Pediatric Tuberculosis: All You Ever Wanted to Know Ann M. Loeffler, MD Pediatric Consultant Francis J. Curry National Tuberculosis Center Legacy Emanuel Children’s Hospital Portland, OR
Pediatric TB Epidemiology • How to evaluate & treat children for TB • Use of IGRA tests in children • Tuberculin skin testing and BCG impact
Reported TB Cases by Age Group, United States, 2006 807 cases <15 yrs (6%) >65 yrs (19%) 15–24 yrs (11%) 13,779 Total cases 25–44 yrs (34%) 45–64 yrs (29%)
Tuberculosis cases by ethnicityin the United States – 2006 485 under 5 yrs White Black Hispanic Asian American Indian/Native American
Interesting Facts • Around 25% of children with TB are diagnosed based on positive culture • 70% of < 15 year olds were started on four drug therapy in CA (93% for > 15 yr olds) • 7.9% drug resistance among < 5 year olds 1993-2007 • 4% resistance among African American • 8% resistance among Whites / Hispanics • 12% resistance among Asians
Screening guidelines • Do not screen every child with a TST • Screen every child at each well child visit with a questionnaire • Questions should relate to risk of TB infection • (Adults risk assessment is risk of progression to TB disease) • Skin test only children with risk factors
Screening guidelines • Was your child born outside the US? • Has your child traveled outside the US? • Has your child been exposed to anyone with TB disease? • Does your child have close contact with anyone with a positive TB skin test? • Risk-assessment questions based on local epi.
TB screening in children • There is no gold standard for diagnosing TB infection • Hard to measure sensitivity and specificity of tests • Tuberculin skin test (5TU of PPD by Mantoux method) is 80-96% sensitive • 10-20% of children with TB disease have TST (-) • Up to 4.5% remain negative during treatment • TST less often positive in infants, malnourished, HIV
Meron • Meron has received a BCG at birth • Does BCG impact a TST ? • At what age?
BCG and TST • Individuals who have received BCG vaccine are more likely to have a positive TST than those who have not • They come from areas with higher rates of TB • BCG efficacy 0 – 80% • Universally acknowledged to prevent disseminated disease in infants • Increased risk of TB disease with increasing TST size
BCG and TST (AAP) • BCG impacts TST least: • Vaccine given at birth • If skin tested long after immunization • Without exposure to NTM • In populations with high TB prevalence • When vaccine has fewer viable bacilli Pediatrics 2004;114;1175-1201 - see handout for table and references http://www.pediatrics.org/cgi/content/full/114/4/S2/1175
BCG / TST Guinea-Bissau Roth Vaccine 2005;23:3991-8
Time after BCG Pediatrics 2004;114;1175-1201 - see handout for table and references
Mexican study 1st and 6th grades enrolled • TB rate 28 / 100,000 • TST rates increased by age (8% of 5-7y; 19% 14-16y) • Higher TST > 10 mm in BCG vaccinated – BUT few unvaccinated and increased risk with vaccination within 4 years and more than one vaccine • TST rates increased by degree of association with a TB case • 3 of 97 children with a positive TST developed TB disease within one year Garcia-Sancho Int J of Epidem 2006;35:1447-54
Variability between regions • India • 16% TST > 10 mm in BCG scar neg • 8% TST > 10 mm in BCG scar pos • Larger studies of > 100,000 children agree • Korea, UK, USA, Japan BCG adversely impacts specificity of TST • Tropical countries may have more rapidly waning TST reaction ? Environmental NTM
Meron • Evaluated in the adoption clinic • TST placed at 8 months of life • 12 mm induration • What do you do now? • ? IGRA test
QuantiFERON (QFT) • The QuantiFERON tests measure release of gamma-interferon from lymphocytes in whole blood stimulated by TB proteins • The original QFT stimulated the lymphocytes with PPD solution • QFT-Gold stimulates with lymphocytes with specific TB proteins (ESAT-6 and CFP10) • QFT-G In-tube has three proteins coating tube
QFT-G or QFT-IT • A handful of studies in children • Different study designs: • Evaluation of TB disease/contacts • assesses sensitivity of test • Evaluation of TB exposure by gradient in otherwise low risk individuals in low prevalence areas • Assesses specificity of the test • Variable results • QFT concordant with TST • QFT more specific than TST • QFT less sensitive than TST
India QFT-GIT: TB suspects or contacts • TST 1 TU PPD RT23 • 10 mm breakpoint • 92% BCG hx 82% scars • No QFT indeterminates • 11 children diagnosed as TB disease • TST 82% sens; QFT 64% sens • 8 children with laboratory confirmed TB • 3 of 8 were TST and QFT negative Dogra J Infect 2007;54:267-76
QFT-G in Cambodian < 5yrs contacts • Good correlation for both QFT and TST by smear / contagion • 5% indeterminate / 10 mm TST breakpoint 2.5TU • 195 evaluable children • 24% positive TST • 17 % positive QFT • 19 TB disease (no cultures or HIV serologies) • 79% positive TST • 53% positive QFT Okada K Epidemiol Infect 2008;in press
Other studies • QFT-G in Australian contacts – poor agreement with TST more sensitive; high rates of inderminates; QFT pos for all 9 with TB disease (defined as TST pos) • Connell Thorax 2006;6:616-20 • QFT-IT in Nigerian contacts • 74% QFT pos in contacts of smear pos (53% TST+) • Nakaoka Emerg Infect Dis 2006;12:1383-1388
Other QFT studies • 2 newborns with miliary TB: positive QFT-G, neg TST • Connell CID 2006;42:e82-5 • High risk South African school children screened by QFT-GIT and TST; 33.2% pos QFT and 43.5% pos by TST • Tsiouris Int J Tuberc Lung Dis 2006;10:939-41
Other QFT studies • QFT-G used to follow up exposed HS students with positive TST; • Higuchi Respirology 2007;12:88-92 • QFT-2G 5 cases of dz QFT pos; 1 of 3 asymptomatic QFT pos developed TB • Mori J Japan Assoc Infect Dis 2005;79:937-44
Elispot based tests • Enumerates reacting lymphocytes after PBMC are removed from whole blood • T-SPOT®.TB is licensed abroad and pending FDA approval
Elispot Pediatric Studies • South African Study of 260 TB suspects – • 83% sensitivity of Elispot vs. 63% of TST in confirmed or highly probable cases • Elispot even more superior in children < 3 yrs, HIV infected and malnourished • 31% of children with “not TB” (defined as TST neg) were Elispot positive • No inderminates • Lieberschuetz Lancet 2004;364:2196-203
Elispot Pediatric Studies • 70 South African TB suspects evaluated with Elispot • 83% positive Elispot for definite TB • Increased responses after 1 month of treatment • One child with culture pos TB remained negative • Decreasing response at 3 and 6 months Nichol CID 2005;40:1301-8
Other Elispot studies • TST neg newborn exposed to mother with MDR-TB. Elispot serially positive – baby eventually developed disease • Richeldi Pediatrics 2007;119:e1-5 • TSpot and QFT-GIT compared in German children with cx pos TB, NTM or other respiratory diseases. TSpot 98% specific, QFT 100% specific and TST 58% • Detjen CID 2007;45:322-8
Other Elispot studies • 535 students exposed in UK school tested by Elispot and TST. Elispot positive more closely related to exposure; TST more positive in BCG vaccinated • Ewer Lancet 2003;361:1168-73
Other Elispot Studies • Turkish study – 979 child contacts • 13 diagnosed with TB (11 +TST, 12+ Elispot) • Increasing Elispot positive with age, child of source, more than one source in household • BCG found to protective against infection and dz • More infection and disease in BCG unvaccinated • Soysal Lancet 2005;366:1443-51
Elispot in Gambian child contacts • Hill Pediatrics 2006;117:1542-8 • Review of Tcell-based diagnosis in children • Lalvani Current Opinion Infect Dis 2007;20:264-71 • Review: new approaches and emerging technologies in the diagnosis of childhood TB • Marais Paediatric Resp Rev 2007;8:124-133
Back to Meron • Would a negative IGRA test rule out TB infection or disease? • How cautious do you want to be? • i.e. How risk averse are you? • I err on the side of evaluating and treating BCG vaccinated children with TST > 10 mm.
Evaluation of a positive TST • History and physical: • History reveals that Meron has had serial respiratory illnesses in the orphanage • She is small for her age • Chest radiograph – 2 views • Alert the radiologist that you are evaluating for TB
Chest radiographs Characteristic: Adults Children Location: Apical Anywhere (25% multilobar) Adenopathy: Rare Usual (30-90%) (except HIV) Cavitation: Common Rare (except adolescents) Signs and symptoms: Consistent Relative paucity
Positive TB skin test Clinically and radiographically Abnormal Normal Consistent with TB More consistent with other diagnosis Treat for LTBI Collect cultures and start 4 drug TB therapy Patient very stable? NO YES TB still possible? Other diagnosis confirmed, Course inconsistent with TB Consider culture collection (NO INH!!!) Treat other diagnosis Reassess weekly *** Cultures only help if they are positive*
Meron’s radiograph • Frontal view is fairly unremarkable • Lateral view shows likely lymphadenopathy • Chest radiographic changes which are more impressive than the history and physical are more likely to be caused by TB • What now?
Laboratory testing • No routine lab testing for LTBI patients • International adoptees are screened for Hepatitis, syphilis, HIV, parasites, lead, etc. • All TB patients should be tested for HIV • Specimens for microbiologic testing should be collected on all patients. If I have a very strong source case, I may collect only one.
Bacteriologic diagnosis • Sputum can rarely be collected from children • Can try sputum induction in older children • Zar Lancet 2005;365:130-4 • Bronchoalveolar lavage is invasive, expensive and should be reserved for situations where the diagnosis is in question
Bacteriologic diagnosis • Gastric aspirates • people swallow mucus in their sleep • collect gastric contents before the stomach empties • www.nationaltbcenter.edu • Pediatric on-line course: resources
Gastric aspirate yield • Literature for 3 gastric aspirates: 40% • Nearly 100% yield for <3 month olds • smear rarely positive after 3 months • First specimen is the very highest yield • Higher yield for pulmonary vs. LAD • A negative culture does not rule out TB
Back to Meron • 2 gastric aspirates collected • Adoption labs showed transaminase elevation • Started on TB therapy after ALT normalized • How many drugs?
National Guidelines “Many experts prefer to treat children with three (rather than four) drugs in the initial phase because the bacillary population is low, because many infants and children cannot tolerate the pill burden required with four oral drugs, and because of the difficulty in performing visual acuity tests in young children who are being treated with EMB. In children suspected or known to have been infected with an M. tuberculosis strain that is fully susceptible, the initial phase should consist of INH, RIF, and PZA.”