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Pediatric Tuberculosis

Rafael Hernandez, MD PhDAttending Physician, Instructor

Pediatric Infectious Diseases

Disclosures

• No financial conflicts• Off-label use:

• Drugs used in typical HZRE regimens are approved for use in children

• Particular combinations or antibiotics used in drug-resistant TBParticular combinations or antibiotics used in drug resistant TB (eg. Fluoroquinolones) may be off label – (not approved for TB or not approved in children), but I will only focus on uses consistent with national and international guidelines

Risk of Complacence Towards Childhood TB

• Uncommon: 485 cases in children < 15yo in U.S. (CDC 2013)

• Typically contagious risk is lower than adult cases• Paucibacillary disease is common – often smear negative

• Diagnosis is difficult• Diagnosis is difficult• Cultures often difficult to obtain and lower yield• More reliance on clinical diagnosis

• BUT….

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Large Global Burden of Pediatric TB

• Approx 550,000 new cases in 2013 (<15yo)

• Estimated 20-40% of cases in high burden nations are children under age 15 yo

• Indirect impact• >9 million orphans worldwide from TB

• Loss of family income if parent diagnosed (average 60%)

AND…

(WHO 2014, Swaminathan and Rekha 2010)

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• Limited circle of contacts• Identify infectious cases in community

Objectives for Lecture

• Review epidemiology of childhood TB• Understand latent TB screening in children• Understand treatment of latent TB in children• Compare/contrast children vs. adults:

• Presentation of active TB disease• Diagnosis of active TB disease

• Develop treatment regimens for active TB in children

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Three Basic Clinical Scenarios

• Screening in healthy children• Screening/evaluation of contacts to contagious

TB cases• Evaluation and treatment of symptomaticEvaluation and treatment of symptomatic

children

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

Risk of Disease Correlates with Age

No clear association between age and initial infection w/TBBUTHighest progression to active disease in infants (<1 yo):

• Disease risk 30-50%• TB Meningitis or miliary disease in 10-20%• TB Meningitis or miliary disease in 10-20%• Mortality risk 5-10% in infants < 1 yo

Lowest risk in 5-10 yo• Overall 2%, <0.5% disseminated

Older children develop adult like disease

Marais, et al 2004

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Transmission

• Generally airborne droplet route (<10 uM)• Smear positive status is most

effective marker of infectiousness• Most childhood TB is smear

negative, with lower bacterialnegative, with lower bacterial burdens (less than 15% smear positive)• 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

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

Screen all children with HIV or other risk for TB progression (transplant, anti-TNF agents, high-dose steroids...)

Screen asymptomatic children in the US w/ risk questionnaireShould 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?

Targeted TB Screening in US

▪ 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?

▪ Consider asking about close contact with other high risk populations (homeless, prison, HIV + persons, foreign visitors)

THESE QUESTIONS REFLECT EPIDIMEOLOGYTest children responding YES (with a NEW risk)

Based on AAP RedBook

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Epidemiology in King County

• 5.8 per 100K (2013) vs. 2.7 WA State• Majority of cases foreign born (84%)• 17% of cases resistant to ≥ 1 drug• Childhood TB (2012):

• 9 cases in <15 yo, 5 cases in <5 yo

• At Seattle Children’s – almost all cases foreign born or with foreign born household contact

Epidemiology 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

Pang, et al. 2014

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AAP RedBook 2015 IGRA vs. TST

Reminder:TB antigens in IGRA are not present in BCG vaccine or common NTM pathogens

Some experts believe IGRA ok in 2-4 yo

Interpretation of TST?Similar to adults

5 mm or greater• Close contact with known or suspected contagious people

with tuberculosis disease• Suspected to have tuberculosis disease:

Fi di h t di h i t t ith ti

AAP RedBook

• Findings on chest radiograph consistent with active or previous tuberculosis disease

• Clinical evidence of tuberculosis disease (exam or lab)• Children receiving immunosuppressive therapy

(corticosteroids, anti-TNF agents) or with immunosuppressive conditions, including HIV infection

Interpretation of TST? (cont.)10 mm or greater• Children at increased risk of disseminated TB disease:

• Children younger than 4 years of age• Children with other medical conditions, including Hodgkin disease,

lymphoma, diabetes mellitus, chronic renal failure, or malnutrition• Children with likelihood of increased exposure to TB disease:

• Children born in high-prevalence regions of the worldChildren born in high prevalence regions of the world• Children who travel to high-prevalence regions of the world• Children 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.)

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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 k t i• 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

• Live Attenuated strain of M. bovis• Widely used at birth (>100 countries)

• www.bcgatlas.org• Estimated 80% protective against

meningitis and miliary TB in children, less effective against pulmonary disease

BCG Vaccination

less effective against pulmonary disease• May cross-react with TST (not IGRA)

• BCG recommendations in US:− HIV-negative, non-immunosupressed AND

Continuously exposed to INH and RIF-resistant TB ORContinuously exposed to contagious TB and cannot be given anti-TB drugs

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 BCGTi i i i 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

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How should a patient with a positive TST or IGRA be treated?

Determine Latent TB Infection (LTBI) vs. TB Disease•Focused History & Physical:

• Cough > 2 weeks w/o improvement• Fever > 1 week/night sweats• Neurologic symptoms (fatigue, persistent irritability)• 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• 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

Antibiotic regimens for LTBI in Children

• Isoniazid (10 mg/kg, max 300) 1x daily x 9 mo• Pyridoxine supplementation recommended for: exclusively breastfed infants,

malnourished children, diets poor in pyridoxine, & HIV+ children to reduce neuropathy

• Hepatotoxicity rare in children

• Rifampin (10-20 mg/kg, max 600) daily x 6 mo• Use if concern for INH resistance or INH intolerance

• INH+Rifapentine weekly x 12 wk (DOT)• Use when concern for compliance• Data for >2 yo, HIV negative children/adolescents (Villarino, et al. 2015)

(Non-inferior to daily INH)

• INH 15 mg/kg weekly• Rifapentine – 10-14kg=300mg, 14.1-25kg=450mg, 25.1-32kg=600mg, 32.1-

49.9kg=750mg, >50kg=900mg

Algorithm for contact evaluation of child <5 yo

Key differences:More complete evaluation than immunocompetent adult: Perform exam & CXR

From CDC Guidelines 2005

If less than 8 weeks from last contact initiate “window therapy”with INH in well children.

Neonates are a special case, contact expert

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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 p gcase – If negative can stop INH

Screening & LTBI Key points:

• Screening- may use TST or IGRA • (but less data for IGRA in <5 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• If exposed- perform complete evaluation, window therapy is

recommended (<5 yo)

• Regimens for LTBI treatment are similar to adults (weight based dosing)

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 nodules on bilateral shins

1 5 k i d l d h R Alb t l /• 1.5 wk prior developed cough - Rx: Albuterol, w/o improvement

• Sent to ED for evaluation, with elevated inflammatory markers

• FH/SH: Paternal GF- Visiting from Nigeria x 6 wks, had stomach illness. Pt is US born to Nigerian parents.

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CXR

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-http://www.currytbcenter.ucsf.edu/products/pediatric tuberculosisguide-gastric-aspirate-procedure

• Tissue (Lymph node, bone, synovial fluid, pleura)• CSF (if any neuro concerns and should be strongly

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 More consistent with

another Dx

Collect culturesStart 4 Drug Therapy Very stable condition?

No

Yes

Consider TB culturesWork-up /treat other Dx

Avoid INH or FQsReassess at least weekly

Response 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 g , ( yalso be Non-TB mycobacteria)

− Pleural TB − Pericardial TB− Abdominal TB− TB of 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%• Diagnosis made on combination of clinical suspicion,

possible contacts, TST/IGRA (only positive is helpful), ruling out other likely diagnosis and response toruling out other likely diagnosis, 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

Dosing: First Line Drugs

Drug Dose and Range(mg/kg/day)

Maximum Daily Dose

Formulation (Not all inclusive)

Isoniazid 10 (10-15) 300 mg Tabs: 100 mg, 300 mgSyrup: 10 mg/mL *

Rifampin 15 (10-20) 600 mg Caps: 150 mg, 300 mgMay be compounded

Pyrazinamide CDC: 15-30WHO: 30-40

2000 mgNA

Tabs: 500

Ethambutol CDC: 15 (15-20)WHO: 20 (15-25)

1600 mgNA

Tabs: 100mg, 400 mg

General note: 10% above or below range is acceptableIntermittent 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: are the same, but some experts recommend aminoglycoside or ethionamide in place of EMB for meningitis

*contains sorbitol- risk of GI upset/diarrhea

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Important follow-up

• Provide DOT if available• Assess compliance (multiple daily medications can be

hard, especially in a toddler)• Are sign/symptoms improving?• Monitor for side effects, include family education?• DO MEDS NEED ADJUSTMENT FOR WEIGHT?

Assessment of response/duration of treatment: • Typical duration 6-9 months• Follow-up cultures difficult: use CXR (2 mo – will not be

normal, should not be worse) and clinical symptoms• 12 months for osteo-articular disease or meningitis

First Line Drugs: Adverse Effects

Drug Adverse Effects MonitoringIsoniazid Hepatotoxicity

RashPeripheral neuropathyPsychosis

JaundiceLiver enzymes PRNClinical observation, symptomsConsider need for B6, symptoms

Rifampin Orange body fluids Advise parents!HyperbilirubinemiaHepatotoxiticy

Pyrazinamide Hepatotoxicity

ArthralgiaRash

JaundiceLiver enzymes PRNClinical observationClinical observation

Ethambutol Optic neuritis Visual exam if able (but rare in children)

Usually baseline labs are drawn, but subsequent labs are only checked if symptoms, other hepatotoxic drugs, or other baseline conditions (such as liver disease)

Consider Possibility of MDR-TB

WHO estimates prevalence of MDR-TB is the same in adults and children

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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, Patient and ContactGroup 1: Use all first line drugs to which isolate is susceptibleINH, RIF, PZA, EMBGroup 2 – Add one fluoroquinoloneOfloxacin 15-20 mg/kg/day Max 800 mg

CONSULT AN EXPERT! – Principals the same as adults

Ofloxacin 15 20 mg/kg/day Max 800 mgLevofloxacin 15-20 mg/kg/day Max 1 gMoxifloxacin 7.5-10 mg/kg/day Max 400 mgGroup 3 – Add one injectable (for at least 6 months)Amikacin 15-30 mg/kg/day Max 1 mgKanamycin 15-30 mg/kg/day Max 1 mgCapreomycin 15-30 mg/kg/day Max 1 mgStreptomycin (resistance a concern)

20-40 mg/kg/day Max 1 mg

Regimens for MDR-TB Similar to Adults

KEEP ADDING to get to minimum of 4-6 active drugsGroup 4 – Additional 2nd Line Drugs (use as many as needed)Cycloserine 10-20 mg/kg in 2

divided dosesMax 1 g per day

Ethionamide 15-20 mg/kg in 2-3 divided doses

Max 1 g per day

Para aminosalicyclic acid 200 300 mg/kg in Max 10 g per dayPara-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-

clavulanateImipenem-cilastin

Clofazimine ClarithromycinNEW AGENTS: (No dosing info in children)Bedaquiline Delamanid

Take Home Points – Active TB Disease

• Children often culture NEGATIVE• Complete work-up whenever there is high suscpicion:

• Collect best specimens possible (Admit)• Identify a source case if possible• Positive IGRA/TST are useful in diagnosis• Positive IGRA/TST are useful in diagnosis

• Risk for disseminated disease is HIGH vs. adults in children under 5

• Children tolerate meds well, principles of therapy are similar to adults

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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 improvedFever resolved, clinically much improved • Source not identified

TB during pregnancy/breastfeeding• Can treat LTBI during pregnancy

• (OK to wait until end of 1st trimester)• But possible increase in hepatotoxicity peripartum period

• Add Pyridoxine (B6) supplement to all pregnant/breast feeding patients

• TB disease should be treated during pregnancy• Use: INH/RIF/EMB for 9 mo (2HRE+7HR)• 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• 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!

What are other radiographic appearances of TB in children?

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Childhood TB - Various X ray Presentations:Adult type pulmonary disease – 15 yo boy

AAP RedBook 2012

CXR

• Nonspecific, intra-observer variation• Features suggesting TB:

• Hilar lymphadenopathy• Bronchial compression• Chronic consolidation• Chronic consolidation• Calcification• Miliary pattern

• Cavity or Lesion in upper lobe(s) is less common in children

Zar, H. University of Cape Town 2009

Hilar lymphadenopathy

Smith Curr Probl Pediatr 2001; 31: 5-30

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Hilar lymphadenopathy

Smith Curr Probl Pediatr 2001; 31: 5-

Paratracheal lymphadenopathy

Zar, H. University of Cape Town, 2009

Childhood TB - Various X ray Presentations:Miliary tuberculosis

AAP RedBook 2012

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Childhood TB - Various X ray Presentations:Preschool aged child, showing infiltrate and atelectasis

AAP RedBook 2012

Other Diagnostic Testing

• Xpert on non-sputum and sputum samples• More sensitive than smear• But less sensitive vs. culture

• Developing technologiesDeveloping technologies• Transcriptional profiling

• Still not as sensitive as culture

Use of Xpert for Diagnosis in Children

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Diagnostic Performance of the Risk Score in the Discovery and Validation Cohorts and as Compared with the IGRA and the Xpert MTB/RIF Assay in the Validation Cohort.

Anderson ST et al. N Engl J Med 2014;370:1712-1723.

Key Resources

Guidance for national tuberculosis programmes on the management of tuberculosis in children – 2nd ed.

AAP Red Book:http://aapredbook.aappublications.orgRed Book 2015: 736-759.

http://www.who.int/tb/publications/childtb_guidelines/en/

CDC, ATS and IDSA Guidelines, 2003http://www.idsociety.org/IDSA_Practice_Guidelines/

Call: Seattle Children’s ID ServiceOr your local children’s hospital