Pediatric Tuberculosis

Pediatric Tuberculosis Rafael Hernandez, MD PhD Attending 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-resistanttb resistant (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 Cultures often difficult to obtain and lower yield More reliance on clinical diagnosis BUT. 1

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 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 2

Three Basic Clinical Scenarios Screening in healthy children Screening/evaluation of contacts to contagious TB cases Evaluation and treatment of symptomatic children Natural History of Pediatric TB Hypersensitivity Occult Bacteremia Incubation 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 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 3

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) Series at Texas Children s Hosp 7 of 59 children potentially infectious (5 smear positive) 15% of family caregivers have undiagnosed TB Auramine- O Cruz, et al 2011. 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 Targeted TB Screening in US 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 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) Based on AAP RedBook 4

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 5

AAP RedBook 2015 IGRA vs. TST Some experts believe IGRA ok in 2-4 yo Reminder: TB antigens in IGRA are not present in BCG vaccine or common NTM pathogens Interpretation of TST? Similar to adults 5 mm or greater AAP RedBook Close contact with known or suspected contagious people with tuberculosis disease Suspected to have tuberculosis disease: Findings on chest radiograph consistent t 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 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.) 6

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 BCG Vaccination 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 May cross-react with TST (not IGRA) BCG recommendations in US: HIV-negative, non-immunosupressed AND Continuously exposed to INH and RIF-resistant TB OR Continuously exposed to contagious TB and cannot be given anti-tb drugs 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 i 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 7

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 If less than 8 weeks from last contact initiate window therapy with INH in well children. Neonates are a special case, contact expert From CDC Guidelines 2005 8

Window Therapy Young Children (<5yo) are AT RISK for DISSEMINATED and/or SEVERE DISEASE Start Latent TB treatment after 1 st 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 (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 15 1.5 wk prior developed d cough - Rx: Albuterol, l 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. 9

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 ucsf edu/products/pediatric-tuberculosis-tuberculosis guide-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) Normal Positive TST/IGRA Clinical and CXR Evaluation TB symptoms or close contact IGRA/TST (negative result not useful) Abnormal Treat for LTBI as indicated Consistent with TB More consistent with another Dx Other Dx conformed or inconsistent with TB Collect cultures Start 4 Drug Therapy No Very stable condition? Yes Reassess at least weekly Response to non-tb therapy? Other signs/sx Consider TB cultures Work-up /treat other Dx Avoid INH or FQs 10

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 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 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 mg Syrup: 10 mg/ml * Rifampin 15 (10-20) 600 mg Caps: 150 mg, 300 mg May be compounded Pyrazinamide CDC: 15-30 WHO: 30-40 Ethambutol CDC: 15 (15-20) WHO: 20 (15-25) 2000 mg NA 1600 mg NA Tabs: 500 Tabs: 100mg, 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 11

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 Rifampin Orange body fluids Advise parents! Hyperbilirubinemia Hepatotoxiticy Pyrazinamide Hepatotoxicity Arthralgia Rash Jaundice Liver enzymes PRN Clinical observation, symptoms Consider need for B6, symptoms 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) Consider Possibility of MDR-TB WHO estimates prevalence of MDR- TB is the same in adults and children 12

Regimens for MDR-TB Similar to Adults CONSULT AN EXPERT! Principals the same as adults GOAL: AT LEAST 4-5 Active Drugs (WHO recommends 6 drugs) Consider drug resistance of Region, Patient and Contact Group 1: Use all first line drugs to which isolate is susceptible INH, RIF, PZA, EMB Group 2 Add one fluoroquinolone 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) 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 20-40 mg/kg/day Max 1 mg concern) Regimens for MDR-TB Similar to Adults KEEP ADDING to get to minimum of 4-6 active drugs Group 4 Additional 2 nd Line Drugs (use as many as needed) Cycloserine 10-20 mg/kg in 2 Max 1 g per day divided doses Ethionamide 15-20 mg/kg in 2-3 Max 1 g per day divided doses Para-aminosalicyclic aminosalicyclic acid 200-300 mg/kg in Max 10 g per day (PAS) 2-4 divided doses Group 5 Limited clinical data (use with caution if additional agents needed) Linezolid Amoxicillinclavulanate 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 suscpicion: Collect best specimens possible (Admit) Identify a source case if possible 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 13

For 18 mo GIRL with 2.5 wks fever: Eventually 1 of 3 gastric aspirates grew: M tuberculosis complex Susceptible to all 1 st line drugs Fever resolved, clinically much improved Source not identified TB during pregnancy/breastfeeding Can treat LTBI during pregnancy (OK to wait until end of 1 st 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) 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? 14

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 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 15

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 16

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 technologies Transcriptional profiling Still not as sensitive as culture Use of Xpert for Diagnosis in Children 17

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 AAP Red Book: http://aapredbook.aappublications.org Red Book 2015: 736-759. Guidance for national tuberculosis programmes on the management of tuberculosis in children 2nd ed. http://www.who.int/tb/publications/childtb_guidelines/en/ CDC, ATS and IDSA Guidelines, 2003 http://www.idsociety.org/idsa_practic e_guidelines/ Call: Seattle Children s ID Service Or your local children s hospital 18