Pediatric Tuberculosis 2011 Dwight A. Powell, MD, FAAP Professor - PowerPoint PPT Presentation

Pediatric Tuberculosis 2011 Dwight A. Powell, MD, FAAP Professor Emeritus of Pediatrics The Ohio State University College of Medicine Member, Section of Infectious Diseases Nationwide Children’s Hospital, Columbus, Ohio

Reported TB Cases by Age Group, United States, 2009 - CDC <15 yrs (6%) >65 yrs 15–24 yrs (20%) ( 11%) 45–64 yrs 25-44 yrs (30%) (34%)

Groups at higher risk of developing disease after infection “LTBI” Major focus for ~35% of PPD screening • Immunosuppressed patients: household contacts are - 15% infected Prolonged steroids; immune Groups at high-risk of exposure and infection suppressants; malignancy • Close contacts of cases of reactivation TB • HIV infected patients 95% • Foreign-born from high risk countries • Underlying poor health: • Residents of high-risk institutions Diabetes, renal failure, • Medically underserved, low-income persons silicosis, chronic lung disease, malnutrition • Injection drug users Bacteremia and dissemination to • Substance abuse • Persons exposed to high-risk adults multiple body organs • Persons < 4 years of age NEJM 345:189, 2001

Adolescent with Latent TB LTBI in a child is a sentinel event indicating contact with a case of active TB

Age Distribution of TB disease in children 40 35 30 25 20 No. of 15 Cases 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Age (years) Burroughs, M et al. PIDJ 18:440, 1999

Major site of TB disease in 11,480 children ≤ 15 yrs old in the U.S. 1993-2001 Site Number (%) Pulmonary 8824 (76.9) Lymphatic 1778 (15.5) Meningeal 249 (2.1) Bone/Joint 156 (1.4) Pleural 132 (1.1) Miliary 125 (1.1) Other 223 (1.9) Nelson LJ et al Pediatr 2004;114:333

Symptoms in Children with TB disease Symptom Frequency (%) Symptom (156 children < 20 yrs) Cough 62 Fever 55 Weight Loss 32 Night Sweats 26 Hemoptysis 12 Burroughs, M et al. PIDJ 18:440, 1999

Primary pulmonary TB in children 10 yr old female with segmental RLL infiltrate and paratracheal lymphadenopathy

Progressive primary pulmonary TB in children 4 mo female with RLL consolidation and R hilar lymphadenopathy

Cavitary TB in an adolescent 17 yr old BF, 2 mo cough, night sweats and 10# wt loss. Born in Virgin Islands; in U.S. x 10 yrs. PPD >20mm; sputum (+) M. tuberculosis

Miliary tuberculosis 3 year old female exposed to her grandfather with pulmonary TB

Tuberculous meningitis 13 month old Honduran male whose grandfather has cavitary tuberculosis diagnosed after this child presented with fever, irritability and nuchal rigidity CSF: Glucose 50, prot 108, RBC 13, WBC 39, 100% mononuclear cells. Gadolinium enhanced T1 weighted MRI

Tuberculous meningitis

Lymphatic TB in children TB Lymphadenitis in children 13 yr old BM. 2 mo hx neck swelling, fever & 4# wt loss. Born in Somalia; moved to U.S. 9 mo PTA. PPD (+) but no Rx. PPD 25mm

Pott’s Disease (TB of vertebral bodies) T1 weighted T2 weighted MRI with MRI T6 gadolinium L2 S1,2 18 yr old college student from Ghana; known PPD positive in 2001; no RX. Developed 2 mo. back pain and leg weakness during football practice in 2005. PPD 30 mm

Inadequately treated Pott’s disease 10 yr old Somali female with severe kyphoscoliosis who was treated with one medication and coining at age 2-3 yrs

Inadequately treated Pott’s disease T1 weighted MRI showing destruction and fusion of C5,6,7 &T1 vertebral bodies.

Diagnosis of TB infection in Children • Tuberculin skin test (TST) or Interferon gamma release assay (IGRA) • CXR if one of the above is positive • Complete physical exam • Search for contact source • Treat for LTBI if CXR and PE are negative • Pursue further evaluation if CXR or PE are abnormal

Further diagnosis of TB disease in Children • Attempt to Isolate organism • induced sputum x2 – AFB smear, culture (cx) and nucleic acid analysis (NAA) • gastric washings x 2-3 – Cx and NAA • biopsy or fluid aspiration – Cx and NAA • lumbar puncture in infants of if signs of meningitis – cells, prot, gluc, cx, NAA • HIV testing

Definitions of Positive PPD Results in Children Induration ≥ 5 mm  Children in contact with known active TB  Children with clinical or radiographic illness consistent with TB  Children who are immunocompromised Induration ≥ 10 mm  Children at increased risk of disseminated disease • Age < 4 yrs or underlying medical illness  Children with increased exposure to TB • Born or parents born in high-prevalence countries • Frequent exposure to adults with high-risk of TB • Travel to high-prevalence countries Induration ≥ 15 mm  Children >4 yrs old without any risk factor s Redbook, 2009

BCG scar after vaccination at birth 6 mos after birth 7.5 wks after birth Santiago EM et al. Pediatr 2003;112:e298

PPD skin test results in persons without known exposure to TB; those with BCG were vaccinated as infants Wang L et al. Thorax. 2002;57:804–809.

BCG vaccine site - Japan

Interferon- γ release assays for detection of M. TB infection QuantiFERON-Gold In Tube (QFT-GIT) and TSPOT.TB Antigens used: ESAT-6, CFP-10, and TB7.7

CDC updated guidelines for using intereron gamma release assays to detect Mycobacterium tuberculosis infection – U.S. 2010 Use of QFT-GIT and T-SPOT for testing children: • Assessing the accuracy of IGRAs has been more difficult in children than in adults • This is especially true for children < 5 yrs old • Use of IGRAs in children is subject to several limitations: • Studies in children are scant • Indeterminant results are more common in children than adults • Some studies have raised concern that IGRAs may have lower sensitivity that TSTs in children Mazuek GH et al. MMWR 2010;59:RR-5

Sensitivity of IGRAs in culture confirmed TB disease in children Ling DI et al. Pediatr Resp Rev 2010;12:9

Specificity of IGRAs in culture confirmed TB disease in children Ling DI et al. Pediatr Resp Rev 2010;12:9

Retrospective review of TST vs IGRAs in 49 children in the UK with culture confirmed TB Test No. tested No. positive (%) TST >15 mm 45 37 (82) TSPOT 25 16 (64) QFT-GIT 43 35 (81) TST or TSPOT (+) 25 24 (96) TST or QFT-GIT (+) 43 39 (91) Bamford AR et al. Arch Dis Child 2010;95:180

Summary of evidence from 12 studies comparing IGRAs vs TST for LTBI in children IGRA type IGRA (+) TST (+) QFT-G 33/195 (17) 47/195 (24) QFT-GIT 60/334 (18) 58/334 (17) QFT-GIT 16/210 (8) 98/227 (43) QFT-GIT 11/105 (10) 10/105 (10) QFT-GIT 31/204 (15) 116/207 (56) QFT-GIT 65/192 (34) 57/193 (57) QFT-GIT 61/184 (33) 80/184 (43) TSPOT 36/120 (30) 84/120 (70) QFT-GIT 29/97 (30) 46/95 (48) TSPOT 25/95 (26) 46/95 (48) BOTH 71/215 (33) 57/215 (27) Ling DI et al. Pediatr Resp Rev 2010;12:9

Results in 217 immigrant children from Africa or Asia screened in Australia with TST, QFT-GIT and TSPOT NONE of the children had known household exposure to TB Lucas M et al. Thorax 2010;65:442

Results in 22 immigrant children from Africa or Asia screened in Australia with TST, QFT-GIT and T.SPOT.TB . All of these children had KNOWN household exposure to TB Lucas M et al. Thorax 2010;65:442

Progression to active TB in 104 German children <16 yrs old followed for 2-4 yrs without treatment after > 40 hrs contact with an adult with active TB QFT-GIT ♦ active TB ♦ no BCG O BCG Diel R et al. Am J Resp Crit Care Med 2011;183:88

Our current policy for tuberculin skin testing and IGRA testing for children • Screening for active TB • Use TST, QFT-GIT, and T-Spot.TB • Further evaluate and treat if any positive • If clinical evidence of miliary TB meningitis, malnutrition, or compromised immunity, further evaluate and treat even if all are negative

Our current policy for tuberculin skin testing and IGRA testing for children • Screening for LTBI in asymptomatic children • Initial PPD skin test • If known TB exposure and TST ≥ 5mm, obtain QFT-GIT and T-Spot.TB (if age < 5 yrs) • If no known TB exposure but high exposure risk: • TST > 15 mm – No IGRA – start RX • TST 10-15 mm, obtain QFT-GIT and T- Spot.TB (if age < 5 yrs). If IGRA (+) treat; if IGRA (-) do not treat • TST < 10 mm – no IGRA

Directly observed therapy of TB Disease Stage of TB RX Duration Pulmonary TB ♦ Non HIV (+), US born INH/Rif/PZA* 6 mo ** ♦ HIV(+) or foreign INH/rifabutin/PZA/eth 6mo** born Extrapulmonary TB  meningitis INH/RIF/PZA/eth 9-12 mo**  bone, joint, miliary Same as pulmonary 6-9 mo** * if INH resistance >4% or high risk of drug resistance in source, add ethambutol until drug susceptibility confirmed. **PZA for only first 2 months

Treatment of LTBI or contact of child with adult case of TB disease Drugs Dosage Duration, mo Interval INH 10-15 mg/kg 9 Daily INH 20-30 mg/kg 9 2-3x/wk, DOT For know exposure to INH resistant case Rifampin 10-20 mg/kg 6 Daily For children who are contacts of adults with TB disease - Tuberculin skin test and CXR; repeat in 8-10 weeks if (-) - If child < age 4 years begin INH as above; continue INH until repeat TST is (-) and index case is on DOT and confirmed to be sputum (-)