MycobacteriumMycobacterium tuberculosistuberculosis infectionsinfections

KarinKarin Nielsen,Nielsen, MD,MD, MPHMPH PediatricPediatric InfectiousInfectious DiseasesDiseases UCLAUCLA MattelMattel ChildrenChildren’’ss HospitalHospital RegardingRegarding tuberculosistuberculosis

TheThe worldworld tuberculosistuberculosis refersrefers to:to: 1.1. MM TBTB complexcomplex 2.2. WhatWhat anan individualindividual withwith aa ++ PPDPPD hashas 3.3. ExposureExposure toto TBTB 4.4. DiseaseDisease 5.5. Exposure,Exposure, latencylatency andand diseasedisease TuberculosisTuberculosis

CommunicableCommunicable diseasedisease causedcaused byby MycobacteriumMycobacterium tuberculosistuberculosis,, oror thethe acidacid--fastfast tubercletubercle bacillus.bacillus. TBTB inin HistoryHistory

IdentifiedIdentified inin StoneStone AgeAge skeletonsskeletons PrevalentPrevalent inin AncientAncient EgyptEgypt UpriseUprise inin thethe MiddleMiddle AgesAges afterafter thethe BlackBlack death.death. DiseaseDisease ofof poverty,poverty, crowding,crowding, war,war, famine,famine, displacement,displacement, insalubriousinsalubrious lifelife && workwork Abreugraphy or chest photofluorography (mass miniature radiography) is a photo-fluorography for mass TB screening using miniature (50 to 100 mm) photograph of the screen of a x-ray fluoroscopy first developed in 1936 by Dr. Manoel Dias de Abreu, Brazil.

January 4- National Abreugraphy Day in Brazil 2012

1/3 of the world’s population has been infected with TB 2012 Countries with 80% of TB cases worldwide Deaths in adults due to infectious diseases in developing countries EpidemiologyEpidemiology InIn thethe midmid--1980s,1980s, aa resurgenceresurgence ofof TBTB occurredoccurred inin thethe US.US. SinceSince 1993,1993, TBTB ratesrates havehave beenbeen decliningdeclining inin thethe U.S.U.S. However:However: – TB cases continue to be reported in every state. – Drug-resistant TB continues to be reported in nearly all states. – An estimated 10 to 15 million are infected with M tb in the US. – With no intervention, 10% will develop TB throughout their lifetime. 25%25% ofof newlynewly diagnoseddiagnosed casescases areare foreignforeign--born.born. TBTB CaseCase Rates,Rates, UnitedUnited States,States, 20102010

D.C.

< 3.5 (year 2000 target) 3.6 - 5.6 > 5.6 (national average) Rate: cases per 100,000 TB incidence coefficient per state, Brazil 2008

Overall incidence: 20.6/ 100,000

Porto Alegre EpidemiologyEpidemiology

HigherHigher riskrisk groupsgroups forfor TB:TB: – First generation immigrants from high risk countries. – Native Americans – Alaskan natives – Homeless individuals – Individuals in correctional facilities – Patients with diabetes mellitus, lymphoma, immunosuppression – Patients with prolonged or high dose use of steroids. – Individuals from urban/ low income areas. Jamer RM, et al. NEJM 2002; 347:1860-6. ReportedReported TBTB CasesCases byby Race/EthnicityRace/Ethnicity UnitedUnited States,States, 20052005

Hispanic White, non-Hispanic (21%) (25%) American Indian/ Alaska Native (1%)

Black, non-Hispanic Asian/Pacific Islander (30%) (22%) Percentage of TB Cases Among Foreign-born Persons

19922010 1999

>50% 25%-49% <25% TransmissionTransmission andand PathogenesisPathogenesis MechanismMechanism ofof transmission:transmission:

PrimarilyPrimarily byby dropletdroplet nucleinuclei expelledexpelled byby someonesomeone withwith infectiousinfectious TB.TB. DropletsDroplets withwith bacillibacilli areare inhaledinhaled andand reachreach alveoli,alveoli, beingbeing ingestedingested byby macrophages.macrophages. BacilliBacilli maymay spreadspread viavia thethe bloodstream.bloodstream. InIn mostmost cases,cases, developmentdevelopment ofof diseasedisease isis containedcontained byby thethe immuneimmune system.system. AboutAbout 10%10% ofof infectedinfected personspersons willwill developdevelop disease;disease; riskrisk inverselyinversely proportionalproportional toto immuneimmune function.function. BackgroundBackground Majority of TB cases are pulmonary in all age groups. Children have more extra-pulmonary disease than adults. May occur at any anatomical site or be disseminated Exposure: Hx of contact; - skin test, CXR and PE Latent Tuberculous Infection (LTBI): + skin test, +/ - CXR, - PE Infected individuals with no TB disease are asymptomatic, and non-infectious. Disease: Symptoms, signs and radiological abnormalities are apparent. Distinction between infection and disease in children is unclear. ProbabilityProbability TBTB WillWill BeBe TransmittedTransmitted

• Infectiousness of person with TB

• Environment in which exposure occurred

• Duration of exposure

• Virulence of the organism

TransmissionTransmission OnlyOnly adultsadults andand adolescentsadolescents withwith TBTB areare contagious.contagious. NumberNumber ofof organismsorganisms inin sputumsputum isis criticalcritical forfor infectivity,infectivity, andand thethe frequencyfrequency ofof cough.cough. InfectivityInfectivity lastslasts aa fewfew weeksweeks afterafter thethe initiationinitiation ofof effectiveeffective therapy.therapy. WhenWhen 33 sequentialsequential sputumsputum smearssmears areare negative,negative, thethe patientpatient isis consideredconsidered nonnon--contagiouscontagious.. TBTB maymay rarelyrarely bebe transmittedtransmitted transplacentallytransplacentally toto thethe fetus.fetus. RegardingRegarding TBTB inin childrenchildren……

MiliaryMiliary TBTB oror TBTB meningitismeningitis willwill occuroccur 1.1.OnlyOnly afterafter aa periodperiod ofof LTBILTBI 2.2.OnlyOnly afterafter aa positivepositive PPDPPD 3.3.FollowingFollowing exposureexposure toto anan adultadult withwith activeactive TBTB beforebefore skinskin testtest reactivityreactivity 4.4.ByBy reactivationreactivation ofof primaryprimary pulmonarypulmonary TBTB inin youngyoung childrenchildren 5.5.OnlyOnly afterafter establishmentestablishment ofof GhonGhon’’ss complexcomplex BurdenBurden ofof TB/HIVTB/HIV inin womenwomen TB HIV 8.8 million new cases 2.6 million new cases 14 million prevalent 33 million prevalent 59% Asia 16% Asia 26% Africa 68% Africa

Women Women – 3.2 million (36% of total) – 15.5 million (52% of total) – Deaths 0.32 million – Deaths 0.85 million Highest burden in reproductive age 15-45 years of age TB HIV

WHO Global TB Report 2011, UNAIDS Global AIDS Report 2011, WHO 2009 Women and Health IncubationIncubation TuberculinTuberculin reactivityreactivity appearsappears 22 toto 1212 weeksweeks afterafter initialinitial infection.infection. MedianMedian isis 33 -- 44 weeks.weeks. ExposedExposed individualsindividuals byby definitiondefinition havehave nono findingsfindings ofof TB,TB, somesome maymay eventuallyeventually developdevelop disease.disease. TheThe riskrisk ofof developingdeveloping diseasedisease isis highesthighest duringduring 66 monthsmonths afterafter infectioninfection andand remainsremains highesthighest forfor 22 yearsyears.. InfantsInfants andand postpost--pubertalpubertal adolescentsadolescents atat highesthighest riskrisk ofof diseasedisease development.development.

CongenitalCongenital TuberculosisTuberculosis,, MiliaryMiliary lunglung lesionslesions andand hepatosplenomegalyhepatosplenomegaly.. ClinicalClinical ManifestationsManifestations

InIn childrenchildren && adolescents,adolescents, mostmost TBTB infectionsinfections areare asymptomaticasymptomatic whenwhen thethe TSTTST (tuberculin(tuberculin skinskin test)test) isis +.+. CXRCXR oftenoften doesdoes notnot demonstratedemonstrate 1ary1ary complexcomplex ofof infection.infection. MostMost immunocompetentimmunocompetent childrenchildren withwith 1ary1ary infectioninfection dodo notnot havehave rapidrapid progressionprogression ofof disease.disease. EarlyEarly findingsfindings (1(1 toto 66 mosmos afterafter infection):infection): – fever – weight loss – cough, night sweats, chills. ClinicalClinical EvolutionEvolution ofof PrimaryPrimary PulmonaryPulmonary TBTB DropletDroplet nucleinuclei causescauses parenchymalparenchymal lunglung disease.disease. ChildChild maymay havehave lowlow gradegrade fever,fever, mildmild cough.cough. RegionalRegional lymphlymph nodesnodes areare involved.involved. EnlargingEnlarging granulomasgranulomas causecause obstructionobstruction ofof bronchiolesbronchioles leadingleading toto hyperaerationhyperaeration.. CaseousCaseous materialmaterial spillsspills intointo airway,airway, atelectasisatelectasis ensues:ensues: fever,fever, weightweight loss,loss, nightnight sweats,sweats, FTTFTT ThereThere maymay bebe anan initialinitial responseresponse toto antibiotics.antibiotics. PrimaryPrimary PulmonaryPulmonary TB,TB, rightright upperupper lobe,lobe, w/w/ atelectasisatelectasis PrimaryPrimary PulmonaryPulmonary TB,TB, 22 yryr oldold ClinicalClinical ManifestationsManifestations

PulmonaryPulmonary radiographicradiographic findings:findings: –– LymphadenopathyLymphadenopathy ((hilarhilar,, mediastinalmediastinal,, cervical)cervical) –– InvolvementInvolvement ofof aa segmentsegment oror lobe.lobe. –– AtelectasisAtelectasis oror infiltrates.infiltrates. –– PleuralPleural effusionseffusions –– CavitaryCavitary lesionslesions –– MiliaryMiliary diseasedisease MeningitisMeningitis isis anan earlyearly manifestationmanifestation ofof disease.disease. GhonGhon ComplexComplex

Calcified focus of infection with an associated lymph node. Particularly common in children. Can retain viable bacteria and be source of reactivation. MycobacteriumMycobacterium tuberculosistuberculosis infectioninfection withwith paratrachealparatracheal lymphlymph nodes.nodes. PrimaryPrimary pulmonarypulmonary tuberculosistuberculosis withwith pleuralpleural effusioneffusion (right(right lung).lung). PulmonaryPulmonary tuberculosistuberculosis withwith rightright–– sidedsided pleuralpleural effusion.effusion. ProgressiveProgressive PrimaryPrimary PulmonaryPulmonary Tuberculosis,Tuberculosis, 1818 monthmonth oldold EndobronchialEndobronchial tuberculosis,tuberculosis, 11 yryr oldold ReactivationReactivation PulmonaryPulmonary TBTB ExtrapulmonaryExtrapulmonary TBTB (1/3(1/3 children)children) PleuritisPleuritis:: PleuralPleural effusioneffusion isis veryvery common;common; – Pleurisy is usually absent. – May be uni/ or bilateral – May be present up to 3 weeks after initiation of therapy. MeningitisMeningitis:: DueDue toto lymphohematogenouslymphohematogenous spread.spread. – Meningeal findings, fever, personality changes, irritability, listlessness, loss of developmental milestones. – Most severe at the base of the brain. – Very low glucose and monocytosis of CSF – Hydrocephalus and cranial nerve palsies are common. ExtrapulmonaryExtrapulmonary TBTB

MiliaryMiliary TBTB:: –– commoncommon inin youngyoung children;children; –– cancan developdevelop withinwithin 99 monthsmonths ofof infection,infection, oftenoften accompaniedaccompanied byby hepatosplenomegalyhepatosplenomegaly,, ARDS,ARDS, andand generalizedgeneralized lymphadenopathylymphadenopathy.. AdenitisAdenitis:: –– Firm,Firm, nontendernontender lymphadenopathylymphadenopathy.. –– SupraclavicularSupraclavicular,, cervical,cervical, uniuni// bilateral,bilateral, skinskin maymay bebe erythematouserythematous.. MiliaryMiliary TB,TB, 1010 monthmonth oldold MiliaryMiliary tuberculosistuberculosis withwith pulmonarypulmonary cavitationcavitation (right(right lung).lung). MiliaryMiliary TB,TB, 2929 yryr oldold mothermother 44 monthsmonths afterafter deliverydelivery MiliaryMiliary TB,TB, 2929 yryr oldold mothermother 44 monthsmonths afterafter deliverydelivery MiliaryMiliary TBTB MiliaryMiliary TBTB MycobacterialMycobacterial tuberculosistuberculosis lymphadenitislymphadenitis withwith ulceration:ulceration: Scrofula.Scrofula. AtypicalAtypical mycobacteriamycobacteria lymphadenitislymphadenitis withwith ulceration.ulceration. AtypicalAtypical mycobacterialmycobacterial lymphadenitis.lymphadenitis. ClinicalClinical ManifestationsManifestations

LateLate extrapulmonaryextrapulmonary manifestationsmanifestations (12 months after 1ary infection or later): –– DiseaseDisease ofof thethe middlemiddle earear oror mastoid:mastoid: chronicchronic drainingdraining earear –– Bones:Bones: collapsecollapse ofof vertebrae,vertebrae, gibbusgibbus formation.formation. –– Joints/Joints/ skin:skin: granulomatousgranulomatous lesionslesions –– RenalRenal TBTB ((hematuriahematuria,, sterilesterile pyuriapyuria)) oror adultadult-- typetype pulmonarypulmonary TB:TB: moremore commoncommon inin adolescents,adolescents, rarerare inin youngyoung children.children. Clinical findings in patients with multi-drug resistant TB are indistinguishable from those of drug-susceptible disease. TuberculosisTuberculosis ofof thethe spinespine withwith paravertebralparavertebral abscessabscess (Potts(Potts disease).disease). TuberculosisTuberculosis ofof thethe spinespine withwith paravertebralparavertebral abscessabscess ((PottPott’’ss Disease)Disease) DiagnosisDiagnosis

HxHx ofof exposureexposure toto anan adultadult withwith activeactive disease.disease. ++ TSTTST ++ CXRCXR ++ PhysicalPhysical examexam AbsenceAbsence ofof otherother etiologiesetiologies ResponseResponse toto TBTB medicationsmedications >> 50%50% ofof childrenchildren areare asymptomaticasymptomatic atat diagnosis.diagnosis. ChildrenChildren << 11 yearyear moremore likelylikely toto bebe symptomatic.symptomatic. DiagnosticDiagnostic TestsTests IsolationIsolation ofof MM tuberculosistuberculosis byby cultureculture:: gastricgastric aspirates,aspirates, sputum,sputum, pleuralpleural fluid,fluid, pleuralpleural biopsy,biopsy, CSF,CSF, urine,urine, otherother bodybody fluids,fluids, oror biopsy.biopsy. OrganismOrganism isis aa slowslow grower,grower, willwill bebe identifiedidentified inin 22 -- 66 weeksweeks byby radiometricradiometric method,method, 1010 wkswks withwith solidsolid media.media. Smears:Smears: ZiehlZiehl--NeelsenNeelsen// auramineauramine--rhodaminerhodamine staining.staining. M tb not distinguished reliably from other mycobacteria with stain only. Histology:Histology: granulomagranuloma formationformation withwith giantgiant cells.cells. PCR:PCR: approvedapproved forfor smearsmear positive/positive/ respiratoryrespiratory tracttract specimens,specimens, pleuralpleural fluid.fluid. Mycobacterium tuberculosis, or AFB

AFB (shown in red) are tubercle bacilli, Koch’s bacillus first identified in1882 Cultures

• Use to confirm diagnosis of TB

• Culture all specimens, even if smear negative

• Results in 4 to 14 days when liquid medium systems used

Colonies of M. tuberculosis growing on media HistopathologicHistopathologic featuresfeatures ofof placentaplacenta thrombusthrombus withwith inflammatoryinflammatory cellscells andand acidacid--fastfast bacillibacilli ofof MycobacteriumMycobacterium tuberculosistuberculosis ((ZiehlZiehl--NeelsenNeelsen stain).stain).

Franz Ziehl Friedrich Neelsen NovelNovel approachesapproaches toto TBTB diagnosisdiagnosis MycobacteriumMycobacterium tuberculosistuberculosis--specificspecific immunoimmuno-- dominantdominant antigensantigens identifiedidentified leadingleading toto thethe developmentdevelopment ofof interferoninterferon gammagamma--releaserelease assaysassays ((IGRAsIGRAs)) withwith highhigh sensitivitysensitivity andand specificityspecificity forfor TBTB disease:disease: eg: Gold QuantiFERON-TB tests. MeasureMeasure inin vitrovitro TT cellcell releaserelease ofof interferoninterferon-- gammagamma followingfollowing stimulationstimulation byby antigensantigens uniqueunique toto M.M. tuberculosistuberculosis – Test-tube PPD: more specific for mTB than PPD antigens in IGRAs are not shared by non-TB mycobacteria. – No need to return for reading/ not sensitive < 4 years. NewNew TBTB diagnosticsdiagnostics

NucleicNucleic acidacid amplificationamplification testingtesting (NAAT):(NAAT): –– RapidRapid diagnosisdiagnosis ofof MTBMTB complexcomplex organismsorganisms –– VeryVery effectiveeffective inin distinguishingdistinguishing TBTB organismsorganisms fromfrom nonnon--tuberculoustuberculous mycobacteriamycobacteria inin AFBAFB smearsmear positivepositive specimens.specimens. –– CanCan identifyidentify tuberculoustuberculous mycobacteriamycobacteria inin thethe presencepresence ofof negativenegative AFBAFB smearssmears inin 5050--80%80% ofof cases.cases. –– CannotCannot replacereplace culture,culture, necessarynecessary forfor susceptibilitysusceptibility determinationdetermination NewNew TBTB diagnosticsdiagnostics

GeneGene XpertXpert MTB/RIFMTB/RIF assay:assay: –– AutomatedAutomated nucleicnucleic assayassay amplificationamplification testtest thatthat cancan simultaneouslysimultaneously identifyidentify TBTB organismsorganisms andand evaluateevaluate forfor rifampinrifampin resistance.resistance. –– IdentifiesIdentifies 98%98% ofof individualsindividuals withwith AFB+AFB+ smearssmears andand 72%72% withwith AFBAFB-- smearssmears PromisingPromising newnew diagnosticsdiagnostics

UrinaryUrinary laterallateral flowflow LAMLAM TBTB teststests forfor TBTB detectiondetection –– AlereAlere DetermineDetermine™™ TBTB LAMLAM AgAg –– rapidrapid testtest detectsdetects thethe LAMLAM antigenantigen ((lipoarabinomannanlipoarabinomannan)) inin urineurine samplessamples TBTB detectiondetection inin stoolstool through:through: –– PCRPCR –– XpertXpert MTB/MTB/ RIFRIF testingtesting inin stoolstool –– CultureCulture EarlyEarly MorningMorning GastricGastric AspirateAspirate

Best diagnostic test in patients with non productive or absent cough. Should be obtained with a NG tube before child awakens and deambulates, with child NPO for at least 8 hours. Stomach contents should be aspirated first. 50 - 75 ml of sterile, distilled water should be added to stomach and included in first collection. Three aspirates should be submitted, and specimens should be sent for acid fast bacilli (AFB) smear and culture. Organisms isolated in < 50% of children & < 75% of infants with pulmonary TB. TBTB sourcesource casescases IfIf therethere isis anan infectedinfected childchild therethere isis aa contagiouscontagious adultadult oror adolescent.adolescent. IdentificationIdentification ofof aa sourcesource casecase shouldshould bebe pursuedpursued to:to: –– supportsupport presumptivepresumptive diagnosisdiagnosis –– definedefine drugdrug susceptibilitysusceptibility ifif organismorganism isis isolatedisolated fromfrom thethe sourcesource casecase –– identifyidentify allall exposedexposed whowho mightmight havehave LTBILTBI oror disease.disease. SuchSuch activitiesactivities shouldshould bebe coordinatedcoordinated withwith locallocal healthhealth departments.departments. ReportingReporting ofof suspected/confirmedsuspected/confirmed casescases isis mandatedmandated byby law.law. TuberculinTuberculin TestingTesting

TSTTST isis thethe traditionaltraditional TBTB diagnosticdiagnostic tooltool inin asymptomaticasymptomatic individuals.individuals. MantouxMantoux test:test: 55 tuberculintuberculin unitsunits ofof purifiedpurified proteinprotein derivativederivative (PPD)(PPD) administeredadministered intradermallyintradermally isis thethe recommendedrecommended TST.TST. OtherOther strengthsstrengths ofof MantouxMantoux shouldshould bebe avoided.avoided. MultipleMultiple puncturepuncture teststests areare notnot recommended,recommended, nono specificityspecificity oror sensitivity.sensitivity. TuberculinTuberculin TestingTesting

PPDPPD reactivityreactivity appearsappears 22 toto 1212 weeksweeks afterafter infectioninfection andand isis lifelife long.long. TSTTST shouldshould bebe usedused onlyonly inin childrenchildren whowho areare atat increasedincreased riskrisk ofof acquiringacquiring TBTB infection.infection. RoutineRoutine testingtesting ofof lowlow riskrisk populationspopulations shouldshould bebe avoided.avoided. ChildrenChildren withoutwithout riskrisk factorsfactors includingincluding infantsinfants underunder 11 yryr ofof ageage shouldshould notnot bebe tested.tested. MayMay bebe administeredadministered withwith immunizations.immunizations. ControlControl skinskin teststests areare notnot indicated.indicated. BCGBCG isis notnot aa contraindicationcontraindication forfor TST.TST. ShouldShould bebe readread inin 4848 toto 7272 hours.hours. TuberculinTuberculin TestingTesting

AA negativenegative PPDPPD doesdoes notnot excludeexclude disease.disease. Technique:Technique: 0.10.1 mlml ofof 55 TUTU ofof PPDPPD intradermallyintradermally intointo thethe volarvolar aspectaspect ofof thethe forearmforearm usingusing aa 2727--gaugegauge needle.needle. AdministrationAdministration andand interpretationinterpretation ofof resultsresults shouldshould bebe donedone byby experiencedexperienced personnel.personnel. TheThe diameterdiameter ofof indurationinduration (by(by ballpointballpoint penpen technique)technique) isis measuredmeasured transverselytransversely toto thethe longlong axisaxis ofof thethe forearm.forearm. TSTTST reactivityreactivity maymay bebe decreaseddecreased byby aa varietyvariety ofof hosthost factors.factors. PositivePositive ReactionReaction toto PurifiedPurified ProteinProtein DerivativeDerivative (PPD)(PPD) InterpretationInterpretation ofof TSTTST ResultsResults

TheThe cutoffcutoff indurationinduration forfor aa ++ resultresult variesvaries dependingdepending onon thethe personperson testedtested andand backgroundbackground epidemiology.epidemiology. InIn USUS areasareas wherewhere nonnon--tbtb mycobacteriamycobacteria areare common,common, onlyonly 5%5% childrenchildren w/w/ 55 -- 9mm9mm ofof indurationinduration areare infectedinfected withwith MM tbtb.. YetYet aa childchild withwith equalequal reactionreaction whowho hadhad contactcontact withwith aa contagiouscontagious adultadult hashas 50%50% chancechance ofof havinghaving tbtb infection.infection. InterpretationInterpretation ofof TSTTST ResultsResults

1515 mmmm oror >> indurationinduration:: ++ TSTTST result.result. 1010 mmmm oror >> indurationinduration:: ++ inin childrenchildren << 44 years,years, presencepresence ofof medicalmedical riskrisk factors,factors, bornborn oror traveltravel toto highhigh prevalenceprevalence regions,regions, exposureexposure toto highhigh riskrisk individuals.individuals. 55 mmmm oror >> indurationinduration:: ++ ifif contactcontact withwith knownknown oror suspectedsuspected casescases ofof TB,TB, ++ CXR,CXR, clinicalclinical evidenceevidence ofof TB,TB, immunosuppressionimmunosuppression.. FollowFollow--upup ofof aa ++ TSTTST

CXRCXR forfor allall childrenchildren withwith aa ++ TSTTST areare recommended,recommended, regardlessregardless ofof BCGBCG status.status. IfIf normalnormal CXR,CXR, LTBILTBI toto bebe assumedassumed andand antituberculousantituberculous therapytherapy initiated.initiated. InIn selectedselected cases:cases: veryvery recentrecent BCG,BCG, multiplemultiple BCGsBCGs,, and/and/ oror immigrationimmigration fromfrom lowlow prevalenceprevalence area,area, treatmenttreatment maymay notnot bebe indicated.indicated. IsolationIsolation

AirborneAirborne isolationisolation isis indicatedindicated forfor childrenchildren withwith aa coughcough andand smearsmear ++ sputumsputum.. ChildrenChildren withwith TBTB maymay gogo toto schoolschool ifif theythey areare onon therapytherapy andand sputumsputum isis negative.negative. OlderOlder childrenchildren areare notnot contagiouscontagious afterafter sputumsputum smearsmear turnsturns negativenegative (after(after 22 weeksweeks ofof therapy).therapy). MotherMother andand newbornnewborn shouldshould bebe separatedseparated ifif mothermother’’ss CXRCXR isis ++ untiluntil therapytherapy isis initiated.initiated. TBTB TreatmentTreatment

TBTB drugsdrugs areare bacteriostaticbacteriostatic oror bactericidal.bactericidal. FirstFirst lineline medications:medications: INH,INH, PZA,PZA, STP,STP, RIF,RIF, ETHETH –– INHINH:: Bactericidal,Bactericidal, rapidlyrapidly absorbed,absorbed, penetratespenetrates wellwell intointo bodybody fluids,fluids, liverliver metabolized,metabolized, kidneykidney excreted.excreted. –– HepatotoxicHepatotoxic effectseffects rare.rare. – Peripheral neuritis and seizures due to pyridoxine metabolism inhibition is rare in normal children, except for those on vegetarian or milk-sparing diets, nutritional deficiencies, with HIV or currently breastfed. Also recd for pregnant or lactating women. TBTB TreatmentTreatment

RIFRIF:: Bactericidal,Bactericidal, rapidrapid absorption,absorption, goodgood penetrationpenetration intointo bodilybodily fluids.fluids. HepaticHepatic metabolism.metabolism. AltersAlters metabolismmetabolism ofof severalseveral drugs.drugs. HepatotoxicityHepatotoxicity isis rare.rare. ExcretedExcreted inin bilebile andand urine,urine, orangeorange colorcolor toto secretions.secretions. BloodBlood dyscrasiadyscrasia withwith influenzainfluenza likelike symptomssymptoms maymay occuroccur ifif drugdrug isis takentaken sporadically.sporadically. RIFRIF resistanceresistance isis rarerare inin thethe US.US. MMWR 2003;52(RR11):1-77. TBTB TreatmentTreatment

PZA:PZA: Bactericidal,Bactericidal, adequateadequate CSFCSF concentrations,concentrations, detectabledetectable inin macrophages,macrophages, metabolizedmetabolized byby thethe liver.liver. RarelyRarely hepatotoxichepatotoxic.. InIn adults,adults, maymay causecause arthralgiasarthralgias duedue toto inhibitioninhibition ofof uricuric acidacid excretion.excretion. STP:STP: Bactericidal,Bactericidal, onlyonly availableavailable IM,IM, renalrenal excretion.excretion. TherapeuticTherapeutic CSFCSF concentrationsconcentrations onlyonly inin meningitis.meningitis. LeadsLeads toto vestibularvestibular andand cochlearcochlear damagedamage-- notnot usuallyusually givengiven >> 1212 wks.wks. TBTB resistanceresistance toto STPSTP isis common.common. TBTB TreatmentTreatment

ETH:ETH: WellWell absorbed,absorbed, goodgood tissuetissue diffusiondiffusion includingincluding CSF,CSF, excretedexcreted inin urine.urine. IsIs bacteriostaticbacteriostatic onlyonly atat usualusual dose.dose. PrimaryPrimary rolerole isis preventionprevention ofof emergenceemergence ofof drugdrug resistance.resistance. MayMay leadlead toto reversiblereversible opticoptic neuritis:neuritis: monitoringmonitoring ofof visualvisual acuity,acuity, visualvisual fields,fields, andand redred--greengreen colorcolor discriminationdiscrimination warranted.warranted. 2nd2nd lineline meds:meds: ciprofloxacin,ciprofloxacin, ethionamideethionamide,, kanamycinkanamycin,, ofloxacinofloxacin,, capreomycincapreomycin NewNew treatmenttreatment approachesapproaches

RifapentineRifapentine:: LongLong actingacting rifamycinrifamycin MoxifloxacinMoxifloxacin:: inin pediatricpediatric trialstrials forfor MDRMDR treatmenttreatment BedaquilineBedaquiline:: FirstFirst antianti--TBTB drugdrug approvedapproved inin 4040 yearsyears byby thethe FDAFDA (last(last dayday ofof 2012).2012). DiarylquinolineDiarylquinoline (DARQ)(DARQ) antibioticantibiotic forfor MDR.MDR. NitroimidazolesNitroimidazoles (same(same classclass asas metronidazolemetronidazole)) OxazilidinonesOxazilidinones (same(same classclass asas linezolidlinezolid)) BactericidalBactericidal activityactivity ofof escalatingescalating dosesdoses ofof RPTRPT

8 R HZ 7 10 P HZ 6 5 P7.5HZ 5 P HZ 4 10 P HZ 3 20 CFU per Lung

10 2

Log 1 0 0 2 4 6 8 10 12 Treatment duration (weeks)

Data provided by E. Nuermberger DrugDrug resistanceresistance

IfIf therethere isis aa riskrisk forfor INHINH resistance,resistance, STPSTP oror ETHETH shouldshould bebe added.added. ForFor allall casescases ofof drugdrug resistantresistant TB,TB, atat leastleast 22 medsmeds toto whichwhich organismorganism isis susceptiblesusceptible shouldshould bebe used.used. LongerLonger treatmenttreatment (12(12 toto 1818 months)months) shouldshould bebe used.used. TwiceTwice aa weekweek regimensregimens notnot toto bebe used.used. DOTDOT (directly(directly observedobserved therapy)therapy) needed.needed. TherapyTherapy forfor LTBILTBI

AllAll childrenchildren withwith aa ++ TSTTST andand nono evidenceevidence ofof TBTB disease,disease, whowho havehave nevernever beenbeen treatedtreated shouldshould receivereceive INHINH alonealone unlessunless resistanceresistance isis suspected.suspected. INHINH toto adultsadults withwith LTBILTBI providesprovides 5454 toto 88%88% protectionprotection againstagainst TBTB diseasedisease forfor atat leastleast 2020 years.years. EfficacyEfficacy inin childrenchildren nearlynearly 100%.100%. CXRCXR shouldshould bebe obtainedobtained once,once, atat baseline.baseline. CDC, April 2013

TherapyTherapy forfor LTBILTBI

ForFor infantsinfants andand children,children, recdrecd durationduration ofof therapytherapy isis 99 months.months. IfIf immunocompromisedimmunocompromised,, 1212 months.months. 1010 mg/mg/ kg,kg, singlesingle dose,dose, QD,QD, notnot >> 300300 mg.mg. IfIf adherenceadherence aa problem,problem, 11 monthmonth ofof dailydaily treatment,treatment, andand 22 xx weekweek DOTDOT thereafter,thereafter, atat 2020 toto 3030 mg/mg/ kg.kg. PreventivePreventive TherapyTherapy forfor ContactsContacts

INHINH recdrecd forfor recentrecent contactscontacts ofof personspersons withwith contagiouscontagious TBTB whenwhen clinicalclinical diseasedisease isis excluded,excluded, eveneven ifif TSTTST resultsresults areare negative.negative. AllAll youngyoung childrenchildren andand immunocompromisedimmunocompromised patientspatients shouldshould bebe separatedseparated fromfrom thethe primaryprimary casecase andand treatedtreated withwith INHINH forfor 33 mosmos,, eveneven ifif TSTTST isis --.. RepeatRepeat testingtesting afterafter 33 mos.mos. –– IFIF -- stopstop INH.INH. –– IFIF ++ treattreat forfor 99 months.months. Nearly 80,000 SA miners evaluated: 89% of miners PPD+ at baseline. • Among employees on INH therapy, incidence of TB reduced by 58% during the 9 month treatment period. • Effect lost immediately after therapy was discontinued • No overall improvement of tuberculosis control in SA miners- additional problems increasing susceptibility to TB were HIV and silicosis. HIV+ children: TB or death in 52 children INH group (19%) and 53 in the placebo group (19.3%); p = 0.93 HIV-uninfected children: TB infection, disease or death: INH group: 39 children (10%) vs. placebo: 45 children (11%), p = 0.44 Rate of TB: HIV+ children: 121 cases per 1000 child-years HIV-uninfected children: 41 cases per 1000 child-years TreatmentTreatment ofof PulmonaryPulmonary DiseaseDisease Goal:Goal: toto achieveachieve sterilizationsterilization ofof thethe TBTB lesionlesion inin thethe shortestshortest possiblepossible time.time. DOTDOT isis recommendedrecommended inin thethe US.US. 66 monthmonth regimen:regimen: INH,INH, RIF,RIF, PZAPZA firstfirst 22 months,months, INHINH ++ RIFRIF lastlast 44 months.months. INH,INH, RIF,RIF, PZAPZA QDQD firstfirst 22 weeksweeks toto 22 months.months. Following,Following, twicetwice weeklyweekly DOTDOT ofof INHINH andand RIFRIF acceptable.acceptable. IfIf resistanceresistance isis suspected,suspected, aa 4th4th drugdrug isis recd.recd. ExtrapulmonaryExtrapulmonary TBTB

ForFor bone,bone, miliarymiliary TBTB andand meningitis.meningitis. 99 monthmonth regimen:regimen: INH,INH, RIF,RIF, PZA,PZA, STPSTP firstfirst 11 toto 22 months,months, followedfollowed byby INHINH ++ RIFRIF QDQD oror twicetwice weeklyweekly withwith DOTDOT forfor 99 toto 1212 months.months. INH/INH/ RIFRIF maymay bebe givengiven parenterallyparenterally atat thethe samesame dosedose ifif needed.needed. PZAPZA bestbest forfor meningitis,meningitis, goodgood CSFCSF penetration.penetration. MonitoringMonitoring ofof therapytherapy

DOTDOT recommended.recommended. RepeatRepeat CXRCXR afterafter 22 -- 33 monthsmonths ofof therapy.therapy. ItIt maymay taketake 22 -- 33 yearsyears forfor hilarhilar lymphandenopathylymphandenopathy toto resolve.resolve. AA normalnormal CXRCXR isis notnot criteriacriteria forfor discontinuationdiscontinuation ofof therapy.therapy. IfIf therapytherapy isis interrupted,interrupted, extendextend duration.duration. LFTsLFTs toto bebe checkedchecked ifif concurrentconcurrent hepatichepatic disease,disease, >> dosesdoses ofof INHINH withwith PZAPZA andand RIF,RIF, pregnancypregnancy andand postpartumpostpartum period.period. RoleRole ofof CorticosteroidsCorticosteroids

Controversial.Controversial. IndicatedIndicated inin childrenchildren withwith TBTB meningitis,meningitis, andand tuberculomastuberculomas.. MayMay bebe consideredconsidered inin pleuralpleural andand pericardialpericardial effusions,effusions, miliarymiliary diseasedisease oror endobronchialendobronchial disease.disease. ToTo bebe usedused forfor 66 toto 88 weeksweeks (if(if prednisoneprednisone 11 toto 22 mg/mg/ kg)kg) withwith appropriateappropriate TBTB medications.medications. BCG Vaccination Recommendations for BCG Vaccination

• Not recommended in immunization programs or TB control programs in the U.S.

• BCG vaccination undertaken after consultation with health department Recommendations for BCG Vaccination (cont.)

Considered for an infant or child with negative skin- test result who • Is continually exposed to untreated or to an ineffectively treated contact • Will be continually exposed to multidrug-resistant TB Recommendations for BCG Vaccination (cont.) HCWs considered on individual basis in settings in which

• High percentage of MDR TB patients has been found

• Transmission of drug-resistant TB strains and subsequent infection are likely, and

• Comprehensive TB infection-control precautions implemented and not successful BCG Contraindications Contraindicated in persons with impaired immune response from • HIV infection • Congenital immunodeficiency •Leukemia • Lymphoma • Generalized malignancy • Receiving high-dose steroid therapy • Receiving alkylating agents • Receiving antimetabolites • Receiving radiation therapy BCG Vaccination and Tuberculin Skin Testing • Tuberculin skin testing not contraindicated for BCG- vaccinated persons. • LTBI diagnosis and treatment for LTBI considered for any BCG-vaccinated person whose skin test reaction is > 10 mm, if any of these circumstances are present: - Was contact of another person with infectious TB - Was born or has resided in a high TB prevalence country - Is continually exposed to populations where TB prevalence is high Estimated TB/ HIV co-infection rates 20092004 ComorbidityComorbidity:: TuberculosisTuberculosis andand ARVARV TherapyTherapy Status Initiating ARV Therapy

Pulmonary TB and CD4 < Initiate TB therapy 50; extrapulmonary TB Initiate ARVs when TB therapy is tolerated

Pulmonary TB+ CD4 50 - Initiate TB therapy 200 (in infants 1000-1200) Initiate ARVs inin 22-4 weeks.

Pulmonary TB+ CD4 >200 Treat TB. Initiate ARV as (infants < 1000) per general guidelines TBTB andand HIVHIV infectioninfection

HIVHIV testingtesting recommendedrecommended forfor allall patientspatients withwith TB.TB. TSTTST ofof 55 mmmm oror >> consideredconsidered +,+, -- PPDPPD maymay occur.occur. YearlyYearly CXRCXR recommendedrecommended forfor patientspatients withwith advancedadvanced HIVHIV disease.disease. SpecimensSpecimens forfor cultureculture shouldshould bebe sentsent inin HIV+HIV+ patientspatients withwith suspectedsuspected TB.TB. AtAt leastleast 33 medsmeds forfor aa minimumminimum ofof 1212 months.months. HIV infection

Moderate or severe immune suppression

Colonization caused by opportunistic organism

Initiation of HAART

Recovery of immunity against the organism

Paradoxical clinical deterioration due to dysregulated immune response

Improvement or progressive deterioration OtherOther newnew developmentsdevelopments

NewNew vaccinesvaccines (recombinant(recombinant BCG/BCG/ adenovirusadenovirus vectorvector vaccinesvaccines inin fieldfield studies)studies) NewNew indicationsindications forfor prophylaxisprophylaxis worldwide:worldwide: –– WhenWhen toto startstart treatmenttreatment inin HIVHIV--infectedinfected individualsindividuals –– RecognitionRecognition ofof IRISIRIS-- ImmuneImmune reconstitutionreconstitution syndromesyndrome inin HIVHIV--infectedinfected patientspatients withwith advancedadvanced diseasedisease initiatinginitiating antiretroviralsantiretrovirals.. Crowded waiting rooms and TB transmission- a worldwide problem TB infection in a guinea pig model was prevented by ionizers and UV light- 70% protection against TB infection identified.

Colistin mist and UV lights in waiting rooms…