Essentialtoruleoutdrug-resistantTBandnewinfection

Drug-drug interactions Rare CommonInteractionsbetweenantiretroviraldrugsandanti-TBtreatmentmayrequirefrequenttreatmentinterruptions.Periodic,closelaboratorymonitoringisrequired

Adverse drug reactions Rare CommonFrequency of Lessfrequentlyrequired Morefrequentlyrequiredradiographic monitoring Mortality Less HigherRelapse after treatment Rare Common

*CD4+T-lymphocytecount<200/mm3.InearlyHIVinfection, theclinicalpresentationofTBissimilar to thatobservedinHIV-seronegativeindividualsTB,tuberculosis;HIV,humanimmunodeficiencyvirus;IRIS,immunereconstitutioninflammatorysyndrome;EPTB,extra-pulmonarytuberculosis;ARDS,acuterespiratorydistresssyndrome;AKI,acutekidneyinjurySource:Refs4,41,58,80-82


presentation.AtypicalclinicalpresentationoftendelaysthediagnosisandtreatmentandmiliaryTBisoftena“misseddiagnosis”.

Acute respiratory distress syndrome

AlthoughARDSmaydevelopanytimeduringthecourseofmiliaryTB,itisusuallyseenatthetimeofinitialpresentation(Fig.5);ARDSmaydevelopasacomponent of the multiorgan dysfunction syndrome(MODS)due toTBorasamanifestationof immunereconstitutioninflammatorysyndrome(IRIS)85-89.InastudyfromtwolargeteachinghospitalsatNewDelhiandTirupatiinIndia89,amongpatientswithTB,prolonged

illness, miliary TB, absolute lymphocytopaenia andelevated alanine aminotransferase (ALT)were foundtobe independentlyassociatedwith thedevelopmentof ARDS. In another study90 from Korea, higherC-reactiveproteinlevelsandanincreasingnutritionalrisk scorewere found to be independent risk factorsforthedevelopmentofARDSinpatientswithmiliaryTB.

Air-leak syndromes

Pneumothorax,whichmaysometimesbebilateral,may be the presenting feature or may sometimesdevelopwhilethepatientisreceivinganti-tuberculosistreatment3,4,91,92.Classicalmiliaryshadowsmaynotbediscernible initially and may become apparent oncelung expands. Intrapulmonary rupture of alveoli andconsequentair-leakthattraversesintothemediastinumafterspreadingalongthevascularsheathcanresultinpneumomediastinum with subcutaneous emphysemawhich may be fatal93. Rarely, pneumothorax maydevelop as a complication in TB-ARDS patientsreceivingmechanicalventilation(Fig.5E).

Acute kidney injury

InadditiontobeingapartofMODS,acutekidneyinjury(AKI)mayoccurduetodirectrenalparenchymalinvolvementinpatientswithmiliaryTB4,94.InHIVco-infectedpatientswithmiliaryTB,AKIcanalsodevelopasamanifestationofIRIS95.Uncommonly,renalfailurecandevelopasaconsequenceofobstructiveuropathycausedbythediseaseprocess58.

Hepatic and gastrointestinal manifestations

Fulminant hepatic failure may rarely be thepresenting manifestation in miliary TB. In some ofthesepatientsthecharacteristicpulmonarylesionsthatconstitute thehallmarkofmiliaryTBareabsent96,97.This could probably be the result of extrapulmonaryfocus discharging the tubercle bacilli into the portalcirculation,resultinginhepaticmiliaryTB.Peritonealinvolvementmaybeevidentbythepresenceofascites.Somepatientsmaymanifestdiarrhoeaoralteredbowelhabit suggestive of intestinal involvement. Smallintestinal perforations at the site of granulomatousinvolvement have been described in some patientswhileontreatment98.

Lesions located elsewhere in the body

Thoracic and abdominal lymphadenopathy:Patients with miliary TB, especially those co-infected with HIV manifest associated intrathoracic

Table IV. Uncommon clinical manifestations andcomplicationsinmiliarytuberculosisSystemic manifestations CrypticmiliarytuberculosisPyrexiaofunknownoriginShock,multiorgandysfunctionIncidentaldiagnosisoninvestigationforsomeotherreason

Pulmonary Acuterespiratorydistresssyndrome“Airleak”syndrome(pneumothorax,pneumomediastinum)Acuteempyema

HaematologicalMyelopthisicanaemiaImmunehaemolyticanaemiaEndocrinologicalThyrotoxicosis

RenalOvertrenalfailureduetogranulomatousdestructionoftheinterstitiumImmunecomplexglomerulonephritis

Cardiovascular PericarditiswithorwithoutpericardialeffusionSuddencardiacdeathMycoticaneurysmofaortaNativevalve,prostheticvalveendocarditis

HepaticCholestaticjaundice

OthersPresentationasfocalextra-pulmonarytuberculosis

Source:Refs2-4,39,58,85-89,91-97,112,114


Fig. 5. Chestradiograph(postero-anteriorview)ofapregnantwomanwhopresentedwithprolongedpyrexiashowingaclassicalmiliarypattern(A).FundusexaminationfollowingmydriaticadministrationinboththeeyesrevealedchoroidtuberclesandhadraisedthesuspicionofmiliaryTB.ThepatientdevelopedARDSduring thecourseofher illness.Chest radiograph (antero-posteriorview),obtainedwithaportableX-raymachine,bed-sideshowingbilateralfrontalopacitiessuggestiveofARDS (B).CTchestobtainedatthesametimerevealsair-spaceconsolidation(C and D);air-bronchogram(arrow)(D).Whileassistedventilationwasbeingadministered,thepatientdevelopedpneumothorax(asterisk)ontherightside;collapsedlungborderisalsoevident(arrow)(E).Thepatientrequiredtubethoracostomyandunderwatersealdrainage.Eventuallythepatientwasweanedofftheventilatorandtheintercostaltubewasremovedfollowingresolutionofthepneumothorax.Thechestradiographobtainedthereaftershowssignificantimprovementinthelesions(F).Thepatientsurvivedtheturbulentin-hospitalcourse,wentontocompletefull-termofpregnancyandwassuccessfullydeliveredalivebaby.ARDS,acuterespiratorydistresssyndrome;CT,computedtomography;TB,tuberculosis.


Fig. 6. CT of the chest showing miliary sarcoidosis.While thelesionsofmiliaryTB(Fig.1B)arerandomlydistributed,thelesionsof miliary sarcoidosis are distributed along the bronchovascularbundle (lymphangitic distribution). Thus transbronchial lungbiopsygivesahigherdiagnosticyieldinmiliarysarcoidosis.

lymphadenopathy. Sometimes, intra-abdominallymphadenopathy involving portahepatis, pre- andpara-aorticandmesentericlymphnodes;retroperitoneallymphadenopathymaybepresent.

Pott’s spine:Pott’sspinewithorwithoutmyelopathymayalsobepresentinpatientswithmiliaryTB.

Cold abscesses: Cold abscesses in association withperipherallymphadenopathyinthecervicaloraxillaryregions,Pott’sspinewithparaspinalcoldabscessmayalsobeevidentinpatientswithmiliaryTB.

Genitourinary lesions: Women with miliary TB canmanifestpelvicascites,tubo-ovarianmasses,pyosalpinxandshouldbecarefullyevaluatedforthesame.

Cardiovascular manifestations

In patients with miliary TB, life-threateningcomplications suchasmyocarditis99, congestiveheartfailure99,native100-102andprostheticvalve103endocarditis,pericarditis, intracardiacmass99,mycoticaneurysm104,infection of a pacemaker pulse-generator pocket105,infectionofventriculoatrialshuntcausingmiliaryTB106 andsuddencardiacdeath107-109havebeendescribed.

Immune reconstitution inflammatory syndrome (IRIS)

TheIRIS,occasionallydescribedinHIV-negativeindividuals with TB, has been reported to occur inaboutone-thirdofpatientsco-infectedwithHIVandTB within days to weeks of the initiation of highlyactiveantiretroviraltherapy(HAART)110,111.TheIRIScan be brief or prolongedwithmultiple recurrences.Manifestationsof IRIS range from isolated instancesof fever to increased or initial appearance oflymphadenopathy, new or worsening pulmonaryinfiltrates, serositis, cutaneous lesions, and new orexpandingcentralnervoussystemmasslesions76,110,111;AKI95,112orARDS85candevelopduringthecourseofIRIS.

Differential diagnosis

Radiologically,themiliarypatternhasbeendefinedas “a collection of tiny discrete pulmonary opacitiesthat are generally uniform in size and widespreadin distribution, each of which measures 2 mm orless in diameter”113. Many conditions can presentwithamiliarypatternon thechest radiographorCT (Fig. 6) and are listed in Table V. These conditionsmust be differentiated from miliary TB by detaileddiagnosticwork-up.

Diagnosis

The diagnosis of miliary TB can be difficult astheclinicalmanifestationsarenon-specific, thechestradiographsdonotalwaysrevealtheclassicalmiliarychangesandpatientsmaypresentwithcomplicationsthusdistractingtheclinicians.Therefore,ahighindexof clinical suspicion and a systematic approach todiagnostictestingisrequiredtoestablishthediagnosisofmiliaryTB.

Followingcriteria areuseful for thediagnosisofmiliaryTB:(i)clinicalpresentationconsistentwithadiagnosisoftuberculosissuchas,pyrexiawitheveningriseoftemperature,weightloss,anorexia,tachycardiaand night sweats of greater than six weeks durationrespondingtoantituberculosistreatment;(ii) classical miliary pattern on chest radiograph; (iii) bilateraldiffuse reticulonodular lung lesionson abackgroundofmiliaryshadowsdemonstrableeitheronplainchestradiographorHRCT;and(iv)microbiologicaland/orhistopathological evidence of TB39. The diagnosticapproach to a patient with suspected miliary TB isshowninFig.7.

Tuberculin skin test

Tuberculin anergy is more common in miliaryTBthaninpulmonaryandEPTB;tuberculinskintest (TST) conversion may occur following successfultreatment. In various published paediatric6-8,22,38 and adult series24-27,31,32-34,36,37,114 tuberculin anergy hasrangedfrom35to74percentand20to70percent, respectively.However, a positiveTSTonly indicates


Fig. 7. Algorithm for the diagnostic work-up of a patient withsuspected miliary TB. The clinical and imaging diagnosticwork-up should also aim at accurately assessing the extent ofextrapulmonary involvement to facilitate monitoring and ensureadequatedurationof treatment.All laboratory testing,especially,antituberculosisdrug-susceptibility testingmustbecarriedout inqualityassured,periodicallyaccreditedlaboratories.*Oftenusedinchildren;†FNAC/excisionbiopsy;‡RadiologicallyguidedFNAC/biopsy; §Mediastinoscopic/video-assisted thoracoscopic surgery,biopsy;||Laparoscopicbiopsy;¶UsefulinadvancedHIVinfection.TB, tuberculosis; TST, tuberculin skin test; IGRA, interferon-γ release assays; HRCT, high resolution computed tomography;CECT,contrastenhancedcomputed tomography;MRI,magneticresonance imaging;FNAC,fineneedleaspirationcytology;HIV,human immunodeficiency virus; AFB, acid-fast bacilli; L-J,Lowenstein-Jensen medium; DST, drug-susceptibility testing;MGIT,mycobacterialgrowthinhibitortube;BACTEC,radiometricculture method; PCR, polymerase chain reaction; GeneExpertMTB/RIF,GeneXpertMTB/RIFassay(Cepheid,Sunnyvale,CA);LPA,lineprobeassay.

Table V. Someconditionspresentingwithamiliarypatternonthechestradiograph

Common causes Infections*

TuberculosisHistoplasmosisBlastomycosisCoccidioidomycosisMycoplasmapneumoniaNocardiosis

Immunoinflammatory disorders*

Sarcoidosis

MalignantBronchoalveolarcarcinoma

CarcinomalungwithlymphangitiscarcinomatosaMetastaticcarcinoma

Tropical pulmonary eosinophilia

Haemosiderosisinlongstandingrheumaticheartdisease,mitralstenosis

Hypersensitivity pneumonitis

Drug-inducedinterstitiallungdisease(e.g.,methotrexate,chrysotherapy,cyclophosphamide,nitrofurantoin,antidepressants)

Uncommon causesInfections

CryptococcosisLegionellosisMelioidosisTularaemiaPsittacosisBrucellosisStaphylococcus aureusbacteraemiaToxoplasmosisSchistosomiasisStrongyloides stercoralishyperinfection

MalignantBronchialcarcinoid

LymphomaLymphomatoidgranulomatosis

Occupational lung diseases

*Fevercommonlypresent

infection with M. tuberculosis and does not alwaysindicate active disease. A positive reaction with necrosis often (but not always) indicates activedisease.


Interferon-gamma release assays

Newer in vitro T-cell based interferon-gammarelease assays (IGRAs) available in the enzymelinked immunosorbent assay (ELISA) and enzymelinked immunospot (ELISPOT) formats appear to bepromisingindetectinglatentTBinfection(LTBI)andhaveseveraladvantagesovertheTST.Thesetestsmaybe particularly useful in children, BCG vaccinatedindividuals and in HIV infection andAIDS115,116.AswithTST, apositive IGRA test result, however,doesnot distinguishbetweenLTBI and activedisease, butanegativeIGRAresultmaybehelpfulinruling-outadiagnosisofTB116.Thesetestsarecostlyandonthebasisofavailableevidencetheirroutineuseisnotindicated.

Haematological and biochemical abnormalities

A number of haematological and biochemicalabnormalities are known to occur in miliary TB (Table VI)6-9,18,22,23,24-27,29,31,32-36,36-42,44 but theirsignificance is controversial. Disseminatedintravascularcoagulation(DIC)86,89hasbeendescribedin patients with miliary TB in the setting ofARDSandMODS and is associated with a high mortality.

Table VI. LaboratoryabnormalitiesinmiliaryTBHaematologicalAnaemiaLeucocytosisNeutrophiliaLymphocytosisMonocytosisThrombocytosisLeucopeniaLymphopeniaThrombocytopeniaLeukaemoidreactionHaemophagocytosisElevatedESR,CRPlevels

BiochemicalHyponatraemiaHypoalbuminaemiaHypercalcaemiaHypophosphatemiaHyperbilirubinaemiaElevatedserumtransaminasesElevatedserumalkalinephosphataseElevatedserumferritinlevels

ESR,erythrocytesedimentationrate;CRP,C-reactiveproteinSource:Refs2-4,39,114

Immune mechanisms have been implicated to causebonemarrowsuppressionandmiliaryTBhasalsobeenimplicated as a cause of pancytopenia, hypoplasticanaemia4,117.HypercalcaemiahasbeendocumentedinmiliaryTB,butisuncommon118.

HyponatraemiainmiliaryTBcanoccurduetoanacquired disturbance of neurohypophyseal functionresulting in unregulated antidiuretic hormone (ADH)release; an antidiuretic principle in the lung tissueaffectedbyTBthatmayeitherproduceADHorabsorbaninappropriatelyreleasedhormonefromtheposteriorpituitary119-121. Hyponatraemia may indicate thepresenceofTBmeningitis34andmayalsobeapredictorofmortality39inpatientswithmiliaryTB.Rifampicin-inducedadrenalcrisisinapatientwithmiliaryTBandAddison’sdiseasewhodevelopedgeneralizedmalaiseandhyponatraemiawhileinitiatedonantituberculosistreatmenthasalsobeendescribed75.

Imaging studies

Miliary pattern on the chest radiograph is oftenthefirstcluesuggestiveofmiliaryTB.Severalotherimaging modalities, such as, ultrasonography, CT,MRI, positron emission tomography (PET) helpto assess the extent of organ involvement and are alsouseful inevaluatingresponse to treatment (Figs.8and9).

Chest radiograph: The chest radiographic abnormalities in miliary TB are depicted in TableVII4,114.Miliarypatternonchestradiograph3,4,113 is thehallmarkofmiliaryTBand isevident inamajorityofpatients.Classically,subtlemiliarylesionsarebestdelineatedinslightlyunderpenetratedfilmsespeciallywhenthediamondshapedareasofthelunginbetweentheribsarecarefullyscrutinizedusingbrightlight122,123.However,in10percentofthecases,thenodulesmaybegreaterthan3mmindiameter124.Beforetheadventof CT, it was observed that classicalmiliary patternwouldnotbeevidentinthechestradiographinupto50percentofthepatientsandwouldbedetectedonlyatthetimeofautopsy14,17,18,24,34,124.

When caseous material, collagen or both arepresent inthetubercles, thesebecamevisibleonthechest radiograph122. Classicalmiliary pattern on thechestradiographrepresentssummationofdensitiesofthetuberclesthatareperfectlyalignedandimperfectlyaligned tubercles result in curvilinear densitiesand a reticulonodular pattern125. Rarely, lymphaticobstruction or infiltration can result in ground glass


Fig. 8. ChestradiographinapatientwithHIV/AIDS(postero-anteriorview)(A)andchestCT(lungwindow)(B) showingclassicalmiliarypattern.TheCECT chest (mediastinalwindow) also reveals intrathoracic lymphadenopathy (arrow) (C) and pericardial thickening andeffusion(D).TheCECToftheabdomenofthesamepatientrevealsfocalmiliarylesionsintheliver(square,arrow)andspleen(circle)(E)andretroperitoneallymphadenopathy(arrow)(F);pelvicCECTshowsaprostaticabscess(arrows)(G).Ultrasoundguidedtrans-rectalprostaticaspiratesmearandcultureexaminationconfirmedthediagnosisofmiliaryTB.Thediagnosticevaluationofthispatientillustratesthejudicioususeofimagingmodalitiestodefinetheextentoforgansysteminvolvementandprocuringtissuefordiagnosticconfirmation.SuchextensiveinvolvementusuallyoccursinHIV/AIDSwithmiliaryTB.HIV,humanimmunodeficiencyvirus;AIDS,acquiredimmunodeficiencysyndrome;CT,computedtomography;CECT,contrastenhancedcomputedtomography;TB,tuberculosis.


Fig. 9. ChestCT(lungwindow)ofthesamepatientasinFig.4showingpulmonaryparenchymallesions(blackarrow)(A).Inadditiontothemiliarypattern,well-defined,linear,branchingopacities(tree-in-bud appearance)(thickwhitearrows)(A and B)arealsoseen.Thispatternisevidentwhencentrilobularbronchiolesaredilated,or,arefilledwithmucus,fluidor,pusandrepresentsendobronchialspreadingofinfection.18FDG-PETCTofthesamepatientshowingincreasedactivityinthepulmonaryparenchymallesions(arrows)butnotinthemiliarylesions(C and D).The18FDG-PEThaspotentialtofurtherunderstandingtheclinico-radiographic-functionalcorrelationinmiliarytuberculosisandmeritsfurtherstudy.However,itmaynotbeusefulinintracranialTB.CT,computedtomography;18FDG-PETCT,18Flabelled2-deoxy-D-glucosepositronemissiontomography-computedtomography;TB,tuberculosis.

appearance126. In some patients, predominance oflesionsonone sidemaybeevident (Fig.10).Somepatientsmayhavenormalchestradiographsinitiallyand the typicalmiliary patternmay evolve over thecourse of disease. This is particularly evident inARDSduetomiliaryTBwherethechestradiographfindingsmaybe identical to that seen inARDSdueto other causes86,89. One of the patients seen by theauthors39 had undergone tonsillectomy and thehistopathological diagnosis was reported as miliaryTB. On further diagnostic testing, a repeat chestradiographrevealedclassicalmiliarypatternthatwasnotdiscernibleintheearlierchestradiographs,thus,emphasizing the importanceofperiodicrepeatchestradiographic examination in patientswith suspectedmiliaryTB4,39.

Ultrasonography:Ultrasonographyhelps indetectingascites which may sometimes be loculated, focalhepatic and splenic lesions and cold abscesses,intra-abdominal lymphadenopathy, involvementof other abdominal organs and pleural effusion(s).Ultrasonography guidance also facilitates diagnosticthoracicorabdominalparacentesis toprocurepleuralor peritonealfluid for diagnostic testing especially ifthefluidisloculated.

Computed tomography (CT) and magnetic resonance imaging (MRI): Incomparisonwithpre-CTera,highresolutionCT(HRCT),thin-sectionmultidetectorrowCT(MDCT)havefacilitatedtheantemortemdiagnosisofmiliaryTB.With theavailabilityof these imagingmodalities, crypticmiliaryTB, that could previously


Fig. 10. Chestradiograph(poster-anteriorview)(A)andchestCT(lungwindow)(B and C)showingpredominanceofmiliarylesionsontherightside.18FDG-PETCTofthesamepatient(D)showingincreasedactivityinthecoalescedpulmonarylesions,which is evidentmoreprominentlyon the right side.CT, computed tomography; 18FDG-PETCT, 18F labelled2-deoxy-D-glucosepositronemissiontomography-computedtomography.

Table VII. ChestradiographicabnormalitiesinmiliaryTB

Classicalpresentation(50%)

Non-miliarypulmonarymanifestations (10-30%)

Otherassociatedfindings(<5%)

Miliarypattern

AsymmetricalnodularpatternCoalescenceofnodulesMottledappearance

“Snowstorm”appearanceAir-spaceconsolidation

Source:Refs3,4,114,122,123

PulmonaryParenchymallesionsandcavitationSegmentalconsolidationThickeningofinterlobularseptae

PleuralPleuraleffusionEmpyemaPneumothroaxPneumomediastinum

OthersIntrathoraciclymphadenopathyPericardialeffusion

bediagnosedonlyat autopsy, cannowbediagnosedantemortem4,40.

The HRCT reveals a mixture of both sharplyand poorly defined, less than 2mmnodules that arewidely disseminated throughout the lungs associatedwithdiffuse reticulation127,128. Importantly, theHRCTmay reveal classical miliary pattern even when thechest radiograph looksapparentlynormal4,39andalsofacilitatesidentificationofadditionalfindingssuchasintrathoracic lymphadenopathy, calcification, pleuralandpericardiallesions(Fig.8D)129.

AirtrappinghasbeendescribedonHRCTbothatpresentationandduringfollowupperiod128.Theclinicalsignificance of these findings is unclear. Rupture oftheseareasofairtrappingmayperhapsberesponsiblefor thedevelopmentofair-leaksyndromesinmiliaryTB.Theinterlobularseptal thickeningorintralobularfinenetworking seenonHRCT inmiliaryTB seemstobecausedbythecaseationnecrosisinthealveolarwalls and interlobular septa. Sometimes, in subjectswithactivepost-primarydisease,centrilobularnodulesand branching linear structures giving a “tree-in-budappearance”maybeevident127,128.Ahigherprevalence


per cent23,31,32,37,39,131. In patientswith dry coughBALfluidobtainedthroughfiberopticbronchoscopyshouldbe submitted for mycobacterial smear, culture andmolecularmethods(iffacilitiesexist).

Laparascopy

Laparascopyprovidesanopportunity tovisualisethe lesions, facilitates biopsy from the liver, spleen,peritoneum, omentum, mesenteric lymph nodes fordiagnosticconfirmation132.Whenassociatedabdominalinvolvement is present, laparascopy should beconsideredforprocuringtissuefordiagnostictesting.

Body fluids and tissue examination

InpatientswithsuspectedmiliaryTB,dependingontheextentoforgansysteminvolvement,appropriatetissue and body fluid samples must be obtained toconfirm histopathological microbiological diagnosis.Elevated serum alkaline phosphatase levels indicatediffuse liver involvement; needle biopsy of the livercanbeusefulinconfirmingthediagnosis.BonemarrowaspirationandneedlebiopsyhavealsobeenfoundtobeusefulforthediagnosisofmiliaryTB.Pleuralfluid,pericardialfluid,asciticfluid,CSF,urine,bronchoscopicsecretions,bloodandtissuebiopsyspecimenshaveallbeenemployedtoconfirmthediagnosisofdisseminatedandmiliaryTB.Thediagnosticyieldofvarioustissueandbodyfluidspecimenshasbeenvariable6-9,18,22-27,29,31-34,36-41,42,44(Fig.11).

Whenimagingstudiesrevealfocallesionsinorgans(e.g., liver, spleen prostate), intrathoracic or intra-abdominal lymphadenopathyor cold abscess, image-guidedFNACortru-cutbiopsycanbecarriedoutandsubjected to histopathological and microbiologicalevaluationtoconfirmtheaetiologicaldiagnosis.

Mycobacterial culture and drug-susceptibility testing (DST)

Mycobacterial culture and drug susceptibilitytesting of sputum, body fluids and tissue specimenscarried out in an accredited laboratorywith externalquality assurance can facilitate identification andappropriatemanagement of drug-resistantTB.RapidculturemethodssuchastheBACTEC-460radiometricmethod,mycobacterialgrowthindicatortube(MGIT),andmolecularmethodsmaybeusefulforrapiddrug-susceptibilitytesting4.

Serodiagnostic methods

TherecentlypublishedWorldHealthOrganization(WHO)policystatementontheuseofserodiagnostic

ofinterlobularseptalthickening,necroticlymphnodesand extrathoracic involvement has been observed inHIV-seropositivepatientswithmiliaryTB80.

CT and MRI have been useful in identifyingmiliary lesions at extra-pulmonary sites. AbdominalCThasbeenusefulinidentifyinglesionsintheliver,spleen,intestine,mesentery,peritoneum,adrenalsandlymphnodes,andalsodetectscoldabscesses4.UnliketheCTofthechestwheretheclassicallessthan2mmnodularlesionsareevident,miliarylesionsintheliverandspleenmayappearasdiscretehypodense lesions(Fig.8E)afewofwhichmaybeconfluent,sometimeswithirregularperipheralrimenhancement130.

TheMRIofbrainandspineisveryuseful in theevaluation of patients with miliary TB and TBM,and spinal TB. The MRI is particularly helpful inidentificationanddelineatingtheextentoftuberculomasand cold abscesses and monitoring the response totreatment4.

Pelvic evaluation with all imaging modalitiesshould be routinely done in all female patients fordefining the extent of involvement. Tubo-ovarianmasses,hydro-andpyosalpinx,fluidcollectioninthepouchofDouglasmaybecomeobvious.Imageguidedradiologicalproceduressuchasfineneedleaspirationforcytologicalexamination(FNAC)andbiopsyunderCTorMRIguidanceareuseful forprocuring tissue/bodyfluidsfordiagnostictesting.

Sputum examination

ThoughnotallpatientswithmiliaryTBmanifestproductive cough, when available, sputum mustbe subjected to smear and mycobacterial cultureexamination.SputumsmearmicroscopyusingZiehl-Neelsen stain is useful in detecting acid-fast bacilli(AFB).Fluorescent stainingmayalso facilitate rapiddiagnosis. Sputum mycobacterial culture and drugsusceptibility testing carried out in an accreditedlaboratorywithexternalqualityassurancecanfacilitateidentification and appropriate management of drug-resistantTB.

Bronchoscopy

Fibreoptic bronchoscopy, BAL, bronchoscopicaspirate,brushings,washings,andtransbronchiallungbiopsy(TBLB)areusefulinconfirmingthediagnosisof miliary TB. The cumulative diagnostic yield forvariousbronchoscopicspecimensbysmearandculturemethodsinpublishedstudieshasbeenfoundtobe46.8


testsstronglyrecommendsthatthecurrentlyavailablecommercialserodiagnostictestsshouldnotbeused forthediagnosisofactivepulmonaryandextra-pulmonaryTBdiseaseincludingmiliaryTB133.

Adenosine deaminase

Adenosine deaminase (ADA) and interferon-gamma level estimation in ascitic fluid, pleural fluidcan be helpful in the diagnosis of miliary TB134-139.A recent study139 has shown that thatCSF-ADA is amoresensitiveindicatorthanPCRforthediagnosisinpatientswithTBmeningitis.However,anotherrecentsystematicreviewandmeta-analysis140hasshownthatCSF-ADAcannotdistinguishbetweenTBmeningitisand bacterial meningitis. Since ADA estimationis a cheap, cost-effective test, utility of CSF-ADAestimation in the diagnosis of TB meningitis meritsfurtherstudy.

Molecular methods

Polymerase chain reaction (PCR) of CSF, tissuebiopsy specimens and blood (especially in HIV-infected patients),may be useful for confirmation ofdiagnosis58.ThePCRhasbeenfoundtobemostusefulwhenappliedtocleanspecimenssuchasCSFwhereitssensitivityandspecificityhavebeenreportedtobe0.5to0.9and1.0,respectively71.

In patients with suspectedmiliaryTB, whereverpossible,automatedmoleculartestsforM. tuberculosis detectionanddrug-resistancetestingmaybeusedforearly confirmation of diagnosis. Based on currentlyavailableevidenceandexpertopinion,molecularassaysto detect gene mutations that signal drug resistancehavebeenendorsedbytheWHOasbeingmostsuitedforrapiddiagnosis141.TheGeneXpertMTB/RIFassay(Cepheid,Sunnyvale,CA) thatusesheminestedreal-time PCR assay to amplifyM. tuberculosis -specificsequenceoftherpoB genewhichisthenprobedwithmolecularbeaconsformutationswithintherifampicin-resistance determining region can facilitate rapiddiagnosis from clinical specimens, such as, sputuminabout2h142,143.Lineprobeassays(LPAs),suchas,theINNO-LiPA®Rif.TBkit(InnogeneticsNV,Gent,Belgium) and the GenoType® MTBDRplus assay(Hain Lifescience GmbH, Nehren, Germany) havebeenfoundtobeusefulforrapidscreeningofpatientsatriskformultidrug-resistantTB(MDR-TB)144.

Positron emission tomography

Positron emission tomography CT (PET-CT)usingtheradiopharmaceutical18Flabelled2-deoxy-D-glucose (FDG) is useful to assess activityof variousinfectiouslesionsincludingTB(Fig.9)145,146.ThePET-CTis ideallysuited todefinetheextentofdiseaseat

Fig. 11. CumulativediagnosticyieldofvariousbodyfluidsandtissuesinthediagnosisofmiliaryTB.Cumulativediagnosticyieldisexpressedaspercentage.Thedataarepooledforvariousspecimencategoriesandmaynotbecomparableacrossvariousseriesbecausedifferentcriteriawereemployed;however,thesecanbeappropriatelyusedintheindividualpatienttoascertainthediagnosisofmiliaryTB.FOB,fibreopticbronchoscopy;CSF,cerebrospinalfluid;LN,lymphnode;BM,bonemarrow;Bx,biopsy.Source:Refs9,18,24-27,29,31-34,36,37,39-42,44


thetimeofinitialpresentation.TheutilityofPET-CTin assessing the activity of lesions thatmight persistfollowingantituberculosistreatmentinmiliaryTBalsomeritsfurtherstudy.

Pulmonary function, gas exchange abnormalities and cardiopulmonary exercise testing

Miliary TB is associated with abnormalitiesof pulmonary function typical of interstitial lungdisease.Impairmentofdiffusionisthemostcommonabnormalityandmaysometimesbesevere59,147.Otherabnormalities include, amild reduction in flow ratessuggestiveofperipheralairwaysinvolvement59.Duringtheacutestage,arterialhypoxaemiaduetowideningofthe alveolar-arterial oxygen gradient and hypocapniadue to tachypnoea are also observed148. Often, thepulmonary function and gas exchange abnormalitiesmaybeofagreatermagnitudethanmightbeexpectedfromthechestradiograph61,148-150.

Abnormalcardiopulmonaryexerciseperformancehas been described in patientswithmiliaryTB.Thesalient abnormalities included lower maximumoxygen consumption, maximal work rate, anaerobicthreshold, peak minute ventilation, breathingreserve, and low maximal heart rate4,114,148,150. Otherabnormalities included higher respiratory frequency,peakminuteventilationatsubmaximalwork,andhighphysiologicaldeadspace/tidalvolume.Ademonstrablefallinoxygensaturation(to4%ormore)withexercisewas observed.Following successful anti-tuberculosistreatment,theseabnormalitiesreversedinamajorityofthepatients148,150.

Treatment

PatientswithmiliaryTBmustbepromptlytreatedwithstandardanti-tuberculosistreatmentasthediseaseisuniformlyfatalifnottreated3,4.However,thereisnoconsensusregardingtheoptimumdurationoftreatment.There are no published randomized controlled trialsassessingtheefficacyofthestandardWHOtreatmentregimens that have been widely used in nationaltuberculosiscontrolprogrammesworldwide151.

The American Thoracic Society (ATS), theCenters forDiseaseControl andPrevention (CDC),theInfectiousDiseaseSocietyofAmerica(IDSA)152 and National Institute for Health and ClinicalExcellence (NICE)153 guidelines fromUKstate thatsixmonthsoftreatment(2-monthintensivephasewithisoniazid,rifampicin,pyrazinamide,andethambutolorstreptomycin,followedbya4-monthcontinuation

phase with isoniazid and rifampicin) , whereas theAmericanAcademyofPediatrics(AAP)154advocatesninemonthsoftreatmentfornewlydiagnosedcasesofmiliaryTBwithoutmeningealinvolvement.WhenTB meningitis is present, it is suggested that thetreatmentbeextendedfor12months136-138.Inseveralparts of the world, patients with miliary TB gettreatedundernationalTBcontrolprogrammes,withDOTSusingshort-courseintermittent,thrice-weeklytreatment151.

IntheWHOguidelinesforthetreatmentofTB155,patientsarecategorizedas“newpatients”or“previouslytreated patients”. In these guidelines, miliary TB isclassifiedaspulmonaryTBbecause thereare lesionsin the lungs.NewpatientswithmiliaryTBreceive6monthsofdailyorintermittenttreatmentasdescribedabove. The guidelines mention that some expertsrecommend 9 to 12 months of treatment when TBmeningitisispresentgiventheseriousriskofdisabilityandmortality;and9monthsof treatmentwhenboneandjointTBisalsopresent.

For previously treated patients, the guidelinesadvocate that specimens for culture andDST shouldbe obtained at or before the start of treatment. TheDST should be performed for at least isoniazid andrifampicinandinsettingswhererapidmolecular-basedDSTresultsareavailable,theresultsshouldguidethechoiceofregimen.

These observations highlight the importanceof accurately assessing the extent of involvementclinically and radiologically. Thus, if underlyingTBmeningitis remains undiagnosed in a patient withmiliaryTB,suchapatienthasariskofreceivinganti-tuberculosistreatmentonlyfor6monthswhichmaybesub-optimal.Therefore,thoughthestandarddurationoftreatmentmaybesufficientformany,eachpatientneedsto be assessed individually, and wherever indicated,treatmentdurationmayhavetobeextended.

Other issues such as quality of anti-tuberculosisdrugs and their bio-availability are important inresource-poornations.EspeciallyinHIV-seropositivepatients,considerationmustalsobegiventoinadequateplasma levels of anti-tuberculosis drugs in spite ofregularintakeinadequatedosageduetomalabsorptionproblem.

Monitoring for adverse drug reactions

PatientswithmiliaryTBreceivinganti-tuberculosistreatment should be carefully monitored for adverse


drug reactions, especially, anti-tuberculosis drug-induced hepatotoxicity (DIH). Asymptomatic risein hepatic transaminases is common in patientswithmiliaryTB and unless definitive evidence ofDIH ispresent156-159,anti-tuberculosistreatmentshouldnotbewithheldonthisevidencealone.Inthisscenario,liverfunctionsshouldbeperiodicallymonitored.Intropicalcountries, acute viral hepatitis must be ruled out inpatientswhodevelopantituberculosisDIH160,161.

When patients with miliary TB develop anti-tuberculosis DIH, the potentially hepatotoxic drugs(rifampicin, isoniazid and pyrazinamide) should bestopped158. These patients should be treated withnon-hepatotoxic anti-tuberculosis drugs, such asethambutol, streptomycin and a fluoroquinolone, tillthe liver functions normalize. In patients who havedevelopedanti-tuberculosisDIH,itisusuallypossibleto reintroduce the same hepatotoxic drugs that havebeen implicated in the causation of DIH once theliverfunctionsnormalize.However,tillrecently,therehas been a lack of consensus regarding the optimalsequence and dosage schedule for reintroduction.Arecentlypublishedprospectiverandomizedcontrolledstudy162, provides useful data on this topic. In thisstudy from India, 175 patients with a diagnosis ofantituberculosis DIH were randomized to receiveone of three different pre-defined reintroductionregimensofanti-tuberculosisdrugsandwereevaluatedprospectively. The recurrence rate of DIH was notsignificantly different between the groups receivingisoniazid, rifampicin, andpyrazinamide administeredsimultaneously at full dosage from day 1; and thegroups receiving reintroduction regimens based ontheATS158andBritishThoracicSocietyguidelines163.Furtherstudiesarerequiredtoclarifytheissue.

Corticosteroids

Only limited published data are availablespecifically evaluating the role of adjunctcorticosteroid treatment in patients with miliaryTB and the results have been conflicting.While abeneficialresponsewasobservedinsomestudies164,such a benefit could not be observed in others165.Associated adrenal insufficiency is an absoluteindication for the administration of adjunctivecorticosteroid treatment. However, in patients withmiliary TB, adjunctive corticosteroid treatment isconsidered to be beneficial with TB meningitis,large pericardial effusion, IRIS, ARDS, immunecomplex nephritis, and histiocyticphagocytosissyndrome4,85,166.

Antiretroviral drugs

The efficacy of standard anti-tuberculosistreatmentregimensinthetreatmentofHIV,miliaryTBco-infectionhasnotbeenstudiedindetailinthefieldsetting under programme conditions. Treatment ofmiliaryTB inpatientsco-infectedwithHIVrequirescareful consideration of drug-drug interactionsbetweenanti-tuberculoisandanti-retroviraldrugs167,168.Co-administration of rifampicin, by inducing thehepatic cytochrome P450 pathway, may result indangerously low levels of anti-retroviral agents.Rifabutinispreferredoverrifampicinespeciallywhenproteaseinhibitorsareusedbutiscostly.Efavirenzispreferredovernevirapinebutshouldbeavoidedduringpregnancy. Pregnancy test needs to be done whilefemale patients are on efavirenz.A closemonitoringof laboratory parameters is required to detect drug-drug interaction when patients are receiving bothtreatments. Recently, there has been a change in theWHO revised recommendations167 based onGradingof Recommendations Assessment, Development andEvaluation(GRADE)system169 regardingthe timeofstartinganti-retroviraldrugs, thechoiceofdrugsandthetimeofinitiationinrelationtoinstitutionofanti-tuberculosis treatment. The algorithm for treatmentandmonitoringofpatientswithmiliaryTBisshowninFigs.12AandB.

In peripheral hospitals in endemic areas whereHIVandTBarecommon,qualityassured laboratoryfacilitiesforHIVELISA,CD4+T-lymphocytecountsand plasma HIV viral load estimation may not beavailable. Timing of initiation and antiretroviraltreatment (ART),choiceofARTandantituberculosistreatmentregimens,drug-druginteractions,allrequirecarefulconsideration.AhighdegreeofsuspicionandappropriatetrainingofthestaffisrequiredtoidentifyIRIS, recognize adverse drug reactions and drugtoxicities,drugadherenceissues.

Mechanical ventilation

Intensivecare,assistedmechanicalventilationandotherinterventionsmayberequiredforthemanagementof patients withmiliaryTB-ARDS86,89. Patients withmiliaryTB receiving assistedmechanical ventilationshouldbecarefullywatchedforcomplicationssuchaspneumothorax(Fig.5F).

Interventional radiology

Image-guidedpigtailcatheterdrainagefordrainingpsoasabscess,coilorgelfoamembolizationfortreating


Fig. 12A. Algorithm for treatment of miliary TB patients with and without HIV co-infection.TB, tuberculosis; HIV, humanimmunodeficiencyvirus;+,seropositive;–,seronegative;ART,anti-retroviraltreatment;IRIS,immunereconstitutioninflammatorysyndrome;DIH,anti-tuberculosisdruginducedhepatotoxicity.

Fig. 12B. Guidelines on timing of antiretroviral treatment in patients with HIV-tuberculosis co-infection. HIV, humanimmunodeficiencyvirus;TB,tuberculosis;ART,antiretroviraltherapy.Source:Ref.167


issuesinthediagnosisandmanagementofmiliaryTBarelistedinTableIX.Astheclinicalsymptomatologyandphysical signsarenon-specific,cliniciansshouldhave a low threshold for suspecting miliary TB.Carefulphysicalexaminationfordiagnosticcluessuchasperipheral lymphadenopathy, coldabscess,pleuraleffusion,ascites,amongotherswillhelpinprocuringtissue and body fluids for confirming the diagnosis.Fundus examination for detecting choroid tuberclesmust be done in all patients with suspected miliaryTBastheirpresenceispathognomonicofmiliaryTB.SpecificeffortsshouldalsobedirectedatdocumentingthepresenceofTBmeningitisas thishas therapeuticsignificance.

Imaging modalities such as CT and MRI areuseful toestablish themiliarypattern.Inconjunction

Table VIII. Predictors of poor outcome in patients withmiliaryTBVariables PredictorsofpooroutcomeDemographicparameters Increasingage,femalegender,

malegenderCo-morbidconditions Presenceofanyunderlying

co-morbiddisease,cirrhosisofliver,Presenceofoneormorepredisposingconditions

Symptoms Historyofcough,nightsweats,dyspnoea,chills

Signs Alteredmentalstatus,meningismus,temperature>39.3°C,icterus,hepatomegaly

Laboratoryabnormalities Hyponatraemia,hypoalbuminaemiaelevatedtransaminaselevels,elevatedserumalkalinephosphataseLeucopenia,leucocytosis,Lymphopenia,Thrombocytopenia

Others Presenceofatypicalchestradiographicpatterns,treatmentdelay,highnutritionalriskscore*

*afour-pointnutritionalriskscorewasdefinedaccordingtothepresenceoffournutritionalfactors:lowbodymassindex(<18.5kg/m2),hypoalbuminaemia(serumalbumin<30g/l),hypocholesterolaemia(serumcholesterol<2.33mmol/l)andsevere lymphocytopenia (<7×105 cells/l).Each risk factorwasassignedavalueof1 ifpresentor0 ifabsent.Patientswith three or four points were classified as having a highnutritionalriskscore90TB,tuberculosisSource:Refs9,18,24-27,29,31-34,36-42,44,90

haemoptysis,amongothersareusefuladjunctsforthemanagementofcomplicationsinpatientswithmiliaryTB.

Surgery

Surgery is often required to procure specimensfordiagnostictestingandtoamelioratecomplications,such as small bowel perforation where it may belifesaving.Surgerymaybeindicatedwhenpatientsfailtorespondtochemotherapywithevidenceofongoinginfectionandforreliefofspinalcordcompressionwithpersistence or recurrence of neurological deficits, orinstabilityofthespine.

Mortality

The mortality related to miliary TB is about 15to 20 per cent in children and is slightly higher inadults (25 to 30%)24-27,31-34,36,37. Delay in diagnosisand consequently, delayed initiation of specific anti-tuberculosistreatmentappearstobethemostimportantfactorresponsibleformortalityinmiliaryTB.

Prognostic factors

Several factorshavebeen identifiedaspredictorsof poor outcome in patients with miliary TB (TableVIII). In patients with miliary TB-ARDS89, acutephysiologicalandchronichealthevaluation(APACHEII)score>18;APACHEIIscore≤18inthepresenceofhyponatraemiaandarterialoxygentensiontofractionofinspiredoxygen(PaO2/FIO2)ratio≤108.5havebeenidentified to be predictors of death. Identification ofthesefactorscanalertthecliniciansmanagingpatientswithmiliaryTB.

Prevention

TheBCGvaccinationiseffectiveinreducingtheincidence of miliary TB, especially in children170.However, it isnoteffective in individualswhohavelatent TB infection and should not be administeredto immunosuppressed hosts, such as, HIV infectedinfants. Targeted tuberculin testing is practised incountries with low prevalence of TB such as theUSA152,171, but anti-TB drug-induced hepatotoxicityis a potential risk with this intervention. Ongoingresearch172,173 is likely to provide a more effectivevaccinethanBCG.

Lessons learnt

MiliaryTB remainsanelusivediagnosiseven inareaswhereTBishighlyendemic.Thekeypractical


Table IX. KeypracticalissuesinthediagnosisandmanagementofmiliaryTBImportance of establishing the diagnosis early

(i) NosinglesymptomorsignispathognomonicformiliaryTB.Cliniciansshouldhaveahighindexofsuspicionandcarefullylookforaconstellationofsigns,symptomssuggestiveofmiliaryTB.

(ii) Physicalexaminationshouldfocusonvaluableclues,suchaschoroidtubercles,skinlesions,palpableperipherallymphnodes,evidenceofmeningitis,pleuraleffusion,pericardialeffusion,ascites,coldabscessetc.Inwomen,carryingoutpelvicexaminationcanprovetobevaluable.

Diagnostic work-up

Diagnosticwork-upshouldincludesputumsmearexaminationforacid-fastbacilli,andmycobacterialcultureandsensitivitytesting;bonemarrowbiopsy,biopsyofskinlesions,peripherallymphnodes,liverbiopsy(especiallyifserumalkalinephosphataselevelsareelevated),testingofurineandbodyfluids(ifpresentataccessiblesites);cerebrospinalfluidexamination;smearandcultureexaminationofmaterialaspiratedfromcoldabscess.Allmycobacterialcultureandsensitivitytestingmustbecarriedoutinanaccreditedlaboratory.

Imaging

Imagingmodalities,suchasMDCT,MRI,abdominalultrasonogrpahyareusefulindocumentingthemiliarypatternandlocalizingthelesions.ThePET-CTishelpfulindefiningtheextentofdiseaseatpresentationandatthetimeofstoppingtreatment.

Clinical monitoring

(i) PatientswithmiliaryTBshouldpreferablybehospitalizedforacompleteandthoroughdiagnosticwork-up.

(ii) Dyspnoeicpatientsshouldbecarefullymonitoredandifpulseoximetryrevealsdesaturation,gas-exchangedatamustbeobtained(ifavailable).ThesepatientsshouldbewatchedforthedevelopmentofARDSandmayrequireassistedmechanicalventilationandadministrationofcorticosteroids.

(iii) Clinicalexaminationandechocardiographyshouldbecarriedouttolookforpericardialeffusionaspericardialtamponadecandevelopinthesepatients.

(iv) TheincidenceofTBmeningitisinpatientswithmiliaryTBisveryhigh.CliniciansshouldhavealowthresholdforperforminglumbarpunctureandcarryingoutCSFanalysistodocumentTBmeningitis.

(v) TheMRIisthepreferredmodalityofinvestigationforpatientswithCNSandspinallesions,expeciallybecause,frequentimagingwillberequiredduringfollow-upandmultipleCTswillresultinanenormousdegreeofradiationexposure.

(vi) Thenumber,sizeandlocationoftuberculomasshouldbecarefullycountedasanincreaseintheirnumberand/orsizeduringfollow-upindicateseitherIRISortreatmentfailure,drug-resistanceorre-infection.

(vii) Itiswellknownthatearlyinstitutionofappropriatespecificanti-TBtreatmentresultsinafavourableoutcomeinpatientswithmiilaryTB.Establishingthediagnosisearlywillfacilitateearlyinstitutionofspecifictreatment.Cliniciansshouldhavealowthresholdtoinitiatespecificanti-TBtreatmentinpatientswithmiliaryTBasthiscanbelifesaving.

MDCT,multidetector row computed tomography; PET-CT, positron emission tomography-computed tomography;MRI,magneticresonanceimaging;IRIS,immunereconstitutioninflammatorysyndrome;CNS,centralnervoussystem;CSF,cerebrospinalfluid

withultrasonography,CT,MRIandPETcanhelp inestablishing the extent of organ system involvementinmiliary TB. Image guided FNAC or biopsy fromvarious organ sites, needle biopsy of the liver, bonemarrowaspirationandbiopsy,sputumsmearandcultureexamination, including drug-susceptibility testing (ifaccesstoanaccreditedlaboratoryisavailable)mustbecarriedoutinallpatients.

Treatment of miliary TB should be started atthe earliest as per the standard WHO guidelines.Adjunct corticosteroid treatment is helpful whenthere is adrenal insufficiency, with TB meningitis,largepericardialorpleuraleffusion,dyspnoeaand/or

disabling chest pain, IRIS,ARDS, immune complexnephritis, and histiocyticphagocytosis syndrome. Inpatients co-infected with HIV, careful considerationmust be given for drug-drug interactions betweenanti-tuberculosis and anti-retroviral drugs. Patientsreceiving anti-tuberculosis drugs must be carefullymonitoredforadversedrugreactions,especiallyDIHandothercomplicationsofmiliaryTB.InnewpatientswithmiliaryTBwithoutTBmeningitis,ninemonthsofanti-tuberculosistreatmentshouldbeadequate.WhenTBmeningitisispresent,12monthsofantituberculosistreatmentmaybe required.However, thedurationoftreatmentmayhavetobeprolongedbasedonindividualrequirements.


InlightofthecontinuingHIV/AIDSepidemicandincreasing use of immunosuppressive and cytotoxicdrugs, the burden of miliary TB will continue torise.TheutilityofnewerdiagnosticmethodssuchasIGRAsneedstobeclarified.Eventhoughclinical trials ofafewnewanti-tuberculosisdrugsareongoing,noothernewanti-tuberculosisdrugsappeartobeonthethresholdofbeingintroducedintopractice.Therefore,judicious use of available drugs to ensure regular,complete and adequate treatment is imperative. Therole of adjunctive corticosteroid therapy needs to beelucidated in future studies.The scope andutility ofPET-CTinassessingtheactivityoflesionsthatmightpersistfollowinganti-tuberculosistreatmentinmiliaryTBneedstobestudiedfurther.Thequestforabettervaccine than BCG is still on and more data on thecandidatevaccines thatarecurrentlybeingevaluatedislikelytoemerge.

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Reprint requests:DrSurendraK.Sharma,Professor&Head,DepartmentofMedicine,AllIndiaInstituteofMedicalSciences AnsariNagar,NewDelhi110029,India

e-mail:[email protected]

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