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TB IntensiveSan Antonio, Texas

May 7-10, 2013

Tuberculosis in ChildrenKim Smith, MD

May 09, 2013

Kim Smith, MD has the following disclosures to make:

• No conflict of interests

• No relevant financial relationships with any commercial companies pertaining to this educational activity

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PEDIATRIC TUBERCULOSISKim Connelly Smith, MD, MPH

OUTLINE•Stages of tuberculosis•Differences of diseasein children and adults

•Diagnostic challengesof pediatric TB

•Treatment of TB in children•Clinical cases

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STAGES OF TUBERCULOSIS

Exposureto Contagious Adult with

Pulmonary Disease

Latent TB InfectionLTBI

Adult Active TB Disease

Child Active TB Disease

20-30%

5-10% Risk varies by age5-50%

Householdcontacts

RISK OF PROGRESSION TO TB DISEASE BY AGE

Age @ primary infectionBirth-12months

1-2 years

Risk of Disease

Disease 50%Pulmonary Dis 30-40%Miliary or TBM 10-20%

Disease 20-25%Pulmonary Dis 75%Miliary or TBM 2-5%

Marais BJ. Int J Tuberc Lung Dis 2004;8:392-402

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TREATMENT OF TUBERCULOSIS IN CHILDRENStages of TB Skin Test or

IGRACXR SXs Treatment

Exposure Child < 4 years of age Household contact with adult with active pulmonary disease

TST Negative Normal None Meds: INH window prophylaxisDuration: 8-10 weeksRepeat skin test: 8-10 wks after expif positive > 5mm, see LTBI

Latent TB infection (LTBI) Positive Normal None Meds: INHDuration: INH 9 mo or for INH resistant LTBI, RIF 6 mo

DiseasePulmonary and extrapulmonary(except disseminated disease and meningitis, see below)

90% positive Abnormal +/- Meds: INH, RIF, PZA(consider EMB or an aminoglycoside) Duration: 6 mo total, Stop PZA after 2 mo, continue INH & RIF for susceptible disease

DiseaseDisseminated including miliary, bone/joint and multi-site disease

TST may be negative early in disseminated TB, most positive by end of treatment

+/- Yes Meds: INH, RIF, PZA and EMB or an aminoglycosideDuration: 9-12 mo total Stop PZA and EMB or aminoglycoside after 2 mo for susceptible disease

DiseaseMeningitis

Often negative early in meningitis and miliary disease90% positive by end of tx

+/- Yes Meds: INH, RIF, PZA and Ethionamide, or an aminoglycosideor EMB daily for 2 mo, then INH and RIF for 7-10 moDuration: 9-12 mo total for drug susceptible diseaseSteroids recommended for first 1-2 mo for meningitis

Daycare Exposure

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DAYCARE EXPOSURE

Index case, teacher assistant with AFB smear positive pulmonary disease and cough for 6 weeks

135 children < 4 years of age, plus adult staff members exposed

Smith, KC. Southern Medical Journal 93(9):877-880, 2000

DAYCARE EXPOSURE MANAGEMENT

o Who is at risk?o Children and staff

o Who needs TST?o Everyone with significant contact with source case

o Who needs CXR?o All children less than 4 years of age even if TST negative o Any contacts with positive TST (> 5mm)

o Who needs treatment?o LTBI (positive TST >5mm and normal CXR) INH for 9 monthso Exposed children less than 4 years of age (window prophylaxis)

o Follow up:o Skin test conversions: 4 adults and 3 children

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WINDOW PROPHYLAXIS FOR EXPOSURE

Household contact with contagious person Teen or adult with pulmonary TB disease Usually > 4 hours of contact

Initial TST negative Window period for TST conversion

(8-10 weeks) CXR and physical exam normal INH prophylaxis recommended:

For children <4 yrs of age Immunosuppressed patients May prevent progression to disease during

window period Repeat TST 8-10 wks after exposure May stop INH if 2nd TST negative <5mm in

immunocompetent patients

PREVENTABLE CASE

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PEDIATRIC TB CASE:MISSED OPPORTUNITY

15 mo old 10 days fussiness & decreased appetite 3 days inability to walk or sit up Lumbar puncture: CSF: 96 WBC (NL <7), 72% Lymphs,

198 Protein (NL <45), Glucose 8 Source case: mother of child Child’s diagnosis: TB Meningitis

Family history Mom with pulmonary TB diagnosed 5 mo earlier on

appropriate treatment Dad diagnosed with LTBI on INH Baby initial TST 0mm @ 10 months of age no CXR no treatment lost to follow up

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TB MENINGITISTREATMENT AND CLINICAL COURSE

9-12 months RIPE therapy Steroids for 1-2 month with 2-3 week taper

decreases CNS inflammation

Fever common for first month, symptoms may initially worsen followed by gradual improvement

Possible complications Seizures Hydrocephalus CNS tuberculoma, stroke, MR, CP Mortality high (>90%) if not diagnosed and treated

*Feigin & Cherry, Text of Pedi ID

TTimetable of Tuberculosis

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DIFFERENCES INADULT AND PEDIATRIC TB

REACTIVATION DISEASE

Occurs years after primary infection

Typical of adult disease Occasionally seen in

teens Often cavitary disease High numbers of

organisms (AFB +) Usually symptomatic

and contagious

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PRIMARY TB DISEASE

Typical of childhood TBUsually not cavitary

Classic x-ray: Hilar lymphadenopathy +/-

infiltrates or Miliary pattern

Low numbers of organisms AFB smears negative (95%) Cultures negative in 60% of

cases

Most children <12 yrs not contagious

Often asymptomatic (50%)

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RADIOGRAPHIC FINDINGS INPEDIATRIC TB Hilar lymphadenopaty

Hallmark of pediatric TB LAN on CT

Central hypodensity Peripheral enhancement

Miliary infiltrates

Not specific for TB Pneumonia in any lobe Cavitary pneumonia & pleural

effusions Rare in young children Common in adults and

sometimes teens

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Pulmonary TB

85%

Extra-pulmonary

TB, 15%

Adult TB Disease

Pulmonary TB

Extrapulmonary TB

Lymphatic25%

Pleural23%GU

16%

Meningeal4%

Bone/Joint10%

Miliary9%

Other13%

Adult Extrapulmonary TB Disease (15%)

Lymphatic

Pleural

GU

Meningeal

Bone/Joint

Miliary

Other

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Pulmonary75%

Extra-pulmonary

25%

Pediatric TB Disease

Pulmonary

Extrapulmonary

Lymphatic65%

Meningeal14%

Pleural6%

Miliary 5%

Other5%

Bone/Joint5%

Extrapulmonary TB Disease in Children (25%)

Lymphatic

Meningeal

Pleural

Miliary

Other

Bone/Joint

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COMMON SYMPTOMS OF TB DISEASE IN CHILDREN

(NONSPECIFIC)

Cough and/or respiratory distressPulmonary findings on examinationLymphadenopathy or lymphadenitisS/Sx of meningitis including seizuresPersistent fever (FUO)Weight loss or failure to thriveUnlike adults, up to 50% of children with TB

disease have no symptoms

DIAGNOSIS FOR TB IN CHILDREN

Gold Standard –Positive TB Culture

OR, Clinical Diagnosis:Abnormal CXR, laboratory,

or physical examination consistent with TB AND1 or more of the following: Positive tuberculin skin test Contagious adult source case

identified Clinical course consistent with

TB disease, or Improvement on TB therapy

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DIAGNOSTIC TRIADPEDI TB DISEASE

1. Positive TST

2. Abnormal CXR

3. Infectious source case

GASTRIC ASPIRATES

Inpatient procedure

Overnight fasting

Lavage with normal saline

Collected in morning x3

Inpatient costs substantial

AFB smear yield: minimal

AFB Culture yield: 20-50%

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INDUCED SPUTUM

Outpatient procedure 2-3h fasting period Pretreatment:

Nebulized bronchodilator and hypertonic saline

Chest physiotherapy (CPT)

Nasopharynx suctioned One specimen sufficient Minimal costs

Lancet. 2005;365:130

TB CULTURES FROM CHILDREN

Bronchoalveolar lavage (BAL) Single specimen with similar yield to 3

GA’s

Lymph nodes Biopsy or FNA for path and culture

(30-70% yield on culture)

For TB meningitis High volume (>6 ml) CSF sample

improves culture yield but still low 20% average (12-50% range)

Negative culture does not rule out disease

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DIAGNOSIS SUMMARY

Combination of findings important Risk factors Contact testing/exposure history Skin testing and/or IGRA blood test Radiographic findings suggestive of TB Rule out other diseases

High index of suspicion urgent with TB meningitis

IGRA TESTS IN KIDS

Sensitivity Variable 50-90%

Highly specific Does not cross react with BCG vaccine or most other

mycobacteria Specificity is 90-95%

Helpful (preferred) in BCG vaccinated patients May save costs by reducing false positives Children <5 yrs - not FDA approved

Due to limited data and concerns about false negatives Consider either test (IGRA or TST) positive in this

vulnerable age

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QUANTIFERON TB META ANALYSIS IN CHILDREN

Systematic review and meta analysis of QFT for LBTI and TB disease in children 20 of 68 studies used

Conclusions: LTBI: QFT has higher specificity compared to TST

Disease: Sensitivity of QFT was no different from the TST

Lower QFT sensitivity was found in high-burden settings (55%) compared with low burden settings (70%)

Machingaidze et al. PIDJ 2011; 30: epub

Machingaidze et al. PIDJ 2011; 30: epub

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TB Risk Questionnaire positive?

Screening Complete

Age < 5 years?

BCG Vaccinated?Likely to return for 

TST reading?

TST Preferred*

Concern for TB disease?*

Concern for TB disease?*

IGRA Preferred

Negative, testing  complete

TST or IGRA Acceptable

Negative Indeterminate Positive, testing complete

TST Result?

Repeat IGRA

Initial TST Done?

Indeterminate

Consider TST if not done

Negative, testing complete

Algorithm for TB Testing in Children

*Either positive TST or IGRA considered significant (indicative of TB infection or disease) if there is clinical suspicion of disease or high risk for progression or poor outcome in patients with latent TB infection 

No

No

No

No

No

No

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Positive

Negative

Geltemeyer A, Smith KC. IUATLD 2012.

What to do with Discordant IGRA and TST Results?

Consider either test positive If disease is suspected If patient is at high risk for progression to disease

(infants or immune compromised)

For healthy patients (5 or older) without risk factors Choose the more specific test (IGRA)

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EXPECTED CLINICAL COURSEFOR TB DISEASE IN CHILDREN

Pulmonary CXR takes months to improve

Hilar lymphadenopathy May take a year or more to regress on x-ray

Cervical lymphadenitis Gets worse before improvement over months-years

Meningitis Inflammation and symptoms sometime increase

initially with treatment

MONITORING CHILDRENON TB TREATMENT

Risk of drug toxicity very low Monitor clinical signs

regular clinical visits (4-6 wks) patient education

Routine blood work not necessary unless symptoms risk factors for toxicity

Monitor and reinforce adherenceWhen to follow up CXR’s for pulmonary TB

Beginning and end of therapy Anytime if clinical change

Completion of therapy certificate

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TB MEDICATIONS IN KIDS

Hepatotoxicity rare INH liquid vs tabletsMedication refusal in children Crush tablets, medication sandwich

Vitamin B6 Not needed for all kids Important in

Breastfed infants Teens and/or picky eaters Patients with symptoms of peripheral neuropathy

Going back to school Children <12 yrs of age are not contagious

CENTRAL NERVOUS SYSTEMTB DRUG PENETRATION

Isoniazid Rifampin PZA Ethambutol Ethionamide Aminoglycosides Fluoroquinolones

Good Inflamed meninges only Good Inflamed meninges only Good Inflamed meninges only Good except Cipro poor

Drug CNS Penetration

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ETHAMBUTOL IN CHILDREN

Risk of optic neuritis: Visual acuity Color perception Dose related Usually reversible Risk around 1-3% in adults Risk in children about the same

EMB probably safe in children Monitor vision on treatment Infants - VEP

Table 2. Studies that have specifically sought optical toxicity in children treated with Ethambutol

Reference Patients (n) Age range Method of evaluation Length of follow up Number with(months) toxicity

2425

Fox*262728

4736

4530276

3-13 years4 months to 16 years1-15 years4-5 years5-15 years9-16 years

Visual evoked responsesAcuity/field/colour

Acuity/field/colourAcuity/field/colourAcuity/field/colourComputerised visual fieldexaminiation

15-1824-48

9-18612-369

00

0000

*Fox W, unpublished data quoted in Tubercle 1986; 67:27.

SM Graham. Arch Dis child 1998; 79:274-278.

Ethambutol in Children

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*B Hampel. Pediatr Inf Dis J, 1997;16:127-9.

FLUOROQUINOLONES IN CHILDREN

Initial clinical trials in children not done Some children have been treated without

problems: CF, chronic UTI, shigellosis and TB

Probably safe in children: Some case series and RCT with good results Germany study: 2030 patients treated, 31 (1.5%)

with self resolving arthralgia*

Not indicated for routine infections in children Consider risks and benefits Monitor clinically for joint and tendon

problems

Comparison of Side Effects with Ciprofloxacin vs Ceftazidime/Tobramycin in Children

No. of Patients

Event CiprofloxacinCeftazidime/TobramycinN = 62 (%)N = 67 (%)

P

Any 52 (78) 43 (69) 0.288Abnormal liver function tests 17 (25) 13 (21) 0.554Injection 16 (24) 5 (8) 0.015Injection site pain 13 (19) 7 (11) 0.203Rash 10 (15) 5 (8) 0.225Phlebitis 7 (10) 1 (2) 0.063Vomiting 11(16) 4 (6) 0.078Central nervous system, any 1 (1) 6 (10) 0.055Respiratory, any 7 (10) 3 (5) 0.328Musculoskeletal, any 15 (22) 13 (21) 0.845

Joint Disorder 8 (12) 10 (16) 0.493Arthralgia 7 (10) 7 (11) 0.878Arthritis 1 (1) 0 (0) 1.0Leg cramps 0 (0) 1 (2) 0.481Myalgia 1 (1) 0 (0) 1.000

DA Church. Pediatr Infec Dis J 1997 Jan; 16 (1): 97-105

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PEDIATRIC TB CASES

LYMPHADENOPATHY

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CLINICAL CASE

CERVICAL LYMPHADENOPATHY

8 yr old with cervical lymphadenopathy

History: LAN for 3 months PMHx: HealthyBCG vaccine at birth

TB skin test 10 mmPhysical Exam:

3 cm anterior cervical LAN 1.5 cm supraclavicular

lymphadenopathy CXR:

Hilar LAN, no infiltratesIs this TB disease?What else could it be?

HILAR & CERVICALLYMPHADENOPATHY

Differential Dx Tuberculosis Non TB mycobacteria (NTM) Lymphoma/Leukemia HIV Other causes

Diagnostic tests Biopsy (FNA or surgical for

culture and path) Interferon Blood test for TB

infection

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RESULTS

Fine needle aspirate of node: Pathology: lymphoma, no TB by culture or microscopy

Interferon Blood test for TB Positive Diagnostic for latent TB infection or disease

Diagnoses: LTBI

AND Hodgkin’s Lymphoma

Treatment: Chemotherapy for lymphoma AND INH daily for 9 months for LTBI

consider prolonged treatment during immunosuppresion

Skin Test in Foreign Born

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SKIN TEST IN FOREIGN BORN

6 year old with positive TST for school entry Born in Asia BCG documented on vaccination records at birth

and BCG scar present TST measures 12mm

CXR NORMAL

How do you interpret the 12 mm skin test?

Is this BCG effect or LTBI?

Are there any other tests that may help?

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TB IN NEWBORN NURSERY

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NEW MOTHER WITH POSITIVE TST

Newborn infant in hospital nursery Mother with 15 mm TST CXR: calcified granuloma no active disease Not on treatment

What is mother’s diagnosis? Do mother or baby need isolation? May baby breast feed and room with mother?

NEW MOTHER WITH POSITIVE TST

What if mother had cavitary disease on CXR with AFB + pulmonary disease?

How should baby be treated?

May baby breastfeed?

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Maternal positive TB skin test or suspected pulmonary TB during 

pregnancy 

Maternal CXR

Normal Maternal CXR

Abnormal Maternal CXR

Ask if household contacts have TB or symptoms of TB

• Refer symptomatic adult contacts for TB test

• Refer adults with positive skin tests for CXR

• Mother is NOT contagious• No separation of mother from infant 

indicated• May breastfeed• No TB treatment or evaluation of 

infant indicated

If adult CXR concerning for active TB disease• Either keep infant separate from 

adult TB case or start infant on INH prophylaxis

Is mother contagious?Mother is contagious if:• Maternal CXR with infiltrates or cavitation (active TB disease) and/or • Recent AFB sputum smear or culture positive for TBMother is NOT contagious if:• No symptoms AND • CXR shows inactive or healed disease (i.e. calcified granuloma or healed 

scars)Mother is NOT contagious if:• Previously diagnosed, on TB treatment for at least 2 weeks AND• Mother’s sputum AFB smears and TB cultures are negative x 3 specimens

Evaluation and treatment for TB exposed infants:• Consider pediatric TB specialist consult• Obtain infant CXR and clinical assessment to rule out TB disease, if negative 

start INH prophylaxis• If infant CXR or clinical assessment are suspicious for TB disease, consult 

pediatric TB or ID specialist for further evaluation and treatment• Separation from mother is NOT required if no drug resistance and mother 

adheres to treatment

Follow up of infant:• Refer infant to TB clinic for follow up• Continue INH prophylaxis for 3‐6 months depending on 

exposure• TB skin test for infant at 3‐6 months• If infant’s skin test negative (<5mm) and no TB exposure for 

3 months, may stop INH prophylaxis• If infant’s skin test positive (> 5mm), complete 9 months 

INH

Management of the NewbornWhen Maternal TB Suspected

NOYES

PREVENTION OF TB DISEASEIN CHILDREN

Contact Investigation

INH Window Prophylaxis

Treatment of LTBI

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RESOURCES

HNTC Pedi TB Toolbox Guidelines and clinical tools Reference materials Patient education materials

Pediatric Radiology for Clinicians