Pediatric TB Theresa Barton, MD

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1 TB Nurse Case Management San Antonio, Texas December 8-10, 2009 Pediatric TB Theresa Barton, MD December 9, 2009 Pediatric Tuberculosis Tess Barton, MD Assistant Professor of Pediatrics UT Southwestern Medical Center December 9,

2 Diagnostic process Objectives Progression from TB infection to TB disease Treatment of LTBI in children Management of TB disease in children Case studies Pediatric TB Background Definition of pediatric tuberculosis (TB): TB disease in a person <15 years old In 2006, 13,779 TB cases were reported among all age groups 807 (5.9%) were pediatric 2

3 States with the Greatest Percent of the National Total Pediatric TB Cases, (N=15,946) 25.2% 2% 39.8% 11.8% 4.4% 5.0% 5.0% 8.8% California Texas New York Florida Illinois Georgia All Others States with Greatest Numbers of Pediatric TB Cases, Pediatric TB Cases State Number Percent* Rate** California 4, Texas 1, New York 1, Florida Illinois Georgia All Others 6, Overall U.S. 15, *Average percent of total state cases that are pediatric, for all years **Time-averaged annual rate per 100,000 3

4 Percent of TB Cases for Selected Areas 2007 Other 25% Bexar 5% Dallas 15% Border 17% Travis 4% Tarrant 7% Harris 27% Percent of Cases by Race/Ethnic Group and Region, Texas 2007 Percent 100% 80% 60% 40% 20% 0% Dallas Harris Border State White Black Hispanic Asian One percent or less fell into other racial/ethnic categories for each place. 4

5 TB Case Rates by Pediatric Age Groups U.S.-born and Foreign-born, N=14, ,000 TB Case Rate per Foreign-born U.S.-born Age < 1, FB Age 1-4, FB Age 5-9, FB Age 10-14, FB Age < 1, USB Age 1-4, USB Age 5-9, USB Age 10-14, USB Year Note: Rates presented on a logarithmic scale. Data not available before USB = U.S.-born, FB=Foreign-born Foreign-born Pediatric TB Cases by Birth Country* and 4-Year Interval, (N=3,231) (n) (n) (n) Mexico (467) Mexico (375) Mexico (323) Philippines (118) Somalia (79) Somalia (65) Viet Nam (73) Philippines (67) Philippines (63) Somalia (43) Haiti (38) Haiti (45) Haiti (39) Viet Nam (36) Viet Nam (37) Russia (38) Sudan (26) India (36) Other (422) Other (417) Other (424) *Ranked by counts 5

6 Percent of Pediatric TB Cases by Age Group, N=15,946 Age % Age < 1 9.2% Age % Age % Epidemiology Most TB cases in children occur in urban, lowincome areas and in non-white racial/ethnic groups Foreign-born children account for cases in children <14 years High risk groups: Immigrants International adoptees Refugees from endemic areas Travelers to endemic areas Homeless Correctional facilities 6

7 Clinical Manifestations Most infections in children and adolescents are asymptomatic Symptoms of active pulmonary disease: Fever Weight loss or growth delay (failure-to-thrive) Cough Night sweats Lymphadenopathy p y Extrapulmonary manifestations: Meningitis, lymphadenitis (cervical or mesenteric), Osteomyelitis Chronic otitis media Progression to TB Disease Risk factors for progression from LTBI to active TB: Infants (<12 months) Post-pubertal adolescents Recent infection (< 2 years) Immune deficiency, especially HIV Immunosuppressive drugs corticosteroids, chemotherapy, TNF-agonists IVDU Diabetes mellitus Chronic renal failure Malnutrition 7

8 Latent Tuberculosis Infection Determining LTBI Risk Has a family member or contact had tuberculosis disease? Has a family member had a positive tuberculin skin test? Was your child born in a high-risk country? Has your child traveled to (or had contact with residents from) a high-risk country for more than 1 week? 8

9 Indications for Testing in Children Immediate TST: Contact with confirmed or suspected contagious TB case (contact t investigation) Radiographic or clinical suspicion for TB Children immigrating from endemic areas, including adoptees (age > 3 months) Children with travel histories to endemic areas Wait 10 weeks to test, if child is well Routine annual TST HIV+ children Incarcerated adolescents Periodic or risk-based testing Certain chronic medical conditions, possible exposure Initial test should be done before starting immunosuppressive agents Timing of Positive Skin Testing Incubation 2-12 weeks Risk of developing TB disease is highest in the first 6 months after infection, up to 2 years Many years may elapse between exposure and disease 9

10 Defining (+) Skin Test Results in Children Induration 5 mm Close contact with known or suspected person with TB disease Chest x-ray consistent with active or old TB Clinical evidence other TB disease (meningitis, lymphadenitis, etc) Immunosuppressive therapy or immune deficient, HIV Induration 10 mm Increased risk for dissemination Age < 4 years Underlying medical condition (lymphoma, DM, chronic renal failure, etc) Increased risk of exposure Born in high prevalence area Frequent exposure to high-risk adults (HIV, homeless, nursing home residents, incarcerated adults, migrant farm workers) Travelers to high prevalence areas in the world Induration 15 mm Age >4years, without other risk factors Interferon Gamma Release Assays (IGRA) in Children Immune competent children >= 5 years, IGRA can be used in place of TST Positive IGRA should be considered indicative of M. tubeculosis infection; negative IGRA may not rule out TB IGRA may be useful to determine whether BCG- immunized child has LTBI or false-positive TST from BCG NOT RECOMMENDED for children <5 years, or immunocompromised children 10

11 Therapy for LTBI Efficacy close to 100% in children, when adherent ALL infants, children and adolescents who have a positive TST but no evidence of disease should receive therapy Duration: 9 months Twice a week DOT can be considered if daily therapy not possible Therapy for LTBI INH-Susceptible (>90% of US cases) Isoniazid mg/kg g once daily x 9 months (max 300 mg/day) 100mg, 300mg tablets, 10mg/mL syrup INH-Resistant Rifampin mg/kg once daily or divided BID (max 600 mg/day 150mg, 300mg capsules, can be made into syrup by pharmacy INH-RIF Resistant Consult Specialist: PZA, fluoroquinolone, ETH are typical choices, depending on source case susceptibilities 11

12 Maternal TB + Infant Exposure Mother with LTBI Household + infant evaluation No therapy unless household contact with active TB Mother with active TB All household members should be evaluated within 7 days Evaluation for congenital tuberculosis Infant separated from mother until (1) mother receiving therapy, (2) infant receiving INH, (3) mother wears mask and is adherent to treatment MDR TB consider infant BCG vaccination Women may breastfeed who have been on treatment for 2 or more weeks Maternal TB + Breastfeeding Breastfeeding is OK for women being treated t with the first-line anti-tb drugs Concentrations of these drugs in breast milk are too small to produce toxicity in the nursing newborn Breastfeeding women taking INH should also take pyridoxine (vitamin B6) supplementation. 12

13 TB Exposure in Children - Summary LTBI or active TB disease in a child almost always indicates recent infection with a contagious adult Foreign-born young children are at the highest risk for TB exposure TB screening questions should be incorporated into routine pediatric i care, and should prompt TST or IGRA testing if risk factors idenitfied TB Exposure in Children - Summary All children & adolescents exposed to a person with active TB disease should be evaluated TST, physical exam, CXR Newborn infants should have full evaluation for congenital tuberculosis (confinement from mother until the mother is receiving therapy) Exposed children with impaired immunity or age <4 years Initiate INH therapy even if TST negative Repeat TST in 12 weeks to determine if continued INH needed 13

14 TB Diseases in Children Intrathoracic Pulmonary TB Pleural disease Cardiac disease Extrathoracic Lymphohematogenous disease (disseminated) includes miliary TB Lymphatic disease Central nervous system Osteoarticular Abdominal/GI Genitourinary (renal disease) Cutaneous Congenital 14

15 Pediatric TB Cases by Site of Disease, 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. Pulmonary TB 15

16 Radiographic findings Pulmonary TB: Hilar lyphadenopathy Other subcarinal, paratracheal, mediastinal lymph nodes Segmental or lobar infiltrate Pleural effusion Miliary disease Cavities unusual in children, except adolescents Sarah Long, Principles and Practice of Pediatric Infectious Diseases, 3rd ed.,

17 Sarah Long, Principles and Practice of Pediatric Infectious Diseases, 3rd ed.,

18 Miliary TB Caused by bacteremic dissemination of M. tuberculosis to 2 or more organs Usually an early complication (2-6 months) of primary infection Tubercle lesions typically found in lungs, spleen, liver and bone marrow Symptoms: High fever, hepatosplenomegaly, generalized lymphadenopathy (50% of children) Respiratory distress, cough, rales, wheezing, hypoxia, pneumothorax Headache, meningeal signs (meningitis) Abdominal tenderness (peritonitis) Diagnosis: Miliary TB At least 30% of children with miliary TB have negative TST AFB culture of blood, bone marrow, tissue biopsy TB PCR of infected body fluids or tissue may provide more expedient diagnosis Prognosis: Excellent if treatment started early 18

19 Miliary TB Craig T. Nakamura, MD University of Hawaii John A. Burns School of Medicine TB Lymphadenitis (Scrofula) Most common extrapulmonary TB in children Occurs 6-9 months after initial iti infection Supraclavicular, anterior cervical, tonsillar, and submandibular nodes are most often involved A primary pulmonary focus is almost always present but is visible radiographically in only 30% to 70% of cases, and is usually asymptomatic Tuberculin skin test result is usually reactive 19

20 AAP Redbook, 2009 TB Meningitis Occurs in 0.5% of primary infections in children Age: 6 months 4 years Onset within 2-6 months of infection May occur with primary disease (dissemination, miliary TB), or with reactivation Onset can be rapid or gradual (often more rapid in younger children) 20

21 TB Meningitis Stage 1: Lasts 1 to 2 weeks Fever, headache, h irritability, it and drowsiness, loss of developmental milestones Stage 2: lethargy, nuchal rigidity, seizures, hypertonia, vomiting, cranial nerve abnormalities, and other focal neurologic signs Encephalitis Communicating hydrocephalus Stage 3: coma, hemiplegia or paraplegia, hypertension, decerebrate or decorticate posturing TB Meningitis Diagnosis TST non-reactive in up to 40% CXR normal in up to 50% CSF findings Markedly elevated protein (>400 mg/dl) Elevated WBC ( cells/mm3), lymphocytic predominance Head CT (with contrast) Basilar cisternal enhancement Communicating hydrocephalus Cerebral edema, focal ischemia AFB culture of CSF, TB PCR 21

22 Sarah Long, Principles and Practice of Pediatric Infectious Diseases, 3rd ed., 2008 Congenital Tuberculosis Extremely rare (fewer than 300 cases reported in literature) Presentation: Respiratory distress, fever, hepatosplenomegaly, poor feeding, lethargy or irritability, lymphadenopathy, abdominal distention, ear drainage, and skin lesions May be present at birth usually 2-3 weeks of life Occurrence and intensity of hematogenous dissemination during pregnancy determine congenital infection 22

23 Diagnosing TB in Children More difficult to diagnose than in adults must have a higher degree of suspicion M. tuberculosis detected in up to 50% of gastric aspirates in non-hiv-infected children About 10% of culture-positive children have negative TST Diagnosis usually made by linking child to TB contact + radiograph + skin test Other Diagnostic Methods Culture for AFB Gold standard for diagnosis, allows susceptibility testing High culture positivity with cavitary disease Low culture positivity in absence of cavity (i.e. most children) Expectorated sputum Gastric aspirate fluid Pleural fluid Bronchoalveolar lavage fluid has low yield Good yield from lymph node tissue 23

24 Other Diagnostic Methods TB PCR IFN-gamma Release Assays (IGRA) Case #1 6-month female infant Brought to Emergency Dept for cough + fever x few days Exam notable for tachypnea, wheezing, but otherwise looked well exam suggestive of bronchiolitis CXR done because of tachypnea + fever to r/o pneumonia RSV testing done (negative) 24

25 Case #1 CXR concerning for miliary TB Further hx + exam done: Family originally from Honduras, infant born in US and no travel to Honduras Lives with parents, grandparents, paternal aunt all reported as healthy Exam: normal growth parameters, no meningeal signs, no lymphadenopathy, no hepatosplenomegaly 25

26 Evaluation of infant with suspected TB PPD skin testing Chest x-ray PPD placement for household members and close contacts +/- CXR for parents regardless of PPD result Gastric aspirate AFB cx Lumbar puncture with AFB cx and TB PCR Brain MRI for abnormal CSF Liver function testing Abdominal imaging if other findings suggest miliary or disseminated disease Case #1 Challenges of this case: Initial exam and history suggestive of common pediatric disease Was a CXR really indicated? Careful history revealed family risk factors Immigrant family should have been screened in their own health care how often do healthy young adult immigrants enter the health care system? 26

27 Case #2 11 month-old Caucasian female from Plano 1 week history fever + cough, not responding to oral antibiotics Exam: mild respiratory distress diminished breath sounds on right chest CXR: miliary pattern, right infiltrate with pleural effusion Case #2 Lumbar puncture done: NUC 65 (elevated) RBC 130 Glucose 70 Protein 244 (elevated) CSF culture negative CSF TB PCR: positive 27

28 Case #2 No known TB risk factors No travel No high-risk family members Parents TST negative Family housekeeper from Honduras TST positive Aunt of child in Case #1 28

29 Treatment for TB Disease AAP Redbook: 3 drug regimen TX: 4 drug regimen Risk of drug-resistant TB in TX Pulmonary TB: INH, RIF, PZA, ETH TB Meningitis: iti INH, RIF, Amikacin, ETH? 29

30 Pediatric Dosing ISONIAZID mg/kg once daily RIFAMPIN mg/kg once daily PYRAZINAMIDE mg/kg once daily ETHAMBUTOL mg/kg once daily AMIKACIN 10 mg/kg IV every 8 hours Use of fluoroquinolones or streptomycin should be in consultation with Pediatric Infectious Disease specialist Pediatric TB Drug Dosing 30

31 Number and Percent of Culture-confirmed Pediatric TB Cases with Drug Resistance, Number of cases that are drug resistant Percent of cases that are drug resistant Year Resistance to any 1st line drug Percent with resistance to any 1st line drug MDR TB Percent with MDR TB First line drugs are Isoniazid, Rifampin, Pyrazinamide and Ethambutol MDR TB = resistance to at least Isoniazid and Rifampin 60 Number of MDRTB Cases Texas Cases MDR INH RIF 31

32 Pediatric TB Cases by Treatment Outcome (N=14,233*) Outcome Cases % Completed treatment 13, Moved Lost to follow-up Died Other** Note: Cause of death not recorded in TB case reports *Pediatric TB cases with patient alive at diagnosis and started on treatment **Other includes refused, other, unknown and missing TB Diseases in Children - Summary Risk of disseminated or extrapulmonary disease is increased in children Infants <12 months of age should be evaluated for dissemination regardless of clinical findings Cavitary pulmonary TB is NOT the typical presentation Hilar adenopathy, non-specific infiltrates PPD testing may not be accurate in infants <6 months 32

33 Gardner Association for the Prevention and Relief of Tuberculosis, c

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