TB Nurse Case Management Norman, Oklahoma October 8-10, 2008

Tuberculosis in Children Jeffrey R. Starke, MD

October 9, 2008

TUBERCULOSIS INTUBERCULOSIS IN CHILDRENCHILDREN

Jeffrey R. Starke, M.D.Jeffrey R. Starke, M.D. Professor and Vice Chairman of PediatricsProfessor and Vice Chairman of Pediatrics

Baylor College of MedicineBaylor College of Medicine Houston, Texas USAHouston, Texas USA

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Tuberculosis is a socialTuberculosis is a social disease with medicaldisease with medical implications.implications.

A Difficult CaseA Difficult Case A 7 yo HIV + girl has cough, abdominal pain, cervicalA 7 yo HIV + girl has cough, abdominal pain, cervical

and axillary adenopathy, bilateral rales and a largeand axillary adenopathy, bilateral rales and a large liver. A 10 day course of clarithromycin did notliver. A 10 day course of clarithromycin did not improve her symptoms. Her CD4 count was 291/20%,improve her symptoms. Her CD4 count was 291/20%, her hemoglobin was 8.9, but other labs were WNL.her hemoglobin was 8.9, but other labs were WNL. After several weeks, her cough improved, she wasAfter several weeks, her cough improved, she was sweating a lot but did not have fever or weight loss.sweating a lot but did not have fever or weight loss. Her adult cousin had pulmonary tuberculosis 2Her adult cousin had pulmonary tuberculosis 2--33 years ago [household contact].years ago [household contact].

Does she have tuberculosis?Does she have tuberculosis?

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i i i i i l i i i i i i i i

i i i l

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25 - 49 50 - 99 100 - 300

0 - 9 10 - 24

300 or more No estimate

Rate per 100 000

Estimated TB incidence rates, 2000

The boundaries and names shown and the des gnat ons used on this map do not mply the express on of any opinion whatsoever on the part of the World Health Organizat on concerning the egal status of any country, territory, c ty or area or of ts authorit es, or concerning the del m tat on of ts front ers or boundaries. Dotted l nes on maps represent approx mate border l nes for which there may not yet be ful agreement.

Global Tuberculos s Control. WHO Report 2002. WHO/CDS/TB/2002.295

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EPIDEMIOLOGY OF TUBERCULOSIS INEPIDEMIOLOGY OF TUBERCULOSIS IN THE WORLDTHE WORLD –– WHO ESTIMATESWHO ESTIMATES

9.2 million incident cases in 20069.2 million incident cases in 2006 4.1 million of these cases were sputum4.1 million of these cases were sputum AFB smear positiveAFB smear positive 14.4 million prevalent cases14.4 million prevalent cases 0.7 million HIV0.7 million HIV--infected persons withinfected persons with new onset TB in 2006new onset TB in 2006 0.5 million new cases of multidrug0.5 million new cases of multidrug--resistant TB in 2006resistant TB in 2006 1.7 million deaths a/w TB in 20061.7 million deaths a/w TB in 2006

EPIDEMIOLOGY OF CHILDHOODEPIDEMIOLOGY OF CHILDHOOD TUBERCULOSIS IN SELECTED 22 HIGHTUBERCULOSIS IN SELECTED 22 HIGH--

BURDEN COUNTRIESBURDEN COUNTRIES ChildhoodChildhood Case RateCase Rate

CountryCountry CasesCases % Total Cases% Total Cases ChildrenChildren TotalTotal Afghanistan 17.540 25.3 1Afghanistan 17.540 25.3 189 32489 324 Brazil 23,520 20.7Brazil 23,520 20.7 47 6647 66 China 86,978 5.3China 86,978 5.3 27 12927 129 Pakistan 61,905 25.3Pakistan 61,905 25.3 103 172103 172 South Africa 35,449 16.1South Africa 35,449 16.1 237 501237 501 Zimbabwe 12,267 16.1Zimbabwe 12,267 16.1 221 603221 603 Range 2.7Range 2.7-25.3 1525.3 15-237 66237 66-603603 Total 659,397 9.6Total 659,397 9.6

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TRANSITIONS IN TUBERCULOSISTRANSITIONS IN TUBERCULOSIS

Cured

Treated

Diagnosed

Susceptible

Exposed

Infected

Diseased

Sick

TIME TABLE OF CHILDHOODTIME TABLE OF CHILDHOOD TUBERCULOSISTUBERCULOSIS

Site of DiseaseSite of Disease Time to DevelopTime to Develop Miliary andMiliary and meningealmeningeal 11--9 months9 months Primary pulmonary 2Primary pulmonary 2--12 months12 months Lymph node [cervical] 2Lymph node [cervical] 2--12 months12 months Pleural effusionPleural effusion 33--9 months9 months SkeletalSkeletal 6 months6 months –– 2 years2 years RenalRenal 11--5 years5 years

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ARE CHILDREN WITHARE CHILDREN WITH TUBERCULOSISTUBERCULOSIS

EVER CONTAGIOUS?EVER CONTAGIOUS?

¾¾ Difficult to answer in the communityDifficult to answer in the community

¾¾ OrphanagesOrphanages –– caretaker with TB led tocaretaker with TB led to transmission; a child with TB did nottransmission; a child with TB did not

¾¾ SchoolsSchools –– only 2 reportedonly 2 reported ““epidemicsepidemics”” causedcaused by children <13 years oldby children <13 years old

¾¾ ChildrenChildren’’s Hospitalss Hospitals –– rare case reports ofrare case reports oftransmission, all with special circumstances,transmission, all with special circumstances,none has been patientnone has been patient -- toto -- patientpatient

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FEATURES OF CONTAGIOFEATURES OF CONTAGI USOUS PEDIATRIC TUBERCULOSISPEDIATRIC TUBERCULOSIS

¾¾Cavitary lung lesionCavitary lung lesion

¾¾ Sputum productionSputum production

¾¾ Positive acidPositive acid--fast stain of sputum smearfast stain of sputum smear

¾¾BronchoscopyBronchoscopy

¾¾Draining lesions or surgical drainage ofDraining lesions or surgical drainage ofan abscessan abscess

DIAGNOSIS OF TUBERCULOSISDIAGNOSIS OF TUBERCULOSIS

All existing diagnostic tests for TB inAll existing diagnostic tests for TB in children have significant shortcomingschildren have significant shortcomings Most tests are not available in settingsMost tests are not available in settings where the vast majority of TB cases arewhere the vast majority of TB cases are diagnoseddiagnosed The utility of most tests is furtherThe utility of most tests is further diminished in children with immunediminished in children with immune compromise [especially HIV infection]compromise [especially HIV infection]

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DIAGNOSTIC TESTS FOR CHILDHOODDIAGNOSTIC TESTS FOR CHILDHOOD TUBERCULOSISTUBERCULOSIS

The sensitivity and specificity of theThe sensitivity and specificity of the available tests are inherent in the testsavailable tests are inherent in the tests However, the positive and negativeHowever, the positive and negative predictive values are inherent in thepredictive values are inherent in the population on whom the tests are usedpopulation on whom the tests are used Therefore, all tests are more accurate whenTherefore, all tests are more accurate when used on children with a high index ofused on children with a high index of suspicion [epidemiologysuspicion [epidemiology –– HISTORY OFHISTORY OF RECENT CONTACT TO A TB CASERECENT CONTACT TO A TB CASE -- oror suspicious symptoms]suspicious symptoms]

Sensitivity = Specificity = 95%

90% prevalence 1% prevalence PPV= 99% (1% false+) PPV=15% (85% false+)

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MANTOUX TUBERCULIN SKIMANTOUX TUBERCULIN SKINN TESTTEST

¾¾ uses 5 TU [2 TU if R23] of purifieduses 5 TU [2 TU if R23] of purifiedprotein derivativeprotein derivative

¾¾ interpret in 48interpret in 48 –– 72 hours72 hours

¾¾ record size ofrecord size of indurationinduration in mmin mm

¾¾ if it makes a reaction at >72 hrs, itif it makes a reaction at >72 hrs, itcounts!counts!

¾¾ false negatives: 10false negatives: 10%% to 20%to 20% in diseasein disease

FACTOFACTORRS THAT CAUSE DECREASEDS THAT CAUSE DECREASED RESPONSE TO TUBERCULINRESPONSE TO TUBERCULIN

HostHost-rerelatlateedd InfecInfecttionionss, v, vaccineacciness Chronic disChronic diseease, mase, maalnutrlnutriitiontion ImmunosuppressivImmunosuppressivee disdiseaseseases (HIV,(HIV, malignancmalignancyy,, CVD)CVD) Drugs (corDrugs (cortiticosteroidscosteroids)) ExtremExtremes oes off age, sage, sttrressess OvOvererwwhhelmielming tuberng tubercculoulossisis

TuberculinTuberculin - relarelatedted ImproperImproper stostorage orrage or diludilutitionon Adsorption to glass oAdsorption to glass orr plplasticastic

AdminisAdministtraratitionon - rerelatlateedd ReadingReading - rerelalatteedd

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INDURATION SIZEINDURATION SIZE –– POSITIVEPOSITIVE TUBERCULITUBERCULIN SKIN SKINN TESTTEST

>> 10 mm10 mm>> 5 mm5 mm

¾¾ ForeignForeign--born from a HRborn from a HR¾¾ HIV coHIV co--ininffectionection countrcountryy¾¾ Immune cImmune coompromisempromise

¾¾ DrugDrug ––usersusers¾¾ Recent contact to TBRecent contact to TB

¾¾ Living in HR congregateLiving in HR congregate¾¾ SuspectSuspected diseaseed disease settingsetting

¾¾ Specific HR groupsSpecific HR groups ¾¾ Children < 4 yChildren < 4 yrrs old (AAP)s old (AAP)

> 15> 15 mmmm

No riskNo risk ffaaccttoorsrs PrevPrevious BCious BCG vG vaccination?accination?

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INTERACTION OF BCG VACCINESINTERACTION OF BCG VACCINES WITH THE TUBERCULIN SKIN TESTWITH THE TUBERCULIN SKIN TEST

¾¾ 50% of vaccinated infants do not react to a TST;50% of vaccinated infants do not react to a TST; most of the rest stop reacting within 5 yearsmost of the rest stop reacting within 5 years

¾¾ most nonmost non--infants who get one or more BCGinfants who get one or more BCG vaccinations will react to a TST (usually < 15vaccinations will react to a TST (usually < 15 mm), but effect wanes over 5mm), but effect wanes over 5 –– 10 years10 years

¾¾ outside infancy,outside infancy, ““positivepositive”” TST more likely toTST more likely to indicate infection withindicate infection with M. tuberculosisM. tuberculosis thanthan bebe residual from BCGresidual from BCG

TUBERCULINTUBERCULI SKIN TESTING OFN SKIN TESTING OF FOREIGNFOREIGN--BORN ADOPTEESBORN ADOPTEES

On one hand, most children have received aOn one hand, most children have received a BCG vaccine within the past year, whichBCG vaccine within the past year, which can cause reaction to a TSTcan cause reaction to a TST

On the other hand, many have lived inOn the other hand, many have lived in conditions conducive to transmission ofconditions conducive to transmission of M. tuberculosisM. tuberculosis …… and we canand we can’’t do ant do an investigationinvestigation

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TUBERCULINTUBERCULI SKIN TESTING OFN SKIN TESTING OF FOREIGNFOREIGN--BORN ADOPTEESBORN ADOPTEES

General GuidelinesGeneral Guidelines

1.1. Assess for symptoms of tuberculosis diseaseAssess for symptoms of tuberculosis disease ––prolonged (>2 wk) cough, weight loss, feversprolonged (>2 wk) cough, weight loss, fevers

2.2. Note a BCG scar and/or immunization recordsNote a BCG scar and/or immunization records

3.3. Place and read a 5 TU TST withoutPlace and read a 5 TU TST without ““controlscontrols””

4.4. Delay or repeat the TST if the child is significantlyDelay or repeat the TST if the child is significantlymalnourishedmalnourished

5.5. ““PositivePositive”” TST reaction is 10mm, though this willTST reaction is 10mm, though this will result in some overtreatment due to recent BCGresult in some overtreatment due to recent BCG vaccinationvaccination

6.6. Treat LTBI with isoniazid unlessTreat LTBI with isoniazid unless specificspecific evidence ofevidence of INHINH--resistance is uncoveredresistance is uncovered

InterferonInterferon γγ teststests

oo MTB specific antigens:MTB specific antigens: GeneGen s in region of difference (RD1) on MTB genomees in region of difference (RD1) on MTB genome Culture filtrate protein 10 (CFPCulture filtrate protein 10 (CFP-10)10) Early secretory antigen target 6 (ESATEarly secretory antigen target 6 (ESAT-6)6)

oo Identifies LTBI &/or diseaseIdentifies LTBI &/or disease oo Does not cross react with BGC vaccine orDoes not cross react with BGC vaccine or

most other mycobacteriamost other mycobacteria oo Requires:Requires:

single medical visitsingle medical visit blood collectionblood collection laboratory equipment and personnellaboratory equipment and personnel

oo Results in 24Results in 24--48 hrs48 hrs

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Commercial TestsCommercial Tests QuantiFEROQuan NtiFERON-TB GoldTB Gold

Company: Cellestis,Company: Cellestis, AustraliaAustralia

US FDA approvedUS FDA approved Available in some areas ofAvailable in some areas of

USUS InIn-Tube improvementTube improvement

oo Method:Method: ¾¾Whole bloodWhole blood ¾¾ Incubated with MTBIncubated with MTB

antigensantigens (ESAT(ESAT-6 & CFP6 & CFP-10)10)

¾¾TT-Cells produce INFCells produce INF- γγ ¾¾Supernate removedSupernate removed ¾¾ INFINF- γγ measured bymeasured by

ELISA readerELISA reader

TT-Spot.Spot.TBTB or ELISPOTor ELISPOT Company: OxfordCompany: Oxford

Immunotec, UKImmunotec, UK FDA reviewingFDA reviewing Available in Europe &Available in Europe &

CanadaCanada oo Method:Method: ¾¾TT-cellscells ¾¾ Incubated with MTBIncubated with MTB

antigensantigens (ESAT(ESAT-6 & CFP6 & CFP-10)10)

¾¾TT-Cells produce INFCells produce INF- γγ ¾¾ IFNIFN- γγ binds to antibodybinds to antibody

in wellsin wells ¾¾Spots develop and areSpots develop and are

counted manually or bycounted manually or by readerreader

Release AssaysComparison of Tuberculin Skin Test and Interferon-٢

OneOneTwoTwoPatient visits requiredPatient visits required NoNoYesYesBoostingBoosting

NoNoNoNoDistinguish between TB infectionDistinguish between TB infection and TB diseaseand TB disease

9090-100%100%7070-95%95%Estimated specificity, TB inEstimated specificity, TB in immunocompetent adultsimmunocompetent adults

7575-95%95%7575-90%90%Estimated sensitivity, TB inEstimated sensitivity, TB in immunocompetent adultsimmunocompetent adults

Less LikelyLess LikelyYesYesCrossCross-reactivity with NTMreactivity with NTM UnlikelyUnlikelyYesYesCrossCross-reactivity with BCGreactivity with BCG ESATESAT-6, CFP6, CFP-1010ManyMany -PPDPPDAntigens studiedAntigens studied

IFNIFN-٢٢ Release AssayRelease AssayTuberculinTuberculin Skin TestSkin Test

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Sensitivity and SpecificitySensitivity and Specificity

QuantiQuant FERONiFERON--TB GoldTB Gold Sensitivity* (95%CI)Sensitivity* (95%CI)

Mori (Mori (‘‘04)04) 89 (8289 (82-94)94) Ravn (Ravn (‘‘05)05) 85 (7285 (72-94)94) Kang (Kang (‘‘05)05) 80 (6780 (67-90)90) Pai (Pai (‘‘05)05) 75 (6475 (64-85)85)

Specificity+ (95%CI)Specificity+ (95%CI) Mori (Mori (‘‘04)04) 98 (9598 (95-99)99) Ravn (Ravn (‘‘05)05) 97 (8797 (87-100)100) Kang (Kang (‘‘05)05) 96 (9096 (90-99)99) Goletti (Goletti (’’05)05) 90 (6890 (68-99)99)

TT--Spot.Spot.TBTB or ELISPOTor ELISPOT Sensitivity* (95%CI)Sensitivity* (95%CI)

Lalvni (Lalvni (‘‘01a)01a) 96 (8596 (85-99)99) Lalvni (Lalvni (‘‘01b) 80 (6601b) 80 (66-90)90) Pathan (Pathan (‘‘01)01) 92 (7492 (74-99)99) Chapman (Chapman (‘‘02) 92 (8102) 92 (81-98)98) Liebeschuetz(Liebeschuetz(’’04) 83 (7504) 83 (75-89)89) Meier (Meier (‘‘05)05) 97 (9097 (90-100)100)

Specificity+ (95%CI)Specificity+ (95%CI) Lalvni (Lalvni (‘‘01a)01a) 91 (8091 (80-98)98) Pathan (Pathan (‘‘01)01) 100(89100(89-100)100) Meier (Meier (‘‘05)05) 92 (6292 (62-100)100)

Pai, Expert Rev Mol Diagn. 6(3):413-422 (2006)

*Sensitivity in pts with active TB, Cx = Gold standard +Specificity in healthy low risk patients without TB

InterferonInterferon γγ teststests ProblemsProblems

Variable sensitivity (75Variable sensitivity (75--97%) in active TB97%) in active TB diseasedisease Specificity reported high (95%) but no goldSpecificity reported high (95%) but no gold standard for LTBI and concordancestandard for LTBI and concordance estimates 60estimates 60--90% with TST and Interferon90% with TST and Interferon γγ teststests

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TT--CELL ASSAYS FOR TUBERCULOSIS INCELL ASSAYS FOR TUBERCULOSIS IN CHILDRENCHILDREN

More data available for TMore data available for T--SPOT.SPOT.TBTB Appear to be more specific for tuberculosisAppear to be more specific for tuberculosis infection, especially in low prevalenceinfection, especially in low prevalence conditionsconditions Sensitivity is a bigger issue, especially inSensitivity is a bigger issue, especially in high prevalence conditions [recent contact]high prevalence conditions [recent contact] Dynamics of tests are largely unknownDynamics of tests are largely unknown Results have been highly variable, andResults have been highly variable, and

indeterminate results are common withindeterminate results are common with QuantiFERONQuantiFERON--TB GoldTB Gold

TRANSITIONS IN TUBERCULOSISTRANSITIONS IN TUBERCULOSIS

Cured

Treated

Diagnosed

Susceptible

Exposed

Infected

*Diseased

Sick

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HOW IS TUBERCULOSIHOW IS TUBERCULOSIS DIAGNOSED?S DIAGNOSED?

AduAdulltsts –– MycobacterialMycobacterial--based diagnosbased diagnosisis pospositive sputum AFB smearitive sputum AFB smear -- 60%60% -- 75%75% pospositive sputum cultureitive sputum culture -- 90%90% pospositive tuberculin skin testitive tuberculin skin test -- 80% [HIV < 50%]80% [HIV < 50%]

ChChildreildrenn pospositive sputum or gastric AFB smearitive sputum or gastric AFB smear -- 10%10% pospositive sputum or gastric cultureitive sputum or gastric culture -- 10%10% -- 40%40% pospositive tuberculin skin testitive tuberculin skin test -- 50%50% -- 80%80%

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DIAGNOSIS OF TUBERCULOSISDIAGNOSIS OF TUBERCULOSIS

““The diagnosis of tubeThe diagnosis rculosis inof tuberculosis in children relies on careful and thoroughchildren relies on careful and thoroughassessment of all the evidence derivedassessment of all the evidence derived from a careful history, clinicalfrom a careful history, clinicalexamination and relevantexamination and relevant investigations, e.g. the tuberculin skininvestigations, e.g. the tuberculin skintest [TST], chest radiography [CXR] andtest [TST], chest radiography [CXR] and sputum smear microscopy.sputum smear microscopy.””

Stop TB Partnership Childhood TBStop TB Partnership Childhood TBSubgroupSubgroup

DIAGNOSIS OF TUBERCULOSISDIAGNOSIS OF TUBERCULOSIS

Even in developed countries, theEven in developed countries, the ““gold standardgold standard”” for the diagnosis offor the diagnosis of tuberculosis in children is the triad of:tuberculosis in children is the triad of:

1.1. a positive TSTa positive TST 2.2. an abnormal CXR and/or physicalan abnormal CXR and/or physical

examexam 3.3. a history of recent contact to ana history of recent contact to an

infectious adult case of TBinfectious adult case of TB

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CLINICAL SCORING SYSTEMS FORCLINICAL SCORING SYSTEMS FOR TUBERCULOSIS IN CHILDRENTUBERCULOSIS IN CHILDREN

17 scoring systems published since17 scoring systems published since 19501950

point systems (5)point systems (5) diagnostic algorithms (2)diagnostic algorithms (2) diagnostic classifications (5)diagnostic classifications (5) combinations (5)combinations (5)

7 systems evaluated [none in HIV+7 systems evaluated [none in HIV+ children]children]

5 prospective, 2 retrospective, none5 prospective, 2 retrospective, none controlledcontrolled

OBTAINING CULTURE AND AFB SMEAROBTAINING CULTURE AND AFB SMEAR SAMPLES FROM CHILDRENSAMPLES FROM CHILDREN

Traditional method is gastricTraditional method is gastric aspiration, performed as an inpatienaspiration, performed as an inpatie tnt on 3 consecutive morningson 3 consecutive mornings –– expensive, invasiveexpensive, invasive Bronchioalveolar lavage has noBronchioalveolar lavage has no advantageadvantage Nasopharyngeal aspirationNasopharyngeal aspiration –– fewfew studiesstudies Other sitesOther sites –– yields usually 0%yields usually 0% -- 25%25% culture positive, <10% smear positiveculture positive, <10% smear positive

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INDUCED SPUTUM COLLECTIOINDUCED SPUTUM COLLECTI N INON IN CHILDRENCHILDREN

ZarZar et al. Lancet 2005; 365: 130.et al. Lancet 2005; 365: 130. Can be done inpatient or outpatientCan be done inpatient or outpatient Infection control precautions importantInfection control precautions important Salbutamol, followed by 15 minutes ofSalbutamol, followed by 15 minutes of 5% hypertonic saline solution5% hypertonic saline solution Sputum obtained via suction with aSputum obtained via suction with a nasopharyngeal catheternasopharyngeal catheter Yield: 30% to 40% culture positiveYield: 30% to 40% culture positive

INTERPRETING CHILDRENINTERPRETING CHILDREN’’S CHESTS CHEST RADIOGRAPHS FOR TBRADIOGRAPHS FOR TB

Rarely available in highest prevalence areasRarely available in highest prevalence areas Marked interMarked inter-- and intraand intra-- observer variabilityobserver variability Reliable in expert hands and in the presenceReliable in expert hands and in the presenceof suspicious symptomsof suspicious symptoms Commonest picture is persistentCommonest picture is persistentopacification together with enlarged hilar oropacification together with enlarged hilar orsubcarinal lymph nodes [though nodes notsubcarinal lymph nodes [though nodes notalways discernable]always discernable] The xThe x--ray is usually sicker than the patient!ray is usually sicker than the patient!

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CHEST RADIOGRAPH TECHNIQUE FORCHEST RADIOGRAPH TECHNIQUE FOR CHILDRENCHILDREN

Check for three important featuresCheck for three important features

1.1. RotationRotation –– can make mediastinum becan make mediastinum be widerwider

2.2. InspirationInspiration –– when inadequate, canwhen inadequate, can causecause ““mass effectmass effect”” of mediastinum,of mediastinum, hilumhilum

3.3. PenetrationPenetration –– difficult to interpret ifdifficult to interpret if xx--ray isray is ““too whitetoo white”” oror ““too blacktoo black””

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TUBERCULOSIS IN HIVTUBERCULOSIS IN HIV--INFECTED CHIINFECTED CHILDRENLDREN Clinical and Radiographic PresentationClinical and Radiographic Presentation

in childrenin children wwiith prth preseeservrveed immunocompetend immunocompetence, pce, presenresentatation ition issindistinguiindistinguisshhable fromable from HIVHIV-uninfecuninfecteted childrend children

mostmost commcommon son syymptoms remmptoms remaain malin malnutrinutrition,tion, fevfeveer, nighr, nightt sswweeaatts, lys, lymphadenopathmphadenopathyy and coughand cough

extrapulmonextrapulmonaarryy diseasedisease (meningiti(meningitis as and tubernd tubercculoulomma,a,abdominal) iabdominal) iss moremore comcommmonon

TB meningiTB meningititis hass has thethe sasame clinime clinical acal and CSF findind CSF findings as in HIngs as in HIVV-uninfecuninfectedted cchildren ehildren excexceptpt thathatt inintratracceerebrrebral maal massss lesionlesions ars aree more commmore commonon

cheschest radt radiiographograph findingfindings ares are tytypical, but morpical, but moree exextensivtensive ande and aa broader dibroader diffefferrential diential diagnosisagnosis

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TUBERCULOSIS IN HIVTUBERCULOSIS IN HIV--INFECTED CHIINFECTED CHILDRENLDREN Diagnostic ConsiderationsDiagnostic Considerations

Diagnosis of TB remains aDiagnosis of TB remains a problem, even in the bestproblem, even in the best of centersof centers –– broader differential diagnosisbroader differential diagnosis

Culture yCulture yiields are about the selds are about the saame for HIVme for HIV--infectedinfected and HIVand HIV--uninfected children when controlled foruninfected children when controlled for extent of diseaseextent of disease

Tuberculin skin test is uTuberculin skin test is useful in immunocompetentseful in immunocompetent HIVHIV--infected children but uinfected children but usefulness diminished withsefulness diminished with wwoorsening immunocompromisersening immunocompromise Interferon release assaysInterferon release assays -- no data for HIVno data for HIV--infectedinfected childrenchildren

TUBERCULOSISTUBERCULOSIS IN HIVIN HIV--INFECTED CHILDRENINFECTED CHILDREN BCG DiseaseBCG Disease

Infect Dis 2006; 42:548HesselingHesseling et al.et al. ClinClin Infect Dis 2006; 42:548

BCG disease diagnosed in 25 children over 3BCG disease diagnosed in 25 children over 3 yeyeaarrss 17/25 were HIV17/25 were HIV--infected; 2 had otherinfected; 2 had other immunocompromiseimmunocompromise Overall, 22 (88Overall, 22 (88%%)) had local disease, 8 (32had local disease, 8 (32%%))had distant or disseminated disease; 5 (20%had distant or disseminated disease; 5 (20%))hahad bothd both Of HIVOf HIV--infected children, 6 (35infected children, 6 (35%%)) hadhad disseminated diseasedisseminated disease MortalitMortality rate for disseminated diseasey rate for disseminated disease -- 75%75%

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IRIS AND MYCOBACTERIAIRIS AND MYCOBACTERIA

SoSo--calledcalled ““paradoxical reactionsparadoxical reactions”” occur inoccur in 22%% toto 2323%% of HIVof HIV--negative adult patients receivingnegative adult patients receiving treatment for tuberculosistreatment for tuberculosis

Most common features are fever and lMost common features are fever and lyymmph nodeph node enlargement, though respiratoryenlargement, though respiratory failure afailure andnd neurologic deterioration also occurneurologic deterioration also occur

Median time is 40Median time is 40--90 days after TB treatment is90 days after TB treatment is startedstarted

AbnormalityAbnormality is at the oris at the origiginalinal site ofsite of infectinfectionion inin 7575%% of cases, at a newof cases, at a new location in 25%location in 25%

Mechanism:Mechanism: increased tumor necrosis factorincreased tumor necrosis factor

IRIS IN CHILDRENIRIS IN CHILDREN

:53PuthanakiPuthanakit et ett alal.. PediaPediattrr InfecInfectt DisDis JJ 20062006; 2; 255:53

32/1532/153 (213 (21%%)) HIVHIV-infected Thai childreninfected Thai children devdeveeloped IRISloped IRIS afteafterr stastarrting HAAting HAARTRT

14/3214/32 (44(44%%) episodes) episodes asassociasociatteded wwiitth myh mycobacteriacobacteria [3[3-TB, 2TB, 2-BCG,BCG, 77-MAC Complex,MAC Complex, 22-otherother]]

In 11 oIn 11 off 1414 ppaatitients,ents, thethe mymycobactericobacteriaal inl infecfecttionsions had not behad not beeenn diagnosed pdiagnosed priorrior to sto sttaarrtiting HAARTng HAART

7 v7 vaaricellaricella-zozosstterer, 7H, 7HSV, 3SV, 3 CrCryptocoyptococccus,cus, 1 Guil1 Guillainlain-BaBarrerre

ChildrenChildren wwhho devo deveelopedloped IRIS haIRIS had significantld significantlyy lolowweer baseliner baseline CD4 lyCD4 lymphomphoccyyte countste counts

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NEEDED IMPROVEMENTS IN DIAGNOSIS OFNEEDED IMPROVEMENTS IN DIAGNOSIS OF CHILDHOOD TUBERCULOSISCHILDHOOD TUBERCULOSIS

Further characterize the TFurther characterize the T--cell assayscell assays Refine and validate clinical scoring systemsRefine and validate clinical scoring systems Study all tests in HIVStudy all tests in HIV--infected childreninfected children Make chest radiography more readilyMake chest radiography more readilyavailableavailable –– much more important role formuch more important role forchildren than for adultschildren than for adults Pediatricians must advocate for resourcesPediatricians must advocate for resources MOST IMPORTANTMOST IMPORTANT –– Design TB controlDesign TB control programs to link children with likely sourceprograms to link children with likely source casescases –– CONTACT TRACING!!!CONTACT TRACING!!!

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