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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. No disclosures. Pediatric TB Epidemiology How to evaluate & treat children for TB

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pediatric tuberculosis all you ever wanted to know

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
Reported TB Cases by Age Group, United States, 2006

807 cases

<15 yrs


>65 yrs


15–24 yrs



Total cases

25–44 yrs


45–64 yrs


tuberculosis cases by ethnicity in the united states 2006
Tuberculosis cases by ethnicityin the United States – 2006

485 under 5 yrs

White Black Hispanic Asian

American Indian/Native American

interesting facts
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
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 guidelines10
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
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 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

bcg tst guinea bissau
BCG / TST Guinea-Bissau

Roth Vaccine 2005;23:3991-8

time after bcg
Time after BCG

Pediatrics 2004;114;1175-1201 - see handout for table and references

mexican study 1 st and 6 th grades enrolled
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
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
  • 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
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
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
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
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 studies28
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
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
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 studies31
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
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 studies33
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 studies34
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
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
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
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




with TB

More consistent with other diagnosis

Treat for LTBI

Collect cultures and

start 4 drug TB therapy

Patient very stable?



TB still possible?

Other diagnosis confirmed,

Course inconsistent with TB

Consider culture


(NO INH!!!)

Treat other


Reassess weekly

*** Cultures only help if they are positive*

meron s radiograph
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
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
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 diagnosis45
Bacteriologic diagnosis
  • Gastric aspirates
    • people swallow mucus in their sleep
    • collect gastric contents before the stomach empties
      • Pediatric on-line course: resources
gastric aspirate yield
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 meron49
Back to Meron
  • 2 gastric aspirates collected
  • Adoption labs showed transaminase elevation
  • Started on TB therapy

after ALT normalized

  • How many drugs?
national guidelines
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.”

national guidelines51
National Guidelines

“When epidemiologic circumstances suggest an increased risk of drug-resistant organisms being present, EMB can be used safely in a dose of about 15–20 mg/kg per day, even in children too young for routine eye testing.”

ats risks
ATS risks
  • Exposure to a person who has known drug-resistant tuberculosis
  • Exposure to a person with active tuberculosis who has had prior treatment for tuberculosis (treatment failure or relapse) and whose susceptibility test results are not known
  • Exposure to persons with active tuberculosis from areas in which there is a high prevalence of drug resistance
  • Exposure to persons who continue to have positive sputum smears after 2 months of combination chemotherapy
  • Travel in an area of high prevalence of drug resistance
  • Meron was treated with a four drug treatment regimen by DOT
  • The second of her gastric aspirates grew Mtb
  • Resistant to INH and RIF, sensitive to PZA, EMB, SM
    • BUT – purity plates also grew MAC
  • What do you do now?
same principles as adults
Same principles as adults:
  • Collect cultures again if possible before changing regimen to look for emergence of drug resistance
  • Use all first line drugs available (unless previously used and associated with a failing regimen)
  • Use an injectable drug (streptomycin, amikacin, capreomycin, kanamycin) by Broviac
  • Use a fluoroquinolone
  • Use additional second line drugs to have 4 – 6 drugs in the regimen
mdr tb in children
MDR-TB in children
  • Screening labs:
    • CBC, CMP, TSH for ethionamide, cycloserine, audiology and vision
  • See for drug doses
  • Meron’s baseline hearing screen showed high frequency hearing loss (adoption paperwork indicated previous receipt of gentamicin)
hearing loss in mdr tb
Hearing Loss in MDR-TB
  • Sometimes inevitable
  • Can sometimes use intermittent therapy to prevent worsening
  • Streptomycin associated with less hearing loss
  • Generally linked to total dose
  • Received four months of aminoglycoside (BARE minimum)
  • Is thrilled to have her Broviac out
  • Has two negative gastric aspirates on therapy
  • Has gained many pounds
  • Repeat chest radiograph is essentially normal

I will treat her with another 14 months of pyrazinamide , ethambutol, ethionamide and levofloxacin (Vitamin B6) by DOT

Monitoring growth & development, musculoskeletal, vision, etc.

  • Pediatric TB is declining in the US – half of the cases of 1992
  • 25% of cases are treated without benefit of culture results (some are treated based on source case susceptibility)
  • Many in CA are treated with three drugs
  • ? Number of failures – 2 cases in AL experience
  • BCG has variable protection
  • BCG has variable impact on TST reaction
    • Likely has less impact in high prevalence / tropical countries
  • IGRA tests are imperfect –
    • QFT tests are easier to perform – seem to have more indeterminate results
    • Elispot tests may be more sensitive for diagnosing TB Dz in children
  • TB screening should be done by questionnaire
  • Only those with risks of exposure should undergo skin testing (or IGRA screening)
  • Patients with suspicion of TB disease should undergo 2 view chest radiography
  • If findings are more consistent with another disease, consider deferring treatment for a few weeks
  • I prefer four drugs for TB disease in children
  • I find them to be very well tolerated
  • The biggest trick is getting the kids to take the drugs