National Guidelines for Management of Tuberculosis in Children

National Guidelines for Management of Tuberculosis

in Children2018

NATIONAL PROGRAMME FOR TUBERCULOSIS AND CHEST DISEASESSRI LANKA

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Convener

NationalProgrammeforTuberculosisControlandChestDiseases (NPTCCD)

Partners

SriLankaCollegeofPulmonologists

SriLankaCollegeofPaediatricians

ISBN 978-955-0742-08-0

PrintedBy: NanilaPublication(Pvt)Ltd. No.227/30,NirmanaMw.NawalaRoad, Nugegoda. Tel:0114809400

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Contents

Foreword ..............................................................................................................viiMessages ............................................................................................................. viiiPreface ............................................................................................................... ixParticipants ................................................................................................................xAbbreviations .............................................................................................................. xii

1. Introduction ........................................................................................................01 1.1 Global,regional,andcountryburden 1.2 Tuberculosisinchildren 1.3 HIVandTuberculosisco-infection 1.4 MultiDrug-ResistantTuberculosis

2. GoalsandobjectivesofthenationalplanformanagementofchildhoodTB ........05 2.1 Goals 2.2 Objectives

3. OrganizationalstructureofNationalProgramme .....................................................07 3.1 OrganizationalstructureoftheNPTCCDatCentrallevel 3.2 OrganizationalstructureofNPTCCDattheProvinciallevel 3.2.1 ProvincialandRegionallevel 3.2.2 Districtlevel

4. Classificationoftuberculosis.......................................................................................11 4.1 Casedefinitions 4.2 Classification 4.3 Treatmentoutcomes

5. Diagnosisoftuberculosisinchildren..........................................................................19 5.1 IntroductiontodiagnosisofTBinchildren 5.2 ApproachtodiagnosisofTB 5.2.1 ContacthistoryofTB 5.2.2 Symptoms 5.2.3 Examinationfindings 5.2.4 Investigations

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5.2.4.1 Tuberculinskintest 5.2.4.2 ChestX-ray 5.2.4.3 Bacteriologicalconfirmation

6. ManagementofChildhoodTB.....................................................................................31 6.1 Administeringtreatmentandensuringcompliance 6.2 Anti-TBmedications 6.2.1 Firstlineanti-TBmedicationsandtherecommendeddoses 6.2.2 Basisoftreatment 6.2.3 ActivityofAnti-TBdrugs 6.2.4 FixedDoseCombination(FDC)formulations 6.3 Recommendedtreatmentregimens 6.3.1 Newcases 6.3.2 Previously-treatedcases 6.4 Treatmentofinfantsaged(0-3)months 6.5 Treatmentinterruption 6.6 ManagementofDrug-resistantTB(DR-TB)inchildren–(Second-linedrugtreatment) 6.6.1 BasicprinciplesoftreatmentofMDR-TB 6.6.2 LongerRegimen 6.6.3 Shorterregimen 6.6.4 DrawbacksinthemanagementofDR-TBinchildren 6.7 Othermanagementissues 6.7.1 RoleofSteroids 6.7.2 NutritionalSupport 6.7.3 Teatmentissuesspecifictoadolescents 6.7.4 Adverseevents 6.8TreatmentAdherence 6.9FollowUp

7. Preventionoftuberculosisinchildren........................................................................53 7.1 Infectioncontrol 7.1.1 Measurestoreduceriskoftransmission 7.2 BCGvaccination 7.2.1 AdverseeventsandcomplicationsrelatedtoBCGvaccination 7.2.2 Managementofadverseevents 7.2.3 BCGvaccinationofinfantsborntoHIV-positivemothers 7.2.4 IndicationsforBCGvaccinationofmigrantchildren

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7.2.5 BCGvaccinationofsuspectedimmunecompromisedbabies 7.2.6 AbsentBCGscar 7.3 Contactinvestigation 7.4 Preventivetherapy(Chemoprophylaxis) 7.5 Intensifiedcasedetectioninhighriskcategories 7.6 PreventionofTBinaninfantborntoamotherdiagnosedwithactiveTB 7.6.1 CongenitalTuberculosis 7.6.2 Managementofthenewbornofamotherwithactivetuberculosis

8. Extra-pulmonaryTB……………………………………………………………………………………………….63 8.1 Diagnosis 8.1.1 TissueBiopsy 8.1.2 Tissueaspirate 8.2 TBLymphadenitis(LNTB) 8.3 TBPleuraleffusion 8.4 TBPericardialeffusion 8.5 Abdominaltuberculosis 8.6 Tuberculosisofthecentralnervoussystem 8.6.2 TBMeningitis(TBM) 8.6.3 Tuberculoma 8.7 SpinalTB 8.8 TBArthritis

9. PerinatalandneonatalTB............................................................................................73 9.1 Clinicalpresentation 9.2 Investigations 9.3 Managementofthenewbornofamotherwithactivetuberculosis

10. TBinHIV-infectedchildren..........................................................................................79 10.1 Diagnosis 10.1.1 DiagnosingTuberculosisinHIV-infectedchildren 10.1.2 DiagnosingHIVinfectioninchildren 10.2 ManagementofTBinHIV 10.2.1 LatentTBinfection(LTBI)andChemoprophylaxis 10.2.2 TreatmentofActiveTBdiseaseinHIVinfectedpatient 10.3 Anti-retroviraltreatment 10.4 Screeningforadverseevents

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10.5 ManagementofRelapse,TreatmentFailure,andDrugResistance 10.6 PreventionofTuberculosis 10.7 Co-trimoxazolepreventivetherapy(CPT)

11 References ........................................................................................................84

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DirectorGeneralofHealthServices

TuberculosisremainsapublichealthprobleminSriLanka.Annually,around9500Tuberculosispatientsareidentified.AhugedisparityinthedistributionofTBcasesacrossdistrictsisobserved.

TherewereseveralchangesinGlobalTBControlStrategiesandtherewerenewdevelopmentsinTBdiagnosis.WHOhas reviseddiseaseclassificationofTB tobealignedwith thesenewchanges.

SincethechildrenwithTBcanpresentwithcomplicationssuchasMilaryTBandMeningitisit is very important todiagnose themearlyandmanageproperly topreventdeathsdue toTB.Thereforeit isessentialthatallchildrenwithtuberculosisaremanagedaccordingtothenationalguidelinesprovidedinthismanual.

Finally,IcongratulatetheDirectorandStaffofNationalProgrammeforTuberculosisControl,CollegeofPulmonologistandCollegeofPediatricians,beingsensitivetothechangesoccurringgloballyaswellasnationallyandtakingtheleadershiproletodeveloptheNationalGuidelinesfortheManagementofChildhoodTB.

Irequestallhealthpersonnelinthecountrytoadheretothenationalguidelinesandjoinhandsinaddressingthechallengeoftuberculosiscontrol.

Dr.AnilJasingheDirectorGeneralofHealthServices

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Director-NationalProgrammefromTuberculosisControl&ChestDiseases

TheNationalProgrammeforTuberculosisControlandChestDiseases(NPTCCD)haspreparedthe“NationalGuidelinesfortheManagementofChildhoodTB”withtheaimtogivepracticalguidancetoallthosewhodiagnose&managetuberculosisinchildrenandtothosewhoareinterestedinknowingthecorrectpractices.

It is a well- known and well accepted fact that the successful outcome of Tuberculosismanagement, as an individual or public healthmeasure, substantially depend on accurateandearlydiagnosis.Thereforeitisessentialthatalldiagnosticandcurativesettings,methods,proceduresandperformancesarenotonlycompilestothecurrentinternationalrequirements,butalsotobestandard,nationally.

“NationalGuidelinesfortheManagementofChildhoodTB”isacombinedeffortoftheNPTCCD,theCollegeofPediatriciansandtheCollegeofPulmonologists.Itisintendedfortheusebyallthemedicalofficersbothinthepublic&privatesector inthemanagementofchildhoodTBandItrustthattheywilladheretotheguidelineslaiddownheretodiagnosetheTBinchildrenearlyinthedisease,toensurecureofthediagnosedpatientsandtopreventtheemergenceofMultidrug-resistantTB.

Iexpressmysinceregratitudetoallthosewhoworkedhardindevelopingtheguidelines.

Dr.KanthiAriyarathneDirector/NationalProgrammeforTuberculosisandChestDiseases

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Preface TheideaofrevisingtheNationalGuidelineonmanagementoftuberculosisinchildrenoriginatedasthepreviousguidelinewasnearly10yearsold.Overthelastdecade,bothgloballyandinSriLanka,manynewdevelopmentshavetakenplaceintuberculosiscontrolstrategies.

Inthelightofthesedevelopments,theNationalProgrammeforTuberculosisandChestDiseasesfunctioningundertheMinistryofHealthandNutritionofSriLankaentrustedthetwoprofessionalColleges,theSriLankaCollegeofPulmonologistsandSriLankaCollegeofPaediatricianswiththetaskofdevelopinganewguideline.WeasCo-editors-inChiefrepresentingthetwoCollegesthank the Presidents and theCouncils of theseColleges for having faith on us to lead thisimportanttask.

We have conceived this guideline with the expectation of providing an essential tool formanagingpaediatricpatientswithtuberculosis.Wetriedourbesttomakeittobeuptodateandasclearaspossible.Keyelementsfrommostupdatedguidelineshavebeenincludedtoproviderelevantinformationtotheusertomakeappropriatechoicesindifferentcircumstances.

Themanualhasbeenenrichedbyvaluablecontributionsmadebyover25authorsincludingPulmonologists, Paediatricians, Neurologists, Community Physicians, Venereologists,Microbiologists,UniversityTeachersandDistrictTuberculosisControlOfficers.Inthisprocess,they worked tirelessly under four subgroups, dedicating their valuable time, sharing theirknowledgeandexpertisewithinashortperiodof3monthsandwewishtothankthemall.WewishtoespeciallyexpressourgratitudetoDr.WijithaSenarathneandDr.BJCPererafortheirspecialcontributionasreviewers.

Thenewmanualconsistsofthreemajorsections:BasicinformationontuberculosisincludingthenewWHOclassification,informationonthenationalplanformanagementoftuberculosisandtheorganizationalstructure,andspecificoperationalguidelineswhichareintheformofchaptersondiagnosis,managementandpreventionoftuberculosisinchildren,perinatalandneonataltuberculosisand,newchaptersonextra-pulmonarytuberculosisinchildrenandTBinHIV-infectedchildren.

Thisupdatedmanualaimstobeavaluabletoolforundergraduateandpostgraduatesinmedicine,paediatricians,pulmonologists,specialistsofotherspecialtiesandallmedicalpersonnelwhomanagepaediatricpatientswithtuberculosiswhomayrefertoitforquickanswersforthemostappropriatewayofmanagingdifferentclinicalsituationsofpaediatrictuberculosisinSriLanka.

Dr.EshanthPerera Dr.KalaSomasundaramConsultantRespiratoryPhysician ConsultantPaediatricianNationalHospitalforRespiratoryDiseases LadyRidgewayHospitalforChildrenWelisara Colombo

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Participants

Editors-in-Chief

●Dr.EshanthPerera -ConsultantRespiratoryPhysician,NHRD ●Dr.KalaSomasunderum -ConsultantPaediatrician,LRH

Editorial Board

Subgroup - 1 – Operational aspects Convener–Dr.PriyadarshaniSamarasinghe

ConsultantCommunityPhysician,NPTCCD

Group members Designation / Affiliations

Dr.EshanthPerera ConsultantRespiratoryPhysician,NHRD

Dr.B.J.C.Perera ConsultantPaediatrician,Privatesector

Dr.NirupaPallewatte ConsultantCommunityPhysician,NPTCCD

Subgroup - 2 – DiagnosisConvener –Dr.AjithAmarasinghe

ConsultantPaediatrician,PrivatesectorGroup members Designation / Affiliations

Dr.AflaSadikeen ResidentConsultantRespiratoryPhysician,NHSL

Dr.GuwaniLiyanage ConsultantPaediatrician,UniversityofSriJayawardanepura

Dr.JithangiWanigasinghe ConsultantPaediatricNeurologist,LRH

Dr.JayadariRanathunge ConsultantVenereologist,CNTH,Ragama

Dr.DhammikaVidanagama ConsultantMicrobiologist,NTRL

Dr.KumuduKarunarathne ConsultantMicrobiologist,LRH

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Subgroup - 3 – ManagementConvener –Prof.RohiniFernandopulle

UniversityofColomboDr.KalaSomasundarum ConsultantPaediatrician,LRH

Dr.DushyanthaMedagedare ConsultantRespiratoryPhysician,THKandy

Dr.KumuduWeerasekera ConsultantPaediatrician,LRH

Dr.JithangiWanigasinghe ConsultantPaediatricNeurologist,LRH

Dr.JayadariRanathunge ConsultantVenereologist,CNTH,Ragama

Dr.GeethalPerera ConsultantRespiratoryPhysician,GeneralHospital,SriJayawardanapura

Dr.ThusharaGalaboda ConsultantRespiratoryPhysician,GHVavuniya

Dr.GaminiRathnayake PMDTCoordinatorandDTCO,DCCGampaha

Subgroup - 4 – PreventionConvener –Dr.AnuraJayawardane

ConsultantPaediatrician,CSTHKalubowila

Dr.WathsalaGunasinghe ConsultantRespiratoryPhysician,DGHMoneragala

Dr.NeranjanDissanayake ConsultantRespiratoryPhysician,DGHBadulla

Dr.ShanthiniGaneshan ConsultantPaediatrician,CSTHKalubowila

Dr.A.Ramachandran DTCO,CCCColombo

Other contributors ●Dr.KanthiAriyarathne -Director,NPTCCD ●Dr.M.C.M.Rifai -DeputyDirector,NPTCCD ●Dr.AmithaFernando -ConsultantRespiratoryPhysician,NHSL

Reviewers ●Dr.B.J.C.Perera -ConsultantPaediatrician ●Dr.WijithaSenarathne -ConsultantRespiratoryPhysician

Coordinator ●Dr.HarshaniVithana -MedicalOfficer,NPTCCD

Other assistance ●Dr.SachiniRathnayake ●Ms.SamaliePerera

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ABBREVIATIONS

ACSM Advocacy,Communication&SocialMobilizationADA Adenosine-DeaminaseAFB Acid-FastBacilliAIDS AcquiredImmuno-DeficiencySyndromeATT Anti-TubercularTreatmentART Anti-RetroviralTherapyBCG BacillusCalmette-GuerinCHDR ChildHealthDevelopmentRecordCDS CentralDrugStoresCNS CentralNervousSystemCP ContinuationPhaseCPT CotrimoxazolePreventiveTherapyCRP ConsultantRespiratoryPhysicianCSF Cerebro-SpinalFluidD/NPTCCD Director/NationalProgrammeforTuberculosisControlandChestDiseasesDCC DistrictChestClinicDDG DeputyDirectorGeneralDDG/MS DeputyDirectorGeneral/MedicalServicesDDG/PHS DeputyDirectorGeneral/PublicHealthServicesDGH DistrictGeneralHospitalDGHS DirectorGeneralofHealthServicesDOT DirectlyObservedTreatmentDPRK DemocraticPeople’sRepublicofKoreaDST Drug-SensitivityTestDTCO DistrictTuberculosisControlOfficerEPTB Extra-PulmonaryTuberculosisFDC Fixed-DoseCombinationsFLD First-LineDrugsFNAC FineNeedleAspirationCytologyGDF GlobalDrugFacilityGFATM GlobalFundtoFightAIDS,Tuberculosis,andMalariaHIV HumanImmuno-DeficiencyVirusIRIS ImmuneReconstitutionInflammatorySyndromeICP IntracranialPressureIP IntensivePhase

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IPT IsoniazidProphylacticTreatmentLFT LiverFunctionTestsTMP TrimethoprimLNTB LymphNodeTuberculosisLTBI LatentTuberculosisInfectionM.bovis MycobacteriumbovisMDR-TB Multi-DrugResistantTuberculosisMO MedicalOfficerMOH MinistryofHealthcareandNutritionMOIC MedicalOfficer-in-ChargeMOTT MycobacteriumotherthanTuberculosisNaCl SodiumChlorideNHRD NationalHospitalforRespiratoryDiseasesNHSL NationalHospitalofSriLankaNPTCCD NationalProgrammeforTuberculosisControlandChestDiseasesNTP NationalTuberculosisProgrammeNTRL NationalTuberculosisReferenceLaboratoryPDHS ProvincialDirectorofHealthServicesPGH ProvincialGeneralHospitalPLHIV PeopleLivingwithHumanImmuno-deficiencyVirusPMDT ProgrammaticManagementDrug-ResistantTuberculosisPPD PurifiedProteinDerivativePTB PulmonaryTuberculosisPZA PyrazinamideRDHS RegionalDirectorofHealthServicesRR RifampicinResistanceSAARC SouthAsianAssociationforRegionalCooperationSEAR South-EastAsianRegionSLD Second-LineDrugsSMX SulfamethoxazoleSOP StandardOperatingProcedureTB TuberculosisTBM TuberculousMeningitisTST TuberculinSensitivityTestTU TuberculinUnitsWHO WorldHealthOrganizationXDR-TB ExtremelyDrug-ResistantTuberculosis

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TREATMENT NOMENCLATURE

• TheFirst-LineAnti-TBdrugsarereferredtobysingle-letterabbreviations; R–Rifampicin H–Isoniazid Z–Pyrazinamide E–Ethambutol S–Streptomycin

• TheSecond-LineAnti-TBdrugsarereferredtobytwoorthreeletterabbreviations; Cfz–Clofazimin Eto–Ethionamide Pto–Prothianomide Km–Kanamycin Cm–Capreomycin Cs–Cycloserine Lfx–Levofloxacin Mfx–Moxifloxacin PAS–p-AminoSalicylicAcid

01.INTRODUCTION

1.1 Global,regional,andcountryburden

1.2 Tuberculosisinchildren

1.3 HIVandTuberculosisco-infection

1.4 MultiDrug-ResistantTuberculosis

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1. INTRODUCTION

1.1 GLOBAL,REGIONAL,ANDCOUNTRYBURDEN

Globally,tuberculosisremainsawidespreadproblemandposesacontinuingthreattothehealthanddevelopmentofpeople. It isestimated that in2014,23%-26.4%(approximately1.7billion)peoplehavebeeninfectedwiththeTBbacillusworldwide.In2015theestimatednew(Incidence)caseswere10.4millionoutofwhich1Million (10%)werechildren.TheestimatedTBdeaths for2015was1.4Millionwithanadditional0.4milliondeathsresultingamongHIVpositivepeople.Itwasoneofthetoptencausesofdeathsworldwide.In2017,accordingtoWHOestimates,therewere239,000paediatricdeathsduetoTB.Furthermore,39,000deathsoccurredamongHIV-infectedchildren.Approximately,80percentofthesedeathsoccurredinchildrenundertheagefive.ChildreninthisagegrouprepresentanimportantdemographicgroupforTBastheyfrequentlyadvancemorerapidlyfromlatentTBinfectiontoTBdisease,withsomeofthemprogressingtosevereforms,suchasmiliaryTBandTBmeningitis.Thesechildrenserveassentinelcases,indicatingrecentand/orongoingtransmissioninthecommunity.

TheWHOSouth-EastAsiaRegion (SEAR)carries thehighestburdenof tuberculosisamongallWHORegions:45%oftheglobalburden.Sixcountriesinthisregion,(Bangladesh,India,Indonesia,Myanmar,ThailandandDPRK)belongtothe‘30HighTB-BurdenCountries’,whichcontributeto84%oftheglobalcaseload.AnotherSAARCmembercountryPakistan,whichbelongstotheWHOEasternMediterraneanRegionalsobelongstothe ‘30HighTB-BurdenCountries’.Furthermore, theWHOSouth-EastAsian,Western-Pacific,andAfricanregionshaveaccountedforaround80%ofthosewithLatentTBInfection.HoweveraccordingtoWHOstatistics,theTBincidencehasfallenbyanaverageof1.5%peryearsince2000, but this needs to be accelerated to 4-5% annually to reach the 2020-mile stone of ‘End-TBStrategy’.

SriLankaisconsideredasamiddle-burdencountryforTB,thesecondlowestintheregion.TheestimatedincidencerateforSriLankais65(57-73)per100,000population(WHOGlobalReport,2015).Therefore,anestimateof13000peoplewerehavingTBin2015.However,thecasedetectionrateforthisyearwas45.9%.Accordingto2016annualstatistics,atotalof8886casesofallformsofTBcaseswerenotifiedtotheNationalProgrammeforTuberculosisandChestDiseases(NPTCCD).Outofthis,8332werenewcases,and550werepreviouslytreated.Outofthenewcases4093werebacteriologicallyconfirmedpulmonaryTB,1714wereclinicallydiagnosedpulmonaryTBand2525wereextrapulmonaryTB.

Abouthalfofthesenewcasesaresputumsmear-positiveand,ifuntreated,theycontinuetospreadtheinfection.ReportedratesofTBaresubstantiallyhigherinmales(2/3)thaninfemales,exceptamongchildren,possiblybecauseadultmenaremorefrequentlyexposedtoinfectionthanwomen.Mostofthesepatientswereintheeconomicallyactiveagegroupsof15–54years.Thehighestratesofinfectionhavebeenfoundinthemostdenselypopulatedareas,suchasColomboandotherurbanareas.

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1.2 TUBERCULOSISINCHILDREN

AccordingtotheWHOnearlyoneMillionchildrendevelopTBand140,000childrenwillcontinuetodieeachyear fromTB.Deathsdue toTB is the leadingcauseofchildrenbeingorphanedmostly indevelopingcountries.In2016,263newchildhoodTBcaseswerefoundinSriLankaandthiswasaround4%ofthetotalcasesreported.Theproportionreportedfortheperiod2012to2015wasaround3%.ThisisstillbelowtheWHOglobalestimateof5to8%ofnewchildhoodTBcasesamongallcases.

ThemainsourceoftransmissionofTBinfectiontoachildisusuallyanadultwithpositivetuberculosisinthelungs.TBinchildrenismainlyduetoafailureindiagnosing,treatingandcuringinfectiousadultpatients.Adultswhodonotcompletetheirtreatmentplaceyoungchildrenbelowtenyearsofageatriskofgettinginfected.

1.3 HIVANDTUBERCULOSISCO-INFECTION

In2015,onethirdofpeoplelivingwithHIV(PLHIV)wereestimatedtobeinfectedwithTuberculosisglobally.TheseHIVandTBcoinfectedpersonsare20to30timesathigherriskofdevelopingtheTBdiseasethanHIVnon-infectedpeople.InSriLanka,currently,itismandatorytoscreenallTBpatientsforHIV,aswellastoscreenallPLHIVforTB.SevenHIV-positivecasesweredetectedamongTBpatientsscreenedduring2016.MajorityoftheseHIVcaseswereinthe20-44-yearagegroup.However,moreHIVandTBcoinfectedcasescanbeexpected tobe founddue toscalingupof targetedHIV testingprogrammes in Sri Lanka. Children coinfectedwith HIV and TB are at higher risk of developing TBmeningitisandoftenresultsindeafness,blindness,paralysisandmentalretardation.

1.4 MULTIDRUG-RESISTANTTUBERCULOSIS

Multi drug-resistant tuberculosis (MDR-TB), is defined as development of resistance against bothisoniazidandrifampicin,andthismayposeaseriousthreattothesuccessofTBcontrolprogrammes.InSriLanka,noneofthe17newMDR-TBcasesdetectedin2016wereunder14-yearsofage.

All smear-positivepatientswhoremainAFB-positiveduringthe followupandpatientswhoareatahigherriskofhavingMDR-TBgettheirsputumsamplestestedforcultureanddrug-susceptibilitytestingandXpertMTB/RIF,whichareperformedattheNationalTuberculosisReferenceLaboratory(NTRL)oratprovinciallevellaboratories.

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02.GOALSANDOBJECTIVESOFTHE NATIONAL PLAN FOR

MANAGEMENT OFCHILDOOD TB

2.1 Goals

2.2 Objectives

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2. GOALSANDOBJECTIVESOFTHENATIONALPLANFORMANAGEMENTOFCHILDOODTB

ANationalStrategicPlanisavailableforSriLankafortheperiodofyear2015to2020andaNationalPlanfortheManagementofChildhoodTBisdevelopedinparwiththis.

2.1 GOALS:1. Increasecasefindingoftuberculosisinchildren

2. Strengtheningdiagnosis,treatment,andpreventivetherapyforchildrentowardsdecreasingchildhoodTBmorbidityandmortality

2.2 OBJECTIVES:1. Tostrengthenadvocacy,communication,andsocialmobilization(ACSM)forensuringthe

managementofTBinchildren.

2. TostrengthendetectionofnewchildhoodTBcases,increasingitspercentageamongallTBcasesdetectedannually,from3%(2014)to6%(2020).

3. ToensureearlytreatmentofchildrenwithTB.

4. To strengthen contact screeningandprovisionof IsoniazidPreventiveTherapy (IPT) forchildrenwithclosecontactwithPTBcases.Thetargetistoensure100%investigationofchildcontacts,provisionofIPTforatleast80%thesecontactsandatleast90%completionofit.

5. Tostrengthenmonitoring,supervision,andresearchonmanagementofTBinchildren.

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03.ORGANIZATIONAL STRUCTURE

OF NATIONAL PROGRAMME

3.1 OrganizationalstructureoftheNPTCCDatCentrallevel

3.2 OrganizationalstructureofNPTCCDattheProvinciallevel

3.2.1 ProvincialandRegionallevel

3.2.2 Districtlevel

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3. ORGANIZATIONALSTRUCTURENATIONALPROGRAMMEFORTUBERCULOSISCONTROLANDCHESTDISEASES

The National Programme for Tuberculosis Control and Chest Diseases (NPTCCD) is one of the keyinstitutionsintheNationalHealthSystem.TheDirectorheadstheprogramme,andisresponsibleforthecontrolactivitiesoftuberculosisandotherrespiratorydiseaseoftheentirecountry,incloseco-ordinationwith the general health services, and other governmental and non-governmental stakeholders. Atpresent,thereare26DistrictChestClinics(DCC)functioningin25AdministrativeDistrictsinthecountry.Inwardcare facilitiesareprovided through theNationalHospital forRespiratoryDiseases (NHRD)atWelisaraandRespiratorywardsin13DistrictHospitals.DiagnosticservicesarecarriedoutthroughtheNTRL,RegionalCultureLaboratories,DCCLaboratoriesandMicroscopicCentres.CentralDrugStoresoftheNPTCCDisresponsiblefortheestimation,procurement,supply,anddistributionofanti-TBDrugstotheDCCs.(Fig.3.1)

3.1 ORGANIZATIONALSTRUCTUREOFTHENATIONALTUBERCULOSISCONTROLPROGRAMMEATCENTRALLEVEL

TheNPTCCDconsistsofseveralinstitutionswhichfunctionsatnationallevel.TheseincludetheCentralUnit,NTRL,CentralDrugStores,CentralChestClinic(CCC)Colombo,andDistrictChestClinicGampaha.

3.2 ORGANIZATIONALSTRUCTUREOFNATIONALTBCONTROLPROGRAMMEATTHEPROVINCIALLEVEL

3.2.1ProvincialandRegionallevel

WiththeintroductionoftheProvincialCouncilsActtotheConstitutionofSriLankain1987,somehealthcareservicesweredevolvedintotheProvincialCouncils.Accordingly,thereisthelineMinistryofHealthatcentrallevelheadedbyaCabinetMinisterandProvincialMinistriesofHealthinthe9provinces.TheProvincialDirectorsofHealthServices(PDHSs)andRegionalDirectorsofHealthServices(RDHSs)areresponsibleforthemanagementandeffectiveimplementationofhealthservicesincludingTBcontrolactivitiesintheirrespectiveprovincesanddistricts.TheseactivitiesarecarriedoutthroughanetworkofDCCsinaccordancewiththepolicyandtechnicalguidanceprovidedbytheNPTCCDandConsultantRespiratoryPhysiciansintheProvince.

3.2.2 Districtlevel

The District Chest Clinic (DCC) is the key organizational unit of the National Tuberculosis ControlProgrammeatthedistrictlevelanditisthefocalpointoftheNTPCCDforallTBcontrolactivitiesintherelevantdistrict.ItisundertheadministrativecontroloftheDistrictTuberculosisControlOfficer(DTCO)andisresponsibleforthecontrolactivitiesoftuberculosisandrespiratorydiseaseinthedistrict.TheDTCO is responsibleadministratively to thePDHSandRDHS,and isprogrammaticallyguidedby theDirectoroftheNPTCCDandtechnicallyguidedbytheConsultantRespiratoryPhysicianoftherelevantdistrict.TheCCCColomboandtheDCCGampahafunctionundertheDirectoroftheNPTCCD.AllDCCsexcepttheabovetwo,functiondirectlyunderthepurviewofthePDHSandtheRDHSs.

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04.CLASSIFICATION OF

TUBERCULOSIS

4.1 Casedefinitions

4.2 Classification

4.3 Treatmentoutcomes

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4. CLASSIFICATIONOFTUBERCULOSIS

CaseDefinitionsandTreatmentOutcomes

Classification of TB patients is important to determine correct management including treatmentregimensand thedurationsof treatment. It is also important for recordingand reportingpurposeswhichwillfacilitatecohortanalysisoftreatmentoutcomes.

4.1 CASEDEFINITIONS

4.1.1 PresumptiveTB(TBsymptomatic)

AcaseofpresumptiveTB(TBsymptomatic) isapersonwhopresentswithsymptomsorsignssuggestiveofTB,particularlycoughfortwoweeksormore.

4.1.2 Caseoftuberculosis

AcaseoftuberculosisisapatientinwhomTBhasbeeneitherbacteriologicallyconfirmedinthelaboratoryorclinicallydiagnosedbasedonaclinician’sdecisionconsideringtheclinicalpicture,resultsofotherinvestigations,andriskfactors.

A) Caseof‘Bacteriologicallyconfirmed’TB

ApatientwhosesputumoranotherbiologicalspecimenispositiveforAFBbysmearmicroscopy,culture,orWHO-approvedRapidDiagnostics(WRD)suchasXpertMTB/RIF.

1. Smear-positivepulmonarytuberculosis

Apatientwithat least twosputumsmearspositiveforAFBbydirectsmearmicroscopyOR A patientwithatleastonesputumsmearpositiveforAFBbymicroscopyandasdeterminedbyaclinicianbasedonChestX-rayfindingssuggestiveofTB.

2. CulturepositiveTB

ApatientwithorwithoutsputumsmearpositiveforAFBbutsputumoranybiologicalspecimenculturetestingpositivebycultureforM.tuberculosis

3. WHO-approvedRapidDiagnostics(WRD)

ApatientwithorwithoutsputumsmearpositiveforAFBbutsputumoranybiologicalspecimentestingpositiveonXpertMTB/RIFforM.tuberculosis.(XpertMTB/RIFmaybeuseddirectlyonabiologicalspecimenwithoutsubjectingthesampletomicroscopyexaminationasdescribedlaterinthismanual).

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B) Caseof‘Clinicallydiagnosed’TBApatientwhodoesnotfulfilthecriteriaforbacteriologicalconfirmationbuthasbeendiagnosedwithactiveTBbyaclinicianandafterconsultationwithaConsultantRespiratoryPhysiciananda decisionmade to treat the patient with a full course of anti-TB treatment. This definitionincludescasesdiagnosedonclinicalsignsandsymptoms,and/orradiologicalabnormalitiesand/or suggestive histology. Clinically diagnosed cases subsequently found to be bacteriologicallypositive(beforeorafterstartingtreatment)shouldbereclassifiedasbacteriologicallyconfirmed.

4.2 CLASSIFICATIONOFTUBERCULOSIS

BacteriologicallyconfirmedorclinicallydiagnosedcasesofTBarealsoclassifiedaccordingto: A) Anatomicalsiteofthedisease

B) Historyofprevioustreatment

C) Drugresistance

D) HIVstatus.

A) Classificationbasedonanatomicalsiteofthedisease

1. Pulmonarytuberculosis(PTB)

AnybacteriologicallyconfirmedorclinicallydiagnosedcaseofTBinvolvingthelungparenchymaorthetracheobronchialtreewithorwithouttheinvolvementofanyotherorgansinthebody.MiliaryTBisclassifiedasPTBbecausetherearelesionsinthelungs.Tuberculousintra-thoraciclymphadenopathy(mediastinaland/orhilar)or tuberculouspleuraleffusion,without radiographicabnormalities in thelungparenchyma,constitutesacaseofExtrapulmonarytuberculosis(EPTB).

2. Extrapulmonarytuberculosis(EPTB)

AnybacteriologicallyconfirmedorclinicallydiagnosedcaseofTBinvolvingorgansotherthanthelungparenchymaor tracheobronchial tree (e.g.pleura, lymphnodes,abdomen,genitourinary tract, skin,bonesandjoints,meninges).

A patient with both pulmonary and extrapulmonary tuberculosis should be classified as a case of pulmonary TB

B) ClassificationbasedonhistoryofpreviousTBtreatment(patientregistrationgroup)– (ref.Table4.1)

In order to identify those patients at increased risk of acquired drug resistance and to prescribeappropriatetreatment,acaseshouldbedefinedaccordingtowhetherornotthepatienthaspreviouslyreceivedTBtreatment.Theregistrationgroupfocusesonlyonhistoryofprevioustreatmentirrespective

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ofbacteriologicalconfirmationorsiteofdisease.Accordingly,allpatientscanbecategorizedas‘New’patientsor‘Previouslytreated’patients.Theyaredefinedasfollows:

1. Newpatients

ApatientwhohasnevertakentreatmentforTB ORApatientwhohastakenanti-tuberculosisdrugsforlessthanonemonthNewpatientsmayhavepositiveornegativebacteriologyandmayhavediseaseatanyanatomicalsite.

2. Previouslytreatedpatients

Thosewhohave receivedonemonthormoreof anti-TBdrugs in thepast are classifiedunder thiscategory. Theymayhavepositiveornegativebacteriologyandmayhavediseaseat any anatomicalsite.Theyarefurtherclassifiedbytheoutcomeoftheirmostrecentcourseoftreatmentas‘relapse’,‘treatmentafterfailure’and‘treatmentafterlosstofollow-up’.

a. RelapsePatientswhohavepreviouslybeen treated for TB,weredeclared ‘cured’or ‘treatmentcompleted’attheendoftheirmostrecentcourseoftreatment,andarenowdiagnosedwitharecurrentepisodeofTB(eitherreactivationofdormantbacillioranewepisodeofTBcausedbyreinfection).

b. TreatmentafterfailurePatientswhohavepreviouslybeentreatedforTBandwhose‘treatmentfailed’duringorattheendoftheirmostrecentcourseofTBtreatment.

c. Treatmentafterlosstofollow-upPatientswhohavepreviouslybeentreated forTBandweredeclared ‘lost to follow-up’at theendof theirmost recent courseof treatment. (Thesewerepreviously knownastreatmentafterdefaultpatients.)

d. OtherpreviouslytreatedpatientsPatientswhohavepreviouslybeen treated forTBbutwhoseoutcomeafter theirmostrecentcourseoftreatmentisunknownorundocumented.

3. PatientswithunknownpreviousTBtreatmenthistory.

Patientswhodonotfitintoanyofthecategorieslistedabove.

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ClassificationbasedonhistoryofpreviousTBtreatment

Registrationgroup(anysiteofdisease) Outcomeofmostrecentpriortreatment

New - -

Previouslytreated

Relapse CuredTreatmentcompleted

Treatmentafterfailure TreatmentfailedTreatmentafterlosstofollow-up Losttofollow-up

Otherpreviouslytreatedpatients

PatientswhohavepreviouslybeentreatedforTBbutwhoseoutcomeaftertheirmostrecentcourseoftreatmentisunknownorundocumented.

PatientswithunknownpreviousTBtreatmenthistory Allcasesthatdonotfitintoabovedefini-tions

Table4.1

New and relapse cases of TB are considered Incident TB cases

i.ClassificationbasedonHIVstatus

1) HIV-positiveTBpatientreferstoanybacteriologicallyconfirmedorclinicallydiagnosedcaseofTBwhohasapositiveresultfromanHIVconfirmatorytest.

2) HIV-negativeTBpatientreferstoanybacteriologicallyconfirmedorclinicallydiagnosedcaseofTBwhohasanegativeresultfromHIVtestingconductedatthetimeofTBdiagnosis.AnyHIV-negativeTBpatientsubsequentlyfoundtobeHIV-positiveshouldbereclassifiedaccordingly.

3) HIVstatusunknownTBpatientreferstoanybacteriologicallyconfirmedorclinicallydiagnosedcaseofTBwhohasnoresultofHIVtesting.Ifthepatient’sHIVstatusissubsequentlydetermined,heorsheshouldbereclassifiedaccordingly.

ii.Classificationbasedondrugresistance

Casesareclassifiedincategoriesbasedondrugsusceptibilitytesting(DST)ofclinicalisolatesconfirmedtobeM. tuberculosis:

1) Mono-resistance:TB inapatient,whose infecting isolatesofM. tuberculosisare resistant in-vitrotooneoffirst-lineanti-tuberculosisdrugsexceptrifampicin.Rifampicinmonoresistanceiscategorisedseparately.

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2) Poly-resistance:TBinapatient,whoseinfectingisolatesofM. tuberculosisareresistantinvitrotomorethanonefirst-lineanti-tuberculosisdrug,otherthantobothisoniazidandrifampicin.

3) MultiDrugResistantTB(MDR-TB):Tuberculosisinapatient,whoseinfectingisolatesareresistantin-vitrotobothisoniazidandrifampicinwithorwithoutresistancetootherfirst-linedrugs.

4) ExtensivelyDrugResistant(XDR-TB):TBinapatient,whoseinfectingisolatesofM. tuberculosis areresistantin-vitrotobothrifampicinandisoniazidalongwithresistancetoanyquinoloneandoneofthesecond-lineinjectableanti-TBdrugs.

5) Rifampicin resistance (RR): Resistance to rifampicin detected using phenotypic or genotypicmethods,withorwithoutresistancetootherantiTBdrugsexceptisoniazid.

Rifampicin resistant tuberculosis is not mutually exclusive with MDR or XDR TB since all MDR and XDR TB cases are also classified as

Rifampicin Resistance Tuberculosis

4.3TREATMENTOUTCOMES

Thetreatmentoutcomedefinitionsmakeacleardistinctionbetweentwotypesofpatients:

4.3.1 Patientstreatedfordrug-susceptibleTB

4.3.2 Patientstreatedfordrug-resistantTBusingSecond-LineDrugs(SLD) - defined as combination chemotherapy for drug-resistant tuberculosis which includes drugs

otherthanthoseinGroup1andstreptomycininGroup2

The two groups aremutually exclusive. Any patient found to have drug-resistant TB andplacedonsecond-line treatment is removed from the drug-susceptible TB outcome cohort. This means thatmanagementof the standardTB register andof the second-line TB treatment register needs tobecoordinatedtoensureproperaccountingoftheoutcomesoftreatment.

4.3.1 Treatmentoutcomesfordrug-susceptibleTBpatients

AllbacteriologicallyconfirmedandclinicallydiagnosedTBcasesshouldbeassignedanoutcomefromthislistexceptthosewithRR-TBorMDR-TB,whoareplacedonasecond-linedrugregimen.

1) Cured ApulmonaryTBpatientwithbacteriologicallyconfirmedTBatthebeginningoftreatmentwho

issmearnegativeorculturenegativeinthelastmonthoftreatmentandonatleastonepreviousoccasion.

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2) Treatmentcompleted ATBpatientwhocompletedtreatmentwithoutevidenceoffailureBUTwithnorecordtoshow

thatsputumsmearorcultureresultsinthelastmonthoftreatmentandonatleastonepreviousoccasionarenegative,eitherbecausetestswerenotdoneorbecauseresultsareunavailable.

3) Treatmentfailed ATBpatientwhosesputumsmearorcultureispositiveatmonth5orlaterduringtreatment.

4) Died ATBpatientwhodiesforanyreasonbeforestartingorduringthecourseoftreatment.

5) Losttofollow-up ATBpatientwhodidnotstarttreatmentorwhosetreatmentwasinterruptedfor2consecutive

monthsormore.

6) Notevaluated A TBpatient forwhomno treatmentoutcome is assigned. This includes cases forwhom the

treatmentoutcomeisunknowntothereportingclinic.

7) Treatmentsuccess Thesumofcuredandtreatmentcompleted.

PatientsfoundtohaveanRR-TBorMDR-TBstrainatanypointintimeshouldbestartedonanadequatesecond-line drug regimen. These cases are excluded from the main TB cohort when calculatingtreatmentoutcomesandincludedonlyinthesecond-lineTBtreatmentcohortanalysis. Iftreatmentwithasecond-linedrugregimenisnotpossible,thepatientiskeptinthemainTBcohortandassignedanoutcomefromamongthoselistedabove.

(ForfurtherdetailsonregistrationandmanagementofRR/MDR-TBcases,pleaserefertotheNationalPMDTGuidelines.)

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05.DIAGNOSIS OF TB

IN CHILDREN

5.1 IntroductiontodiagnosisofTBinchildren

5.2 ApproachtodiagnosisofTB

5.2.1 ContacthistoryofTB

5.2.2 Symptoms

5.2.3 Examinationfindings

5.2.4 Investigations

5.2.4.1 Tuberculinskintest

5.2.4.2 ChestXray

5.2.4.3 Bacteriologicalconfirmation

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5. DIAGNOSISOFTBINCHILDREN

5.1 INTRODUCTIONTODIAGNOSISOFTBINCHILDREN

Diagnosis of TB in children is often difficult as many small children cannot produce sputum forexamination.Adetailedhistory,examinationandcontactwithaknownor likelycaseoftuberculosisshouldprecedediagnostictests.Ininfants,thepresentationmaybemoreacuteorpersistentandtheycanhavenon-resolvingsymptomswhencomparedtoolderchildren.Adolescentsusuallypresentwithsymptomssimilartothoseinadults.

DiagnosingExtra-PulmonaryTB(EPTB)ischallenging.(Itisdescribedinaseparatechapter)

5.2 APPROACHTODIAGNOSISOFTB

Thediagnosisshouldbebasedon:• Adetailedhistory(includingacontacthistoryofTBandsymptomsconsistentwithTB)

• Clinicalexamination(includinggrowthassessment)

• Investigations

- Tuberculinskintesting

- ChestX-rayandotherrelevantradiologicalinvestigations

- BacteriologicalconfirmationincludingXpertMTB/RIF(wheneverpossible)

- Investigationsforextra-pulmonaryTB

- HIVtesting

5.2.1 ContacthistoryofTB

All child-contacts should be screened clinically (history and examination). Children aged 0–4 years(regardlessofsymptoms)andchildrenaged5yearsandabovewhoaresymptomatic,mustbefurtherevaluatedforTB.ChildrenofallageslivingwithHIV,whohavebeeninclosecontactwithaTBcasemustbeevaluatedforTB.

Whenachild isdiagnosedwithTB,effortsshouldbemadetodetectthesourcecase(ifnotalreadyidentified)andanyotherundiagnosedcases in thehousehold.Sourcecases include, thehouseholdmembers,neighboursincrowdedareas,frequentvisitors,servants,schoolvandrivers,staffinday-carecentres,nurseriesetc.IfachildpresentswithTB,otherchildcontactsmustbesoughtandscreened,asforthesourcecase.Childrenshouldberegardedasinfectiousiftheyhavesputumsmear-positivepulmonaryTBorcavitatoryTBonchestX-ray(notuncommoninolderchildrenandadolescents).

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5.2.2 Symptoms

Mostchildrenwouldpresentwithchronicunremittingsymptomssuchas;• Persistentcoughformorethantwoweeks

• Pneumonianotrespondingtoantibiotics

• Poorcontrolof‘asthma’/wheezingdespiteappropriatetreatment

• Undiagnosedfebrileillnesscontinuingformorethan2weeks

• Poorfeeding/anorexia

• Weightlossorgrowthfaltering(itisveryimportanttolookatthechild’sgrowthchartifavailable)

• Childrenwhoarereceivingtherapeuticnutritionaltreatmentornutritionalsupplementationbutarestillnotgainingweight,orarecontinuingtoloseweight

• Fatigue,lethargyanddecreasedactivity

ThereshouldbealowerthresholdtodiagnoseTBinchildrenwhoareatriskofseverediseasesuchas;• Infantsorveryyoungchildren(under3years)

• ChildrenlivingwithHIVinfectedpatients

• ChildrenwithSevereAcuteMalnutrition(SAM)

• Immunocompromisedchildren

• Immigrantandrefugeechildren

Specificoradditionalsymptomswillbepresentindifferentformsofextra-pulmonaryTB.(Seechapter8formanifestationsofextrapulmonaryTB). 5.2.3 Examinationfindings

There are no specific features on clinical examination of the respiratory system that can confirmpulmonaryTB.PhlyctenularconjunctivitisanderythemanodosummaybemanifestationsofTB. Inasymptomaticchildbelow5yearsofage, theabsenceofaBCGscarmaybeapoint in favourofTB.ExaminationfindingsofextrapulmonaryTBmayvarydependingonthesiteofdisease.(Seechapter8fordetails).

5.2.4 Investigations

5.2.4.1Tuberculinskintest

There are several methods of performing the Tuberculin Test. In Sri Lanka, Mantoux test is used.TuberculinisapurifiedproteinderivedfromMycobacteriumbovisbacilli.InfectionwithMycobacteria,causesthedevelopmentofhypersensitivitytotuberculin.Thisisusefulinidentificationoftuberculousinfection.However,theTuberculinskintestisoflimitedvalueinclinicalwork,especiallyincountries

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withahigherprevalenceofTB.Apositivetestonlyindicatestheinfectionbutnotthepresenceortheextentoftuberculousdisease.Atthesametime,anegativetestdoesnotnecessarilyexcludeactiveTB.Itdoesnothaveasignificantvalueinthediagnosisofre-activationoftuberculosis.ArepeatMantouxisnotroutinelyrecommendedinthediagnosisofTB.

OutofseveralpreparationsofTuberculinavailable,theNationalTBControlProgrammeatpresentusesPPD5TUwhichisbioequivalenttothepreviouslyusedPPD-RT-23(2TU/0.1ml)solution.ThefollowingprecautionsshouldbetakentoensurethequalityandpotencyoftheMantouxsolution.

• Itshouldnotbefrozen,butkeptrefrigeratedandtheoptimaltemperatureforstorageis2-80C

• Anopenedmulti-dosevialshouldbeusedwithin30days

• Skintestshouldbeperformedsoonafterthesyringeisfilled.

SincetheMantouxsolutioncomesinmulti-dosevials,usageofMantouxshouldbedonecosteffectively.The days for Mantoux testing can be arranged considering the number of patients and storageprecautions,onceorseveraldaysaweek.

Mantouxtestisdonebyintradermalinjectionof0.1mloftuberculintotheanterioraspectoftheleftforearm.Thetransversediameteroftheindurationismeasuredat72hours.

AdministrationandReading

Locationofacleaninjectionsite

• Select an area in themiddle one third oftheanterioraspect(palmarside)oftheleftforearm.

• Placethepalmsideoftheleftforearmuponafirmwelllitarea.

• Select an area free of barriers (e.g. scars,sores)forplacingandreading.

• Cleantheareawithanalcoholswab.

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Preparationofsyringe• Checktheexpirydateofthevialandensurevialcontainstuberculin.

• Useasingledosetuberculinsyringe(1mlsyringe)withashortbevelneedle(27gauge).

• Fillthesyringewith0.1mloftuberculin.

InjectingTuberculinInsertslowlywiththebevelupintradermallyata5-15oangle.

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Reading• Visuallyinspectthesiteundergoodlight.

• You may see an induration as well aserythemaaroundit.

- Induration(Hard,dense,raisedformation)

- Do not measure erythema (reddening oftheskin)

• Thereadingshouldbetakenat72hours.

• Induration is the one that should bemeasuredwithelbowextendedpreferablyusingaflexibletransparentruler.

Markinginduration• Runaballpointpenfromtheouterforearm

tothewealuntiltheresistanceisfelt.Drawalineperpendiculartotheweal.

• Repeatthesameintheinneraspectoftheforearm.

• Mayusefingertipsasaguideformarkingwidestedgesof the indurationacross theforearm.

Measurement• Should not be documented as Positive

or Negative. The exact measurement isnecessary.

• Measure between the two perpendicularlines

• Place“0”markofruler line insidethe leftmark

• Readrulerlineinsiderightmark(uselowermeasurementifbetweentwogradientsonmmscale)

• Documentmeasurementinmm

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InterpretationofTuberculinSkinTest

• InHIV-negativeindividuals, - 0-9mm:Negative

- 10-14mm:Positive

- 15mmormore:Stronglypositive

• In immunosuppressedchildren(HIVpositive,severelymalnourishedetc.)aMantouxtestof5mmormoreisconsideredaspositive.

• InallthechildrenwhethertheyhavereceivedtheBCGvaccinationornot,agreaterthan10mmindurationisregardedaspositive.

TuberculintestperseisnotadiagnostictestforTB.Itshouldbeinterpretedinthecontextofclinicalpictureandresultsofotherinvestigations.Apositivetuberculintest isonlyasupportiveevidenceinfavourofadiagnosisofactivetuberculosis.

TuberculintestcanbepositiveintheabsenceofactiveTBinthefollowingconditions:• PastTBdisease

• BCGvaccination

• LatentTBinfection

• Incorrectinterpretationoftest

• PrimaryTBinfection

• Exposure/Infectionwithnon-tuberculousmycobacteria

Adiameterofskinindurationlessthan10mmdoesnotexcludethediagnosisoftuberculosis.

Mantouxcanbenegativeinthepresenceofactivetuberculosisinthefollowingconditions:• HIVinfection

• Severeundernutrition

• DisseminatedTBandmilliaryTB

• Severebacterialinfections.e.g.typhoid,leprosy,pertussis

• Recentinfectionssuchaswhoopingcough,measles,chickenpoxetc.

• Incorrecttechniqueandinterpretationoftuberculintest

• Improperstorageoftuberculin

• Neonates

• Thosevaccinatedwithliveviralvaccines(within6weeks)

• Immunosuppressive medications, primary immune-deficiencies, immunocompromisedconditions

• Diseasesoflymphoidtissue(e.g.Hodgkin’sdisease,lymphoma,leukaemia,sarcoidosis)

• Diabetes

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5.2.4.2 ChestXray

ChestX-rayisagoodscreeningtoolbutanormalCXRdoesnotexcludepulmonaryTB.ThemajorityofchildrenwithpulmonaryTBhaveCXRchanges.FollowingchangesmaybeobservedintheCXR:

• Persistentopacity/sinthelungtogetherwithenlargedhilarorsubcarinallymphglands

• Amiliarypatternofopacificationinanon-HIV-infectedchild

• Persistentopacificationnotimprovingafteracourseofantibiotics

• Pleuraleffusionsandinfiltrateswithcavityformationespeciallyintheupperzonesmaybeseeninadolescents.

• Adolescentscouldalsomanifestprimarydiseasewithhilarlymphadenopathyandsegmentallungcollapse.

AbnormalitiesseenonachestX-raymaybemimickedbyavarietyofotherconditions.Therefore,thechestX-rayhasa limitedrole inconfirmingthediagnosisofpulmonarytuberculosis.Thedecisiontostartonanti-TB treatmentonpatients shouldnotbebasedsolelyonabnormalchestX-rayfindingsand all efforts should be made to perform sputum microscopy and other microbiological tests. Ifmicrobiological tests are negative, then chest X-ray findingsmay be substantiatedwith a thoroughhistory,clinicalexamination,andotheravailableteststodiagnoseTB.

ChestX-rayhasaroleinassessingtheresponsetotreatment,butithasnoroleindeclaringcurefromTBassomeoftheradiologicalchangesmaypersistevenafterthediseasehasbeencured.ChestX-raysmayalsobeusedattheendoftreatmenttoassesstheextentoflungdamageandtodetectanyresidualcomplicationssuchasbronchiectasis,fibrosis,pleuralthickening,andlungcollapse.

5.2.4.3 Bacteriologicalconfirmation

1. Sputumsmearmicroscopy

Sputum smearmicroscopy is among the least expensivemethods of diagnosing infectious cases ofpulmonarytuberculosis.Whenevertuberculosisissuspected,threesputumsamplesshouldbecollectedandexaminedmicroscopicallyforacidfastbacilli(AFB).Amongyoungerchildren,sputumsmearscanbenegativeduetothepaucibacillarynatureofthediseaseanddifficultyinobtainingthesputumsample.

2. SputumcultureforAFB

SputumcultureforAFBismoresensitiveandspecificthandirectsmearmicroscopyandisrecommendedtobedoneinallpaediatricpatients.Itisusefulindetectingcaseswherethenumberoforganismsarefewerthanthatcanbedetectedbydirectsmearmicroscopy.Butthisismoreexpensiveandtakesatleast 6-8weeks. Culturemethods basedon liquidmedia aremore sensitive and can showpositiveresultsrelativelyearlywhencomparedwithsolidmedia.

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3. Rapiddiagnostictest-XpertMTB/RIF

Xpert MTB/RIF (GeneXpert®) is a WHO recommended rapid diagnostic test for Mycobacteriumtuberculosis complex, which uses Polymerase Chain Reaction (PCR) to test specimens for geneticmaterial specific to M. tuberculosis. It simultaneously detects a gene which confers resistance torifampicin.Resistancetorifampicinisalsousedasapossibleindicatorofmultidrugresistance.

Thetesttakesaroundtwohours,andrequiresminimalman-powertoperform.XpertMTB/RIFcandetectTBbacilliatmuch lowerconcentrationsascompared tosmearmicroscopyandhence isconsideredmuchmoresensitive.ThistestisofferedtoallpaediatricTBpatients.However,anegativetestresultinchildrendoesnot excludeTB.

TypeofspecimenstobesentforXpertMTB:• Sputumandotherrespiratoryspecimens(2-3ml)(Bronchialwash,broncho-alveolerlavage,

endotrchealaspiratesetc)

• Earlymorninggastricaspiratesinchildrenwhocannotcoughoutsputum.

• Extra-pulmonarysamplese.g.CSF,pusaspirates,lymphnodeaspirateandotherfluids.

Bloodstainedsamples,urine,faeces,andpleuralfluidsarenotsuitabletoforXpertMTB/RIF)

Methodsofcollectingsputumsamples

ApatientwithsymptomssuggestiveofpulmonaryTB (PTB)needs toprovide3sputumsamples formicroscopy.Sputumshouldalwaysbeobtainedfromchildren10-15yearsofagewithapresumptivediagnosisofTB.

Inhospitalizedpatients3earlymorningspecimensarepreferable.Iftheamountofsputumisinsufficient,encouragethechildtocoughagainuntilasatisfactoryspecimenisobtained.Outpatientsmayprovidesputumspecimensasfollows

• Firstspotspecimen-supervisedspotspecimenatthefirstvisit

• Earlymorningspecimen-Patientisgivenasputumcontainertotakehometocollectanearlymorningspecimenonthefollowingday

• Secondspotspecimen-Secondsupervisedspotspecimen iscollectedwhenthepatientreturnswiththeearlymorningspecimenonthesecondday.

Inclinicsorwards,sputumsamplesshouldbeproducedinadesignatedplacewithgoodventilationandsunlight,awayfromotherpeopleandnotinenclosedspaces(suchastoilets).

Howtoproduceagoodsputumsample?

Patient should be advised to collect sputum but not saliva by vigorous coughing following a deepinspiration.

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• Rinsemouthwithwater

• Inhaledeeply2-3timeswithmouthopen

• Coughoutdeeplyfromthechest

• Openthecontainerandbringitclosertothemouth

• Spitoutthesputumintoitandclosethecontainer

Inchildrenwhoareunabletoproducesputum,earlymorninggastricaspirateshouldbetaken.IfonlyonespecimenistakenitshouldbesentforXpertMTB/RIFandculture.

AllsputumspecimensproducedbychildrenshouldbesentfordirectsmearmicroscopyandatleastonesampleformycobacterialcultureandXpert(MTB/RIF).

Sputuminductionmayhavetobeundertakeninchildrenwhoareunabletoproducesputumvoluntarily.• This procedure generates aerosols and wherever possible, should be performed in an

isolationroomthathasadequateinfectioncontrolprecautions.

• Itissafeandeffectiveinchildrenofallagesandthebacterialyieldsareasgoodasorbetterthanforgastricaspirates.

• Adverseeffectsincludecoughingspells,mildwheezing,andnosebleeds.

• Trainingandspecializedequipmentarerequiredtoperformthisprocedure.

Sputuminductionshouldnotbedoneinchildrenunderfollowingcircumstance:• If a child has not been fasting for at least 3 hours- postpone the procedure until an

appropriatetime.

• Respiratorydistress

• Lowplateletcount,bleedingtendencies,historyofseverenosebleeds

• Reducedlevelofconsciousness

• Historyofsignificantasthma

Thefollowingstepsshouldbefollowedincarryingoutsputuminduction:• Nebulisewithabronchodilatortoreducetheriskofwheezing

• Administernebulizedhypertonicsaline(3%NaCl)for15minutesoruntil5mlofsolutionhavebeenfullyadministered

• Givechestphysiotherapytomobilizesecretions

• Sputumcouldbecollectedfromolderchildrenwhoareabletoexpectoratefollowingtheabovesteps

• For young children, unable to expectorate or collect gastric aspirate, a nasopharyngealaspiratecanbeconsidered.

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SpecimencollectionandtransportformycobacterialcultureandXpert(MTB/RIF)• Sterilescrewcappedtransparent,disposablecontainersshouldbeused.

• Containersshouldbelabelledonthesidewithpatient’sidentificationandtheplacefromwhereitwassent.

• Specialrequestform(TB06)shouldbecompleted.ForXpertMTB/RIF,theformshouldbesignedbytherequestingConsultant.

• Specimenshouldbetransportedtotherelevantlaboratoryat2-8⁰Ctemperatures.

• Samplesshouldbesentinasafe3-layerpackingdevice.

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06.MANAGEMENT OF

CHILDHOOD TB6.1 Administeringtreatmentandensuringcompliance6.2 Anti-TBmedications 6.2.1 Firstlineanti-TBmedicationsandtherecommendeddoses 6.2.2 Basisoftreatment 6.2.3 ActivityofAnti-TBdrugs 6.2.4 FixedDoseCombination(FDC)formulations6.3 Recommendedtreatmentregimens 6.3.1 Newcases 6.3.2 Previously-treatedcases6.4 Treatmentofinfantsaged(0-3)months6.5 Treatmentinterruption6.6 ManagementofDrug-resistantTB(DR-TB)inchildren= (Second-linedrugtreatment) 6.6.1BasicprinciplesoftreatmentofMDR-TB 6.6.2LongerRegimen 6.6.3 Shorterregimen 6.6.4 DrawbacksinthemanagementofDR-TBinchildren6.7 Othermanagementissues 6.7.1 RoleofSteroids 6.7.2 NutritionalSupport 6.7.3 Treatmentissuesspecifictoadolescents 6.7.4 Adverseevents6.8 TreatmentAdherence6.9 FollowUp

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6.MANAGEMENTOFCHILDHOODTB

TreatmentoftuberculosisisthecornerstoneofanyNTP.Themoderntreatmentstrategyisbasedonstandardizedshortcoursechemotherapyregimensandpropercasemanagementtoensurecompletionof treatment and cure. Treatment outcomes in children are generally good even in the face of co-infectionwithHIV,providedthetreatmentisstartedpromptly.Childrengenerallytolerateanti-TBdrugsbetterthanadults.

6.1 ADMINISTERINGTREATMENTANDENSURINGCOMPLIANCE

• Children,theirparents,familymembersandothercaregiversshouldbeintensivelyeducatedaboutTBandtheimportanceofcompletingthefullcourseoftreatment.Theirsupportisvitaltoensureasatisfactorytreatmentoutcome.

• Oftenahealthcareworkercanobserveoradministertreatmentbutifthisisnotconvenient,a trainedcommunitymember (preferablysomeoneother thanthechild’sparentsoranimmediatefamilymember)shouldundertaketheresponsibility.

• Fixed-dosecombinationsofdrugsshouldbeusedwheneverpossibletoimprovesimplicityandadherence.

• Patienttreatmentcardsarerecommendedfordocumentingtreatmentadherence.

• ChildrenwithsevereformsofTBshouldbeinitiallyhospitalizedforintensivemanagementuntiltheirconditiongetsstabilized.

AimsoftreatmentofTBare:

• Tocurethepatient

• TopreventdeathfromactiveTBoritslateeffects

• TopreventrelapseofTB

• TodecreasetransmissionofTBinthecommunity

• TopreventtheemergenceofdrugresistantTB

and achieveallthiswithminimaltoxicity

Anappropriatecombinationofqualityassuredanti-tuberculosisdrugs(ATT),incorrectdosageaccordingtotheweight-band,takenregularly fortheprescribedperiodwill fulfillaboveaims.ThebestwaytoensureadherenceisbyDirectlyObservedTreatment(DOT). 6.2 ANTI-TBMEDICATIONS

Anti-TBtreatmentisdividedintotwophases,anIntensivePhase(IP)andaContinuationPhase(CP).

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6.2.1 Firstlineanti-TBmedicationsandtherecommendeddoses

- Isoniazid(H) -10mg/kg(range7–15mg/kg) –maximumdose300mg/day

- Rifampicin(R) -15mg/kg(range10–20mg/kg) –maximumdose600mg/day

- Pyrazinamide(Z) -35mg/kg(range30–40mg/kg)

- Ethambutol(E)-20mg/kg(range15–25mg/kg)

• Youngage influencesdrugmetabolism.Highermg/kgdosages are required in young childrento achieve levels that are needed to produce effective bactericidal activity. Revised dosageswill result inhigherblood levels inyoungchildrenwithanexcellentsafetyprofileandarenotassociatedwithanincreasedriskoftoxicity.

• Ethambutol may be avoided in small children who cannot report visual impairment.

• Streptomycin is not used as part of a First-line drug regimen.

6.2.2Basisoftreatment

1. Bacteriologicalbasis

a) Existenceofnaturallyoccurringdrugresistantmutants

Inanuntreatedtuberculosispatient,naturallyoccurringbacterialmutantsresistanttodifferentdrugsexistatvarying frequencies.Asa rule,mutants resistant toonedrugaresusceptible tootherdrugsandviceversa.Therefore,duringtheinitialintensivephase(whenthebacterialloadishigh), if foureffectivedrugsaregivenconcurrently,thechancesofsurvivalandselectionofdrugresistantorganismtoanysingledrugwouldbeminimized.

RoleoftheIntensivephase

Theobjectiveofcombining fourdrugs in the IntensivePhase (IP) is toachieve rapidkillingofactivelymultiplyingbacillarypopulationandeliminatenaturallyoccurringdrugresistantmutants.

RoleoftheContinuationPhase

The Continuation Phase (CP) with fewer drugs for a comparatively longer periodwill ensureeliminationofsemi-dormantformswhichareresponsibleforrelapses.

b) Existenceofsub-bacillarypopulation

InalesionofTB,therecanbefourbacterialsub-populationswithdifferentmetabolicratesthatdependontheirsurroundingenvironment.Thesedifferentbacillarypopulationsandthetypesofanti-mycobacterialagentsactingonthemareshowninthefigure6.1.

35

AExtra-cellular

RapidlyMultiplying>108

Extra-cellularIntermittentlyMultiplying

(Semi dormant)

BH

R

S

E

Intra-cellular semi dormantform (inside macrophagesin an acidic environment)

C

DormantNo drugActs on them

D

R

Z

Fig.6.1

2. Pharmacologicalbasis Itisimportanttoachievepeakserumlevelsofallthedrugssimultaneously,sothatmaximumbactericidaleffectisobtained.Thisisachievedbyadministrationofalldrugsatthesametime.Thisalsorendersoperationalconvenience.

6.2.3 ActivityofAnti-TBdrugs

Drugs Earlybactericidal SterilizingactivityPreventionofemergence

ofdrugresistance

Isoniazid ++++ ++ ++++

Rifampicin +++ ++++ +++

Streptomycin +++ -- ++

Pyrazinamide ++ +++ +

Ethambutol + -- ++

Table6.1

36

6.2.4 Fixed-DoseCombination(FDC)formulations

Sri Lanka has introduced FDCs for TB treatment regimens in 2005. However, paediatric FDCswereintroducedlaterin2009.

a) NewpaediatricFDCformulationscontains:

RHZ–Rifampicin75mg+Isoniazid50mg+Pyrazinamide150mg RH–Rifampicin75mg+Isoniazid50mg

Advantagesofthechild-friendlyfixeddosecombinations:

• Nonecessityforbreaking,crushingorchoppingoftablets

• Quicklydispersibleinliquid-easyforchildrenofallagestotake

• Palatableflavours

• Prescriptionerrorsarelikelytobelessfrequent

• Asthenumberoftabletsareless,treatmentadherenceisencouraged

• Monotherapyisavoided.

Disadvantages:

• Over/underdosage(sub-therapeuticbloodlevels)ifthenumberoftabletsismoreorlessthanthenumberthatshouldhavebeenprescribed.

• HealthcareworkersmaybetemptedtoevadeDOT,believingthatadherenceisautomaticallyguaranteed.

• Poor rifampicin bioavailability is a problemwith low quality FDCs. Quality assurance isthereforeessential.

• UsingFDCsdoesnotobviatetheneedforindividualdrugsforaminorityofpatientswhodevelopdrugtoxicity.

37

NewformulationsofPaediatricFDCdrugdosagesaccordingtothebodyweight-Table6.2Ithasrecentlyreplacedtheoldformulations.

PhaseandDrug

Weight–(Rounded off to nearest kg)

4-7kg 8-11kg 12-15kg 16-24kg ≥25kg

Intensivephase–dailydoses

Useadultformulations**

RHZ**(75mg+50mg+150mg)-(tablets)

1 2 3 4

E*100mg-(tablets)

Shouldnotbeusedforveryyoungchildren

Continuationphase–dailydoses

RH**(75mg+50mg)-(tablets)

1 2 3 4

Table6.2

* Ethambutol is specially indicated for children with extensive disease or living in settings where the prevalence of HIV or INAH resistance is high. However, it should be avoided in very small children who cannot report visual impairment. Patients in this age group is managed with RHZ + HR as the incidence of INAH resistance and the burden of HIV are both low in Sri Lanka. Nevertheless, clinicians can decide on starting Ethambutol even in smaller children, considering benefits versus risks and taking into account the extent of the disease and renal functions. It is believed that the risk of optic neuritis is very minimal with normal renal functions.

For older children who can report visual impairment, Ethambutol can be safely added according to the weight in the Intensive phase. Ophthalmological opinion must be sought for very young children who are started on Ethambutol and other children with visual complaints.

** Additional INAH and Rifampicin may have to be added when using adult FDCs in obese children.

6.3 RECOMMENDEDTREATMENTREGIMENSFORDRUG-SUSCEPTIBLEPATIENTS (First-linedrugtreatment)

6.3.1 Newcases • Intensivephase:2HRZ/2HRZE-(Ethambutolmaynotbeusedforveryyoungchildren) • Continuationphase:4HR

Streptomycinisnotusedaspartofa1stlinedrugregimen.

38

6.3.2 Previously-treatedcases

This category comprises previously treated pulmonary TB that includes Relapse, Treatment failure,Treatmentafterlosttofollow-upandotherpreviouslytreatedcases.RecommendedtreatmentisgiveninTable6.4

Whereverpossible,mycobacterialcultureanddrugsusceptibilitytestingshouldbeperformedforallre-treatmentcasesbeforestartingtreatment.

CaseDefinitions TreatmentcategoryTreatmentregimen

IntensivePhase ContinuationPhaseNewcases

• Pulmonary• Extrapulmonary

New

2HRZE*/2HRZ

* Needfrequentophthalmic evaluationtoruleoutopticneuritis

4HR

Previously treatedpatients without drugresistance

• Relapse• Treatment after

failure• Treatment after

losttofollow-up• Other previously

treatedcases

Retreatment

3HRZE

AddStreptomycinfor2months

ifthereisaperceivedriskofpolyormonoresistance

5HRE

Table6.4

6.4 TREATMENTOFINFANTSAGED(0-3)MONTHS

Suspected or confirmed pulmonary TB should be promptly treated with the standard treatmentregimens.Treatmentmayrequiredoseadjustmenttoreconciletheeffectofageandpossibletoxicityinyounginfants.Thedecisiontoadjustdosesshouldbetakenbyaclinicianexperiencedinmanagingpaediatricpatients.

39

6.5 TREATMENTINTERRUPTION

a)Managementof‘NewCases’whohaveinterruptedtreatment-(Table6.5)

Length of treatment

Length of

interruption

Do a smear?

Results of smear

Register again as

Treatment

< 1 month

< 2 weeks

No

-

-

Continue New patient

regimen*

2 – 8 weeks

No -

-

Start again on New patient regimen**

≥ 2 weeks

Yes

Positive

Treatment after lost to follow up

Start on Retreatment patient regimen**

after Xpert MTB/RIF test and

culture & DST

Negative -


regimen*

1 – 2 months

< 2 weeks

No

-

-


regimen*

2 – 8 weeks

Yes

Positive

-

1 extra month of intensive phase of

New patient regimen after Xpert

MTB/RIF testing if RR not found

Negative

-


regimen*

≥ 2 weeks

Yes

Positive

Re-treatment case - Treatment after lost

to follow up



culture & DST

Negative -


regimen*

≥ 2 months

< 2 weeks

No

-

-


regimen*

2 – 8 weeks

Yes

Positive

With no RR


to follow up



culture & DST

Negative -


regimen*

≥ 2 weeks

Yes

Positive With no RR


to follow up



culture & DST

Negative -


regimen*

Table6.5

40

* Treatment taken before interruption is also counted to complete 60 doses. **A patient who must “start again” should start the Re-treatment regimen from the beginning. Should always seek Consultant Respiratory Physician opinion before deciding the treatment courseFirst line drugs should be continued for all patients found not to have RR till complete DST results are available.

b) Managementof‘Previously-treatedCases’whohaveinterruptedtreatment.-(Table6.6)

• Thisregimenisapplicabletoallpreviouslytreatedcases–relapses,treatmentafterfailure,treatmentafterlosstofollow-up,otherpreviouslytreatedpatients

• Re-treatmentregimen–3HRZE/5HRE.Streptomycinmaybeaddedfortheinitialtwomonthsifthereisaperceivedriskofpolyormonoresistance.

41

Length of

treatmanet

Length of

interruption

Do a

smear?

Results of

smear

Register again as

Treatment

< 1 month

< 2 weeks

No

-

-

Continue Retreatment regimen*

2 – 8 weeks

No

-

-

Start again on Retreatment regimen**

≥ 2 weeks

Yes

Positive



Check previous pre-treatment culture and DST reports Request another culture

if previous reports were negative Repeat X-pert MTB/RIF test

Negative

-


1 – 2 months

< 2 weeks

No

-

-


2 – 8 weeks

Yes

Positive

-

1 extra month of intensive phase of Retreatment regimen after a

repeat X-pert MTB/RIF testing and RR not found

Repeat culture if previous pre-treatment culture is negative

Negative

-


≥ 2 weeks

Yes

Positive

Re-treatment case -



after a repeat X-pert MTB/RIF test and RR not found


Negative

-


≥ 2 months

< 2 weeks

No

-

-


2 – 8 weeks

Yes

Positive

with no RR on

X-pert MTB/RIF

Re-treatment case -





Negative

-


≥ 2 weeks

Yes

Positive

with no RR on

X-pert MTB/RIF

Re-treatment case -





Negative

-


Table6.6

*A patient must complete all 90 days of the initial intensive phase.**A patient who must “start again” should restart treatment from the beginning.

42

6.6 MANAGEMENTOFDRUG-RESISTANTTB(DR-TB)INCHILDREN-(Second-linedrugtreatment)

DR-TBinchildrenismainlytheresultoftransmissionofastrainofM.tuberculosiswhichisdrug-resistantfromanadultsourcecase.Multidrug-resistantTB(MDR-TB)isresistanttobothisoniazidandrifampicin,withorwithoutresistancetootheranti-TBdrugs.InXDR-TB,inadditiontoresistancetoisoniazidandrifampicin,thereisalsoresistancetoquinoloneandoneofthesecond-lineinjectabledrugs.

Drug-resistantTBshouldbesuspectedwhen:

- thereiscontactwithaknownorsuspectedDR-TBpatient.- patientisnotrespondingtofirst-linetherapydespiteadherence.- previouslytreatedforTBpresentswithrecurrenceofdisease.

WherewilltheRR/MDR-TBtreatmentbeinitiated?

TreatmentofDR-TBisdifficultandreferraltoadesignatedspecialistcentreismandatory.AtpresentallregimensforRR/MDR-TBareinitiatedatNHRD.TreatmentforDR-TBmaybestartedinothercentresafterestablishmentofnecessaryfacilitiesinfuture.

WhatisCulture-conversion?

Itisdefinedastwoconsecutivesputumsamplestaken30daysapartarenegativeforculture.Ofthetwoconsecutive,negative samples thedateof collectionof thefirst sample is takenas thedateofconversion.

6.6.1 BasicprinciplesoftreatmentofMDR-TB

• Donotaddasingledrugtoafailingregimen.

• Thedrugdosageshouldbedeterminedbybodyweight.

• Dosecond-lineDSTasthismaycallforadditionaldrugsearlyintherapy.

• SelectdrugsaccordingtotheDSTresultsfromthelikelysourcecase,unlessM.tuberculosiscultureandDSTresultsareavailableforthechild.

• DirectlyObservedTherapy(DOT)isessentialthroughoutthetreatment.Atreatmentcardismarkedforeachobserveddose.

• Follow-upisclinicalandbacteriological.Clinicalmonitoringforadverseeffectsshouldbedoneduringin-wardtreatmentandateveryout-patientvisit.

• Sincethere isariskofototoxicity, If thechild isgivenaSLD injectableagent,baselineandmonthlyhearingtestsaremandatory.

• Counselthechild‘scaregiverateveryvisit,toprovidesupport,adviseontheimportanceofcomplianceandcompletionoftreatment,andtheadverseevents.

43

6.6.2 LongerRegimen–(Pleasereferto“NationalPMDTguidelines-2015”)-(Table6.7)

• Theregimenshouldconsistofatleast4second-linedrugs(SLD)includinganinjectableagentandaquinolonewhicharelikelytobeeffective.

(whichthepatienthasnotbeenexposedto)• StartwithGroup1first-lineoraldrugstowhichDSTresultsshowsusceptibility (e.g.ethambutol,PZA)• AddoneGroup2injectableagentbasedonDST. Preferably,anaminoglycosidesuchasamikacin.Avoidstreptomycinifpossible.• AddoneGroup3fluoroquinolonebasedonDSTresults. Levofloxacinandmoxifloxacinarepreferred.Ciprofloxacinisnotrecommended.• Group4second-lineoraldrugsshouldbeadded,untilthereareat leastfourdrugs inthe

regimentowhichtheisolateislikelytobesusceptible. (thesearechosenbasedontreatmenthistory,adverseeffects,andcost)• IffoureffectivedrugscannotbebuiltfromGroups1-4,consideradding,atleasttwoGroup5

third-linedrugsinconsultationwithanMDR-TBexpert.• Oraldrugsaregiveninasingledailydosageonall7daysoftheweekthroughoutthetreatment.• Aninjectableagent(anaminoglycosideorcapreomycin)isadministeredsixdaysinaweek. It isgiven foraminimumof8monthsor4monthsafter theculture-conversion (Intensive

phase)whicheverislonger.• Treatmentshouldbecontinuedforatleast12monthsafterculture-conversion(Continuation

phase)• Thetotaldurationoftreatmentisatleast20months.

44

GroupsofdrugsusedintheLongerregimen

Drug group Drug name

Daily adult dose

(mg/kg)

Maximum adult daily dose (mg)

Paediatric dose in mg/kg (Max.

daily dose in mg)

Group 1: 1st line oral drugs

Ethambutol Pyrazinamide

20 – 25 30 – 40

2000 2000

15

Group 2: Injectable agents Aminoglycosides Cyclic polypeptides

Amikacin Kanamycin (Km)

Capreomycin (Cm)

15 – 20 15 – 20

15 – 20

1000 1000

1000

15 – 22.5 (1000) 15 – 30 (1000)

15 – 30 (1000)

Group 3: Fluoroquinolones

Ofloxacin

Levofloxacin – (Lfx) Moxifloxacin (Mfx)

15 – 20

7.5 – 10 7.5 – 10

800

750 400

15 – 20 (800), 2×

daily 7.5 – 10

(750) 7.5 – 10

(400) Group 4: 2nd line oral drugs

Ethionomide (Eto) (or Prothionomide)

15 – 20

1000

15 – 20 (1000), 2×

Cycloserine (Cs) (or terizidone)

P-Amino Salicylic Acid (PAS): 4g sachets

10 – 20 150

1000 12000

daily

10 – 20 (1000), 1×/2× daily

150

(12000), 2×/3× daily

Group 5: 3rd line oral drugs of unclear efficacy (not recommended by WHO for routine use in MDR-TB)

High-dose isoniazid Linezolid

Amoxycillin/ clavulanate

Clarithromycin

Thioacetazone Imipenem/Cilastatin

Clofazimine

15 – 20 10 – 12, 2×

daily 15 Amox, 3×

daily 7.5 – 15, 2×

daily 3 – 4

Only iv 3 – 5

400 300, 1×/2×

daily

500, 2× daily

150

300

Table6.7

45

• StandardLongerRegimens: –8(Km-Lfx-Cs-Eto-Z-+/-E),12(Lfx-Cs-Eto-Z-+/-E) OR –8(Cm-Lfx-Cs-Eto-Z-+/-E),12(Lfx-Cs-Eto-Z-+/-E)

• PAS-sodiumisthecurrentreservedruginpatientsinwhomoneofthedrugsoutofthelongerregimencannotbeused.

6.6.3 Shorterregimen–(Please refer to ‘Interim SOP for Shorter Regimen, Sri Lanka - 2017’)

InSriLanka,ashorterMDR-TB treatment regimenisbeingintroducedunderseveralconditions.

ExclusionCriteria:

1. ConfirmedresistanceorsuspectedineffectivenesstoamedicationintheshorterMDR-TBregimenincludingfluoroquinolonesandSecond-lineinjectableagents

(exceptIsoniazidresistance)2. ExposuretomorethanoneSecond-linemedicationsintheshorterMDR-TBregimenfor

morethanonemonth.3. IntolerancetomorethanonemedicationintheshorterMDR-TBregimenorriskoftoxicity

anddruginteractions.4. Pregnancy.5. Extra-pulmonarydisease.6. AtleastonemedicationintheshorterMDR-TBregimenisnotavailableintheprogramme.7. Chronicliverdisease(alcoholic/non-alcoholic)orhistoryofATTinducedhepatitis.8. Clinicallyunstablepatientsorthosewithprogressiveorextensivepulmonaryinvolvement

who’sSLDcannotbedelayeduntilfurthertestingwithFL-LPAandSL-LPAarecompleted.9. ThoseshowingHresistancewithmutationsonbothkatGandinhAgenesonFL-LPA

Keychangesfromlongerregimen–(Table6.8)

• A shorterMDR-TB treatment regimen of 9-12months is used for RR/MDR-TB patients(includingchildren).

• Itusesadifferentregroupingofsecond-linemedicines.

• A regimen with at least 5 effective anti-TB medications during the Intensive phase isrecommendedincludingpyrazinamideandfour5second-lineanti-TBmedications.

• Adifferentdrugselection

■ OnefromgroupA

■ OnefromgroupB

■ AtleasttwofromgroupC

46

• Iftheminimumnumberoffivemedicinescannotbecomposedasabove,anagentfromD2andagentsfromD3maybeaddedtobringthetotaltofive.

• Maybefurtherstrengthenedwithhigh-doseisoniazidand/orethambutol

• Delamanidmaybeusedinchildrenabove6years.

GROUP A Fluoroquinolones

LevofloxacinMoxifloxacin (Mfx)

GROUP B Second-line injectable agents

Amikacin Capreomycin Kanamycin

GROUP C Other Core Second-line Agents

Ethionamide / Prothionamide(Pto) Cycloserine / Terizidone Linezolid Clofazimin (Cfz)

GROUP D Add-on agents (not core MDR-TB regimen components)

D1 PyrazinamideEthambutol High-dose isoniazid

D2

Delamanide Bedaquiline

D3

P-amino salicylic acidImipenem-Cilastatin Meropenem Amoxicillin-Clavulanate (Thioacetazone)

Table6.8

Shorterregimen: 4-6(Km-Mfx-Pto-Cfz-Z-Hhighdose-E)/5(Mfx-Cfz-Z-E)

• “Informedconsent”mustbetakenatthetimeofstartingtheshorterregimenornewdrugsgivingfullinformationtopatientaboutbenefitsandpotentialadverseeffectsthatthedrugmaycause.

• IncaseoffailingofshorterregimenduetoADRs/Culturenon-conversionby4/12,changetolongerregimen.

6.6.4 DrawbacksinthemanagementofDR-TBinchildren

• Very few second-line drugs are in paediatric formulations, and their optimal dosing isunknown.

47

• Thetasteofmedicationsisoftenunpalatable,andthepillburdencanbequitealot.• DailyinjectabledrugshavetobegivenintheIntensivephase.• ThenumberofdrugstotreatMDR-TBinchildrenhasnotbeenprospectivelyevaluated.• TheoptimaldurationoftreatmentforMDR-TBinchildreniscontroversial.

6.7 OTHERTREATMENTANDMANAGEMENTISSUES

6.7.1 Roleofsteroids

RationaleofaddingoralsteroidstoantiTBtreatmentisthatsteroidswillreducetheorganizationandsubsequentfibrosisofexudatesandreduceinflammation.RoutineadditionoforalsteroidstoantiTBtreatmentisrecommendedin:

• TBmeningitis• TBpericardialeffusion• GenitourinaryTBwithuretericobstruction• LaryngealTBwithlife-threateningairwayobstruction(ENTopinionshouldalsobesought)• SpinalTBwithcordcompression(NeuroSurgeon’sopinionshouldalsobesought)

Additionof steroids shouldbedecidedonan individualbasis in the following situationsas credibleevidenceissparse.

• TBpleuraleffusion• AbdominalTBincludingTBperitonitis• TBsalpingitis• TB lymphadenitis (progressive enlargement of existing nodes and appearance of new

nodes)

Otherspecificoccasionswheresteroidsareindicated:• SteroidsareusedinthemanagementofImmuneReconstitutionInflammatorySyndrome

(IRIS)aswell.• Rifampicin increasesmetabolism of steroids through liver enzyme induction and it can

precipitate hypoadrenalism (increased metabolism of adrenocortical hormones) whichnecessitatesadditionofintravenoushydrocortisone.

• Tuberculosiscanaffectadrenalglands(TBadrenalitis)resultinginhypoadrenalism. Inwhichcase,hydrocortisonereplacementtherapyshouldbeinitiated.

Prednisolone isused in2mg/kgdaily, increasedup to4mg/kg in thecaseof themost seriously illchildren,(maximumdosageof60mg/day)for4weeks.Thedoseshouldthenbetaperedover2weeks.Dexamethasoneinequipotentdosescouldbesubstituted.

48

6.7.2 Nutritionalsupport

Severe malnutrition is associated with increased mortality in TB patients. Child’s nutritional statusshouldbeassessedandsupportedregularlyduringtreatmentofTB.Breastfeedingshouldbecontinuedand adequate intake of food should be ensured. Additional energy is particularly important duringthe intensive phase of treatment and is best given through additional household foods, based onlocallyavailableandaffordablefoodsaspartofabalancedvarieddiet.‘Thriposha’isusuallygivenasasupplementation.Infantsunder6monthsofagewithgrowthfailurerequirereferraltoatherapeuticfeedingprogramme.Ifthisisnotavailableorfeasible,breastfeedingmothersshouldbegivensupporttooptimizebreastfeeding.Nutritionalsupplementationcannotbegivendirectlytoaninfantunder6monthsofagebutcanbeprovidedforthelactatingmother.

6.7.3 Treatmentissuesspecifictoadolescents

The treatment of TB in adolescents follows the same guidelines as for adults. Regarding dosagerequirements,riskofMDR-TBanddrugtolerance,adolescentsshowgreatersimilaritytoadultsthantoyoungerchildren.Thus,adolescentsandolderchildren(oncetheyreachabodyweightof25kg)shouldbetreatedwithadultdosages.

Adolescentsareatriskforpooradherence.Thiscanbeexacerbatedbytheuniquechallengesforthisagegroupofhavingpooraccessandsupportfromeitherchildhealthservicesoradulthealthservices.Theyareoftenseenasnotbelonging toeithergroup.TreatingadolescentswithTB requiresspecialattentiontobepaidtoensureadherence.Involvingadolescentsintheircaremayhelptoengagethemasactiveparticipants intheirtreatmentplan.Forexample, individualizedandfamilycounsellingand“brainstorming” on adherence strategies may empower adolescents and motivate them towardsadheringtreatment.

6.7.4 Adverseevents

Adverseeventscausedbyanti-TBdrugsaremuchlesscommoninchildren.

• Thecommonestseriousadverseeventisthedevelopmentofhepatotoxicitywhichcanbecausedbyisoniazid,rifampicin,orpyrazinamide.Ideally,baselineALT(SGPT)andbilirubinestimationsshouldbedonebeforestartingATTandtheymayhavetoberepeatedifthepatient becomes symptomatic. If there is only a slight elevation of ALT, further regularmonitoringofthelevelsisnotroutinelyrequiredasatransientelevation(lessthanthreetimestheupperlimitofnormal)isnotunusualandnotanindicationtostoptreatment.

However,adeteriorationofappetite,nauseawithorwithoutvomiting,livertenderness,hepatomegalyorjaundiceshouldleadtorepeatassessmentofALTandserumbilirubin.IftheALTismorethanthreetimestheupperlimitofnormalorserumbilirubinissignificantlyabovenormalorboth,allanti-TBdrugsshouldbestopped.

49

Patientsshouldbescreenedforothercausesofhepatitistoo,andnoattemptshouldbemadetoreintroducethesedrugsuntiltheliverfunctionshavebeennormalized.APaediatricPulmonologist/RespiratoryPhysician shouldbe involved in furthermanagementof suchcases.

Children whose clinical condition warrants continuation of ATT despite having aderangement in liver functions, a less hepatotoxic regimen consisting of streptomycin,ethambutolandofloxacinshouldbeusedtobridgethisperioduntilfirst-lineanti-TBdrugscouldbereintroducedin‘challengedoses’andalldrugshavereachedthestandarddoses.Whencalculatingthetotaldurationoftheanti-TBregimenthe‘bridgingperiod’ofATTisnotcounted.

In the event of one or more first-line ATT cannot be recommenced, alternate anti-TBregimenscanbeconsidered.InthepresenceofanisolatedhyperbilirubinaemiawithoutanobviouscauseanalternativeregimenwithoutRifampicinshouldbeused.TheperiodoftreatmentwithalternativeregimenswithoutINAH,Rifampicinorpyrazinamidearealwayslongerthanthestandardregimens.

• Isoniazid may cause symptomatic pyridoxine deficiency, particularly in severelymalnourished children and HIV-infected children on highly active antiretroviral therapy(HAART).Supplementalpyridoxine(5-10mg/day)isrecommendedin:

■ Malnourishedchildren ■ HIV-infectedchildren ■ Breastfedinfants ■ Pregnantadolescents

Pyridoxineshouldbegiven12hoursapartfromtheATT/INAH.

• Streptomycinmaycausenephrotoxicityandirreversibleauditorynervedamage.

• Ethambutolmaycauseopticneuritisbutthisisrare.Red-greencolourdiscriminationcanbetestedinolderchildren.

• SkinrashescanoccurduetoanyofthefirstlinedrugsandwillentailstoppageofalldrugsandreferraltoaPaediatricPulmonologist/RespiratoryPhysician.

• ImmuneReconstitutionInflammatorySyndrome(IRIS)

Atemporaryclinicaldeterioration,withneworworseningsymptoms,signsorradiologicalmanifestations,sometimesoccursafterstartinganti-TBtherapyduetorestorationofcapacitytomountaninflammatoryimmuneresponse.Thisparadoxicalreactioncansimulateworseningdisease, with fever, increased size of lymph nodes and tuberculomas, and worsening ofpulmonaryinfiltrates.Immunereconstitutioncanoccurwithimprovednutritionalstatusoranti-TB treatment itself. In TBpatientswhoare co-infectedwithHIV, clinical deteriorationdue toimmunereconstitutioncanoccurafterinitiationofantiretroviraltherapy(ART).

50

Inallsuchcases,anti-TBtreatmentshouldbecontinued.Theadditionofcorticosteroidsisusefulinmanycases.Ifthereisadoubt,thechildshouldbereferredtothenextlevelofcare.

6.8 TREATMENTADHERENCE

• Adherencetothefullcourseoftherapyisfrequentlyachallengebecause:■ Clinicalimprovementcanbeseenin2-4weeksofanti-TBtreatment.■ Childrenwoulddependupontheparentstobringthemtothetreatmentcentre■ Timingsofvisitsmayalsointerferewithschoolhours.■ Otherriskfactorsforpooradherencesuchasadolescents,longdistancetohealthcare

facility,lack,andcostsoftransport,beingorphanedorprimarycare-giverunwell.

• Compliancecanbeimprovedby:■ UsingFDCsofdrugswheneverpossibletosimplifydrugadministration.■ Explainandemphasizetocare-giverandthechildwhytheymusttakethefullcourse

oftreatmenteveniftheyarefeelingbetter.■ Identifyriskfactorsforpooradherence■ Often a health care worker can observe or administer treatment but, a trained

communitymember(preferablysomeoneotherthanthechild’sparentsoramemberofimmediatefamily)canassumethisresponsibility.

■ Patienttreatmentcardsarerecommendedfordocumentingtreatmentadherence.

6.9 FOLLOWUP

• Outcomes in children are generally good if treatment adherence is maintained untilcompletion.

• Theriskofseriousadverseeventsinchildrenassociatedwiththeuseoftherecommendedtreatmentregimensisverylow.

• Severe disseminated disease such as tuberculous meningitis is associated with highmortalityandhighmorbidityamongsurvivors.

• Ideally, each child should be assessed by the referring Consultant Paediatrician/Pulmonologistatfollowingintervals:■ everytwoweeksintheintensivephase■ everymonthduringcontinuationphaseuntilthecompletionoftreatment

• Assessmentsshouldinclude:■ symptomassessment■ assessmentoftreatmentadherence■ enquiryaboutanyadverseevents■ weightmeasurements

• Ifthereisaweightgainthedosesshouldbeadjustedappropriately

• Afollow-upsputumsampleforsmearmicroscopyshouldbeobtained,wheneverpossible,attheendoftheIntensivePhase,atthe5thmonthandoncompletionoftreatment.

51

■ IfthesmearispositiveattheendoftheIntensivephase,sputumforXpertMTB/RIFandcultureanddrugsensitivityshouldbecarriedout,andsametreatmentshouldbecontinuedforanotheronemonth.

The resultof sputum forXpertMTB/RIF shouldbe tracedat theearliestwhileontreatment.

■ Ifsputumremainspositiveattheendof3rdmonthtoo,sputumforXpertMTB/RIFandcultureanddrugsensitivity shouldbecarriedoutagainand theContinuationphaseiscommenced.

The resultof sputum forXpertMTB/RIF shouldbe tracedat theearliestwhileonContinuationPhase.

■ Ifthesmearispositiveattheendof5thmonth,itisconsideredasTreatmentfailureandRe-treatmentregimeniscommenced.

• Follow-upCXRsarecarriedoutattheendof01monthoftreatmentinchildrenwithsmear-negativepulmonaryTB.

• Onassessmentat02months,ifachildhasworseningofsymptomsorhasnoX-rayresolutionthepossibilityoftreatmentfailureshouldbeconsideredandshouldbereferredforfurtherassessmentandmanagement.

Thesechildrenmayhave:■ Problemswithtreatmentadherence■ Drug-resistantTB■ Othercausesoflungdisease■ TBandHIVcoinfection.■ AnunusualcomplicationofpulmonaryTB

52

53

07.PREVENTIONOF

TUBERCULOSIS IN CHILDREN

7.1 Infectioncontrol

7.1.1 Measurestoreduceriskoftransmission

7.2 BCGvaccination

7.2.1 AdverseeventsandcomplicationsrelatedtoBCGvaccination

7.2.2 Managementofadverseevents

7.2.3 BCGvaccinationofinfantsborntoHIV-positivemothers

7.2.4 IndicationsforBCGvaccinationofmigrantchildren

7.2.5 BCGvaccinationofsuspectedimmunecompromisedbabies

7.2.6 AbsentBCGscar

7.3 Contactinvestigation

7.4 Preventivetherapy(Chemoprophylaxis)

7.5 Intensifiedcasedetectioninhighriskcategories

7.6 PreventionofTBinaninfantborntoamotherdiagnosedwithactiveTB

7.6.1 CongenitalTuberculosis

7.6.2 Managementofthenewbornofamotherwithactive

tuberculosis

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7.PREVENTIONOFTUBERCULOSISINCHILDREN

Preventionoftuberculosiscanbedividedintothefollowing6maindomains.

I. InfectioncontrolII. BCGvaccinationIII. ContactinvestigationIV. Preventivetherapy(Chemoprophylaxis)V. IntensifiedcasedetectioninhighriskcategoriesVI. PreventionofTBinaninfantborntoamotherdiagnosedwithactiveTB

7.1 INFECTIONCONTROLFORRESPIRATORYINFECTIONS/TB

ApersonwithpulmonaryTBcanreleasedropletnucleiwithM.Tuberculosisbacilliintoairbycoughingor sneezing; smaller numbers of droplet nuclei are released during normal activities like talking orbreathing.Thesedropletnucleiparticlesareinvisibletothenakedeyeandcanremainairborneinroomenvironmentforalongperiodoftime,untiltheyareremovedbynaturalormechanicalventilation.ForTBtospread,theremustbeasourceandasusceptiblehost.ApersonwhosharesairwithapatienthavingpulmonaryTBisatriskofgettingtheinfection.However,TBisnotusuallyspreadbybriefcontact.

7.1.1Measurestoreduceriskoftransmission

a. StandardprecautionsPrecautionsincludingproperrespiratoryhygieneandcoughetiquetteareapplicabletopatientsinallhealthcaresettings.

• SeparatechildrenwithsuspectedpulmonaryTBinanappropriateisolationarea.

• Diagnoseandtreatthemwithminimaldelay.

• Hospitalization should be reduced or avoided to the greatest extent to reduce risk ofspreadingthediseasetootherchildren.

• Educateinpatientsonrespiratoryhygiene,coughetiquetteandsputumdisposal.Thiscanbedonethroughposters,signboardsandothermeans.Provisionofdisposablesurgicalmaskswithinstructionstousethemisalsorecommended.

b. VentilationImprovedventilationinhealth-carefacilitiesisessentialinpreventingtransmissionofairborneinfectionsandisstronglyrecommended.

• Naturalventilation

Simple natural ventilation may be optimized by maximizing the size of the windows,openingfixedwindowpanes,andbylocatingwindowsonopposingwalls.

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• Mechanicalventilation

Mechanicalventilationwithorwithoutclimatecontrolmaybeappropriatewherenaturalventilationcannotbeimplementedeffectively.Thesimplestformofmechanicalventilationistheuseofexhaustfans.Healthcarestaffshouldbemindfulofthedirectionofairflowtoensurethattheyareclosesttothecleanairsource,andpatientsareclosesttotheexhaust.

Schematic diagram showing seating arrangement for patient and healthcare worker (red cross)

c. Personalprotectiveequipment• Ordinarysurgicalmasks-couldbegiventopatientswithuncontrolledcoughtoreduce

aerosolspread.

• N95Mask(Respirator)–maybegivenforhealthcareworkers,inspecialsituationslike;

• highriskaerosolgeneratingproceduressuchassputuminduction,bronchoscopyetc.• laboratoryworkwheresputumneedstobeprocessedforTBculture• evaluatingorprovidingcareforPTBpatientsinspecialsituationssuchashavingENT,

ophthalmologicalanddentalconditions• providingcaretodiagnosedorpresumptiveMDR-TB/XDR-TBpatients.

Thesemaskscanbereusedfewtimesduringasessionoraday,providedtheyarenotdamaged.

7.2 BCGVACCINATION

InSriLanka,theBCG(BacilleCalmette-Guérin)vaccineisgiventoallbabiesincludinglow-birthweightbabiesatbirthorbeforedischargefromhospitalandthevaccinationcoverageisaround99%.It isaliveattenuatedvaccinemadefromMycobacteriumbovis.Itprotectsyoungchildrenagainstdevelopingcomplicationsof‘Primaryinfection’,suchasTBmeningitisandmiliaryTB.However,ithasnoimpactonthetransmissionofTBinthecommunityasitdoesnotconferprotectionagainstthedevelopmentof‘Post-primarydisease’.

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TheBCGvaccineissuppliedasalyophilizedfreeze-driedvaccinewithadiluentasaseparateampoule.Thereconstitutedvaccineisgivenatadosageof0.05mlforchildrenbelowoneyearand0.1mlforthoseagedoneyearorabove.

Themulti-dosevaccinecanbestoredatroomtemperatureuptoonemonthandinarefrigeratorat40Cuptooneyear. Itshouldbeprotectedfromlightas it isreadilydestroyedbysunlight.Boththevaccineandthediluentshouldbetransportedbetween+2to+80C.Oncereconstituted,itshouldbeusedwithin4hoursandany remaining solutionshouldbediscarded. Ifnotused immediatelyafterreconstitution,thevaccineshouldbekeptcool(+2to+80C)andprotectedfromsunlight.

7.2.1AdverseeventsandcomplicationsrelatedtoBCGvaccination

Thesecouldbelocalorsystemic.

Thelocalcomplicationsmayoccurduetoimpropervaccinationtechniquessuchassubcutaneous/intramuscular injection,or inadequatesterilityduringvaccination. Inolderchildrenoradults, thesemayresultfromprevioussensitizationtomycobacteria.Theseinclude:

a) Non-healingulcer.-ThisisanulceratBCGsitewhichpersistsformorethan6weeks.b) Abscessformationatthesiteandthismayleadtoanon-healingsinusformation.c) Enlargementofregionallymphnodeswithorwithoutabscessformation(BCGadenitis). Aminordegreeofadenitis(1-2cm)in leftaxillathatoccur intheweeksfollowingvaccination,

shouldnotberegardedasacomplication.Infact,suchnodalenlargementisasignofsuccessfulvaccination.However,rarely,enlargedregionalnodesmaybecomelargerandsuppurate.

Thesystemiccomplicationsare:

a) DisseminatedinfectionwithM. bovis. BCGisalivevaccineofattenuatedM. bovis.Therefore,systemicordisseminatedinfectioncan

occuronlyifthereisanimpairmentofimmunity.b) Anaphylacticreactionsmayoccurrarely.

7.2.2Managementofadverseevents

• Localcomplicationssuchasnon-healingulcersorsinusesareusuallyself-limiting.Iftheydonotrespondtoaninitialcourseofantibioticssuchaserythromycin,maybetreatedwithINAHfor3to6months.

• Enlargednodeswithoutsuppurationusuallyresolvespontaneouslyandarenotanindicationfortreatmentwithisoniazidorsurgery.

• Progressivelyenlargingnon-suppurativenodesmayneedsurgicalexcision.• Suppurativenodeswhichhavenotrupturedneedcarefulsurgicalexcision(notaspiration)and

samples shouldbe sent for histology,AFBdirect-smear,mycobacterial andpyogenic cultures.

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However, ifasuppurativelymphnodehasalreadyrupturedorrupturedduringtheprocessofsurgicalexcision,samplesshouldbecollectedforAFBdirect-smear,mycobacterialandpyogeniccultures.Thechildmaybetreatedwithacourseof3to6monthsofINAHinabovesituationsafterthesurgicalprocedure.

• Samples from sites of BCG related complications should not be sent for Xpert-MTB/RIF as the infection is assumed to be related to M. bovis infection.

7.2.3BCGvaccinationofinfantsborntoHIV-positivemothers

BCG vaccination shouldbedeferred in infants born toHIV-positivemothers until theirHIV-status isknown.IftheyarefoundtobeHIV-positivetheyshouldnotbevaccinatedduetotheriskofdevelopingdisseminatedinfectionwithM. bovis.IfthebabyisHIVnegative,BCGvaccinationshouldbegiven.SinceHIVpositivemothersaremorepronetodevelopTBdiseasethenewbornsshouldbespeciallyevaluatedtoexcludecongenitalTBbeforeofferingBCGvaccination.(Discussedbelow)

7.2.4IndicationsforBCGvaccinationofmigrantchildren

• Childrenlessthan5yearsoldwhohadnotbeenpreviouslyvaccinated.• Children more than 5 years and Mantoux negative. (preferably after recommendation by a

specialist)

7.2.5BCGvaccinationofsuspectedimmunecompromisedbabies

The babieswho are suspected to have primary immune deficiencieswith a positive family history,shouldnot tobevaccinatedatbirthandBCGvaccinationshouldbeconsideredoncethesuspecteddiseasehasbeenexcluded.

7.2.6AbsentBCGscar

This isacommonoccurrence. Ifahealthcareworkerhasclearlymarked in theappropriateareaontheCHDR that theBCGscarhasbeenpresent, there isnoneed for revaccination.Childrenup to5yearsofagebroughtwithouttheBCGscarandwithoutproperdocumentationofaBCGscarearlier,revaccinationcanbedoneafter6monthsoftheinitialvaccination,withoutperformingaMantouxtest.

For children between 5-10 years of age, revaccination is not routinely indicated.However, if underspecial circumstances revaccination is considered, it should be preceded by aMantoux test. If theMantouxisnegative(lessthan10mm)revaccinationcanbeperformed.

7.3 CONTACTINVESTIGATIONS

Whoisacontact?

Anypersonwhohasbeenexposedtoanindexcase.

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Whoisanindexcase?The initially identifiedpatientofanyagewithnewor recurrentTB ina specifichouseholdorothercomparablesettinginwhichothersmayhavebeenexposed. Purposeofcontactinvestigationandmanagement

a) ToidentifypeopleofallageswithundiagnosedTBdiseaseamongthecontactsofanindexcase.b) ProvidepreventivetherapyforcontactswithouttheTBdiseasewhoaresusceptibletodevelop

thediseasefollowingrecentinfection.ThecontactswhowereinfectedrecentlyareatahigherriskofdevelopingTBfor1–2yearsafterinfection.Theriskofdevelopingdiseaseafterinfectionismuchgreaterforinfantsandyoungchildrenunder5yearsofage.

Typesofcontacts a) Closecontacts b) Casualcontacts

a) Closecontacts Closecontactscouldbeeitherhouseholdornon-household.

i. Householdcontacts

Apersonwhosharedthesameenclosedlivingspaceforoneormorenightsorforfrequentorextendedperiodsduringthedaywiththeindexcaseduringthe3monthsbeforecommencementofthecurrenttreatmentepisode.

ii. Non-householdcontact

Apersonwhoisnotinthehouseholdbutsharedanenclosedspace,suchasasocialgatheringplace,workplaceorfacility,forextendedperiodsduringthedaywiththeindexcaseduringthe3monthsbeforecommencementofthecurrenttreatmentepisode.

b) Casualcontact Acontactwhodoesnotbelongtotheabovecategories.

Contactsshouldbeinvestigatedfromtwoangles. a) fromthepointofviewoftheindexcase b) fromthepointofviewofthecontacts

a) Contactinvestigationfromthepointofviewoftheindexcase

The close contacts should be investigated when the index case has any of the followingcharacteristics.

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1. Sputumsmear-positivePTBPatientswithsputumsmear-positivePTBaremore infectious than thosewithsputumsmear-negative disease. Therefore, contact investigation should generally be prioritized to new orrecurrentcaseswithpositivesputumsmears.

2. Child<5yearsofageWhenachild<5yearsofagedevelopsTB,itislikelythattheinfectionwasacquiredfromanadultinthehousehold.Therefore,inthissituationtherationaleofinvestigatingistofindthesourcecase,nottofindsecondarycasesfromthechild.

3. MDR-TBorXDR-TB(provenorsuspected)

4. PLHIV

b) Contactinvestigationfromthepointofviewofcontact

Household andnon-household close contacts should be investigated if they have any oneoffollowingcharacteristics.

a) ContactsofallageswithsymptomssuggestiveofTB.b) Childcontacts<5yearsofagewhethertheyhavesymptomsornot.c) Contactswithknownorsuspectedimmunocompromisingconditions.d) ContactsofindexcaseswithMDR-TBorXDR-TB(provenorsuspected),whethertheyhave

symptomsornot.

• Contactscreeningshouldinclude:

1. Detailedmedicalhistory2. Clinicalexamination3. Sputumexaminationifcoughisasymptom4. ChestX-ray5. Mantoux(wheneverindicated)

AllsymptomaticandasymptomaticcontactsofTBpatients(irrespectiveoftheirsputumstatus)shouldbetracedandregisteredbytheRangePHIsorbythePHIsoftheDCCandtheyshouldbereferredtotheDCCforfurtherevaluation.Anysuggestivesymptomswhichcouldberelatedtotuberculosis(eitherpulmonaryorextrapulmonary),orevenconstitutionalsymptoms,irrespectiveoftheduration,needtobeinvestigated.Ahighindexofsuspicionistheneedofthehour.

• Screeningchildrenundertheageof5years

ThosewhoareclosecontactsshouldbescreenedbyclinicalevaluationandchestX-rays,andshouldbefollowedupforsignsandsymptomsofTBforthenext2yearsat6-monthlyintervals.Inaddition,parentsshouldbeadvisedtobringtheirchildtotheDCCifsymptomssuggestiveofTBappearatanytime.

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• Screeningadultsandchildrenabove5yearsofage

Thoseclosecontactswhohavesymptoms,shouldbeinvestigatedwithsputumsmears,chestX-rayorotherrelevantinvestigation(e.g.forEPTB)irrespectiveofthedurationoftheirsymptoms.Theasymptomaticclosecontacts,shouldbefollowedupbytheRangePHIsforappearanceofsymptomsfor next 2 years at 6-monthly intervals and they shouldbe advised to attend theDCC if symptomssuggestiveofTBappearatanytime.

7.4 PREVENTIVETHERAPY

TheaimofpreventivetreatmentistopreventprogressionofM.tuberculosisinfectiontoTBdisease.ItmeanstreatmentofLatentTBinfection(LTBI).

ProphylactictreatmentisgiventothefollowingcategoriesafterexcludingActiveTBdisease.a) Childrenunder5yearswhoareclosecontactsofbacteriologicallyconfirmedpulmonaryTB

patientsb) PLHIVwhoareclosecontactsofbacteriologicallyconfirmedpulmonaryTBpatientsc) OtherPLHIVwhohaveaMantouxreactionof≥5mmd) Otherspecialcategories

a. Transplantrecipientsb. Patientswho are going to be commencedon anti TumourNecrosis Factor alpha

(TNF–α)treatment

DecisiontostartsuchpatientsonchemoprophylaxismustbetakenonanindividualbasisbyaConsultantRespiratory Physician / Paediatric Pulmonologist, considering the contact history, risk of developingactiveTB,riskofdrugtoxicityagainstprotectionfordevelopingactiveTBetc.

Whatchemoprophylacticregimenshouldbeused?

Isoniazid10mg/kgdailyforchildren(maximum300mg)for6months.ThisisreferredtoasIsoniazidProphylacticTreatment (IPT). Otherprophylactic regimenswith rifampicinaloneor combinationofisoniazidwithrifampicinshouldbeavoided.

PatientshouldbefollowedupmonthlywhiletheyareonprophylaxisattheDistrictChestClinic,andafterthecompletion,every6monthsupto2years,bytheRangePHI.

7.5 INTENSIFIEDCASEDETECTIONINHIGHRISKCATEGORIES

a) ScreeningofallHIVpositivechildren

HIVinfectedchildrenhaveahighsusceptibilityratetodevelopTBinfectionandthosewhoarealreadyinfectedwithMycobacterium tuberculosis haveahighriskofdevelopingactiveTBdisease.Therefore,

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all children infectedwith HIV should be referred to a Consultant Respiratory Physician / PaediatricPulmonologistforevaluationforTB.

b) Otherprioritygroups• Migrantsandreturningrefugees• Othervulnerableormarginalizedgroups;e.g.thoselivinginslums,estatepopulations,

prisoninmatesetc.Sub-populationsthatneedstobescreenedmayvaryfromdistricttodistrict.HencethedecisiononselectionofsubpopulationstobescreenedshouldbetakenatlocallevelbytheDTCOinconsultationwithnationalandprovincialleveltechnicalexpertsandprogrammemanagers.

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08.EXTRA-PULMONARYTB

8.1 Diagnosis

8.1.1 TissueBiopsy

8.1.2 Tissueaspirate

8.2 TBLymphadenitis(LNTB)

8.3 TBPleuraleffusion

8.4 TBPericardialeffusion

8.5 Abdominaltuberculosis

8.6 Tuberculosisofthecentralnervoussystem

8.6.1 TBMeningitis(TBM)

8.6.2 Tuberculoma

8.7 SpinalTB

8.8 TBArthritis

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8. EXTRAPULMONARYTB:

8.1 DIAGNOSIS

Extrapulmonary TB takesmany forms, and the diagnosis can be challenging in many ways. This ismainlyduetothenon-specificnatureofsymptomsthatmimicothercommonchildhooddiseases.Thedisease is usually paucibacillary andmanyneed invasive investigations for thediagnosis.DiagnosticevaluationofextrapulmonaryTBisbasedonthesymptomatologyandrelevantimportantphysicalsigns.Ininvestigating,tissuebiopsyandtissueaspiratesplayasignificantrole.WhenadiagnosisofEPTBismade,alleffortsshouldbemadetodetecttheexistenceofpulmonaryTBinaddition.WhenbothEPTBandPTBispresent,thepatientisregisteredasacaseofPTB.

8.1.1TissueBiopsy

Tissuebiopsy is useful in thediagnosisof extrapulmonaryTB (EPTB). Biopsywill alsoexcludeotherpathological processes like malignancy. Therefore, biopsy should be attempted in suspected EPTBprovidedthelesionisamenabletoasurgicalapproach.BiopsyspecimensshouldbecollectedinsterilenormalsalineandcanbeculturedforAFBinadditiontoperforminghistology.DirectsmearforAFBandXpertMTB/RIFcanalsobedoneonbiopsysampleswhenanadequatespecimenofsignificantvolumeisobtained.

8.1.2Tissueaspirates CytologyanddirectsmearforAFBcanbedoneonaspiratesfromextrapulmonarysitessuchaslymphnodesandcollectionsofpus.Ifanadequateamount(atleast0.8ml,butlargervolumesarepreferable)of aspirate is obtained, XpertMTB/RIF can be performedwhich, if positive, confirms the diagnosismicrobiologically.ForAFBcultureandXpertMTB/RIFatleast1mlofaspiratewouldberequired.

8.2TBLymphadenitis(LNTB)

ThisisthemostcommonformofextrapulmonarytuberculosisanditmaybethesolemanifestationofTBinfection.Infectionwithmycobacteriaotherthantuberculosis(MOTT)iscommoninchildrenasitisharbouredindecidualteeth.Enlargedlymphnodespersistingformorethan2weeksneedsfurtherevaluation.Onexaminationitmaybefirm,minimallytenderornon-tender,fluctuatingormattedandwithorwithoutchronicsinusformation.Inaddition,fever,weightloss,nightsweatsandcoughmaybepresent.

• ChestX-rayismandatoryinallpatientspresentingwithsymptomsconsistentwithLNTB.

• Afineneedleaspirationcytology(FNAC)isdoneformicroscopy,culture,andXpertMTB/RIFtestwithdrugsusceptibilitytesting.

• When FNAC is not feasible, inconclusive or malignancy is suspected, excision biopsy forhistopathologyandmicrobiologicalconfirmationshouldbeundertaken.

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Management

Standardfirst-line anti-TBdrugs are recommended for 6months (2HRZE+ 4HR). In themajority ofchildren the lymph node size regresses slowly without any complications. Sometimes, while ontreatment,nodesmayenlargewithoverlyingerythema,fluctuations,andevensinustractsmayappear.Furthermore,newnodesmayalsooccur.Thiscanbeattributedto:• Immuneresponsetodyingorganisms• Poordrugpenetrationintothelymphnode• Co-existenceofadditionalpathology• DiseasecausedbyMOTT• Relapse• DrugresistanceTominimize the above complications, confirmation of the bacteriological diagnosis, evaluation andclosemonitoringduringtreatmentareessential.Repeatbiopsywithmicrobiologicalevaluationwillhelptodifferentiateatruebacteriologicalrelapsefromimmunologicalreactionsandneoplasticpathologies.

Surgicalmanagement

Whenlymphnodesarefluctuantandreadytodrain(abscessformation),aspirationshouldbeperformed.Increasingsizeofaresidualnodeisanindicationforexcisionbiopsyforhistopathologyandculture.IftheLymphnodespersist(>1cm)after4monthsoftreatment,itneedsspecializedcare.Smallresidualnodesattheendoftreatmentisnotunusual.

Mediastinal lymphadenopathycanbemonitoredwithChestX-rays,butCT scan is indicated inpoorresponders after4monthsof treatment. Systemic corticosteroidsmaybe considered if thenode iscompressingavitalstructuresuchasabronchus.

8.3 TBPLEURALEFFUSION

PleuralTBisthesecondcommonestformofEPTB.Patientscanpresentwithcough,pleuritictypeofchestpainorshortnessofbreath,withorwithoutfeverandotherconstitutionalsymptoms.

• OnceclinicallysuspectedthepleuraleffusionneedstobeconfirmedbyChestx-ray/ultrasoundscanofchest.

• Pleuralaspiration (thoracocentesis) shouldbedoneunderultrasoundguidanceandspecimenshouldbesentfor:■ Protein,glucose,andlactatedehydrogenase(LDH)levels(sendconcurrentbloodsample

forserumproteinandLDH)■ Differentialcellcount■ MicroscopyandcultureforMycobacterialTB■ Cytology■ AdenosineDeaminase(ADA)

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• ExudativeeffusionswithlymphocytepredominancesuggestTBpleuraleffusion,butisnot100%confirmatory.TheexudativenatureofaneffusionisdeterminedbasedonLight’scriteria.(pleural fluid/serum protein >0.5; pleural fluid/serum LDH >0.6; pleural fluid LDH > two-thirds the upper limit of serum LDH)

• Inchildren,partiallytreatedparapneumoniceffusionisthemostcommondifferentialdiagnosisandADAmayyieldahigherproportionoffalsepositives.

• ThoracoscopicpleuralbiopsyismoresensitiveforthediagnosisofpleuralTB,bothbacteriologicallyand histologically. But it is only indicated where diagnosis is uncertain and a malignancy issuspected.

Management

Standardfirst-lineanti-TBdrugsarerecommendedfor6months (2HRZE+4HR).Corticosteroidsarenotroutinelyrecommended.Surgicaldrainageisindicatedincasesofmoderatetolargeeffusionswithrespiratorydistress, forsymptomreliefandtominimizecomplicationssuchasa trapped lung.Mostpatientswillshowclinicalimprovementby2weeksofATTandresolutionofeffusionby6-8weeks.

8.4 TBPERICARDIALEFFUSION

TBpericarditiscommonlypresentsasanacutepericarditisandhasahighmortalityifuntreated.Thismayprogresstoconstrictivepericardialdiseasewhichcantakeamoreprotractedcourse.Thepresentationmaybewithchestpain,shortnessofbreath,withorwithoutfeverandweightlossorhaemodynamicabnormalities.

ChestX-ray(CXR),electrocardiogram(ECG)andechocardiogramshouldbedonetoconfirmpericardialeffusionorconstriction.

• Transthoracicechocardiogramconfirmspericardialeffusionand/orconstriction,andcandetectsignsofimpendingtamponadewhichrequiresurgentintervention.

• CTof the chest isnot routinely indicatedbutuseful fordemonstratingpericardial thickening,calcificationorassociatedlung/mediastinalabnormalities.

• Pericardiocentesiscanbeconsideredfordiagnosticpurposes.Itshouldbecarriedoutbytrainedpersonnelusingultrasoundguidance.

• PericardialfluidissentforcultureofmycobacteriaandXpert(MTB/RIF)despitelowsensitivityofthetest.Adifferentialcellcountmaybesupportiveforthediagnosis.

• If surgical intervention is attempted, biopsy samples should be sent for histology, culture ofmycobacteriaandXpert(MTB/RIF).

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Management

Standardfirst-lineanti-TBdrugsarerecommendedfor6months (2HRZE+4HR).Corticosteroidsareroutinelyrecommendedduringthe initialperiodoftherapy.Pericardiocentesis isurgentlyneededincases of cardiac tamponade. Pericardiotomymay be indicated in childrenwho develop constrictivepericarditisasalatecomplication.

8.5 ABDOMINALTUBERCULOSIS

Patients may present with abdominal pain, distension, fever, unexplained weight-loss, chronicdiarrhoea, failuretothriveoranabdominalmass.Theymayhave localizeddiseaseas inmesentericlymphadenopathyandintestinaldiseasewithamass,oramoredisseminateddiseasewithdistendedabdomenduetoascitesorsystemicdisseminateddiseasepresentingashepatosplenomegaly.

• Asciticfluidsamplingspecimensshouldbesentforcytology,albumin,protein,ADA,microscopyforAFB,cultureforMTBandotherorganisms.

• Ultrasoundscanofabdomenshouldbedoneinallcasestodemonstrateintra-abdominalfluid(freeorloculated),inter-loopascites,bowelwallthickening,enlargedlymphnodes(withcentralnecrosisandperipheralenhancement)andperitoneal/omentalthickening.

• US-guided FNAC or core biopsy of mesenteric or retroperitoneal lymph nodes and biopsyof omentum or peritoneum may need to be performed for bacteriological and histologicalconfirmation.

Management

Standardfirst-lineanti-TBdrugsarerecommendedfor6months(2HRZE+4HR).Thismaybeextendedatthediscretionofthetreatingclinician.Nutritionalsupportisveryimportantasmalabsorptionmaybeacomplication.Surgeryisindicatedinintestinalobstruction,strictures,perforation,fistulaorabscessformationandbowelnecrosis.Gastroenterologisthasamajorroleinthemanagement.

8.6 TUBERCULOSISOFTHECENTRALNERVOUSSYSTEM

8.6.1 TBMeningitis(TBM)

RiskfactorsforTBMincludeage<5years,contactwithanadultsufferingfromtuberculosis,ProteinEnergyMalnutritiongradesIIIandIV,andHIVinfection.

ChildrenwithTBMmaypresentwitharatherlonger(>1week)durationoffever,withvagueCNSsymptomssuchasbehaviouralchanges,irritability,drowsiness,headache,vomitingandseizures.Meningitisnotrespondingtoantibiotictreatment,withasubacuteonsetand/orwithfeaturesofraisedintracranial

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pressuremaybesuggestiveofTBM.Physicalexaminationmayrevealaglobalencephalopathywithorwithoutfocaldeficits,hydrocephalus,andmovementdisorders.

ComplicationsofTBmeningitis• Hydrocephalus–symptomsandsignsofraisedintracranialpressure(ICP).• Stroke–focalneurologicaldeficitconsistentwithastrokesyndrome• Optico-chiasmatic arachnoiditis – sudden visual loss, during treatment or on withdrawal of

corticosteroids• Seizures–seizurescanbesecondarytoencephalopathy,tuberculomaorinfarction

8.6.2 Tuberculoma

Tuberculomaisoftenseeninolderchildren.ItmaysometimesalsobeasequelofTBmeningitis.Patientsmaypresentwithfocalseizuresifthelesionsareinasupra-tentorialcorticallocation.Inposteriorfossalesions,theremaybesymptomsandsignsofraisedintracranialpressure,withmultiplelocalizingsignsandhydrocephalus.

Investigations

1. Cerebrospinalfluid(CSF)sampling

ThediagnosisofCNSTBcanbedifficult.Sometimesitmaybebasedonlyonclinicalandpreliminarycerebrospinalfluid(CSF)findingsevenwithoutdefinitivemicrobiologicalconfirmation.

Typically,CSFiscleartoopalescentinappearanceandtheclassicaldescriptionisthedevelopmentofacobwebonstanding.Usuallythecellcountisnothigh(under500cells/mm3withalymphocytosis).Biochemicalinvestigationsrevealincreasedproteinandreductioninglucosetousuallylessthan45mg/dl.ThetypicalCSFpicturemayhowevernotalwaysbeseen.Furthermore,theCSFpicturedescribedabovecanalsobemimickedbypartiallytreatedpyogenicmeningitis.Insuchasituation,reassessingafter48-72hoursoftreatmentwithafreshsetofintravenousantibioticstoevaluateimprovementinclinicalstatusaswellasinCSFcanbeuseful.CSFabnormalitiesinTBMmaytakeavariabletime,evenuptoafewmonths,toreturntonormal.

XpertMTB/RIFonCSFshouldbedoneasafirst line investigationwheneverCNSTBwithmeningealinvolvementissuspected.Atleast0.5mlofCSFshouldbesentforthetest.AnegativeXpertresultdoesnotruleoutTBM.DecisiontogiveATTshouldbebasedonclinicalfeaturesandtheCSFprofile.

Mycobacterialculturewillneedatleast1mlofCSF.Culturehaspoorsensitivity(16%)thoughspecificityishigh(90%)anditwouldalsohelptodeterminethedrugsusceptibility.AlargervolumeofCSFdeliveredtoalaboratoryquicklyandanalysedwithoutdelaycanhelptoimprovethesensitivity.

2. Neuroimaging NeuroimagingisanimportantdiagnosticmodalityinCNS-TB.Itmayrevealoneormoreofthefollowingfindings:

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• Basalmeningealenhancement• hydrocephaluswithorwithoutperi-ventricularooze• tuberculoma(s)• infarctsmaybeseenindifferentareas,especiallyinthebasalganglia.

MagneticResonanceImagingisthetestofchoiceforvisualizingabnormalitiesofTBM,andissuperiortoCTwhenevaluatingforTBinthebrainstemandspine.NormalneuroimagingdoesnotruleoutTBMandincaseofstrongclinicalsuspicionofdiagnosis,arepeatfollow-upscanafterafewdaysmayshownewlydevelopinglesions.

ManagementofTBmeningitisandMiliaryTB

● MiliaryTBhasa60-70%riskofmeningealinvolvementandshouldbemanagedinawaysimilartoTBmeningitis.AllchildrenwithsuspectedorconfirmedmiliaryTBshouldhavealumbarpuncturetodiagnosemeningitis.

● ChildrenwithTBmeningitisormiliaryTBshouldbehospitalizedinitiallyuntiltheirclinicalstatehasstabilized.

● Sincetherapycanbelifesaving,itisimportanttocommencetherapyempiricallyifTBmeningitisisstronglysuspected.

● Theregimenis2monthsofIntensivePhasefollowedby10monthsofContinuationPhase.Thetreatmentoptionsfortheintensivephaseare2HRZSinchildrenunabletocommentoncolourvisionand2HRZEinthosewhocancomplainoflossofcolourvision.Thecontinuationphaseis10HR.

● Concomitant commencement of steroid therapy with the first dose of Anti-TB therapy ismandatoryinallchildrenwhoarenegativeforHIV.TherecommendationsareforPrednisoloneinadoseof2mg/kg/dayfor4weeksandshouldbetapereddownover1-2weeksbeforestopping.Thedosecanbe increasedto4mg/kg(maximum60mg/day) inseriously illchildrenbecauseRifampicinwilldecreasesteroidconcentrations,buthigherdosescarryariskofgreaterimmunesuppression.

● DexamethasonecanalsobeusedinsteadofPrednisolone.IntravenousDexamethasone0.4mg/kg/24hin3–4divideddosesshouldbegivenfor4weeks.Doseshouldbesteppeddownwithoraltherapyover1-2weeks.

● Somepatientsmayneedlongertreatmentwithsteroids,ofupto6–8weeks.ThisdecisionshouldbemadebasedondiseaseseverityandcomplicationsofTBM.

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Complicationsandmanagement-(Table8.1)

Complication MMaannaaggeemmeenntt

Hydrocephalus Ventriculo-peritoneal shunt insertion is indicated for patients of all stages of severity with hydrocephalus or raised ICP not responding to ATT and steroids. Early shunt insertion may be beneficial.

Treatment with 3% NaCl and diuretics such as mannitol should be limited to emergency management until shunt insertion can be performed.

Stroke Most effective treatment strategy is uncertain and evidence is lacking. Acute stroke or evidence of on-going vasculopathy may warrant continuation of steroids, usually intravenously.

Optico-chiasmatic Arachnoiditis

Steroid therapy is the 1st line treatment, using intravenous dexamethasone.

Seizures Acute management with anti-epileptic drugs as per local protocol for seizures. The use of anti-epileptic drugs (AEDs) alongside ATT must be carefully managed due to the potential for drug interactions and increased risk of liver dysfunction with multiple hepatotoxic agents. Prophylactic AEDs are not required in TBM patients who have not had seizures during their clinical course. Continued treatment with AED is necessary only in patients with recurrent seizures and decisions about duration and withdrawal should be individualized.

Complication

Hydrocephalus

Stroke

Optico-chiasmaticArachnoiditis

Seizures

Table8.1TreatmentofCNStuberculoma

Tuberculomaofthecentralnervoussystem(CNS)islesscommonthanTBMandhasalowermorbidityandmortality,butremainsanimportantcauseofintracranialspace-occupyinglesions.

Theaimsoftreatmentare: a) Resolutionofneurologicalandconstitutionalsymptoms b) Resolutionofthelesiononneuroimaging

ThereisalackofevidenceastotheoptimumdurationoftreatmentinCNStuberculoma.ExpertopinionsuggeststhatATTshouldbegivenfor9to12monthsinitially,withrepeatneuroimagingat3monthsand9–12monthstomonitorresponsetotreatment.Treatmentshouldthenbetailoredtotheclinicalandradiologicalresponseofthepatient.

Paradoxicalreactionwithanincreaseinthesizeandnumberoflesionscanoccur,usuallyinthefirst3monthsoftreatment,andrequirestreatmentwithsteroidsaswellascontinuationofATT.

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Treatmentfailureshouldbesuspectedwhenlesionseitherincreaseinsizeorfailtoreduceinsizeafter3to6monthsofATTdespiteappropriatedosingandgoodadherence.Thetreatingclinicianneedstoweighthebenefitsandrisksofbiopsyagainstthoseofcommencingsecond-linetreatmentempiricallyforsuspectedMDR-TB,orpersistingwithfirst-linetreatmentforsuspectedparadoxicalreaction. Ifabiopsyisperformedduetostrongconsiderationofanalternativediagnosis,thespecimensshouldbesentfor:

a) HistopathologywithstainingforAFB b) TBcultureanddrugsusceptibilitytesting c) Othermicrobiologicaltestsasindicatedbythecasehistory.

8.7 SPINALTB

Achildwithlocalizedbackpainformorethan6weekswithtendernessonthespinousprocesses,fever,andweightloss,withorwithoutsignsofspinalcordcompressionshouldbesuspectedtohavespinalTB.Inaddition,failuretothriveandnightcries,inabilitytowalk,cautiousgait,progressivedifficultyinwalking,prolongedbackpainanduseofhandstosupporttheheadortrunkareimportantsigns.GibbusdeformityofthespineespeciallyofrecentonsetmaybetheresultofvertebralTB.

MRIisusefulinmakingadiagnosisintheearlystagesofdiseaseandvertebralbodyabnormalitiessuchasspondylo-discitisarehighlysuggestiveofadiagnosisofspinalTB.

TreatmentofspinalTB

SpinalTBneedsmulti-disciplinaryapproach.First-lineanti-TBdrugsaregiven–2HRZE+10HR (Streptomycintoreplaceethambutolinaveryyoungerchild)

Allpatientsrequireclosemonitoringfordevelopment/progressofneurologicaldefect.Somepatientsneed surgery to treat spinaldeformity/instabilityandneurologicaldeficit. X-ray is repeated inevery3months.RepeatMRIshouldbedoneat6monthsandrepeated if indicatedasperdecisionofthetreatingspecialist.

8.8 TBARTHRITIS

Typically,TBarthritispresentwithnon-painfulenlargedjoints.Amono-arthropathyofmorethanonemonthdurationrequiresexclusionofTBasthecause.Althoughanyjointmaybeinvolved,handandwristjointinvolvementismorecommoninchildrenunder5yearsofage.Shoulder,hip,knee,andanklejointInvolvementismorecommoninchildrenover5yearsofage.

First-lineanti-TBdrugsarerecommendedfor12months(2HRZE+10HR).Amulti-disciplinaryapproachisindicated.Restinsplint,bracesarerecommendedbutprolongedimmobilisationshouldbeavoided.Surgeryisrarelyindicated.

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09.PERINATAL ANDNEONATAL TB

9.1 Clinicalpresentation

9.2 Investigations

9.3 Managementofthenewbornofamotherwithactivetuberculosis

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9. PERINATALANDNEONATALTB

Perinatal andneonatal Tuberculosis is a diseasewithhighmortality. Tuberculousbacillaemiaduringpregnancymayresultininfectionofplacentaormaternalgenitaltract.Infantscangetinfectedviathetrans-placental route through theumbilical vein (forming theprimary complex in liver), by infectedamnioticfluid ingestion/aspiration(formingprimarycomplex ingastrointestinal tractor lungs)orviaairborneinoculationfromclosecontacts.However,thediseaseisrareifmotherhasbeenoneffectivetreatment.

9.1 Clinicalpresentation

The clinical presentation of neonatal TB is non-specific but is usually marked by multiple organinvolvement. Symptomsmaybepresent at birthbutmore commonly beginby the secondor thirdweekoflife,withamedianageofpresentationaround24days.Theneonatemaylookacutelyill.Fever,lethargy,irritability,respiratorydistress,hepatosplenomegaly,lymphadenopathyorfailuretothrivemayindicateTBinaneonatewithahistoryofexposure.Inaddition,jaundice,vomiting,apnoea,cyanosis,seizuresandpetechiaecanalsobepresent.

9.2 Investigations

AneonatewithsuspectedcongenitalTBshouldhaveachestx-ray,directsmearandcultureoftrachealaspirates,gastricwashings,urineandCSFforacid-fastbacilli.However,tuberculintestingisnotverysensitiveinthissituation.Biopsyoftheliver,lymphnodes,lung,orpleuramaybeneededtoconfirmthediagnosis.Inadditiontoroutinetestsfortuberculosisintheneonate,thehistologicalandmicrobiologicalevaluationofplacentaoranendometrialbiopsyofthemothershouldbeconsiderehed.

9.3 Managementofthenewbornofamotherwithactivetuberculosis

Themainconsiderationsinthemanagementofanewbornofamotherwithactivetuberculosisare:

a) WhetherthechildhasgotcongenitalTBornotb) Thesputumstatusofthemother;topreventpost-natalinfectionoftheinfant

Otherissuesthatneedconsiderationare:

a) Safetyinbreastfeeding- Breastfeedingcanbesafelycontinued.Allanti-TBdrugsarecompatiblewithbreastfeeding.b) Whetherthereisaneedtoseparatethechildfromthemother- Donotseparatethechildfrommotherunlesssheisacutelyill.Recentlydiagnosedsputum

smear-positivemothersshouldbeadvisedtowearafacemaskduringbreastfeedingandavoidcoughingontotheinfant’sface.Theyshouldbreastfeedinanadequatelyventilatedplace,minimizingsharingcommonbreathingspacewiththeinfant.

c) NeedforandtimingofBCGvaccinationd) NeedforIPT

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• IftheinfantisillatbirthandcongenitalTBissuspected;a) BCGvaccinationshouldnotbegiven.b) Afullcourseofanti-TBtreatmentshouldbegiven.

• Ifthemotherissputumsmear-positiveatthetimeofdelivery,a) The infant should be carefully examined for evidence of active disease and should be

regularlyfollowedupfordevelopmentofthedisease.• Ifthechildiswell,giveprophylactictreatmentofINAH10mg/kgbodyweight,daily

forthreemonths.• BCGvaccinationiswithheld.

b) After three months, the child is carefully evaluated for active disease with physicalexamination,chestX-ray,andaMantouxtestisperformed.• IftheMantouxtestisnegativeandthechildiswell,- prophylactictreatmentwithINAHisstopped- thechildisgivenBCG.• IftheMantouxtestispositiveand,

• ifTBactivediseaseisdiagnosed,afullcourseofanti-TBtreatmentshouldbecommenced.

• ifthephysicalexaminationandthechestX-rayarenormal,INAHprophylaxisiscontinueduptosixmonths.

• NoBCGisgiven.

• Ifthemotherissputumsmearnegativeatthetimeofdeliveryand,• iftheinfanthasnoevidenceofcongenitalTB,

a) BCGisgiventotheinfantaftertheevaluation.b) IPTisnotgiven.

• Even if themother is non-infectious, the infant shouldbe regularly screened for TB toensurethatTBdiseasedoesnotdevelop,andifTBdiseaseissuspected,afullcourseofATTshouldbeconsidered.

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AlgorithmformanagementandpreventionofTBofaninfantborntoamotherwithactiveTB

Confirm PTB in mother during pregnancy

Start ATT

Check mother's sputum statusAt delivery

Smear positiveExamine baby for congenitalTB

Congenital TB present

Congenital TBabsent

IPT for 3/12No BCG

At - 3/12Examine the baby for TB

Congenital TB absentMantoux test

Mantoux- positive

IPT up to 6/12No BCG

Mantoux - negative

BCG givenNo IPT

Congenital TB present Start ATTNo BCG

Smear negative Examine baby for congenital TB

Congenital TB present

Start ATTNo BCG

Congenital TB absent

BCG givenNo IPT

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10.TBINHIV-INFECTED

CHILDREN

10.1 Diagnosis

10.1.1 DiagnosingTuberculosisinHIV-infectedchildren

10.1.2 DiagnosingHIVinfectioninchildren

10.2 ManagementofTBinHIV

10.2.1 LatentTBinfection(LTBI)andChemoprophylaxis

10.2.2 TreatmentofActiveTBdiseaseinHIVinfectedpatient

10.3 Anti-retroviraltreatment

10.4 Screeningforadverseevents

10.5 ManagementofRelapse,TreatmentFailureandDrugResistance

10.6 PreventionofTuberculosis

10.7 Co-trimoxazolepreventivetherapy(CPT)

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10. TBINHIV-INFECTEDCHILDREN

The clinical presentationof TBdisease among childrenwithHIV infectionmaybe similar to that inchildrenwithoutHIVinfection.However,poorweightgainmaybetheonlypresentingfeatureinitially.However,HIVinfectedchildrenhavehigherratesofseverediseaseandhigherratesofextra-pulmonaryTBcomparedtotheHIVuninfected.AllchildrenwithTBshouldbescreenedforHIVinfectionandviceversa.

10.1 DIAGNOSIS

10.1.1DiagnosingTuberculosisinHIV-infectedchildren

ThechallengesindiagnosingTBinHIV-infectedchildrenaremultiple.Theoptimalapproachisstillnotclear,andmaydifferbetweenareasofhighandlowTBendemicity.Thepresentationmaybenon-specificandtheclinicalfeaturesfrequentlyoverlapwithothercommonclinicalpresentations.TheChestX-RayfindingsmaynotbeconfirmatorytoowithanoverlapofradiologicalfindingsbetweenTBandotherHIVrelatedlungdiseases,includinglymphocyticinterstitialpneumonitis(LIP).Furthermore,paediatricTBinHIVinfectedchildrenisoftenpauci-bacillary,makingmicrobiologicalconfirmationlesslikely.However,microbiologicalconfirmationwithXpertMTB/RIFandmycobacterialculturesonappropriatespecimensshouldalwaysbeattempted.Thetuberculinsensitivitytest(TST)tooislesssensitiveintheHIV-infected,especiallyatlowCD4countsandanindurationof5mmormoreshouldbetakenassignificant.

10.1.2DiagnosingHIVinfectioninchildren

a) Childrenyoungerthan18monthsofage• Virologicalassays(i.e.HIV-RNAandHIV-DNAtests)thatdirectlydetectHIVmustbeusedto

diagnoseHIVinfectioninchildrenyoungerthan18monthswithperinatalHIVexposure.• HIV antibody tests should not be used due to transplacental passive transmission of

maternalHIVantibodies.• Apositivetestresultshouldbeconfirmedassoonaspossiblebyarepeatvirologicaltest

onasecondspecimen,becausefalse-positiveresultscanoccurwithbothRNAandDNAassays.

• HIV infection can be definitively diagnosed by virological assays inmost non-breastfedinfantswithHIVexposurebytheage1to2months,andvirtuallyinallinfantsby4monthsofage.

ThespecificityoftheHIV-DNAPCRis99.8%atbirthand100%atages1,3,and6months.

b) Childrenolderthan18months

• HIVantigen/antibodycombinedELISAshouldbeusedasascreeningtestanditshouldbeconfirmedbyusingaconfirmatorytest.

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10.2 MANAGEMENTOFTBINHIV-INFECTED

10.2.1LatentTBinfection(LTBI)andChemoprophylaxis

ChildrenlivingwithHIVwhoareclosecontactsofanactiveTBcasewithnoevidenceofTBdiseasesshouldbeginchemoprophylaxisregardlessofage.However,children living insettingswithahighTBprevalenceevenwithoutaknownclosecontactwithactiveTBmaybeofferedchemoprophylaxis.Recommendedchemoprophylaxis:Isoniazidpreventivetherapy(IPT)10mg/kg/dayforsixmonths.

10.2.2TreatmentofActiveTBdiseaseinHIVinfectedpatient

Management of TB-HIV co-infection, especially concurrent anti-tuberculous therapy (ATT) and anti-retroviraltherapy(ART),requiresselectionofantiretroviraldrugswithminimaldruginteractionswherepossible,doseadjustmentsandcarefulmonitoringofoverlappingtoxicities.(Iffacilitiesareavailable,performtherapeuticdrugmonitoring)

- ChildrenwithTBco-infectionshouldbejointlymanagedbyrelevantspecialistsincludingVenereologist,Pulmonologist,andPaediatrician.

- ChildrenwithTB-HIVco-infectionshouldreceiveDirectlyObservedTherapy(DOT).- Duration of therapy in uncomplicated TB should be the same as in non-HIV infected

children.- IncomplicatedTBorinthepresenceofmoderatetosevereimmune-compromisedstatus,

thedurationofanti-TBtreatmentmaybeextendedconsideringtheresponsetotreatment.- Corticosteroids may be used for the management of complicated forms of TB, e.g.

tuberculousmeningitis,pericardialTBandsevereairwayobstructionbyTBlymphglands.- Each child should be assessed 2 weeks after the start of TB treatment then reviewed

monthly.- Dosagesofanti-TBdrugsandARTshouldbeadjustedtoaccountforanyweightgain.- AllchildrenlivingwithHIV,aftersuccessfulcompletionoftreatmentforTB,shouldreceive

IPTforanadditionalsixmonths.

10.3 ANTI-RETROVIRALTREATMENT(ART)

- AllchildrendiagnosedwithTBandHIVshouldbestartedonART.- InachildwithactiveTBdisease,ARTshouldbestarted2to8weeksfollowingtheinitiation

ofanti-TBtreatment,regardlessoftheCD4cellcountandclinicalstage.- SelectingARTregimensthatarecompatiblewithTBtherapyisessentialandwillbedecided

bytheConsultantVenereologist.- ChildrenwhoarealreadyonaneffectiveARTshouldhavetheirregimenpreserved,asfar

aspossible.

10.4 SCREENINGFORADVERSEEVENTS

- Children should be monitored clinically for signs of toxicity, especially hepato-toxicity.SuggestedscheduleformonitoringofLFTsis:2,4,and8weeks,andthen2-3monthly.

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• ImmuneReconstitutionInflammatorySyndrome(TB-IRIS)

TB-IRISshouldbeconsideredinallchildrenwhopresentwitheitheranexacerbationofknownTBdiseaseorwiththedevelopmentofTBsymptomsfollowingcommencementofART.DespitethedevelopmentofIRIS,anti-TBtreatmentshouldbecontinued.Thecommencementofcorticosteroidsandfurthercareshouldbedoneatatertiarycarecenter.

10.5 MANAGEMENTOFRELAPSE,TREATMENTFAILUREANDDRUGRESISTANCE

- Treatmentadherence,druglevels,drugresistance,TB-IRISandalternativediagnosesshouldbeconsideredintheeventofpoortreatmentresponse,treatmentfailureorrelapse.

- Aspecialistindrug-resistantTB(DR-TB)shouldbeinvolvedinthemanagementofDR-TBcontactsandcases.

- Non-tuberculous mycobacteria may present in a similar fashion to TB in severelyimmunocompromisedchildrenandshouldbeconsideredintheeventoftreatmentfailure.

10.6 PREVENTIONOFTUBERCULOSIS

BCGvaccination shouldbedeferred in infantsborn toHIVpositivemothersuntil theirHIV-status isknown.AninfantfoundtobeHIVpositive,shouldnotbevaccinated.IfthereisahighriskofTBexposure,BCGvaccinationmaybegiventoHIVexposedinfantsatlowriskofHIVtransmission(maternalviralloadundetectableatorafter36/40gestation).

BCGdiseaseshouldbeconsideredininfantswhoweregivenBCGvaccinepriortoadiagnosisofHIVinfectionandpresentingwithlymphadenopathyorothersymptomsconsistentwithTB.DisseminatedBCGiosisisararebutseriouscomplicationinHIV-infectedchildren.LocalreactionatthesiteofBCGismuchmorecommonandlessserious,butmayresultinlocalizedBCG-IRISafterstartingART.

10.7 CO-TRIMOXAZOLEPREVENTIVETHERAPY(CPT)

CPTisrecommendedforallHIVexposedinfantsandchildrenlivingwithHIVincludingthosewithTB.

Dailyco-trimoxazoleprophylaxisdosesare:

• 20mgTMP+100mgSMX-if<6monthsofage• 40mgTMP+200mgSMX-if<5years• 80mgTMP+400mgSMX-if5-15years

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References1. National Manual for Tuberculosis Control, Sri Lanka – (2016 update)

2. Guidelines for management of Tuberculosis in children, Sri Lanka – 2008

3. Extrapulmonary Tuberculosis Guidelines, Sri Lanka – 2013

4. WHO Guidelines for treatment of drug-susceptible tuberculosis and patient care – (2017

update)

5. WHO treatment guidelines for drug-resistant tuberculosis (2016 update)

6. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in

Children: second edition, World Health Organization, 2014.

7. Index-TB Guidelines, India – 2016

8. National Strategic Plan for Tuberculosis Control, Sri Lanka – 2015-2020

9. Laboratory Manual for Tuberculosis Control, Sri Lanka – 2010

10. 5th Joint Monitoring Mission of the National Programme for Tuberculosis Control, Sri

Lanka – 2014

11. Management guidelines of TB/HIV Co-Infection, Sri Lanka – 2011

12. Guidelines for the use of antiretroviral agents in pediatric HIV infection; Diagnosis of HIV

infection in infants and children.

13. Consolidated Guidelines on HIV Testing services, World Health Organization July 2015.

14. Whittaker E, Turkova A, Bamford A. HIV-tuberculosis co-infection in children. Children’s

HIV Association. June 2015.

15. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing

HIV infection. World Health Organization, Second edition 2016.

16. Aidsinfo. Guidelines for the prevention and treatment of opportunistic infections in HIV

17. UpToDate® - 2017

18. Mantoux Tuberculin Skin Test Wall Chart, Centers for Disease Control and Prevention

Documents

National Guidelines for Management of Tuberculosis in Children