Pediatric Tuberculosis Nadia Sam Agudu

Pediatric TuberculosisND DOH HIV/STD/TB Hepatitis ForumNadia Sam-Agudu, MD, DTM&HPediatric Infectious DiseasesPediatric Travel ClinicImmigrant, Refugee and Adoption MedicineMeritCare Childrens Clinic and HospitalMay 20, 2010.

ObjectivesBe familiar with the epidemiology of pediatric TB in the US, ND (and MN)Understand the differences in pediatric TB presentations, compared to adultsKnow the differences between, and isolation guidelines for, patients with LTBI and active TBBe familiar with guidelines for pediatric TB workup and management

OutlineMycobacteriology 101Epidemiology of pediatric TB in US, ND & MNTB overview: infection, active disease, testingDifferences between adult and pediatric TBWorkup and management of pediatric TB Summary and Pearls

Mycobacteriology 101Mycobacterium tuberculosis130+ Mycobacterium speciesTB and non-TB mycobacteria (NTM)Grouped in complexes of mycobacteria that are similar to each otherM TB complex (M bovis, M africanus, M microti, M Tb)

Mycobacteriology 101What do we mean by acid-fast bacilli (AFB)?Mycobacteria are rod/bacillus shapedThick lipid cell wall (mycolic acid) that repels standard stains (eg gram stains)Concentrated dyes are used, thenAcid decolorization is performedMycobacteria resist the acid and retain colorAcid-fast

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TB EPIDEMIOLOGY

Percent of US Pediatric TB Cases by Age Group19932006N=15,946CDC data

Percentage of Tuberculosis Cases by Race/Ethnicity, MN, 2004 - 2008

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54.7

22.6

2.4

8.7

11.6

54.7

22.6

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11.6

8.7

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Black54.7

Asian22.6

Native American2.4

White8.7

Hispanic/Latino11.6

To resize chart data range, drag lower right corner of range.

TB Epidemiology: NDPercentage of Tuberculosis Cases by Race/Ethnicity 2005 - 2009

TB Epidemiology: NDPercentage of Tuberculosis Cases that are U.S.-born or Foreign-born, 2005 - 2009

TB OVERVIEW: INFECTION AND ACTIVE DISEASE

TB overview: infection and diseasePrimarily spread by respiratory routeLargely a lung diseaseTransmission by skin and gut can also occurPerson with active disease coughsTB bacilli suspended in very tiny particlesCan stay airborne for extended periodExposed individual directly inhales the contaminated particlesRisk of infection depends on disease burden in the index case, proximity and duration of exposureHousehold exposure from adult with active disease is strongest sourceChildren are typically less infectious than adults

Marais BJ et al., 2004

Risk of progression to TB diseaseAge at primary infection (yr)No diseasePulmonary diseaseDisseminated disease or TB meningitis

TB infection and diseaseIn any TB case, one needs to be infected before developing diseasePrimary infection may stay latent: LTBIPrimary infection may proceed immediately to primary active TB diseasePrimary infection may be latent for a while, and may proceed to disease years later (secondary active TB)Overall risk is ~5% in the first 2 yrs after infection, and ~10% over a lifetime, as one agesRisk higher with immunodepression eg HIV, cancer, medsEg TB rate in untreated HIV is 7-10% per yearA positive PPD only indicates that someone is infectedIt does not give you any info on the time of acquisition, latency, or activity of TB disease

TB clinical manifestations

TB TESTING AND DIAGNOSIS

Purified Protein Derivative (PPD) testAka tuberculin sensitivity test (TST), Mantoux test, TB skin testFirst described by Robert Koch in 1890Test further developed and refined by Charles Mantoux in 1907Purified protein extracts from M TB cultures are injected into skinImmune T cells that have been sensitized to TB from prior infection migrate to the injection siteRelease chemicals that produce local inflammation and induration (bumpy reaction)After initial infection, it takes 2-10 wks (median 3-4 wks) to develop hypersensitivity to the PPD test.At best, PPD is ~90% sensitive, ~90% specific

PPD/TST/Mantoux testOnce positive, a PPD will always be positive. It will not go away with treatment, either for LTBI or for active diseaseDont bother to recheck it after the patient has been treatedIt is a badge that will always be worn by the patientExceptions: immune compromise that affects the T cells that are supposed to react eg HIV; and young infants, elderlyThis is called anergy-negative PPD test in one who you know/suspect has been infectedMinimum recommended age for PPD: 3 months

*How does one determine a positive PPD?*It depends on the patient being evaluatedWhere they were born/coming from,Household or close contact exposure, Immune statusSubject to the providers interpretation, clinical experience and skillEither way, you still need a measuring tape!Do not measure rednessMeasure induration (bumpiness) onlyMeasure perpendicular to forearm plane ( short arm of a cross) Is it 5, 10 or 15 mm?Based on risk of acquiring infection and progression to active disease

Definitions of positive PPD (Red Book 2009 ,p 681)CategoriesMeasurement cut-off1. Child in close contact with known or suspected contagious TB case2. Child suspected to have active TB -CXR findings consistent with active or previous untreated, non-healed TB -Clinical evidence of active TB3. Child immunosuppressed eg HIV or meds5mmChild at increased risk of disseminated TB -

Negative PPDNo need for CXR-If recent close-contact exposure, repeat PPD in 8-10 weeks -To make sure you havent missed a new conversionNo TB infection

Variations of +PPDBlisters, granulomas, local necrosis may occur

So, the PPD is positiveNow what?This means your patient is infected with TBBCG or non-TB mycobacteria may cause a false positive PPDThis effect fades significantly by 2-5 yrs after BCG vaccine-should not even be an issue with adolescents or adultsIn practice, BCG is not taken into consideration with +PPD. This is the recommendation from TB experts.BCG is certainly irrelevant in a contact investigation.You have to determine if they have active diseasePerform a CXR: two-view, PA/AP and lateralLooking for most common manifestation of active TB

Positive PPDNegative CXR+=Latent TB Infection

Positive PPDTB-Positive CXR+

= active TB

TB-positive CXR: adult-like presentation TeenagerPPD 25mmCavitary lesion in right upper lobeContains many TB bacilliEfficient coughing mechanismSputum AFB smear -positiveVery contagiousCXR findings take months to resolve

Miliary (disseminated) TB in an infanthttp://www.hawaii.edu/medicine/pediatrics/pemxray/v4c06b.jpgCongenital TB may present like this

A TB evaluation curveball6 yr old child being evaluated for TB infectionForeign-born, new immigrant (10mm)PPD is positive at 14mmChild gets CXR a few days laterWhile having a cold

Nasal congestion with runny noseFew crackles on lung exam, occasional coughExam otherwise normalNo recent fever, weight loss or changes in appetiteI think hes got LTBII start treatment with INHCall me with any illnessRepeat CXR in 1 monthCleared!Continue 9 month INH treatment for LTBIA TB evaluation curveball

TB: adults vs childrenCompared to adults, children:Tend to develop primary active TB more often after initial infection (0-4yrs)Are more likely to have extrapulmonary disease, especially TB meningitis (0-4yrs)Are more likely to have disseminated TB infectionAre less contagiousPaucibacillary disease (fewer organisms)Cannot cough/spread infection as wellAre more difficult to diagnoseMay not show typical symptomsMay have TB disease in unexpected placesHave less FDA-approved treatment meds and formulation options

TB: adults vs childrenA child with active TB is an indicator of an unidentified contagious adult/adolescent with TBContact investigation: Public Health staffMany other children may be diagnosed this way (26-80%, vs 3-25% by routine screening and 17-44% by symptoms)A child suspected of having active TB may not yield any positive cultures/smearsNeed the adult contacts culture results for drug sensitivities and to determine treatment regimen for the childA thorough contact investigation is critical in the evaluation, management, and prevention of TB infection in the child.

TB treatment: LTBIBacilli are well-contained in the lungforever?Risk of secondary active TB (from this personal collection of TB) increases as one gets olderCancer diagnosis, steroids, immune suppressive drugs for autoimmune disease, HIVAka reactivation TBNeed to eliminate this small collection to avoid future reactivationPeople with LTBI are latent reservoirs of TB bugsOf Public Health importanceTreatment with 1 drug (INH) for 9 months: TB is a slow-growing bugNo need for any isolation: LTBI is not contagiousYoung children or compliance issues: may get DOT (directly observed therapy) for LTBI

TB Treatment: active diseaseRIPE drugs-firstline: 1. Rifampin (RIF) , 2. Isoniazid (INH) 3. Pyrazinamide (PZA) 4. Ethambutol/Ethionamide (ETH)Typically 6 month tx: all 4 drugs x 2 months, then INH/RIF x 4 monthsTB meningitis and disseminated TB: 9-12mo4 drugs x 2mo, then 2 drugs x 7-10 mo.MDR and XDR TB: 4-6 drugs for 18-24 monthsHIV coinfection: 3 drugs for 9 months recommendedNo differences in adult vs child treatment regimensDOT critical for all patients on treatment, to ensure consistency and completionMay not be feasible in remote areas/understaffed

Pediatric TB treatment: medication issuesFree TB drugs available for LTBI and active disease treatment, from State Depts of Health.All 4 standard drugs are taken orallyDosing for children is weight-basedINH and RIF are the backbone of treatmentINH-RIF and INH-RIF-PZA combo tablets availableNot for use in childrenNot available free from Depts of HealthINH comes in syrup form, but due to sugar type (sorbitol), osmotic diarrhea is likelyPrescribe INH tablets to be crushedRIF can be made into suspension; no such luck for Ethambutol/EthionamideHepatitis is biggest concern with TB drugs: adults >> childrenI still do baseline liver tests (comprehensive metabolic panel) for all children on any TB treatment.

Summary and PearlsClinical manifestations in pediatric TB may be non-specificTB is much more difficult to diagnose in children Undiagnosed or untreated TB in a child is potentially serious, More likely to develop severe or disseminated diseaseDiagnosis of TB in a child is a sentinel eventContact investigation is criticalKnowing how to administer and read PPDs, and to contextually interpret PPDs and CXRs is vitalOur low-prevalence status in ND does not let us off the hookWe are less experienced than other states because of low volume of cases

ReferencesRed Book 2009. Tuberculosis.Pediatric practice: Infectious Disease. Ed: Shah,S. Chapter 36: Childhood tuberculosis.CDC/ATS/IDSA TB guidelines 2003. MMWR June 20, 2003; 52:#RR11. www.idsociety.orgPediatric TB: an online presentation.http://www.nationaltbcenter.edu/pediatric_tb/presentation.cfmMarais BJ et al. The natural history of childhood intra-thoracic TB: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8(4): 392-402.

ReferencesCenters for Disease Control. www.cdc.gov/tb/www.cdc.gov/tb/statistics/reports/2008/default.htmhttp://www.cdc.gov/tb/publications/slidesets/pediatricTB/default.htmCDC. Decrease in reported TB cases, 2009. MMWR March 19, 2010. 59(10); 289-294.MN Dept of Health.www.health.state.mn.us/divs/idepc/diseases/tb/index.htmlND Dept of Health. www.ndhealth.gov/disease/tb

*********The pediatric age group (< 15) can be divided into four groups that reflect age-dependent differences in TB pathophysiology that have been noted historically:Age < 1: Infancy. Cases in this age group represent the most recent transmission and also are slightly more likely to be the severe forms of disease that were uniformly fatal before the discovery of chemotherapy.Age 14: Toddler/preschool. In this transitional age group, primary pulmonary TB is the most common form, and self-resolution of recent infection is a greater possibility.Age 59: School age. In this age group, primary pulmonary TB is the expected form of disease, but rare instances of contagious adult form/reactivation disease are reported.Age 1014: Early adolescence. Another transitional period, where disease patterns more similar to adult forms become more prevalent.*********TB most typically is a pulmonary disease, but the infection can manifest in any organ system. More than a quarter of pediatric cases involve a extrapulmonary site. Of these sites, disease in the lymphatic system is most common.***********http://info.med.yale.edu/intmed/cardio/imaging/findings/hilar_adenopathy2/graphics/rad2.gif********Slightly more than a half of pediatric TB cases are verified by the clinical case definition only, and slightly less than a quarter of cases have bacteriological confirmation, and this is matched by the fraction that are counted because of the decision of a medical provider, which has the least specific verification criteria. Furthermore, these proportions are different for the subgroups of pediatric age that were defined for earlier slides in this series.********