Pediatric TB Intensive Houston, Texas November 13, 2009 Extrapulmonary TB James B. McAuley MD MPH November 13, 2009 PEDIATRIC TB EXTRAPULMONARY DISEASE James B. McAuley MD MPH Rush University Medical Center Chicago, Illinois 1
Percent of Pediatric TB Cases by Age Group 1993 2006 N=15,946 3 Age 10-14 18.2% Age < 1 9.2% Age 5-9 Age 14 1-4 23.1% 49.5% Pediatric TB Cases by Site of Disease, 1993 2006 4 Pulmonary 71.1% Both 7.0% Extra pulmonary 21.9% Any extrapulmonary involvement* (totaling 28.9%) Lymphatic 18.9% Meningeal 3.1% Miliary 1.5% Bone & Joint 1.5% Other 3.9% *Any extrapulmonary involvement which includes cases that are extrapulmonary only and both Patients may have more than one disease site but are counted in mutually exclusive categories for surveillance purposes. 2
Percent of Pediatric TB Cases by Site of Disease*, 1993 2006 N=15,946 5 Age < 1 n=1,471 Age 1-4 n=7,884 14.7% 10.1% 75.2% 20.7% 7.2% 72.1% Age 5-9 n=3,691 4.4% Age 10-14 n=2,900 5.9% 25.5% 27.0% 70.1% 67.1% Pulmonary Extrapulmonary Both Percent of Pediatric TB Cases with Any Extrapulmonary Involvement* by Age Group and Selected Sites of Disease, 1993 2006 N=15,946 Age < 1 Age 1-4 Age 5-9 Age 10-14 Site of Disease (n=1,471) (n=7,884) (n=3,691) (n=2,900) Lymphatic 8.0 19.3 22.3 19.2 Meningeal 7.5 3.5 1.4 1.8 Miliary 5.6 1.2 0.6 1.2 Bone & Joint 0.3 1.3 1.7 2.4 Other 3.4 2.6 3.9 8.3 Total 24.8 27.9 29.9 32.9 *Any extrapulmonary involvement includes extrapulmonary only and both 6 Note: Combine the total extrapulmonary percent shown with the pulmonary percent in slide #21 to obtain 100% for each age group. 3
Percent of TB Cases in Children Age < 1 Year With Any Extrapulmonary Involvement, 1993 2006 N=1,471 Site of disease U.S. S-born Foreign-born Lymphatic 7.2% 17.7% Meningeal 7.8% 3.5% Miliary 5.8% 3.5% Bone & Joint 03% 0.3% 09% 0.9% Other 3.4% 1.8% Total 24.5%* 27.4%* *Any extrapulmonary involvement includes extrapulmonary only and both 7 Percent of TB Cases in Children Age 1 4 Years With Any Extrapulmonary Involvement, 1993 2006 N=7,884 Site of disease U.S. S-born Foreign-born Lymphatic 19.4% 19.0% Meningeal 3.8% 2.0% Miliary 1.3% 1.0% Bone & Joint 11% 1.1% 20% 2.0% Other 2.7% 2.0% Total 28.3%* 26.0%* *Any Extrapulmonary involvement includes extrapulmonary only and both 8 4
Percent of TB Cases in Children Age 5 9 Years With Any Extrapulmonary Involvement, 1993 2006 N=3,691 Site of disease U.S. S-born Foreign-born Lymphatic 23.1% 20.8% Meningeal 1.4% 1.0% Miliary 0.6% 0.6% Bone & Joint 16% 1.6% 21% 2.1% Other 4.1% 3.8% Total 30.8%* 28.3%* *Any Extrapulmonary involvement includes extrapulmonary only and both 9 Percent of TB Cases in Children Age 10 14 Years With Any Extrapulmonary Involvement, 1993 2006 N=2,900 Site of disease U.S. S-born Foreign-born Lymphatic 20.4% 18.1% Meningeal 1.6% 1.8% Miliary 1.5% 0.8% Bone & Joint 20% 2.0% 28% 2.8% Other 9.0% 7.3% Total 34.5%* 30.8%* *Any Extrapulmonary involvement includes extrapulmonary only and both 10 5
Pediatric TB Cases by HIV Status, 1993 2005* N=14,990 Information on HIV result is not available for the majority of pediatric TB cases (80.7%) Percent of pediatric TB cases with HIV positive test results, minimum estimate** (1.0%) Percent of pediatric cases with HIV positive test results of those patients with known results (5.1%) *California HIV data through 2004 only **Pediatric TB cases with positive HIV test results divided by all pediatric TB cases. California only reports positive HIV test results based on TB and AIDS registry matching; all other California TB cases are classified as Unknown. 11 Pediatric TB Chicago (n=498) 1974 1994 49% female 23% < 1yr 72% black 18% hispanic 5% white 6% foreign born 74% pulmonary 9% hilar nodes 9% lymph node (other) 3% miliary 6% meningitis 79% cultures sent 61% positive (261) Reinhard, Paul, McAuley, June 1997 Am J Med Sci 6
AFB Smears in Children Age (yrs) N AFB Done AFB + <2 394 58% 23% 2-4 519 44% 16% 5-9 392 48% 12% 10-1414 253 77% 20% TOTAL 1558 54% 18% 1995 US Surveillance data, CDC AFB Culture in Children Age (yrs) N MTB Done MTB + <2 394 62% 60% 2-4 519 46% 37% 5-9 392 48% 25% 10-1414 253 75% 40% TOTAL 1558 55% 41% 1995 US Surveillance data, CDC 7
Pediatric TB Chicago (n=498) 1974 1994 77 community areas in Chicago 11.3 cases per 100,000 for African American SES variables only significant factors: percent below poverty percent unemployed percent female headed households Reinhard, Paul, McAuley, June 1997 Am J Med Sci Pathophysiology of Extrapulmonary TB Primary Infection TB reaches alveoli, replicates extra and intracellularly, lack of immediate host immune repsonse Replication intracellularly within macrophages, MTb prevents acidification of phagosome and multiplies for weeks within macrophages 8
Pathophysiology of Extrapulmonary TB Metastatic foci established in regional nodes, seed blood and travel to tissues favoring multiplication Alveolar macrophages secrete interleukins 12 and 18, which attracts CD4 cells, CD4 cells meet TB antigens on surface of infected macrophages and are transformed, proliferate and secrete gamma interferon TNF alpha stimulates granuloma formation and increases ability of Macrophages to kill MTb 9
TIMETABLE OF PEDIATRIC TB: from infection to disease Miliary and meningeal develop rapidly Adenopathy segmental Lymph node (cervical) Pleural effusion Skeletal Renal 1 12 months 2 12 months 2 12 months 3 9 months 6 months 2 years 1 5 years TST Positive window period Time From Exposure 10
Extrapulmonary Tuberculosis Proportion in all TB in USA : 7% (1963) to 18% (1987) to 20% (now) Increase maybe due to HIV infection More in minorities and foreign borns Lymphatic TB (30%) > Pleural TB (24%) > Bone and joint TB (10%) > Genitourinary TB (9%) > Miliary TB (8%) > Meningeal TB (6%) (New York, 1995) Case History 2 9/12 year old with fever and cough in August, treated as outpatient two months ago for pneumonia PMH of prematurity, tracheomalacia and tracheostomy Admitted, left lower lobe infiltrate, started on antibiotics, i seizure on hospital day 2 11
Case History CSF: 107 WBC (84L), protein=145, glucose=74 MRI done, PPD placed Case History Aunt diagnosed with TB 10 months ago (lived in separate house) Uncle in hospital with pneumonia Child was not identified as a contact 9 year old sibling in school 12
CNS Tuberculosis Pathogenesis and clinical presentation Tuberculous meningitis (TBM) May produce damage to vessels, infarction of brain, edema, fibrosis Predilection: base of brain In AIDS: cerebral abscess or tuberculomas Space occupying sign: headache, seizure, paralysis, personality change, CN defects, neck stiffness, papilledema CNS Tuberculosis Diagnosis and Treatment CSF: clear or slightly opalescent; elevated protein and low glucose (virus: high) AFB and culture: limited Meningeal biopsy: difficult CT and MRI: helpful Tx: chemotherapy, surgery (hydrocephalus) and py, g y( y p ) steroids 13
CSF Findings in TB Meningitis Median WBC = 114 cells (20 530), 82% lymphocytes y (0 99 range) g) Median protein = 141 (17 356 range) Median glucose = 30 (range 5 103) CSF values were not predictive of outcome Saitoh, Ped Infect Dis J, March 2005 CSF Microbiology in TB Meningitis, San Diego 9/20 (45%) positive CSF culture, 2/20 (10%) positive ii gastric aspirate culture 7/14 (50%) positive CSF TB pcr 14/20 (70%) had either CSF/gastric aspirate culture or CSF pcr positive Saitoh, Ped Infect Dis J, March 2005 14
CSF Microbiology in TB Meningitis, Vietnam 107/132 (81%) with microbiologic confirmation: AFB smear sensitivity 52%, culture sensitivity 64% Multivariate analysis showed increased CSF volume increased sensitivity (> 6 ml gave 80% sensitivity) as did time examining slide (> 30 min) Thwaites, J Clin Micro, Jan 2004 CNS Imaging, San Diego Basal enhancement present on non contrast CT study 13/20 (68%) of children with definite TB CT findings did not correlate with long term neurological outcome Saitoh, Pediatr Infect Dis J. March 2005 15
Typical MRI Findings Tuberculoma 32 16
Summary of Diagnostic Tests for CNS TB in Children TEST SENSITIVITY AFB smear gastric aspirate 5 10% AFB smear csf 0 50% Mycobacteria culture csf 0 64% Nucleic acid amplification 0 60% CSF TB PCR 0 60% Combination of CSF smear, or culture or NAA or PCR likely increases sensitivity, but NOT likely to greater than ~75%. Treatment Considerations Adjunct dexamethasone was associated with reduced d death (81/274, 32% vs. 112/271, 41%) and adverse events, but not disability in adolescents and adults with TB meningitis. Thwaites NEJM Oct. 2004 Generally 1 2 mg/kg/day of prednisone given for 4 6 weeks 17
Tuberculosis Lymphadenitis Most common form of extrapulmonary TB Peak age: children, recent shift to 20 40 y/o High risk: Asians, female (2x to male), HIV Hilar, paratracheal and neck lymphnodes Self limited (>90%) Tuberculosis Lymphadenitis Differential Diagnosis Nontuberculous mycobacteria (young age, unilateral and normal CXR, MAI, M. scrofulum) Virus (CMV), toxoplasmosis, bartonella Neoplasm Tuberculin skin test, history and CXR Total excision biopsy pyand culture preferred for NTM adenitis Emerging consideration for medical therapy for NTM (typically MAI) 18
Tuberculosis Lymphadenitis Treatment Anti tuberculous chemotherapy for 6 months course (1 st line: pyrazinamide, isoniazid, rifampin; ethambutol if high rates of drug resistance) Surgical intervention generally to be avoided Steroids may be helpful with large nodes that are obstructing, particularly l in the chest Extra pulmonary Intrathoracic TB 19
Hilar adenopathy with infiltrate and collapse Collapse in a 9 year old 20
Hilar Adenopathy with Atelectasis Hilar Adenopathy 21
Hilar Disease in HIV Infected Person Treatment of Hilar Disease Often pulmonary disease as well Isolated TB adenopathy is paucibacillary ill and thus risk of resistance is low Nodes are slow to resolve, common error is to treat too long waiting for radiograph to resolve If the hilar nodes are too subtle to be clearly visible on plain radiographs, treating as for LTBI is unlikely to be a problem 22
Chest Radiograph Pearls Hilar nodes, pleural disease extrapulmonary, few bacteria Cavitary disease many bacteria Parenchymal scars NOT active, only needs treatment for LTBI IF scar is > 2.5 cm Calcified node is functionally like a normal chest radiograph (very very few live AFB) Pleural TB 23
Extensive Pleural Disease Post Therapy 24
Pleural Tuberculosis Pericardial Tuberculosis 25
Case History 18 yo AA female with unremarkable PMH presents with 1 2 days of left breast swelling Enlarged, painful, no fever, left axillary pain PMH/SH sexually active, multiple partners, tobacco and non injection drug use 26
Work Up WBC = 2.4 (65P/25L/8M), Hgb = 10.8, Platelets = 210 Chem 30 notable for: Na = 132, K = 4.1, TP = 7.5, alb = 3.2, cholesterol = 102 CXR 27
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Diagnosis? HIV positive, CD4 = 20 MTb infection culture positive LN biopsy, sputum, pericarditis Miliary Tuberculosis 30
Miliary TB in a child Miliary TB child with hilar adenopathy 31
Miliary TB Data from Malawi suggests 70% with Miliary TB will have disc abnormalities Miliary Tuberculosis Lympho hematogenous dissemination Infants and children: primary Elderly or HIV infection: reactivation Fever, weakness, anorexia, Wt loss, cough Dx: CXR, HRCT Tx: Chemotherapy for 9 12 months (HIV at least 12 months), steroids? 32
HIV and Extrapulmonary TB Immunosuppression increases rate and dissemination and makes its symptoms atypical Outside US TB is greatest cause of death in 24 44 y/o with AIDS; treatment of LTBI critical EPTB occurs in 25% (US) 80% (developing country) in HIV(+). Lymph node involvement most common, but miliary, CNS, or cutaneous TB are seen as in HIV( ) Treatment complicated by interaction of PI and rifampin, WHO recommends Rx TB first MDR TB, XDR TB Clinical and immunopathological course of HIV associated TB 33
Case History 3 year old with right arm pain two weeks after falling, no fever Uncle diagnosed with TB 15 months ago Child was not identified as a contact Afebrile, lytic lesion in proximal ulna US born, parents from India 67 Bone Spinal Tuberculosis 68 34
Large Paraspinal Abscess with T 6 Destruction Bone and joint Tuberculosis Pott s disease Increasing since 1980s 13 25% HIV positive in several adult series Location: lumbar spine (29.5%) > thoracic spine (20.5%) > knee (13.2%) > hip (8.2%) > soft tissue or muscle (4.5%) (Los Angeles, 1990 1995) Results from hematogenous dissemination 35
Bone and joint Tuberculosis Pathophysiology Invasion of joint space: direct or indirect Cartilage preservation Cold abscess and sinus tract formation Fibrosis and ankylosis, calcification Bone and joint Tuberculosis Clinical Presentation Tuberculous spondylitis Tb Tuberculous osteomyelitis i Tuberculous arthritis Tuberculous tensynovitis Tuberculous myositis 36
Bone and joint Tuberculosis Tuberculous spondylitis Most common, especially in developing countries Back pain and rigidity Vertebral body involvement and diskitis Kyphosis and paraplegia Bone and joint Tuberculosis Tuberculous osteomyelitis Initial: painful mass attached to bone with soft tissue swelling Predilection to metaphysis of long bones May extend to a joint Single in adults; multiple in children, elderly, immunosuppressive and HIV infection 37
Bone and joint Tuberculosis Tuberculous arthritis Large weight bearing joint like hip, knee Pifl Painful, ankylosed kl or swollen mono arthropathy, h limitation of motion Granulation, necrosis, narrowing of the joint space Has been reported in prosthesis infections Bone and joint Tuberculosis Tuberculous myositis More in immunosuppressed and AIDS Most with ih psoas muscle involvement extension from vertebral body Swelling, less pain; a solitary nodule with cold abscess, limitation of muscle function; iliac fossa pain or tenderness in some case 38
Bone and joint Tuberculosis Diagnosis and DDx DDx: collagen vascular arthritis and pyogenic arthritis; fungal infection; neoplasm Monoarthritis, chronic pain, minimal systemic signs Tuberculin skin test Plain radiography, open biopsy CT, MRI, CT guided fine needle aspiration biopsy Bone and joint Tuberculosis Treatment Early diagnosis Anti tuberculosis i drugs with ih minimal i operative intervention for abscess drainage (85 90% complete recovery) Operative decompression (laminectomy should be avoided), bracing may be helpful Arthroplasty 39
Genitourinary Tuberculosis Developing >> developed countries Ml/f Male/female=2:1, l most 20 40y/o (45 55y/o) Vague urinary tract symptoms: painless frequent micturition is common Microscopic hematuria: 50% Recurrent E. coli infection Urine WBC, suprapubic pain, hemospermia, painful testicular swelling: all rare Genitourinary Tuberculosis Diagnosis Tuberculin skin test Ui Urine examination i and culture Elevated ESR Plain film, IVP, percutaneous antegrade pyelography Limited value: endoscopy, biopsy, py, ultrasonography and CT 40
Genitourinary Tuberculosis Pathology Kidney: chronic parenchymal abscess, large renal calcification; may spread to ureter, bladder, seminal visicle Bladder: bullous granulation from ureteric orifice, obstruction; fistula to rectum Epididymis: bloodstream spread, present with discharging i sinus; may spread to testis Genitourinary Tuberculosis Treatment Anti tuberculous chemotherapy (effective) Surgery (>80%): nephrectomy, nephroureterectomy, epididymectomy and reconstructive surgery 41
Cutaneous Tuberculosis Uncommon (<1% in the west) Contagious, may spread by direct contact Exogenous source: Tuberculous chancre and prosector s wart Endogenous source (disseminated): scrofuloderma Hematogenous source: Lupus vulgaris and multiple soft tissue cold abscess (most in AIDS) Tuberculous masitis: most in 20 50 y/o female as in our previous case Cutaneous Tuberculosis Diagnosis and Therapy Excisional biopsy for AFB stain and culture ELISA and PCR Tx: chemotherapy (3 4 drug) and surgery (excisional biopsy and debridement) 42
Other Extrapulmonary Otologic Tuberculosis Ocular Tuberculosis Cardiovascular Tuberculosis Tuberculous Peritonitis Tuberculous Enteritis more common in places with unpasteurized dairy consumption, M. bovis Tuberculosis of the liver and biliary tract Treatment Extrapulmonary TB Similar treatment regimen for pulmonary TB* 6 to 9 month regimens that include INH and RIF are effective (CNS 12+) Corticosteroids used as adjunctive therapy for patients with TB meningitis and pericarditis If PZA cannot be used in the initial phase, continuation i phase must be increased to 7 months 43