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
TB Epidemiology: US
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
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 10-14
18.2%
Age < 1
9.2%
Age 1-4
49.5%
Age 5-9
23.1%
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 foreign-
born 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 Foreign-
born, 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)
No disease Pulmonary disease Disseminated disease
or TB meningitis
<1 50% 30-40% 10-20%
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
Extra
pulmonary
21.9%
Both
7.0%
Pulmonary
71.1%
Any extrapulmonary involvement*
(totaling 28.9%)
Lymphatic 18.9%
Meningeal 3.1%
Miliary 1.5%
Bone & Joint 1.5%
Other 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 Measurement cut-off
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
5mm
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
10mm

1. Children 4 yrs with no identifiable risk factors 15mm

Negative PPD No need for CXR
-If recent close-contact exposure, repeat PPD in 8-10 weeks
-To make sure you havent missed a new conversion
No TB infection
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
http://www.hawaii.edu/medicine/pediatrics/pemxray/v4c06b.jpg
Congenital TB may present like this
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
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
A TB evaluation curveball
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)
Clinical Case Definition 51%
(Exposure, PPD+, CXR)
Laboratory confirmed
25%
Sputum smear <10-15%
Sputum cx + 30-40%
Gastric aspirates + ~50%

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 (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/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 slow-
growing 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