Pediatric Tuberculosis

Rafael E. Hernandez, MD PhD Attending Physician, Instructor

Pediatric Infectious Diseases 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

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

• BUT….

Large Global Burden of Pediatric TB

• Approx 1 million new cases in 2014 (<15yo) and 140K pediatric deaths

• 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 2015, 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 • Opportunity to identify infectious cases in community

Natural History of Pediatric TB

Incubation

Hypersensitivity Occult Bacteremia

Milary TB TBM

Segmental lesion Pleural dz

Osteo-articular dz Adult-type dz

Reactivation

Marais, et al 2004 Based on Wallgreen, 1948

Risk of Disease Correlates with Age

No clear association between age and risk of initial infection w/TB

BUT Highest progression to active disease in infants (<1 yo):

• Disease risk 30-50% • 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

Objectives for Lecture

• Explain the key differences in clinical presentation, diagnosis (including interpretation of chest x-rays) and infection control concerns in children vs. adults

• Plan treatment courses for TB disease and LTBI in children

• Identify strategies to make children medication dosing more effective

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

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 in King County

• 5 per 100K (2014) vs. 3 for WA State • Majority of cases foreign born (87%) • 23% of cases resistant to ≥ 1 drug

• 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 (85% with identified source)

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

Screen asymptomatic children in the US w/ risk questionnaire 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? ▪ Consider asking about close contact with other high risk populations

(homeless, prison, HIV + persons, foreign visitors) THESE QUESTIONS REFLECT EPIDIMEOLOGY Test children responding YES (with a NEW risk)

Targeted TB Screening in US

Based on AAP RedBook

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 3-4 yo

Interpretation of TST? Similar to adults, + if:

5 mm or greater • Close contact with known or suspected 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

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 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.)

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

Should prior receipt of BCG vaccine affect your interpretation of TST?

GENERALLY NO But 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

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 B6, & HIV+ to reduce neuropathy • Hepatotoxicity rare in children • Alternate DOT twice weekly (20-30 mg/kg, max 900) x 9 mo

• Rifampin (10-20 mg/kg, max 600) daily x 4 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

From CDC Guidelines 2005

Key differences: More complete evaluation than immunocompetent adult: Perform complete exam & CXR At same time as TST If less than 8 weeks from last contact initiate “window therapy” with INH in well children.

Neonates are a special case, contact expert

“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 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

recommended (<5 yo)

• Regimens for LTBI treatment are similar to adults with weight based dosing BUT INH-RPT only for >2 yo

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 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. Patient is US born to Nigerian parents.

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-guide-gastric-aspirate-procedure

• Tissue (Lymph node, bone, synovial fluid, pleura) • CSF (if any neurologic 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 CXR Evaluation

Abnormal

IGRA/TST (negative result not useful)

Normal

Treat for LTBI as indicated Consistent with TB

Collect cultures Start 4 Drug Therapy

More consistent with another Dx

Very stable condition? No

Yes

Consider TB cultures Work-up /treat other Dx

Avoid INH or FQs Reassess at least weekly

Response to non-TB therapy? Other signs/sx

Other Dx conformed or inconsistent with TB

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 positive is helpful), ruling 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 (mg)

Formulation (Not all inclusive)

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

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

Pyrazinamide CDC: 15-30 WHO: 30-40

2000 NA

Tabs: 500 mg

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

2500 - AAP NA

Tabs: 100 mg, 400 mg

General note: 10% above or below range is acceptable Intermittent dosing (2-3 x weekly) is possible in continuation phase but there is less evidence than in adults to support practice – see CDC/WHO guidelines Regimens 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 (consider crushing tablets)

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 Monitoring Isoniazid Hepatotoxicity

Rash Peripheral neuropathy Psychosis

Jaundice Liver enzymes PRN Clinical observation, symptoms Consider need for B6, symptoms

Rifampin Orange body fluids Hyperbilirubinemia Hepatotoxiticy

Advise parents!

Pyrazinamide Hepatotoxicity Arthralgia Rash

Jaundice Liver enzymes PRN Clinical observation Clinical 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)

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 candies

and have a reward system • Try tipping head forward for capsules and back for pills • If they can do capsules but not pils, consider crushing tablet and filling

empty capsules • Crushed pills/capsules can be ’mixed’ in food

• Practice first without medicine • Chocolate syrup, jelly/jam, apple sauce, peanut butter • Practice w/o medicine and with crushed candies first

• Crush and suspend in liquid (water) and give with syringe or medication pacifier

• http://www.currytbcenter.ucsf.edu/products/pediatric-tuberculosis-online-presentation/resources

Consider Possibility of MDR-TB

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

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) Ofloxacin 15-20 mg/kg/day Max 800 mg 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 mg Kanamycin 15-30 mg/kg/day Max 1 mg Capreomycin 15-30 mg/kg/day Max 1 mg Streptomycin (resistance a concern)

20-40 mg/kg/day Max 1 mg

CONSULT AN EXPERT! – Principles the same as adults

Dosing based on CDC/AAP/WHO

Regimens for MDR-TB Similar to Adults 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 12 g per day

Group 5 – Limited clinical data (use with caution if additional agents needed) Linezolid Amoxicillin-

clavulanate Imipenem-cilastin

Clofazimine Clarithromycin NEW 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 suspicion:

• Collect best specimens possible (admit 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

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/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 • 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?

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

AAP RedBook 2012

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

Hilar lymphadenopathy

Smith Curr Probl Pediatr 2001; 31: 5-30

Paratracheal lymphadenopathy

Zar, H. University of Cape Town, 2009

Childhood TB - X ray Presentations Miliary tuberculosis

AAP RedBook 2012

Childhood TB - 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 technologies

• Transcriptional profiling

• Still not as sensitive as culture

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 Red Book 2015: 736-759.

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

Call: Seattle Children’s ID Service Or your local children’s hospital

http://www.currytbcenter.ucsf.edu/topics-interest/pediatric-tb