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Pediatric Tuberculosis
Rafael E. Hernandez, MD PhD
Attending Physician, Asst. Professor
Pediatric Infectious Disease
Seattle Children’s Hospital & University of Washington
Disclosures
• No financial conflicts related to content in this presentation
• Off-label use: • HZRE regimens are FDA approved for use in children
• BUT particular combinations or antibiotics used in drug-resistant TB (eg., fluoroquinolones) may be off label – (not approved for TB or not approved in children). I will only focus on uses consistent with national and international guidelines.
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Risk of Complacence Towards Childhood TB
• Uncommon: 429 cases in children < 15yo in U.S. (CDC 2017)
• Typically contagious risk is lower than adult cases• Paucibacillary disease is common – often smear negative
• Diagnosis is difficult• Cultures often difficult to obtain and lower yield
• More reliance on clinical diagnosis
• BUT….Age group N
Percentage of all cases
0–1 years 53 0.6%
1–4 years 175 1.9%
5–9 years 93 1.0%
10–14 years 108 1.2%
Additional reasons for concern
• Young children are at increased risk for severe or disseminated disease (meningitis, miliary TB)
• Sentinel public health event –• Likely recent/ongoing transmission
• Limited circle of contacts
• Opportunity to identify infectious cases in community
• Approx 1 million new cases in 2016 (<15yo) and 252K pediatric deaths (201K HIV neg)
• Estimated 20-40% of cases in high burden nations are children under age 15 yo
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Objectives for Lecture
• Explain the key differences in clinical presentation, infectiousness, and diagnosis (including interpretation of chest x-rays) in children vs. adults
• Plan treatment courses for TB disease and LTBI in children
• Identify strategies to make medication dosing in children more effective/tolerable
Natural History of Pediatric TB
Incubation
HypersensitivityOccult Bacteremia
Milary TBTBM
Segmental lesionPleural dz
Osteo-articular dzAdult-type dz
Reactivation
Marais, et al 2004Based on Wallgreen, 1948
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Risk of Disease Correlates with Age
No clear assoc. between age and risk of initial infection w/TB
BUT risk of disease is increased in very young
Highest progression to active disease in infants (<1 yo): • Disease risk 30-50%• TB Meningitis or miliary disease is 10-20%• Mortality risk 5-10% in infants < 1 yo
Lowest risk in 5-10 yo• Overall 2%, <0.5% disseminated
Older children (>10 yo) develop adult like diseaseMarais, et al 2004
Percentage of TB Cases in Children with Any Extrapulmonary Involvement by Age Group, Summed and Averaged Over
2013–2017
27.5
2.90.5
2.3
5.6
61.2
Age 5–9, n=443
21.4
2.60.6
2.8
14.6
58.0
Age 10–14, n=500
Lymphatic
Bone and Joint
Meningeal Miliary
Other Pulmonary Only
7.5
11.2
1.5
0.7
3.0
76.1
Age <1, n=267
17.3
6.4
0.5
1.6
2.6
71.6
Age 1–4, n=987
From CDC
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Review Four Basic Clinical Scenarios
• Infection control related to child with possible TB disease
• Screening healthy children
• Screening, evaluation & treatment of contacts to contagious TB cases
• Evaluation & treatment of symptomatic children
Transmission
• Generally airborne droplet route (<10 uM)
• Smear positive status is most effective marker of infectiousness
• Most childhood TB is smear negative, with lower bacterial burdens (less than 15% smear positive)
• One series at Texas Children’s Hosp:• 7 of 59 children potentially infectious
(5 smear positive)
• 15% of family caregivers have undiagnosed TB
Cruz, et al 2011.
Auramine-O
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For once children are not the vectors of disease!!!
To understand the epidemiology of childhood TB, you need to understand the epidemiology of adult TB in your community
Epidemiology Childhood TB in United States
• Observational x-sectional study at 20 U.S. sites 2005-6
(Pang, et al. Pediatrics 2014 cases in children < 5yo)
• 83% of Cases in US Born Children (vs. adults)
• Estimated TB Rates per 100K children:• 2.57 All Children
• 24.03 Foreign-born children
• 4.81 US born with ≥ 1 foreign born parent
• 0.75 US born, with US born parents
• Source cases most often in home/family
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800
Cases
U.S.‐born with parents/guardians with unknown originU.S.‐born with Non‐U.S.–born parents/guardians*U.S.‐born with U.S.‐born parents/guardians
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Cases
Mexico Philippines Somalia Vietnam Ethiopia Haiti
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Screen Children:• Contacts of confirmed or suspected contagious TB
• With radiographic or clinical findings suggesting TB
• Immigrating from countries with endemic TB
• With significant travel to countries with endemic infection and
substantial contact with local population
• With HIV (annually)
• Other risk for TB progression (based on risk and history - Diabetes,
transplant, anti-TNF agents, high-dose steroids…)
• Screen otherwise asymptomatic children in the US w/ risk
questionnaire
Targeted TB Screening in US
Based on AAP RedBook
▪ Should be done at 2 wk, 6 mo, 12 mo, annual WCCs
▪ Has a family member or contact had TB disease?
▪ Has a family member had a positive tuberculin skin test result?
▪ Was your child born in a high-risk country? (countries other than the
U.S., Canada, Australia, New Zealand, or Western/Northern Europe)
▪ Has your child traveled (had contact with resident populations) to a
high-risk country for more than 1 week?
THESE QUESTIONS REFLECT EPIDIMEOLOGY
Test children responding YES (with a NEW risk)
Screen asymptomatic children in the US w/ risk questionnaire
Based on AAP RedBook
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AAP RedBook 2018 IGRA vs. TST
Reminder:TB antigens in IGRA are not present in BCG vaccine or most NTM pathogens
Age ≥ 2 y
Interpretation of TST?Similar to adults, + if:
5 mm or greater
• Close contact with known or potentially contagious people with tuberculosis disease
• Suspected to have tuberculosis disease:
• Findings on chest x-ray c/w active or previous TB disease
• Clinical evidence of tuberculosis disease (exam or lab)
• Children receiving immunosuppressive therapy (corticosteroids, anti-TNF agents) or with immunosuppressive conditions, including HIV infection
AAP RedBook
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Interpretation of TST? (cont.)
10 mm or greater• Children at increased risk of disseminated TB disease:
• Younger than 4 years of age• Other medical conditions, including Hodgkin disease, lymphoma,
diabetes mellitus, chronic renal failure, or malnutrition• Children with likelihood of increased exposure to TB disease:
• Born in high-prevalence regions• Travel to high-prevalence regions• Frequently exposed to adults who are HIV infected, homeless,
users of illicit drugs, residents of nursing homes, incarcerated or institutionalized
15 mm or greater• Children ≥ 4 years without any risk factors (Generally do not need
testing – but sometimes required by schools, volunteer positions, etc.)
Live virus vaccine in prior 4-6 weeks is contraindication to TST (and IGRA)
• MMR vaccine known to blunt response to PPD(assume similar effect on IGRAs)
• Give at same time as TST
• OR WAIT 4-6 weeks post vaccine
• No data for other live viral vaccines (Varicella, Influenza, Yellow Fever) – general rec is wait 4-6 weeks
• No evidence that inactivated/subunit vaccines affect TST
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Should prior receipt of BCG vaccine affect your interpretation of TST?
GENERALLY NOBut multiple factors affect how individuals who received BCG react to TST and subsequent clinical action:
• Age at receipt of BCG• Time since receiving BCG• Number of doses of BCG• Strain of BCG given• Symptoms consistent with TB disease• Known exposure (more likely to represent TB infection)• CXR findings consistent with current or past disease
• General Rule: TEST ONLY IF YOU WOULD TREAT POSITIVES
How should a patient with a positive TST or IGRA be treated?
Determine Latent TB Infection (LTBI) vs. TB Disease•Focused History & Physical for signs and symptoms:
• Cough > 2 weeks w/o improvement• Fever > 1 week/night sweats (maybe shorter)• Neurologic symptoms (persistent irritability)• Fatigue/malaise• Weight loss OR Failure to thrive (Review growth charts!)• Symptoms in family/contacts• Physical Exam:
• Lung findings- uncommon (rales, “wheeze” from nodes compressing airway)
• Neurologic- alertness, behavior, meningeal signs, CNs• Check lymph nodes and musculoskeletal symptoms
•Screening chest X-ray•If asymptomatic and CXR w/o evidence of active TB: LTBI•All children with positive TST/IGRA should be considered for treatment
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Antibiotic regimens for LTBI in Children
• INH+Rifapentine weekly x 12 wk (DOT)• Data for >2 yo, HIV negative children/adolescents INH 15 mg/kg weekly
• Once weekly dosing
• Rifapentine: 10-14kg=300mg, 14.1-25kg=450mg, 25.1-32kg=600mg, 32.1-49.9kg=750mg, >50kg=900mg
• Isoniazid: ≥12 yo 15 mg/kg; 2-11 yo 25 mg/kg (Max 900 mg)
• Rifampin (15-20 mg/kg, max 600mg) daily x 4 mo• Use if concern for INH resistance or INH intolerance
• Isoniazid (10-20 mg/kg, max 300) daily x 9 mo• Pyridoxine supplementation recommended for: exclusively breastfed infants,
malnourished children, diets poor in B6, & HIV+ to reduce neuropathy
• Hepatotoxicity rare in children
• Alternate DOT twice weekly (20-40 mg/kg, max 900) x 9 mo
Better Compliance
Antibiotic regimens for LTBI in Children
• Better Completion Rates• Cruz and Starke, PEDIATRICS 2018 doi: 10.1542/peds.2017-2838
• 9H – SAT 52% completed
• 4R – SAT 84% completed
• 3HP – DOT 97% completed
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“Window Therapy”
• Young Children (<5yo) are AT RISK for DISSEMINATED
and/or SEVERE DISEASE
• Start Latent TB treatment after 1st TST
• Repeat in 8-10 weeks after last contact with contagious
case – If negative can stop LTBI treatment
Screening & LTBI Key points:
• Screening- may use TST or IGRA • IGRA acceptable in 2 yo or older
• TST preferred in younger than 2 yo
• Young children are at increased risk:• Use lower 10 mm cut off for TST (<4 yo)
• If exposed- perform complete evaluation
• “Window” therapy is recommended for under 5 yo
• Regimens for LTBI treatment are similar to adults with weight based dosing BUT INH-RPT only for >2 yo
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Case: 18 mo girl rash, fever, cough
• 2.5 wk daily fevers, Tmax 102.9
• At onset, clinical dx of pharyngitis- 5d azithro, no improvement
• 2 wk ago developed nodules on bilateral shins
• 1.5 wk ago developed cough - Rx: Albuterol, no improvement
• Sent to ED for evaluation, with elevated inflammatory markers
• FH/SH: Paternal GF visiting from Nigeria x 6 wks, had stomach illness. Patient is US born to Nigerian parents.
CXR
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Specimens for Culture
• Expectorated sputum• Induced sputum
• can be done in young children with RT expertise
• Gastric aspirate (preferred if sputum not possible)• young children, collected in AM after NPO• Video instructions from Curry Center Website:http://www.currytbcenter.ucsf.edu/products/pediatric-tuberculosis-guide-gastric-aspirate-procedure
• Tissue (Lymph node, bone, synovial fluid, pleura)• CSF (if any neurologic concerns especially under 2 yo and should
be considered in all children less than 1 yo undergoing TB w/u)
• RELATIVES/CONTACTS
Algorithm for Diagnosis(preadolescent children)
Positive TST/IGRA TB symptoms or close contact
Clinical and CXREvaluation
Abnormal
IGRA/TST(negative result not useful)
Normal
Treat for LTBIas indicated Consistent with TB
Collect culturesStart 4 Drug Therapy
More consistent with another Dx
Very stable condition?No
Yes
Consider TB culturesWork-up /treat other Dx
Avoid INH or FQs
Reassess at least weeklyResponse to non-TB therapy?
Other signs/sx
Other Dx conformed or inconsistent with TB
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Assess for Extrapulmonary Tuberculosis
• TB Meningitis — meningitis not responding to antibiotics, with a subacute onset, communicating hydrocephalus, stroke, and/or elevated intracranial pressure
• TB Adenitis — painless, fixed, enlarged lymph nodes, especially in the cervical region, with or without fistula formation (may also be Non-TB mycobacteria)
Pleural TB
Pericardial TB
Abdominal TB
TB of bone/joints
Vertebral TB
Skin
Renal
Eye
Decision to treat
• Most childhood TB is SMEAR Negative in young children
• Culture yield is likely only 30-60%
• Negative micro evaluation does not rule out TB in children
• Diagnosis made on combination of clinical suspicion, possible contacts, TST/IGRA (only + is helpful), ruling out other likely diagnoses, and response to treatment
• If you have high clinical suspicion TREAT!
• You will end up treating some children for TB who in fact have another diagnosis
• Obtain baseline labs/HIV testing
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Dosing: First Line Drugs
Drug Dose and Range(mg/kg/day)
Maximum Daily Dose (mg)
Formulation (Not all inclusive)
Isoniazid 10 (10-15) 300 Tabs: 100 mg, 300 mgSyrup: 10 mg/mL *
Rifampin 15 (10-20)2018 RedBook: Meningitis or toddlers 20-30 mg/kg
600 Caps: 150 mg, 300 mgMay be compounded
Pyrazinamide 35 (30-40) 2000 Tabs: 500 mg
Ethambutol 20 (15-25) 2500 Tabs: 100 mg, 400 mg
General note: Weight based band tables are availableIntermittent dosing (2-3 x weekly) is possible in continuation phase but there is less evidence than in
adults to support practice – see CDC/WHO guidelinesRegimens for Extrapulmonary TB: same, but some experts recommend aminoglycoside or ethionamide
in place of EMB for meningitis (also now increased RIF dose for TBM)
*contains sorbitol- risk of GI upset/diarrhea (consider crushing tablets)
Important follow-up• Provide DOT whenever possible
• Assess compliance and challenges (multiple daily medications can be hard, especially in a toddler)
• Are sign/symptoms improving?
• Monitor for side effects & include family education (red secretions, jaundice, rash, etc)
• DO MEDS NEED ADJUSTMENT FOR WEIGHT?
Assessment of response/duration of treatment:
• Typical duration 6 months
• Follow-up cultures difficult: use CXR (2 mo – will not be normal, should not be worse) and clinical symptoms
• 9-12 months for meningitis or M bovis
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First Line Drugs: Adverse Effects
Drug Adverse Effects Monitoring
Isoniazid Hepatotoxicity
RashPeripheral neuropathyPsychosis
JaundiceLiver enzymes PRNClinical observation, symptomsConsider need for B6, symptoms
Rifampin Orange body fluidsHyperbilirubinemiaHepatotoxiticy
Advise parents!
Pyrazinamide Hepatotoxicity
ArthralgiaRash
JaundiceLiver enzymes PRNClinical observationClinical observation
Ethambutol Optic neuritis Visual exam if able (but optic neuritis is rare in children)
Draw baseline labs, but subsequent labs are only checked if symptoms, other hepatotoxic drugs, or other baseline conditions (such as liver disease)
Suggestions for medication administration
• It may take a little while to get the child in a routine – avoid establishing a power struggle
• If they can take pills that will be easiest, practice with small candy and have a reward system• Try tipping head forward for capsules and back for tablets
• If can do capsules but not tablets, consider crushing tabs and filling empty capsules
• Crushed pills/capsules can be mixed in food• Practice first without medicine, then with crushed candies
• Chocolate syrup, jelly/jam, apple sauce, peanut butter/nutella
• Crush and suspend in liquid (water) and give with syringe or medication pacifier
• http://www.currytbcenter.ucsf.edu/products/pediatric-tuberculosis-online-presentation/resources
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Regimens for MDR-TB Similar to Adults
GOAL: AT LEAST 4-5 Active Drugs (WHO recommends 6 drugs)Consider drug resistance of Region and Contact (Patient if available)
Group 1: Use all first line drugs to which isolate is susceptible
INH, RIF, PZA, EMB
Group 2 – Add one fluoroquinolone (AAP or WHO)
Levofloxacin 15-20 mg/kg/day Max 1 g
Moxifloxacin 7.5-10 mg/kg/day Max 400 mg
Group 3 – Add one injectable (for at least 6 months) (CDC)
Amikacin 15-30 mg/kg/day Max 1 g
Kanamycin 15-30 mg/kg/day Max 1 g
Capreomycin 15-30 mg/kg/day Max 1 g
Streptomycin (resistance a concern)
20-40 mg/kg/day Max 1 g
CONSULT AN EXPERT! – Principles the same as adults
Dosing based on CDC/AAP/WHO
Regimens for MDR-TB Similar to Adults(Can consider shorter course treatments)
KEEP ADDING to get to minimum of 4-6 active drugs
Group 4 – Additional 2nd Line Drugs (use as many as needed) (CDC)
Cycloserine 10-20 mg/kg in 2 divided doses
Max 1 g per day
Ethionamide 15-20 mg/kg in 2-3 divided doses
Max 1 g per day
Para-aminosalicyclic acid (PAS)
200-300 mg/kg in 2-4 divided doses
Max 10 g per day
Group 5 – Limited clinical data (use with caution if additional agents needed)
Linezolid Amoxicillin-clavulanate
Imipenem-cilastin
Clofazimine (NOT crushable) Clarithromycin
NEW AGENTS: (Limited dosing info/availability in children)
Bedaquiline Delamanid
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Take Home Points – Active TB Disease
• Childhood TB is often culture NEGATIVE
• Complete work-up whenever there is high suspicion:• Collect best specimens possible (admit inpatient if needed)
• Identify a source case if possible
• Positive IGRA/TST are useful in diagnosis
• Negative IGRA/TST/cultures DO NOT rule out TB disease
• Risk for disseminated disease is HIGH vs. adults in children under 5
• Children tolerate meds well, principles of therapy are similar to adults
For 18 mo GIRL with 2.5 wks fever:
• Eventually 1 of 3 gastric aspirates grew:• M. tuberculosis complex
• Susceptible to all 1st line drugs
• Fever resolved, clinically much improved
• Source not definitively identified
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TB during pregnancy/breastfeeding• Can treat LTBI during pregnancy
• (OK to wait until end of 1st trimester)
• But possible increase in hepatotoxicity during peripartum period
• Add Pyridoxine (B6) supplement to all pregnant/breastfeeding on INH
• TB disease should be treated during pregnancy• Use: INH/RIF/EMB for 9 mo (2HRE+7HR)
• PZA avoided in US due to lack of data, but used by WHO
• Avoid streptomycin or injectables
• Congenital tuberculosis is rare, but consider evaluation (call expert)
• Post-partum exposure is greater concern for infant• Separate Mom and infant if Mom is still infectious
• Consider whether infant needs INH (once infant disease is ruled out)
• If Mom has new diagnosis, evaluate the household members!
Key Resources
Guidance for national tuberculosis programmes on the management of tuberculosis in children – 2nd ed.http://www.who.int/tb/publications/childtb_guidelines/en/
AAP Red Book:http://aapredbook.aappublications.org
CDC, ATS and IDSA Guidelines, 2003https://www.idsociety.org/practice-guideline/treatment-of-drug-susceptible-tb/
Call: Seattle Children’s ID ServiceOr your local children’s hospital
http://www.currytbcenter.ucsf.edu/topics-interest/pediatric-tb
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What are other radiographic appearances of TB in children?
Childhood TB - Various X ray Presentations:Adult type pulmonary diseaseUNUSUAL for children (but more common in teens)
AAP RedBook 2012
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CXR
• Nonspecific, intra-observer variation
• Features suggesting TB:• Hilar lymphadenopathy
• Bronchial compression
• Chronic consolidation
• Calcification
• Miliary pattern
• Cavity or Lesion in upper lobe(s) is less common in children
Hilar lymphadenopathy
Smith Curr Probl Pediatr 2001; 31: 5-30
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Hilar lymphadenopathy
Smith Curr Probl Pediatr 2001; 31: 5-30
Paratracheal lymphadenopathy
Zar, H. University of Cape Town, 2009
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Childhood TB - X ray PresentationsMiliary tuberculosis
AAP RedBook 2012
Childhood TB - X ray Presentations:Preschool aged child, showing infiltrate and atelectasis
AAP RedBook 2012
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Other Diagnostic Testing
• Xpert on non-sputum and sputum samples• More sensitive than smear
• Most labs will need to validate on gastric specimens
• But less sensitive vs. culture
• Developing technologies• Transcriptional profiling
• Still not as sensitive as culture
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