Transcript Pediatric Tuberculosis

Epidemiology
Pathophysiology
Clinical Presentations
Diagnostic Challenges
Treatment
Epidemiology TB in
st
21
Century
 1/3 of world population infected w/ TB
 9.4 M new cases & 1.8M deaths/ yr worldwide (2008)
 15-20% global TB disease burden: children < 15 yrs
 Indicates continued transmission in setting w/ poor epidemic control
 4% reported cases, but 95% cases in <12yr age are smear -
 80% in 22 highest burden countries
 Increasing numbers developing world
 HIV epidemic (> 34% co- infected)
 Poverty, overcrowding, malnutrition. Travel
 MDR-TB and XDR-TB /Incomplete treatments
 Breakdown 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 disease
 95% 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 mortality
 Disseminated TB/meningitis: 10-20%
 Pulmonary TB: 30-40%
Pediatric TB stages
 Exposure
 Contact w/ infectious pulmonary TB
 Child asymptomatic
 TST -, CXR normal
 Infection (LTBI)
 Contact w/ infectious pulmonary TB (adult)
 Child asymptomatic
 TST +, CXR normal
 Disease
 Contact w/ infectious pulmonary TB
 TST+/ Child symptomatic or CXR positive for TB
Pediatric TB – Epi challenges
Diagnosis 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 USA
 Increasing 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 born
 Concentrated in cities w/ pop > 250,000
TB in HIV + children
 Important factor contributing to persistence TB
 HIV adults horizontally transmit TB to children
 HIV exposed /infected children
 TB incidence 100 x higher (underestimation)
 HIV + children
 Weaker cell mediated immunity (CD4+Tcells)
 Increased risk progressing from TB infection to TB disease
 Similar presentation but more severe/extensive/EPTB/CNS
 Higher recurrence/reinfection rates
 Higher TB mortality
Pathogenesis of Peds TB
 1st 2 months post infection
 Primary Complex: Ghon focus + adenopathy (usually hilar)
 Cell mediated response TST +, TB antibodies formed

Febrile 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: Timetable
 Symptomatic lymphohematogenous , miliary/meningitis
 2-6 mos
 Endobronchial TB w/ segmental pul changes
 4-9 mos
 Significant bone/joint lesions
 1 yr
 Renal lesions
 5-25 yrs
 Infants and young children
 Rapid progression: 1 st yr/5yr post infection respectively
 Reactivation of Pul TB
 Function of age of primary infection
 Cavitation, lung/bone/joint/renal lesions
 HIV/measles/varicella co infection, malnutrition
Pregnancy & NN
 Congenital 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
 Lymphadenopathy
 w/in 6 mos infection, ant cervical/submandibular
 Primary Pulmonary TB (PTB)
 Most common presentation
 Children > 10 yrs age more like adult disease
 Intra thoracic adenopathy & parenchymal changes
 Progressive Pulmonary disease
 Common in young children: TB broncho-pneumonia
 Chronic Pulmonary Disease/ reactivation
 Most common in adolescents (1ary infection > 7 yrs age)
 Cavitation, typically upper lobe
Endothoracic
 Asymptomatic
 80-95% infected children, 40-50% infected infants
 Pulmonary
 1ary pulmonary complex
 Progressive pulmonary disease
 Chronic pulmonary disease
 Pleural effusion
 Pericarditis
Endothoracic
Pulmonary
 1ary pulmonary complex
 Adenopathy large w/ small parenchymal foci
 CXR
 hilar adenopathy,
 localized hyperaeration, atelectasis
 localized pleural effusion
 segmental infiltrate (foci)
 Signs/symptoms infrequent (except in infants)
 1ary complex: fever + cough
 Fever, cough, night sweats, FTT
 Localized wheeze, diminished BS
 Dysphagia, edema hand/arm
Hilar Adenopathy
Endothoracic:
Progressive pulmonary disease
 Rare but serious
 CXR bronchopneumonia/lobar pneumonia w/ cavities
 Signs/symptoms significant
 Fever, night sweats, wt loss, cough
 Diminished 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 generalized
 4-30% of TB cases in young adults, rare children
 Signs/symptoms abrupt
 Fever, chest pain, SOB, dull percussion, decreased BS
 Dx difficult
 Acid 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 nodes
 Can lead to constrictive pericarditis
 Signs/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/prolonged
 Multiple organ involvement
 HSM & adenitis (superficial/deep), Pulmonary, Meningitis
 Papulonecrotic tuberculides
 Miliary
 Massive # organisms released, > 2 organs affected
 Early complication 1ary infection (2-6 mos)
 Common infants/children: explosive or insidious onset
 Fever, wt loss, anorexia, malaise, HSM, gen. lymphadenopathy,
resp distress
 CXR: tubercules
 Dx difficult: TST -, liver/bone biopsy needed (33%+)
 Prognosis w/ treatment excellent , resolution slow
CNS Manifestations
 Rich focus, vessels infiltrated by exudate
 Inflamation/infarction
 Brain stem: CN III,VI,VII dysfunction
 Basilar cisterns obstructed: hydrocephalus
 TB meningitis
 Children < 4 yrs age, most w/in 3-6 mos of 1ary infection
 Gradual onset, rapid in infants Hydrocephalus
 Tuberculomas (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
 Tuberculoma
 Most common in < 10yrs age
 Infratentorial: 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 Sites
 More common, not infectious
 Infants
 HIV + children
 Scrofula
 Skeletal
 Vertebrae most common: Pott’s Disease
 Knee, hip, elbow, smaller joints
 Abdominal/peritoneal TB
 Adolescents
 Eye, middle ear, sinuses, kidneys, skin
 Rare in children
Osseous Clinical manifestations
 TB 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 untreated
 Knee/hip/elbow/dacylitis
 Thick, inflammatory synovium, invades articular surface, w/
erosion and fibrosis joint
Pott’s Disease
TB osteitis
GI & GU Manifestations
 Abdominal/peritoneal TB
 Thickened gut, peritoneal lymph nodes
 Obstruction, fistula formation, ascitis, perforation,
malapsorption
 Palpation doughy abdomen w/ masses of adherent lymph
nodes
 R/o malignancy (laparoscopic biopsy)
 Poor prognosis, long term intestinal problems
 Renal TB
 Uncommon in children
 Sterile pyuria
 TB epididymitis and orchitis
GI TB
Adolescents
 Acquired as initial infection during adolescence
 Chronic pulmonary TB w/in 1-3 yrs
 Acquired in early childhood
 Rare if acquired as infant
 More likely if acquired 1ary infection from 7-10 yrs age
 Propensity to progress to contagious TB
 Target group for TST & case finding
Neonates
 Clinical symptoms 2-3wk
 FTT, respiratory distress, fever, HSM, meningitis
lymphadenopathy, sepsis, lethargy
 Dx difficult
 TST -, CXR nl or miliary
 AFB in gastric aspirate, urine, BM, liver biopsy, ear
 TB in mother
 Infants of + mother TB
 INH & BCG to newborn, treat mother /contacts
 Breastfeed if mother on Rx
Diagnosis TB in Children
General Principles
 Triad
 TST+
 History of recent exposure to adult w/ probable /definitive TB
 CXR abnormal
 Symptom based scoring systems
 Immunocompetent children
 Definitive diagnosis
 Acid fast smear of sputum/gastric secretions microscopy
 Isolation of TB
 Automated liquid culture systems (gold standard now)
Challenge of Childhood TB
diagnosis
 Establishing accurate diagnosis
 Challenges collecting adequate sample for micro
 <15% of cases are sputum AFB smear + (paucibacillary)
 Mycobacterial cx yields: 30-40%
 Case detection & contact tracing not routine
 Most individuals acquire infection childhood/adolescence
 CXR nl in significant proportion of children w/ confirmed
pul TB
 Most new Dx not validated in children
 No widely available gold standard dx of TB in children
TST
 Hallmark of 1ary TB infection
 Appears 3wks-3mos after initial infection, lasts yrs
 Infants less enduration, more anergy
 Sensitivity/Specificity 95%
 PPV – function of TB prevalence in community
 AAP/CDC recommendations in USA
 Screen w/ questionnaire
 TST only for high risk children
 BCG
 <50% infants TST + at 9-12 mos post vaccination
 80-90% TST- by 3-5yrs post vaccination
TST + interpretation
 > 5 mm
 Persons w/ contact w/ infectious persons
 Persons w/ abnl CXR
 HIV infected/immunocompromised
 < 10mm
 Infants
 Children in contact w/ adults at high risk
 Foreign born persons from hi prevalence countries, IVDU,
residents prisons, institutions
 >15 mm
 No risk factors
Specimen collection Methods
 Sputum
 Induced Sputum
 Gastric aspirate
 Nasopharyngeal aspiration
 String Test
 BAL
 Urine/stool
 Blood/BM
 CSF
 Find needle aspiration adenitis
Diagnosis TB in Children
Direct smears, acid fast stains & Cultures
 Sputum smears
 Sputum rarely produced <10yrs age, paucibacillary TB
 Insufficient alone to dx or r/o TB
 Induced sputum w/ 5% saline neb, serial collections in infants
 Gastric washings (x3): acid fast stains/cultures
 Sensitivity Cx: 30-50% children, 70% infants
 Better 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 microscopy
 sputum
 Solid culture
 Chest radiography
 Tuberculin skin testing (TST)
Traditional Approaches to
Diagnose TB in Children
 TB culture
 CXR
 Symptom-based
 TST
New diagnostic approaches
 Organism – based
 Colorimetric culture systems (TK-Medium)
 Phage-based tests (FASTPlaque-TB)
 Microscopic observation drug susceptibility (MODS)
 Assay PCR based test
 Antigen- based essays
 LAM detection assay
 Immune-based
 Antibody-based assays
 MPB-64 skin test
 T-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 2007
 Liquid 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 two
 Molecular 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 + & - pts
 Hi accuracy for determination rifampicin resistance
 Simple to use system
 Detects M tuberculosis directly from sputum in <2 hrs
 IGRAs (interferon-γ release assays)





T-cell assays
T-Spot.TB (IGRA)
QuantiFERON-TB Gold
Blood test
Results in 24hr
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 diode
POC: point of care
LTBI: latent tuberculosis infection
Dx Active TB
 Sputum-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 & EPTB
 Serological 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 pleuritis
 Phage 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 TB
 TST for latent TB infection
 T-cell-based IGRAs for latent TB infection
 IGRAs 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 lowincidence countries
 IGRA sensitivity varies across populations & tends to be lower
in high-endemic countries & in HIV-infected individuals
Dx Drug Resistant TB
 Phage 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
Biomarkers
Predication 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 of
eradication of latent infection
 Tuberculosis-specific T-cell function
 Interferon 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 activity
 Whole blood culture
 Mononuclear cells
Treatment General Principles
 Short treatments: key - intensive initial therapy
 Most peds resistance is primary (paucibacillary TB)
 Higher rates of disseminated /meningitis TB
 Drugs that penetrate tissues/tissues/meninges well
 Pharmacokinetics different in children
 Young children w/ more severe disease, malnutrition
experience more hepatotoxic reactions
 Formulations mainly for adults
 Crushing pills/suspensions
 Inadequate absorption, diarrhea
Treatment Anti TB drugs for
Children
 First line drugs
 INH, RIF, PZA, Streptomycin, Ethambutol
 Second line drugs
 Ethionamide
 Kanamycin
 Cycloserine
 Para-amino salicylic acid
 Fluoroquinolones (cipro, levofloxacin)
Treatment Specific Regimes
Exposure
 INH alone in children < 5yrs age if exposed to
potentially infectious adults w/ pul disease
 Regardless of TST result
 If HIV infected


Exclude active TB
treat as if TB infection, 6-12 mos
 After 3 mos treatment, TST repeated
 If TST -: INH discontinued
 If TST +: treat for total 9mos
Treatment Specific Regimes
Infection w/out Disease
 TST + w/ known contact to infectious adult case
 Highest risk of developing disease: always Treat
 TST + w/out known contact to infectious adult case
 Treat if < 5yrs age & adolescents
 WHO
 Min 6 mos with INH + regular follow up
 AAP/CDC
 9 mos with INH
 Daily under self supervision or Twice weekly DOT
 Rifampicin
 If INH resistant TB
Treatment Specific Regimes
Pulmonary Disease
 Most commonly used
 INH + RIF + PZA x 2 mos (daily)
 INH + RIF for total 6 mos DOT twice weekly
 When source case risk factors for MDR TB
 Add 4th drug: ethambutol, streptomycin
 Continue 6 mos unless drug susceptibility available
 PZA stopped after 2 mos
Treatment Specific Regimes
Extrapulmonary
 INH, RIF & PZA
 6 mos
 Bone/Joint TB
 9-12 mos
 Meningitis/ disseminated TB
 INH, RIF, PZA & ethionamide or streptomycin x 2 mos
 INH & 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 used
 Duration 18-24 mos if resistance to INH+RIF
 Usually 4-7 drugs daily DOT
Treatment Specific Regimes
HIV-related Tb
 Principles same as those for non HIV + children
 HIV+ children w/ exposure to TB
 Exclude active TB
 Treat as if infected w/ INH (or RIF if resistant)
 HIV+ children w/ INH susceptible TB
 4 drugs (INH,RIF, PZA, ethambutol/strepto) x2 mos
 INH & RIG for total 9-12 mos (+pyridoxine)
 HAART-TB drug interactions


Rifampicin CI w/ PI
IRIS
 HIV + children w/MDR TB
 4-6 drugs for 24mos
 Second line anti TB drugs
 HAART
Doses
 INH
 Faster elimination
 Requires higher body wt dose
 10mg/kg
 RMP
 10-20mg/kg
 PZA
 30mg/kg
 EMB
 20mg/kg (15-30mg/kg) day
 30mg/kg given 3x/wk
Drug formulations
 Individual & fixed drug combinations tabs
 With good bioavailabiltiy
 Liquids
 Easy to administer to young children
 Bulky
 More expensive
 Unacceptable toxicity

INH syrup → diarrhea (sorbitol based solution)
Treatment
Corticosteroids
 When host inflammatory reaction creating tissue
damage/impairment in function
 Always used w/ anti TB drugs
 Meningitis
 Mediastinal lymph nodes
 Miliary disease
 Pericardial effusion
 Prednisone 1-2mg/kg x 4-6wk, taper 1-2 wks
Monitoring responses
 Trend to lower cure rate w/ twice weekly regimens
 Symptomatic improvement, weight gain
 Regression of Radiographic findings
 Months/years
 F/u sputum examinations when possible
HIV and TB
 Optimal timing of HAART yet to be defined
 RMP lowers level of protease inhibitors (except ritonavir)
 By > 75%
 RMP lowers level of nevirapine
 By 35%
 RMP lowers level of efavirenz
 By 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
levels
 Age, nutritional status, genetic polymophisms in cytochrome p450 enzymes
New TB Drugs
 Fluoroquinolones
 TMC207
 OPC67683
 PA824
 Treatment of children laggs:
 Difficulty confirming active TB
 Concerns about ped specific adverse effects
 Uncertainties about appropriate time to involve children in
drug dev
 Optimal trial designs for drug dev
 Complex regulatory requirements
Prevention
 MDG
 Improved living conditions
 Improved Dx, contact tracing, treatment TB/LTBI
 WHO guidelines for National TB programs

International standards TB care: Symptom bases screening
 Global Drug Facility
 WHO Stop TB Strategy
 Stop TB Partnership’s Global Plan to Stop TB
 Treatment HIV/AIDS
 BCG
 CI in HIV + infants
 New vaccine development
Peds TB Cases
Meron 4 ½ months old
 Evaluated in adoption clinic, from Haiti
 Well appearing, Normal PE (wt in 10%) developmental
screen.
 Screened for TB, Hepatitis, syphilis, HIV, parasites, lead
 Vision/hearing screening: high frequency hearing loss
 Received BCG at birth
 TST 12 mm enduration, HIV –
 Hx repeated respiratory infections in orphanage, treated w/
multiple antibiotics
Meron
 CXR 2 views
 Alert radiologist you are looking for TB
Meron
 Laboratory testing
 Microbiological testing



Sputum, sputum induction (?)
BAL (?)
Gastric aspirates
 CBC, U/A & U/Cx, electrolytes & renal fct, LFT
 LFT increased
 Treatment? 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, SM
 MAC 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 fluroquinolone
 Use 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 therapy
 Gained many pounds
 CXR normalized
 Normal growth and development
Resources
 www.nationaltbcenter.edu
 Pediatric on line course
 WHO
 CDC
References
 Swaminathan, S. Tuberculosis in HIV infected children. Paed Resp reviews (2004) 5, 22530
 Marais , B. New Approaches & emerging technologies in the diagnosis of childhood
tuberculosis. Paed Resp Reviews (2007) 8, 124-133
 Lewinsohn, D. Tuberculosis immunology in children. Int J Tuberc Lung Dis 8 (5): 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 non
infected children in Rio de Janeiro. Int J Tuberc Lung Dis 13(3):413-15
 Lonnroth,K. Tuberculosis Control & Elimination 2010=2050. Lancet (2010) 375: 1814-29
 Nakaoka, H. Risk for tuberculosis among children. Emerg Infect Dis. (2006) 12, 9:1383-88
 Marais, BJ. The burden of childhood tuberculosis: a public health perspective. Int J
Tuberc Lung Dis 9(12):1305-13\
 Marais, BJ. Well defined symptoms are of value in the diagnosis of childhood pulmonary
tuberculosis. Arch Dis Child (2005)90:1162-65
 Marais, BJ. Diagnostic and management challenges for childhood tuberculosisi in the era
of HIV. J of Infect Dis(2007);196:s76-85
 Starke, J. new concepts in childhood tuberculosis. Curr Opin Pediatr (2007)19:306-13
 WHO. Guidance for national tuberculo0sis programmes on the management of
tuberculosis in children. Int J Tuberc Lung Dis10(2006)10(10)1091-97
 Harries, AD. Tuberculosis. Annals of Trop Medi & Parais (2006)100(5&6):415-31
 Reichman and Hershfield’s Tuberculosis. 3rd Part A Ed Raviglione, M (2006) Informa
Health Care USA
 Swaminathan, S Pediatric Tb: Global Overview & Challenges. CID 2010;50(S3):S184-194