EpidemiologyPathophysiologyClinical PresentationsDiagnostic ChallengesTreatment

Epidemiology TB in 21st Century1/3 of world population infected w/ TB9.4 M new cases & 1.8M deaths/ yr worldwide

(2008)15-20% global TB disease burden: children < 15

yrsIndicates continued transmission in setting w/ poor epidemic

control4% reported cases, but 95% cases in <12yr age are smear -

80% in 22 highest burden countriesIncreasing numbers developing world

HIV epidemic (> 34% co- infected)Poverty, overcrowding, malnutrition. TravelMDR-TB and XDR-TB /Incomplete treatmentsBreakdown of TB control programs

Pediatric TB Recent transmission from infected adult

Measure of TB control in community, rarely transmit TB

Higher risk & more rapid progression to active disease95% of children who develop TB, w/in 12 mos (1ary infection)Reflection of immature immune system

Innate (macrophages), DC (dendritic cells) & acquired T-cell (CD4) immunity

EPTB more common

Infants: high morbidity and mortalityDisseminated TB/meningitis: 10-20%Pulmonary TB: 30-40%

Pediatric TB stagesExposure

Contact w/ infectious pulmonary TBChild asymptomaticTST -, CXR normal

Infection (LTBI)Contact w/ infectious pulmonary TB (adult)Child asymptomaticTST +, CXR normal

DiseaseContact w/ infectious pulmonary TBTST+/-Child symptomatic or CXR positive for TB

Pediatric TB – Epi challengesDiagnosis TB childhood difficult

clinical presentation variable & nonspecific

confirmation by culture < 40% absence productive cough , paucibacillary disease

contact investigation of adults w/ infectious pulmonary TB

60-80% children infected when exposed to AFB + sputum

30-40% children infected when exposed to AFB - sputum most efficient method dx children w/ TB

Factors influencing Ped Epi in USAIncreasing rates of TB in foreign-born immigrants Worldwide HIV epidemic & MRTB

Transmission of TB among undx individuals w/ limited access to health care, poor housing/nutrition

80-87% childhood TB in USA among AA, Hispanics, Asians, Native Americans

1 out of 4 children w/ TB is foreign bornConcentrated in cities w/ pop > 250,000

TB in HIV + childrenImportant factor contributing to persistence

TBHIV adults horizontally transmit TB to

childrenHIV exposed /infected children

TB incidence 100 x higher (underestimation)

HIV + childrenWeaker cell mediated immunity (CD4+Tcells) Increased risk progressing from TB infection to TB diseaseSimilar presentation but more severe/extensive/EPTB/CNSHigher recurrence/reinfection ratesHigher TB mortality

Pathogenesis of Peds TB1st 2 months post infection

Primary Complex: Ghon focus + adenopathy (usually hilar)

Cell mediated response TST +, TB antibodies formedFebrile reaction w/ onset of delayed hypersensitivity

Hematogenous/lymphatic seeded areas

Massive dissemination 1-3% cases (miliary/meningeal TB)

10-15% live organisms persist (potential for reactivation)

Pathogenesis: TimetableSymptomatic lymphohematogenous ,

miliary/meningitis2-6 mos

Endobronchial TB w/ segmental pul changes4-9 mos

Significant bone/joint lesions1 yr

Renal lesions5-25 yrs

Infants and young childrenRapid progression: 1 st yr/5yr post infection respectively

Reactivation of Pul TBFunction of age of primary infectionCavitation, lung/bone/joint/renal lesionsHIV/measles/varicella co infection, malnutrition

Pregnancy & NNCongenital Infection Rare (risk higher if mother HIV+)

Transplacental, hematogenous spead via UV/placenta Bacille: fetal liver (primary focus w/ periportal lymph nodes) or

wide spread miliary disease. Bacille: liver to main circulation (1ary focus in lung) active after

birth. Aspiration/ingestion infected amniotic fluid in utero

multiple 1ary foci (lung, gut, middle ear)

Postnatal infection by inhalation from TB + mother

Breastfeeding not CI if mother on treatment

NN needs treatment

Clinical Forms Peds TB

Endothoracic

Lymphohematogenous

CNS

Other Extrapulmonary Sites

Adolescents

Neonates

Clinical manifestations Most infected children asymptomatic

Lymphadenopathyw/in 6 mos infection, ant cervical/submandibular

Primary Pulmonary TB (PTB)Most common presentationChildren > 10 yrs age more like adult diseaseIntra thoracic adenopathy & parenchymal changes

Progressive Pulmonary diseaseCommon in young children: TB broncho-pneumonia

Chronic Pulmonary Disease/ reactivationMost common in adolescents (1ary infection > 7 yrs age)Cavitation, typically upper lobe

EndothoracicAsymptomatic

80-95% infected children, 40-50% infected infants

Pulmonary1ary pulmonary complex

Progressive pulmonary disease

Chronic pulmonary disease

Pleural effusion

Pericarditis

Endothoracic Pulmonary1ary pulmonary complex

Adenopathy large w/ small parenchymal fociCXR

hilar adenopathy,localized hyperaeration, atelectasis localized pleural effusionsegmental infiltrate (foci)

Signs/symptoms infrequent (except in infants)1ary complex: fever + coughFever, cough, night sweats, FTTLocalized wheeze, diminished BSDysphagia, edema hand/arm

Hilar Adenopathy

Endothoracic: Progressive pulmonary disease

Rare but serious

CXR bronchopneumonia/lobar pneumonia w/ cavities

Signs/symptoms significantFever, night sweats, wt loss, coughDiminished BS, rales, dullness, egophony

High fatality w/out treatment

Endothoracic: Chronic pulmonary disease

“Adult reactivation” type/recent or reinfection

6-7% pediatric patients (TB acquired > 7yrs age)

Most common pul sites original parenchymal focus, regional lymph nodes, or

apical seedings

Usually remains localized to lungs

Identical to Adult pulmonary disease

Endothoracic: Pleural effusion

Subpleural 1ary pul focus /subpleural caseous lymph nodes

Small, localized or generalized4-30% of TB cases in young adults, rare

childrenSigns/symptoms abrupt

Fever, chest pain, SOB, dull percussion, decreased BS

Dx difficultAcid fast stain pleural fluid-/cult + 30% biopsies

Prognosis good in treated children

Endothoracic Pericarditis

Rare in children (0.4-4%)Direct invasion from subcarinal lymph nodesCan lead to constrictive pericarditisSigns/symptoms nonspecific

Fever, malaise, fatigue, wt loss, chest pain friction rub distant HS/pulsus paradoxus

Dx: acid fast stain -/cx + 30-70%Pericardectomy

Lymphohematogenous Clinical course acute/indolent/prolongedMultiple organ involvement

HSM & adenitis (superficial/deep), Pulmonary, Meningitis

Papulonecrotic tuberculidesMiliary

Massive # organisms released, > 2 organs affectedEarly complication 1ary infection (2-6 mos)Common infants/children: explosive or insidious onsetFever, wt loss, anorexia, malaise, HSM, gen.

lymphadenopathy, resp distressCXR: tubercules

Dx difficult: TST -, liver/bone biopsy needed (33%+)

Prognosis w/ treatment excellent , resolution slow

CNS ManifestationsRich focus, vessels infiltrated by exudate

Inflamation/infarctionBrain stem: CN III,VI,VII dysfunctionBasilar cisterns obstructed: hydrocephalus

TB meningitisChildren < 4 yrs age, most w/in 3-6 mos of 1ary infectionGradual onset, rapid in infants HydrocephalusTuberculomas (20-37%)Mortality (<10% w/ Rx) Morbidity high (MR, Sz, hemiparesis)TST – in 40%, CXR nl 50% CSF: cell # 10-100, glucose low, protein high

TuberculomaMost common in < 10yrs ageInfratentorial: headaches, Seizures, increased ICP

Tuberculomas

CN palsy 3, 6, 7

Fever of Unknown Origin

Common in developing countries

Few clinical findings

Primary infection: cellular immune response

Reactivation old/hidden focus

Other Extrapulmonary SitesMore common, not infectious

InfantsHIV + children

Scrofula

Skeletal Vertebrae most common: Pott’s DiseaseKnee, hip, elbow, smaller joints

Abdominal/peritoneal TBAdolescents

Eye, middle ear, sinuses, kidneys, skinRare in children

Osseous Clinical manifestationsTB osteitis

Synovitis/epiphysitis, destructive arthritis, fusion in deformed positions

Abscesses may track through tissues (psoas)

TB arthritis (Ponchet’s Disease)1-5% children if TB untreatedKnee/hip/elbow/dacylitisThick, inflammatory synovium, invades articular

surface, w/ erosion and fibrosis joint

Pott’s Disease

TB osteitis

GI & GU ManifestationsAbdominal/peritoneal TB

Thickened gut, peritoneal lymph nodesObstruction, fistula formation, ascitis, perforation,

malapsorptionPalpation doughy abdomen w/ masses of adherent

lymph nodesR/o malignancy (laparoscopic biopsy)Poor prognosis, long term intestinal problems

Renal TBUncommon in childrenSterile pyuriaTB epididymitis and orchitis

GI TB

Adolescents Acquired as initial infection during

adolescenceChronic pulmonary TB w/in 1-3 yrs

Acquired in early childhoodRare if acquired as infantMore likely if acquired 1ary infection from 7-10 yrs

age

Propensity to progress to contagious TBTarget group for TST & case finding

Neonates

Clinical symptoms 2-3wkFTT, respiratory distress, fever, HSM, meningitis

lymphadenopathy, sepsis, lethargyDx difficult

TST -, CXR nl or miliaryAFB in gastric aspirate, urine, BM, liver biopsy, earTB in mother

Infants of + mother TBINH & BCG to newborn, treat mother /contactsBreastfeed if mother on Rx

Diagnosis TB in ChildrenGeneral Principles

TriadTST+History of recent exposure to adult w/ probable

/definitive TBCXR abnormal

Symptom based scoring systemsImmunocompetent children

Definitive diagnosisAcid fast smear of sputum/gastric secretions microscopyIsolation of TB Automated liquid culture systems (gold standard now)

Challenge of Childhood TB diagnosis

Establishing accurate diagnosisChallenges collecting adequate sample for micro<15% of cases are sputum AFB smear +

(paucibacillary) Mycobacterial cx yields: 30-40%Case detection & contact tracing not routineMost individuals acquire infection

childhood/adolescenceCXR nl in significant proportion of children w/

confirmed pul TBMost new Dx not validated in childrenNo widely available gold standard dx of TB in children

TSTHallmark of 1ary TB infection

Appears 3wks-3mos after initial infection, lasts yrsInfants less enduration, more anergy

Sensitivity/Specificity 95%PPV – function of TB prevalence in community

AAP/CDC recommendations in USAScreen w/ questionnaireTST only for high risk children

BCG<50% infants TST + at 9-12 mos post vaccination80-90% TST- by 3-5yrs post vaccination

TST + interpretation> 5 mm

Persons w/ contact w/ infectious personsPersons w/ abnl CXRHIV infected/immunocompromised

< 10mmInfantsChildren in contact w/ adults at high riskForeign born persons from hi prevalence countries,

IVDU, residents prisons, institutions>15 mm

No risk factors

Specimen collection MethodsSputumInduced SputumGastric aspirateNasopharyngeal aspirationString TestBALUrine/stoolBlood/BMCSFFind needle aspiration adenitis

Diagnosis TB in ChildrenDirect smears, acid fast stains & Cultures

Sputum smearsSputum rarely produced <10yrs age, paucibacillary TBInsufficient alone to dx or r/o TBInduced sputum w/ 5% saline neb, serial collections in

infantsGastric washings (x3): acid fast stains/cultures

Sensitivity Cx: 30-50% children, 70% infantsBetter than BAL

Other body fluids/tissue specimens Sensitivity Cx: 30-50% children, 70% infants

Difficulty isolating TB in children should not greatly influence approach to therapy

Attempt to isolate no source case, source case MDR TB, child has suspected

extrathoracic TB

Diagnostics

Traditional direct smear microscopysputum

Solid culture Chest radiography

Tuberculin skin testing (TST)

Traditional Approaches to Diagnose TB in Children

TB cultureCXRSymptom-based TST

New diagnostic approachesOrganism – based

Colorimetric culture systems (TK-Medium)Phage-based tests (FASTPlaque-TB)Microscopic observation drug susceptibility (MODS) Assay PCR based test

Antigen- based essaysLAM detection assay

Immune-basedAntibody-based assaysMPB-64 skin testT-cell assays

T-Spot.TB (IGRA) QuantiFERON-TB Gold

Symptoms-based: Refined symptom based diagnosis

TB Research Movement initiated by the Stop TB Partnership & WHO

engaging TB researchers, programme managers, & affected communities in a

collaborative & concerted strategic effort to

↑ scope, scale, & speed of TB research across the continuum

linking basic research development of new methods, & operational research

New Diagnostics since 2007Liquid media for culture &

DST Def of a new sputum-smear-

positive TB case one acid fast bacilli in at

least one sputum sample in countries

↓ of number of smears for diagnosis of pul TB WHO recommends the

number ↓ from three to twoMolecular line-probe assays

for rapid screening pt at risk of MDR TB

Same day dx by microscopy

LED-based microscopy conventional fluorescence

microscopy replaced by LED microscopy using auramine staining

LED microscopy phased in as alternative for conventional Ziehl-Neelsen light microscopy

Non-commercial culture DST methods Microscopically observed

drug susceptibility Nitrate reductase assay,Colorimetric redox

indicator methods

New Diagnostics 2009 Xpert MTB/RIF

First automated molecular test for TB (NAAT assay)Excellent performance in Smear + & - ptsHi accuracy for determination rifampicin resistanceSimple to use systemDetects M tuberculosis directly from sputum in <2 hrs

IGRAs (interferon-γ release assays) T-cell assaysT-Spot.TB (IGRA)QuantiFERON-TB GoldBlood testResults in 24hr

Blood testResults in 24h

TBDST: drug-susceptibility test MODS: microscopic observation drug susceptibility NRA: nitrate reductase assay CRI: colorimetric redox indicator assay LPA: line-probe assay NAAT: nucleic acid amplification test LED: light-emitting diodePOC: point of careLTBI: latent tuberculosis infection

Dx Active TBSputum-smear microscopy for pulmonary TB

FM, conventional, LED FM • When serial sputum specimens are examined, the mean incremental yield and/or

A same-day-diagnosis approach (microscopy of two consecutive spot-spot sputum specimens)

NAATs for pulmonary & EPTBSerological antibody detection tests for pulmonary

& EPTB ADA for TB pleuritis, pericarditis, peritonitis

Measurement of ADA concentrations in pleural, pericardial, ascitic fluid

Interferon γ for TB pleuritisPhage amplification assays for pulmonary TB Automated liquid cultures for pulmonary TB

Automated liquid cultures are more sensitive than are solid cultures time to detection is more rapid than for solid cultures.

Dx Latent TBTST for latent TB infection

T-cell-based IGRAs for latent TB infectionIGRAs have excellent specificity (higher than the

TST), unaffected by previous BCG vaccination.IGRAs cannot distinguish between latent TB

infection & active TB, &have no role for active TB dx in adults.

IGRAs correlate well with markers of TB exposure in low-incidence countries

IGRA sensitivity varies across populations & tends to be lower in high-endemic countries & in HIV-infected individuals

Dx Drug Resistant TBPhage amplification assays for rapid detection of

rifampicin resistance

Line-probe assays: INNO-LiPA Rif & GenoType MTBDR assays for rapid detection of rifampicin resistance

CRI methods and NRA for rapid detection of rifampicin & isoniazid resistance

MODS for rapid detection of rifampicin & isoniazid resistance

TLA for rapid detection of rifampicin & isoniazid resistance

BiomarkersPredication of durable (non-relapsing) TB cure

Microbial markers in sputum 2-month culture conversion Serial colony counts or time to

culture positivitys

Other microbial markers Urine M tuberculosis DNA,

lipoarabinomannan1 Volatile organic compounds

Mycobactericidal activity Whole blood culture

TB-specific T-cell function Interferon γ,interleukin 4δ2

splice variant

Macrophage activation markers Neopterin, procalcitonin, C-

reactive protein soluble intercellular adhesion

molecule soluble urokinase plasminogen activator

receptor, monocyte CDllc

Multiple host markers Proteomics Transcriptomics

Indication of reactivation risk & prediction oferadication of latent infection

Tuberculosis-specific T-cell functionInterferon γ Interferon-induced protein Interleukin 4δ2 splice variant Skin test

Macrophage activation Neopterin Procalcitonin

Prediction of vaccine efficacy

Tuberculosis-specific T-cell function Interferon γ Polyfunctional T cells

Mycobactericidal activityWhole blood culture Mononuclear cells

Treatment General PrinciplesShort treatments: key - intensive initial therapyMost peds resistance is primary (paucibacillary

TB)Higher rates of disseminated /meningitis TB

Drugs that penetrate tissues/tissues/meninges wellPharmacokinetics different in children

Young children w/ more severe disease, malnutrition experience more hepatotoxic reactions

Formulations mainly for adultsCrushing pills/suspensionsInadequate absorption, diarrhea

Treatment Anti TB drugs for Children

First line drugsINH, RIF, PZA, Streptomycin, Ethambutol

Second line drugsEthionamideKanamycinCycloserine Para-amino salicylic acidFluoroquinolones (cipro, levofloxacin)

Treatment Specific RegimesExposure

INH alone in children < 5yrs age if exposed to potentially infectious adults w/ pul diseaseRegardless of TST result If HIV infected

Exclude active TB treat as if TB infection, 6-12 mos

After 3 mos treatment, TST repeatedIf TST -: INH discontinuedIf TST +: treat for total 9mos

Treatment Specific Regimes Infection w/out Disease

TST + w/ known contact to infectious adult caseHighest risk of developing disease: always Treat

TST + w/out known contact to infectious adult caseTreat if < 5yrs age & adolescents

WHOMin 6 mos with INH + regular follow up

AAP/CDC9 mos with INH

Daily under self supervision or Twice weekly DOTRifampicin

If INH resistant TB

Treatment Specific Regimes Pulmonary Disease

Most commonly usedINH + RIF + PZA x 2 mos (daily)INH + RIF for total 6 mos DOT twice weekly

When source case risk factors for MDR TBAdd 4th drug: ethambutol, streptomycinContinue 6 mos unless drug susceptibility available

PZA stopped after 2 mos

Treatment Specific Regimes Extrapulmonary

INH, RIF & PZA 6 mos

Bone/Joint TB9-12 mos

Meningitis/ disseminated TBINH, RIF, PZA & ethionamide or streptomycin

x 2 mosINH & RIF x 9-12 mos total

Treatment Specific Regimes MDR TB

Patterns of resistance reflect those found among adults in same population

Treatment regimes guided by drug susceptibility pattern of the isolate

At least 2 bactericidal drugs to which susceptible

Duration 9-12 mos if INH or RIF can be usedDuration 18-24 mos if resistance to INH+RIFUsually 4-7 drugs daily DOT

Treatment Specific Regimes HIV-related Tb

Principles same as those for non HIV + childrenHIV+ children w/ exposure to TB

Exclude active TBTreat as if infected w/ INH (or RIF if resistant)

HIV+ children w/ INH susceptible TB4 drugs (INH,RIF, PZA, ethambutol/strepto) x2 mosINH & RIG for total 9-12 mos (+pyridoxine)HAART-TB drug interactions

Rifampicin CI w/ PI IRIS

HIV + children w/MDR TB4-6 drugs for 24mosSecond line anti TB drugsHAART

DosesINH

Faster eliminationRequires higher body wt dose10mg/kg

RMP10-20mg/kg

PZA30mg/kg

EMB20mg/kg (15-30mg/kg) day30mg/kg given 3x/wk

Drug formulations

Individual & fixed drug combinations tabsWith good bioavailabiltiy

LiquidsEasy to administer to young childrenBulkyMore expensiveUnacceptable toxicity

INH syrup → diarrhea (sorbitol based solution)

Treatment Corticosteroids

When host inflammatory reaction creating tissue damage/impairment in function

Always used w/ anti TB drugsMeningitisMediastinal lymph nodesMiliary diseasePericardial effusionPrednisone 1-2mg/kg x 4-6wk, taper 1-2 wks

Monitoring responsesTrend to lower cure rate w/ twice weekly

regimens

Symptomatic improvement, weight gain

Regression of Radiographic findingsMonths/years

F/u sputum examinations when possible

HIV and TBOptimal timing of HAART yet to be definedRMP lowers level of protease inhibitors (except ritonavir)

By > 75%

RMP lowers level of nevirapineBy 35%

RMP lowers level of efavirenzBy 17%Doses for children <3yrs not established

Many physicians delay HAART until anti TB treatment completed or use higher dose Nevirapin

Many other unknown factors impacting on antiretroviral blood levelsAge, nutritional status, genetic polymophisms in cytochrome

p450 enzymes

New TB DrugsFluoroquinolonesTMC207OPC67683PA824Treatment of children laggs:

Difficulty confirming active TBConcerns about ped specific adverse effectsUncertainties about appropriate time to involve

children in drug devOptimal trial designs for drug devComplex regulatory requirements

PreventionMDG

Improved living conditionsImproved Dx, contact tracing, treatment

TB/LTBIWHO guidelines for National TB programs

International standards TB care: Symptom bases screeningGlobal Drug FacilityWHO Stop TB StrategyStop TB Partnership’s Global Plan to Stop TB

Treatment HIV/AIDSBCG

CI in HIV + infantsNew vaccine development

Meron 4 ½ months old

Evaluated in adoption clinic, from HaitiWell appearing, Normal PE (wt in 10%)

developmental screen.Screened for TB, Hepatitis, syphilis, HIV,

parasites, leadVision/hearing screening: high frequency hearing

loss Received BCG at birthTST 12 mm enduration, HIV –Hx repeated respiratory infections in orphanage,

treated w/ multiple antibiotics

Meron

CXR 2 viewsAlert radiologist you are looking for TB

Meron

Laboratory testingMicrobiological testing

Sputum, sputum induction (?) BAL (?) Gastric aspirates

CBC, U/A & U/Cx, electrolytes & renal fct, LFT

LFT increasedTreatment? How many drugs?

Meron

Gastric aspirate positive Mtb on second aspirate

Started on 4 drug regime by DOT

Resistant to INH, RIF. Sensitive to PZA, EMB, SMMAC also grew on purity plates

Meron

Use all first line drugs available (unless previously used & associated w/ failing regime)

Use injectable drug (SM, amikacin, capreomycin, kanamycin) by Broviac

Use fluroquinoloneUse additional second line drugs to have 4-6 drugs

in the regime

Meron

Treatment changed: aminoglycoside (by broviac x 4 mos), PZA, EMB, ethionamide and levofloxacin, Vit B6 by DOT

2 negative gastric aspirates on therapyGained many poundsCXR normalizedNormal growth and development

Resourceswww.nationaltbcenter.edu

Pediatric on line courseWHOCDC

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658-74 Newton, S. Paediatric tuberculosis. Lancet Infect Dis 2008;8:498-510 Pedrozo, C. Clinical scoring system for paediatric tubersulosis in HIV infected and

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