Pediatric Tuberculosis ND DOH HIV/STD/TB Hepatitis Forum

Nadia Sam-Agudu, MD, DTM&H Pediatric Infectious Diseases Pediatric Travel Clinic Immigrant, Refugee and Adoption Medicine MeritCare Childrens Clinic and Hospital May 20, 2010.

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

Outline
Mycobacteriology 101 Epidemiology of pediatric TB in US, ND & MN TB overview: infection, active disease, testing
Differences between adult and pediatric TB

Workup and management of pediatric TB Summary and Pearls

Mycobacteriology 101
Mycobacterium tuberculosis 130+ Mycobacterium species TB and non-TB mycobacteria (NTM) Grouped in complexes of mycobacteria that are similar to each other M TB complex (M bovis, M africanus, M microti, M Tb)

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

http://www.ihcworld.com/royellis/gallery/zn.htm

TB EPIDEMIOLOGY

 As of 2009, TB rates have dropped significantly in the US TB cases with HIV coinfection dropped to ~10% Total ~12,000 TB cases, down 11.4% from 2008 rate, across all age and racial groups. Foreign-born and racial/ethnic minorities rates still higher
11x in foreign-born compared to US-born Compared to Caucasians, 8x higher in Hispanics and Blacks, 26x in Asians ~5x higher in Native Americans

TB Epidemiology: US

Children <15 yrs: 6% of 2008 TB cases

MMWR March 19, 2010

Percent of US Pediatric TB Cases by Age Group 19932006 N=15,946

Age < 1 9.2%

Age 10-14 18.2%

Age 5-9 23.1%

Age 1-4 49.5%

CDC data

TB Epidemiology: MN
Rates have increased for most of last 10 yrs
New TB cases: 211 in 2008, 161 in 2009

From 2004-2008, average 81% of new cases were in foreign-born persons

US 2008 stats: ~60% were foreign born

~40% of foreign-born TB patients were <5yrs, vs 6% in US-born Minnesotans

Nearly all the US-born under-5 cases had foreignborn parents

HIV co-infection in all cases 5%

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

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

TB Epidemiology: ND
Percentage of Tuberculosis Cases that are U.S.-born or Foreignborn, 2005 - 2009

TB OVERVIEW: INFECTION AND ACTIVE DISEASE

TB overview: infection and disease

Primarily spread by respiratory route
Largely a lung disease Transmission by skin and gut can also occur

Person with active disease coughs

TB bacilli suspended in very tiny particles Can stay airborne for extended period

Exposed individual directly inhales the contaminated particles

Risk of infection depends on disease burden in the index case, proximity and duration of exposure Household exposure from adult with active disease is strongest source Children are typically less infectious than adults

TB overview: infection and disease

Primary TB infection -acquiring TB directly after exposure to someone with active disease
Inhaled TB bacilli penetrate into lungs and settle- set up shop

1. Infection is contained in a small area without spread or replication (latent TB infection or LTBI)
These individuals are not infectious to anyone The TB bacilli are well-contained and cannot be released

2. Infection spreads to nearby lymph nodes and the lung tissue itselfTB pneumoniaprimary active TB
Risk of spread chiefly depends on age and immune status Very young children <4 yrs, immune compromised eg HIV, cancer, immunosuppressive meds eg steroids

Risk of progression to TB disease

Age at primary infection (yr) <1 No disease Pulmonary disease Disseminated disease or TB meningitis 10-20%

50%

30-40%

1-2

75-80%

10-20%

2-5%

2-5

95%

~5%

~0.5%

5-10

98%

~2%

<0.5%

>10

80-90%

10-20%

<0.5%
Marais BJ et al., 2004

Pediatric (<15 yrs) TB Cases by Site of Disease, 19932006

Both 7.0% Extra pulmonary 21.9% Pulmonary 71.1%

Any extrapulmonary involvement*

(totaling 28.9%)
Lymphatic Meningeal Miliary Bone & Joint Other 18.9% 3.1% 1.5% 1.5% 3.9%

All ages US 2008: 80% pulmonary + EP, and 20% EP only

*Any extrapulmonary involvement includes cases that are extrapulmonary with or without pulmonary involvement.

TB infection and disease

In any TB case, one needs to be infected before developing disease 1. Primary infection may stay latent: LTBI 2. Primary infection may proceed immediately to primary active TB disease 3. Primary 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 ages Risk higher with immunodepression eg HIV, cancer, meds Eg TB rate in untreated HIV is 7-10% per year

A positive PPD only indicates that someone is infected

It does not give you any info on the time of acquisition, latency, or activity of TB disease

TB clinical manifestations
Hemoptysis (bloody sputum), persistent fevers, night sweats with a nicely diagnostic CXR is largely a myth in Peds, especially <5yrs
Symptoms are usually nonspecific

Poor appetite, weight loss, failure to thrive, intermittent fevers, +/-cough, listlessness, decreased activity, irritability (TB meningitis) Persistent cough > 2 weeks, failure to thrive, fatigue were best indicators in a study done in 1000+, non HIV infected children in S Africa
Marais et al Pediatrics 2006;118: 1350-1359

Other studies have had similar findings

For extrapulmonary TB, think of additional signs and symptoms based on site of disease eg lymph node, kidney, bone, brain

TB TESTING AND DIAGNOSIS

Purified Protein Derivative (PPD) test

Aka tuberculin sensitivity test (TST), Mantoux test, TB skin test
First described by Robert Koch in 1890 Test further developed and refined by Charles Mantoux in 1907

Purified protein extracts from M TB cultures are injected into skin Immune T cells that have been sensitized to TB from prior infection migrate to the injection site Release 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 test
Once positive, a PPD will always be positive. It will not go away with treatment, either for LTBI or for active disease Dont bother to recheck it after the patient has been treated It is a badge that will always be worn by the patient Exceptions: immune compromise that affects the T cells that are supposed to react eg HIV; and young infants, elderly This is called anergy-negative PPD test in one who you know/suspect has been infected Minimum recommended age for PPD: 3 months

*How does one determine a positive PPD?*

It depends on the patient being evaluated
Where they were born/coming from, Household or close contact exposure, Immune status

Subject to the providers interpretation, clinical experience and skill Either way, you still need a measuring tape!
Do not measure redness Measure induration (bumpiness) only Measure 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)

Categories
1. Child in close contact with known or suspected contagious TB case 2. Child suspected to have active TB -CXR findings consistent with active or previous untreated, non-healed TB -Clinical evidence of active TB 3. Child immunosuppressed eg HIV or meds 1. Child at increased risk of disseminated TB -<4yrs old, -other medical conditions eg cancer, diabetes, malnutrition 2. Child with increased exposure to active TB -born in TB-endemic areas -lives with people born in TB-endemic areas -Native American children -frequently exposed to HIV infected adults, homeless, drug users, incarcerated, migrant workers -travel to TB endemic regions 1. Children 4 yrs with no identifiable risk factors

Measurement cut-off
5mm

10mm

15mm

Negative PPD

No need for CXR

No TB infection

-If recent close-contact exposure, repeat PPD in 8-10 weeks -To make sure you havent missed a new conversion

Variations of +PPD

Blisters, granulomas, local necrosis may occur

So, the PPD is positive

Now what? This means your patient is infected with TB
BCG or non-TB mycobacteria may cause a false positive PPD This effect fades significantly by 2-5 yrs after BCG vaccine-should not even be an issue with adolescents or adults In 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 disease Perform a CXR: two-view, PA/AP and lateral Looking for most common manifestation of active TB

Positive PPD

Negative CXR

+
=Latent TB Infection

Positive PPD

TB-Positive CXR

= active TB

Another TB screening test: the IGRA

Interferon gamma release assay
Quantiferon TB Gold most well-known

Uses specific M TB antigens to stimulate primed T cells They release inflammatory protein: interferon gamma IGRA antigens are more specific to M TB, not shared with NTM or BCG vaccine
Not enough data for use in children <4yrs old Have replaced PPDs in some institutions/clinics, $$

Requires blood sample, processing of live immune cells Need <24 hr delivery to reference lab Call before drawing blood sample to make sure it will get there on time

TB-positive CXR: adult-like presentation

Teenager PPD 25mm Cavitary lesion in right upper lobe Contains many TB bacilli Efficient coughing mechanism Sputum AFB smear positive Very contagious CXR findings take months to resolve

Miliary (disseminated) TB in an infant

Congenital TB may present like this

http://www.hawaii.edu/medicine/pediatrics/pemxray/v4c06b.jpg

A TB evaluation curveball
6 yr old child being evaluated for TB infection Foreign-born, new immigrant (10mm) PPD is positive at 14mm Child gets CXR a few days later While having a cold

A TB evaluation curveball
Nasal congestion with runny nose Few crackles on lung exam, occasional cough Exam otherwise normal No recent fever, weight loss or changes in appetite I think hes got LTBI I start treatment with INH Call me with any illness Repeat CXR in 1 month Cleared! Continue 9 month INH treatment for LTBI

So, your pediatric patient has active TB (+PPD and +CXR)

We need to find the bugs
Establish definitive diagnosis-a challenge in pediatric TB Obtain drug sensitivities from M TB culture

Sputum AFB smear and culture is the gold standard

Children <8yrs dont do sputum very well Often sputum smear and culture negative: low bacterial burden

Gastric aspirates: they cough up the TB bacilli, then swallow them into the stomach
Perform every morning for 3 days-need admission Alternative: bronchoalveolar lavage (BAL) Isolation in negative-pressure room with Airborne TB precautions (fitted N95 mask) Isolation during BAL , induced sputum, gastric aspirate procedures Exception: children <10yrs with non-cavitary disease and negative sputum smears (Red Book 2009 p 697-8)

US Pediatric TB Cases by Case Verification Criterion, 19932006 N=15,946

Provider Diagnosis 24% (Sx, Physical exam)
Laboratory confirmed 25%
Sputum smear <10-15% Sputum cx + 30-40% Gastric aspirates + ~50%

Clinical Case Definition 51% (Exposure, PPD+, CXR)

Based on CDC data, Peds Practice: ID

TB: adults vs children

Compared 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 infection Are less contagious
Paucibacillary disease (fewer organisms) Cannot cough/spread infection as well

Are more difficult to diagnose

May not show typical symptoms May have TB disease in unexpected places

Have less FDA-approved treatment meds and formulation options

TB: adults vs children

A child with active TB is an indicator of an unidentified contagious adult/adolescent with TB
Contact investigation: Public Health staff Many other children may be diagnosed this way (2680%, vs 3-25% by routine screening and 17-44% by symptoms)

A child suspected of having active TB may not yield any positive cultures/smears Need the adult contacts culture results for drug sensitivities and to determine treatment regimen for the child A thorough contact investigation is critical in the evaluation, management, and prevention of TB infection in the child.

TB treatment: LTBI
Bacilli are well-contained in the lungforever?
Risk of secondary active TB (from this personal collection of TB) increases as one gets older Cancer diagnosis, steroids, immune suppressive drugs for autoimmune disease, HIV Aka reactivation TB

Need to eliminate this small collection to avoid future reactivation

People with LTBI are latent reservoirs of TB bugs Of Public Health importance

Treatment with 1 drug (INH) for 9 months: TB is a slowgrowing bug No need for any isolation: LTBI is not contagious Young children or compliance issues: may get DOT (directly observed therapy) for LTBI

TB Treatment: active disease

RIPE 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 months

TB meningitis and disseminated TB: 9-12mo

4 drugs x 2mo, then 2 drugs x 7-10 mo.

MDR and XDR TB:

4-6 drugs for 18-24 months

HIV coinfection:
3 drugs for 9 months recommended

No differences in adult vs child treatment regimens DOT critical for all patients on treatment, to ensure consistency and completion
May not be feasible in remote areas/understaffed

Pediatric TB treatment: medication issues

Free TB drugs available for LTBI and active disease treatment, from State Depts of Health. All 4 standard drugs are taken orally
Dosing for children is weight-based

INH and RIF are the backbone of treatment INH-RIF and INH-RIF-PZA combo tablets available
Not for use in children Not available free from Depts of Health

INH comes in syrup form, but due to sugar type (sorbitol), osmotic diarrhea is likely
Prescribe INH tablets to be crushed

RIF can be made into suspension; no such luck for Ethambutol/Ethionamide Hepatitis is biggest concern with TB drugs: adults >> children
I still do baseline liver tests (comprehensive metabolic panel) for all children on any TB treatment.

Summary and Pearls

Clinical manifestations in pediatric TB may be non-specific TB 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 disease

Diagnosis of TB in a child is a sentinel event

Contact investigation is critical

Knowing how to administer and read PPDs, and to contextually interpret PPDs and CXRs is vital Our low-prevalence status in ND does not let us off the hook We are less experienced than other states because of low volume of cases

References
Red 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.org

Pediatric TB: an online presentation.

http://www.nationaltbcenter.edu/pediatric_tb/presen tation.cfm

Marais 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.

References
Centers for Disease Control.
www.cdc.gov/tb/ www.cdc.gov/tb/statistics/reports/2008/default.htm http://www.cdc.gov/tb/publications/slidesets/pediatri cTB/default.htm

CDC. 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 .html

ND Dept of Health.
www.ndhealth.gov/disease/tb