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Pediatric Tuberculosis

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  1. PediatricTuberculosis Ramona Sunderwirth, MD, MPH Global Health Fellowship Department of EM St Lukes/Roosevelt Hospital Center

  2. Objectives Epidemiology Pathophysiology Clinical Presentations Diagnostic Challenges Treatment

  3. Epidemiology TB in 21st 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

  4. 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%

  5. 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

  6. 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

  7. Factors influencing PedEpi 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

  8. 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

  9. 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)

  10. 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

  11. 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

  12. Clinical Forms Peds TB • Endothoracic • Lymphohematogenous • CNS • Other Extrapulmonary Sites • Adolescents • Neonates

  13. 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

  14. Endothoracic • Asymptomatic • 80-95% infected children, 40-50% infected infants • Pulmonary • 1ary pulmonary complex • Progressive pulmonary disease • Chronic pulmonary disease • Pleural effusion • Pericarditis

  15. EndothoracicPulmonary • 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

  16. Hilar Adenopathy

  17. 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

  18. 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

  19. 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

  20. EndothoracicPericarditis • 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

  21. Lymphohematogenous • Clinical course acute/indolent/prolonged • Multiple organ involvement • HSM & adenitis (superficial/deep), Pulmonary, Meningitis • Papulonecrotictuberculides • 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

  22. 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

  23. Tuberculomas

  24. CN palsy 3, 6, 7

  25. Fever of Unknown Origin • Common in developing countries • Few clinical findings • Primary infection: cellular immune response • Reactivation old/hidden focus

  26. 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

  27. 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

  28. Pott’s Disease

  29. TB osteitis

  30. 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

  31. GI TB

  32. 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

  33. 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

  34. Diagnosis TB in ChildrenGeneral 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)

  35. 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

  36. 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

  37. 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

  38. Specimen collection Methods • Sputum • Induced Sputum • Gastric aspirate • Nasopharyngeal aspiration • String Test • BAL • Urine/stool • Blood/BM • CSF • Find needle aspiration adenitis

  39. Diagnosis TB in ChildrenDirect 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

  40. Diagnostics • Traditional direct smear microscopy • sputum • Solid culture • Chest radiography • Tuberculin skin testing (TST)

  41. Traditional Approaches to Diagnose TB in Children • TB culture • CXR • Symptom-based • TST

  42. 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 • LAMdetection 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

  43. TB Research Movementinitiated 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

  44. 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

  45. 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 • Blood test • Results in 24h

  46. TBDST: drug-susceptibility test MODS: microscopic observation drug susceptibility NRA: nitrate reductase assay CRI: colorimetricredox indicator assay LPA: line-probe assay NAAT: nucleic acid amplification test LED: light-emittingdiode POC: point of care LTBI: latent tuberculosis infection