Pediatric Tuberculosis 2011 - Global TB Centerglobaltb.njms.rutgers.edu/downloads/courses/2011/netbc2011/POWELL... · Pediatric Tuberculosis 2011. Dwight A. Powell, MD, ... Our current

Pediatric Tuberculosis 2011

Dwight A. Powell, MD, FAAP Professor Emeritus of Pediatrics

The Ohio State University College of Medicine Member, Section of Infectious Diseases

Nationwide Children’s Hospital, Columbus, Ohio

25-44 yrs (34%)

Reported TB Cases by Age Group, United States, 2009 - CDC

<15 yrs (6%)

15–24 yrs (11%)

45–64 yrs (30%)

>65 yrs (20%)

Groups at higher risk of developing disease after infection

• Immunosuppressed patients:

Prolonged steroids; immune suppressants; malignancy

• HIV infected patients

• Underlying poor health:

Diabetes, renal failure, silicosis, chronic lung disease, malnutrition

• Substance abuse

• Persons < 4 years of age

Groups at high-risk of exposure and infection

• Close contacts of cases of reactivation TB

• Foreign-born from high risk countries

• Residents of high-risk institutions

• Medically underserved, low-income persons

• Injection drug users

• Persons exposed to high-risk adults

~35% of household

contacts are infected

95%

NEJM 345:189, 2001

Bacteremia and dissemination to

multiple body organs

“LTBI” Major focus for PPD screening

- 15%

Adolescent with Latent TB

LTBI in a child is a sentinel event indicating contact with a case of active TB

Age Distribution of TB disease in children

Burroughs, M et al. PIDJ 18:440, 1999

0

5

10

15

20

25

30

35

40

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Age (years)

No. of Cases

Major site of TB disease in 11,480 children ≤ 15 yrs old in the U.S. 1993-2001

Site Number (%) Pulmonary 8824 (76.9) Lymphatic 1778 (15.5)

Meningeal 249 (2.1) Bone/Joint 156 (1.4) Pleural 132 (1.1)

Miliary 125 (1.1) Other 223 (1.9)

Nelson LJ et al Pediatr 2004;114:333

Symptoms in Children with TB disease

Burroughs, M et al. PIDJ 18:440, 1999

Symptom Frequency (%) Symptom (156 children < 20 yrs)

Cough 62 Fever 55

Weight Loss 32 Night Sweats 26 Hemoptysis 12

Primary pulmonary TB in children

10 yr old female with segmental RLL infiltrate and paratracheal lymphadenopathy

Progressive primary pulmonary TB in children

4 mo female with RLL consolidation and R hilar lymphadenopathy

Cavitary TB in an adolescent

17 yr old BF, 2 mo cough, night sweats and 10# wt loss. Born in Virgin Islands; in U.S. x 10 yrs. PPD >20mm; sputum (+) M. tuberculosis

Miliary tuberculosis

3 year old female exposed to her grandfather with pulmonary TB

13 month old Honduran male whose grandfather has cavitary tuberculosis

diagnosed after this child presented with fever,

irritability and nuchal rigidity

CSF: Glucose 50, prot 108, RBC 13, WBC 39, 100%

mononuclear cells.

Tuberculous meningitis

Gadolinium enhanced T1 weighted MRI

Tuberculous meningitis

13 yr old BM. 2 mo hx neck swelling, fever & 4# wt loss. Born in Somalia; moved to U.S. 9 mo PTA. PPD (+) but no Rx. PPD 25mm

Lymphatic TB in children TB Lymphadenitis in children

Pott’s Disease (TB of vertebral bodies)

T6

L2

S1,2

T2 weighted MRI

T1 weighted MRI with

gadolinium

18 yr old college student from Ghana; known PPD positive in 2001; no RX. Developed 2 mo. back pain and leg weakness during football practice in 2005.

PPD 30 mm

Inadequately treated Pott’s disease

10 yr old Somali female with severe kyphoscoliosis who was treated with one medication and coining at age 2-3 yrs

Inadequately treated Pott’s disease

T1 weighted MRI showing destruction and fusion of

C5,6,7 &T1 vertebral bodies.

Diagnosis of TB infection in Children

• Tuberculin skin test (TST) or Interferon gamma release assay (IGRA)

• CXR if one of the above is positive • Complete physical exam • Search for contact source • Treat for LTBI if CXR and PE are negative • Pursue further evaluation if CXR or PE are

abnormal

Further diagnosis of TB disease in Children

• Attempt to Isolate organism • induced sputum x2 – AFB smear, culture

(cx) and nucleic acid analysis (NAA) • gastric washings x 2-3 – Cx and NAA • biopsy or fluid aspiration – Cx and NAA • lumbar puncture in infants of if signs of

meningitis – cells, prot, gluc, cx, NAA • HIV testing

Definitions of Positive PPD Results in Children Induration ≥5 mm Children in contact with known active TB Children with clinical or radiographic illness consistent with TB Children who are immunocompromised Induration ≥10 mm Children at increased risk of disseminated disease

• Age < 4 yrs or underlying medical illness Children with increased exposure to TB

• Born or parents born in high-prevalence countries • Frequent exposure to adults with high-risk of TB • Travel to high-prevalence countries

Induration ≥15 mm Children >4 yrs old without any risk factors Redbook, 2009

BCG scar after vaccination at birth

Santiago EM et al. Pediatr 2003;112:e298

7.5 wks after birth 6 mos after birth

PPD skin test results in persons without known exposure to TB; those with BCG

were vaccinated as infants

Wang L et al. Thorax. 2002;57:804–809.

BCG vaccine site - Japan

Interferon-γ release assays for detection of M. TB infection

QuantiFERON-Gold In Tube (QFT-GIT) and TSPOT.TB

Antigens used: ESAT-6, CFP-10, and TB7.7

CDC updated guidelines for using intereron gamma release assays to detect Mycobacterium

tuberculosis infection – U.S. 2010

Use of QFT-GIT and T-SPOT for testing children: • Assessing the accuracy of IGRAs has been

more difficult in children than in adults • This is especially true for children < 5 yrs old • Use of IGRAs in children is subject to several

limitations: • Studies in children are scant • Indeterminant results are more common in

children than adults • Some studies have raised concern that

IGRAs may have lower sensitivity that TSTs in children Mazuek GH et al. MMWR 2010;59:RR-5

Sensitivity of IGRAs in culture confirmed TB disease in children

Ling DI et al. Pediatr Resp Rev 2010;12:9

Specificity of IGRAs in culture confirmed TB disease in children

Ling DI et al. Pediatr Resp Rev 2010;12:9

Retrospective review of TST vs IGRAs in 49 children in the UK with culture confirmed TB

Test No. tested No. positive (%) TST >15 mm 45 37 (82) TSPOT 25 16 (64) QFT-GIT 43 35 (81) TST or TSPOT (+) 25 24 (96) TST or QFT-GIT (+) 43 39 (91)

Bamford AR et al. Arch Dis Child 2010;95:180

Summary of evidence from 12 studies comparing IGRAs vs TST for LTBI in children

IGRA type IGRA (+) TST (+) QFT-G 33/195 (17) 47/195 (24) QFT-GIT 60/334 (18) 58/334 (17) QFT-GIT 16/210 (8) 98/227 (43) QFT-GIT 11/105 (10) 10/105 (10) QFT-GIT 31/204 (15) 116/207 (56) QFT-GIT 65/192 (34) 57/193 (57) QFT-GIT 61/184 (33) 80/184 (43) TSPOT 36/120 (30) 84/120 (70) QFT-GIT 29/97 (30) 46/95 (48) TSPOT 25/95 (26) 46/95 (48) BOTH 71/215 (33) 57/215 (27) Ling DI et al. Pediatr Resp Rev 2010;12:9

Results in 217 immigrant children from Africa or Asia screened in Australia with TST, QFT-GIT and TSPOT

NONE of the children had known household exposure to TB

Lucas M et al. Thorax 2010;65:442

Results in 22 immigrant children from Africa or Asia screened in Australia with TST, QFT-GIT and T.SPOT.TB .

All of these children had KNOWN household exposure to TB

Lucas M et al. Thorax 2010;65:442

Progression to active TB in 104 German children <16 yrs old followed for 2-4 yrs without treatment after > 40 hrs

contact with an adult with active TB

QFT

-GIT

Diel R et al. Am J Resp Crit Care Med 2011;183:88

♦ active TB ♦ no BCG O BCG

Our current policy for tuberculin skin testing and IGRA testing for children

• Screening for active TB • Use TST, QFT-GIT, and T-Spot.TB • Further evaluate and treat if any positive • If clinical evidence of miliary TB meningitis,

malnutrition, or compromised immunity, further evaluate and treat even if all are negative

Our current policy for tuberculin skin testing and IGRA testing for children

• Screening for LTBI in asymptomatic children • Initial PPD skin test • If known TB exposure and TST ≥ 5mm, obtain

QFT-GIT and T-Spot.TB (if age < 5 yrs) • If no known TB exposure but high exposure risk:

• TST > 15 mm – No IGRA – start RX • TST 10-15 mm, obtain QFT-GIT and T-

Spot.TB (if age < 5 yrs). If IGRA (+) treat; if IGRA (-) do not treat

• TST < 10 mm – no IGRA

Directly observed therapy of TB Disease Stage of TB RX Duration Pulmonary TB ♦ Non HIV (+), US born INH/Rif/PZA* 6 mo** ♦ HIV(+) or foreign INH/rifabutin/PZA/eth 6mo** born Extrapulmonary TB meningitis INH/RIF/PZA/eth 9-12 mo** bone, joint, miliary Same as pulmonary 6-9 mo** *if INH resistance >4% or high risk of drug resistance in source, add ethambutol until drug susceptibility confirmed. **PZA for only first 2 months

Treatment of LTBI or contact of child with adult case of TB disease

Drugs Dosage Duration, mo Interval INH 10-15 mg/kg 9 Daily INH 20-30 mg/kg 9 2-3x/wk, DOT For know exposure to INH resistant case Rifampin 10-20 mg/kg 6 Daily For children who are contacts of adults with TB disease - Tuberculin skin test and CXR; repeat in 8-10 weeks if (-) - If child < age 4 years begin INH as above; continue INH

until repeat TST is (-) and index case is on DOT and confirmed to be sputum (-)

Importance of therapy for LTBI

• New cases of active tuberculosis in the United States, as in other low prevalence countries, generally occur as re-activation of LTBI.

• Children are estimated to have a 5-15% lifetime risk of conversion from LTBI to active disease.

• Monotherapy with isoniazid (INH) for 9 months has been demonstrated to reduce risk of conversion to active disease in children by greater than 90%.

• A primary objective in the US strategy for tuberculosis (TB) control is to achieve successful completion of a course of treatment for ≥ 85% of high-risk individuals.

NCH LTBI clinic 2005-present • Persons ≤ school age screened by school nurses, refugee center,

or Columbus Public Health • Persons with (+) TST sent for CXR at NCH • CXR read within 15 minutes

• Those with (+) CXR admitted to full evaluation • Those with (-) CXR sent to LTBI clinic

• CPNP obtains full Hx and PE, orders IGRA if indicated, and initiates therapy in those with (+) IGRA or > 15 mm TST

• CPNP provides educational material in English, Spanish, or Somali

• CPNP follows patients monthly with pill count and incentives • Patients on INH are considered to have completed therapy

with 270 doses taken over 12 months

0%10%20%30%40%50%60%70%80%90%

100%

Mexico, Central& South America

Sub-SaharanAfrica

Northern Africa &Middle East

Eastern Europe United States Asia

Completion of therapy for LTBI in 545 children from 54 different nationalities (overall completion rate = 54.4%

Powell DA et al. PIDJ 2008;28:272

Powell DA et al. PIDJ 2008;28:272

Evaluation of 1521 children from 91 different countries enrolled in the NCH LTBI clinc from

6/1/06 to 12/31/09 and offered treatment based on TST ≥ 10 mm

• Therapy was refused by 138 (9.1%) patients • Only patients from countries in Pacific Asia (47.6%),

Eastern Europe (38.9%), and North Africa and the Middle East (19.0%) had greater than 10% rate of treatment refusal.

• Therapy was initiated by 1383 patients (mean age = 10.9 years, median = 11.5) and completed by 1000 (72.3%).

• Patients who initiated therapy were given the option to follow up monthly in the main NCH LTBI clinic or in one of two NCH Close to Home Clinics

Completion of therapy by clinic location

Variable CTH clinic NCH clinic p (N=188) (N=1195) Completed therapy 88.3% 69.8% < .001 Foreign born 98.4% 89.3% < .001 Birth region < .001 SSA 67% 46.2% MSCA 18.6% 26.8% NA/WE 1.6% 11.5%

Data analysed by Kevin Spicer MD, PhD, MPH

Completion of therapy by clinic location analyzed by propensity score matching

Variable CTH clinic NCH clinic p (N=179) (N=179) Completed therapy 88.8% 75.4% .001 Foreign born 98.3% 99.4% 0.67 Birth region 0.86 SSA 65.4% 65.9% MSCA 19.6% 22.9% NA/WE 1.7% 1.1%

Data analysed by Kevin Spicer MD, PhD, MPH

Take home messages regarding Pediatric Tuberculosis

• Childhood TB is most often pulmonary and may appear like many other forms of pneumonia

• Interferon-γ release assays are currently used to complement PPD skin testing pending future research

• Identification and treatment of LTBI should remain a key focus of TB control in the US

• LTBI treatment requires intense efforts to maximize completion of therapy