Download PEDIATRIC TUBERCULOSIS UPDATE

Pediatric Tuberculosis Update
J. Podgore ,DO, MPH
Department of Pediatrics
TCOM
Dec. 19,20012
TUBERCULOSIS...
The greatest killer of all time...
The captain of all these men of death...
...during this century and the last,
one billion people have died from tuberculosis
Tuberculosis
A Global Emergency
• One third of the world’s population is infected
• TB kills 5,000 people a day – 2-3 million each year
• HIV and TB co-infection is producing explosive
epidemics
• Hundreds of thousands of children will become TB
orphans this year
• MDR threatens global TB control
Leading Infectious Disease
Causes of Death, 1998
3.5
2.3
2.2
1.5
1.1
WHO Report 2000
0.9
TB in USA
Summary of Epidemiology of TB
• Cases and case rates are on the decline
• Foreign born persons account for more than 50% of U.S. cases
• TB in children:
– Highest risk for disease:
• <5 years of age
• Foreign born children
– 60% of cases develop within 18 months of arrival in U.S.
– Varies depending on immigration patterns, i.e., recent increases in cases
among children from Sub-Saharan Africa, Asia, and the MiddleEast
• Racial and ethnic minorities
TB Life-Cycle
TB Pathogenesis
PRIMARY Infection:
Lympho-hematogenous spread
• 8-14 weeks after onset of TB
• usually occult
• Mantoux positive during this
phase
• body wide seeding occurs
during this phase
– bone, kidney, meninges etc.
– 3% of children with nl CXR’s
develop calcifications in lung
apices (SIMON FOCI)
Risk factors : infection to disease
HIV
Malnutrition
Recent exposure
Young age
Short incubation period
More severe
Highest risk
More difficult to diagnose
Host factors
Effect of HIV?
Mantoux Tuberculin Skin Test
• Specificity of the test varies depending on the prevalence of
LTBI and the frequency of cross-reactions to the PPD antigen in
a given population
• In a population with relatively high frequency cross-reactions
the specificity of the PPD is <95%
– Decreases the positive predictive value of positive test in a low
risk population
– If the specificity is 90% in a low risk population with a prevalence
of LTBI of 1%:
• Positive predictive value of TST: 8%
• 92% of positives are false positives
– As prevalence of LTBI increases the PPV increases
Huebner RE. Clin Infect Dis 1993;17:968
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
Positive PPDs
Generally, skin test conversion occurs within 2 months of contact
Measure only induration, and record millimeters of induration
Any induration seen only in the first 24 hours should be ignored
Induration after 72 hours counts; blistering also counts
What is a Positive PPD?
• ≥ 5 mm:
– HIV+ or other immunocompromise
– Contact with suspected source case
– Suspected TB disease
• ≥ 10 mm:
–
–
–
–
Immigrants from high-prevalence areas
Children under 4 years of age
Children exposed to adults in high-risk categories
Other immunocompromising conditions
• ≥ 15 mm:
– anyone, even without risk factors
2009 Red Book
BCG and TST (2)
• Review of studies that compared TST responses to
BCG during and after infancy
• Vaccination during infancy estimated to cause
false-positive TST in 6.3% overall, but only 1% of
those tested more than 10 years after vaccination
• Vaccination at 2 years of age or older estimated to
cause false-positive TST in 40% of persons overall,
20% of those tested 10 years or more after
vaccination
Farhat M et al, Int J Tuberc Lung Dis 2006; 10: 1192-204
TB and BCG Vaccination
• Efficacy for adult pulmonary TB 0-80% in
randomized clinical trials
• Best efficacy against serious childhood
disease
– 64% protection against TB meningitis
– 78% protection effect against disseminated TB
• BCG important for young children,
inadequate as single strategy
Colditz GA et al. JAMA 1994; 271: 698-702.
PPD Limitations
False positives:
• Exposure to mycobacteria
other than TB
• BCG vaccine
False negatives:
• Corticosteroid usage
• Other immunocompromise
• Viral suppression: measles,
mumps, influenza
• Inter-observer variability
• Sliding scale for what is
considered positive can be
confusing
• Until very recently, lack of
any confirmatory tests
Factors causing decreased ability to respond
to tuberculin
•
Factors related to the person being tested
– Infections
• Viral (measles, mumps, chickenpox)
• Bacterial (typhoid fever, brucelosis, typhus, pertussis, overwhelming TB,
• Fungal (South American blastomycosis)
– Live virus vaccinations (MMR)
– Metabolic derangements (chronic renal failure)
– Nutritional factors (severe protein depletion)
– Diseases affecting lymphid organs (Hodgkin’s lymphoma, chronic lymphocytic leukemia,
sarcoidosis)
– Drugs (corticosteroids, other immunosuppressive agents)
– Age (newborn, elderly)
– Recent overwhelming infection with M. tuberculosis
– Stress (surgery, burns, mental illness, graft versus host reactions)
•
•
•
Factors related to the tuberculin used
Factors related to the method of administration
Factors related to reading the test and recording results
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
Why Measure Interferon-?
•
•
•
•
•
•
TB infection induces T-cell response (CMI)
IFN-  is the ‘classic’ CMI cytokine
Produced in vitro in response to specific antigen
Secreted in measurable and stable amounts
Absent from normal circulation
Extensive literature showing importance of IFN- in
TB infection
In Vivo and In Vitro Diagnostic
Tests
Presentation of
mycobacterial antigens
IFN-
TNF-
IL-8, etc.
IFN-
Antigen
presenting
cell
Memory
T-cell
Andersen P, et al. Lancet 2000;356:1099
TNF-
IL-8, etc.
Interferon Gamma Release Assay
o TB specific antigens:
Genes in region of difference (RD1) on TB genome
Culture filtrate protein 10 (CFP-10)
Early secretory antigen target 6 (ESAT-6)
TB-7.7
o Requires:
single medical visit
blood collection
laboratory equipment and personnel
o Results in 24-48 hrs
o 2 tests: Quantiferon; T-SPOT
Whole Blood IFN- Assay
QuantiFERON-TB Test
Stage 1 Whole Blood Culture
Nil
ESAT-6 CFP 10Mitogen
Control
Control
Aliquot blood
& add antigen
Draw blood
+ heparin
Stage 2 IFN-gamma ELISA
Incubate → INF-
from sensitized Tcells
COLOR
TMB
Harvest plasma
from above settled
cells
Measure [ IFN- ] in
‘Sandwich’ ELISA
Computerized
interpretation
Cellestis
T-Spot.TB: “Six easy Steps”
Nil Control
Infection
Infection
Positive Control
Oxford Immunotec
The IGRAs
QuantiFERON®-TB Gold Test Method
Advantages and Disadvantages
• Advantages:
– Only one visit required
– Objective and reproducible; not operator-dependent
– No cross reactivity with BCG, little cross-reactivity with
non-tuberculous mycobacteria
– Controls for low or no immune response
– No chance of ulceration due to brisk skin test reaction
• Disadvantages:
– Blood must be received in lab within 12 hours
– Labor intensive for the lab
– Not much data for some patient groups
IGRAs: Summary (2)
• IGRAs represent an exciting new opportunity
to learn more about a very old disease
• IGRAs are not perfect tests, so clinicians need
to be aware of their limitations
• Can we replace the TST? – Not yet!
Treatment of
Latent Tuberculosis Infection in Children
• INH 10 mg/kg (max., 300 mg) PO daily for 270
doses
• Alternative: Twice weekly directly observed (DOT)
INH 20-40 mg/kg (max., 900 mg) PO for 72 doses
• Monitor index case isolate sensitivities
• Hepatotoxicity from INH is rare in children:
– A monthly assessment for clinical evidence of
hepatotoxicity should be made: loss of appetite or
weight, nausea, vomiting, abdominal pain, jaundice
– Routine monitoring of LFTs is not indicated
New 12 Dose Regimen
Evaluation of the Child
with a Positive TST
• Evaluation of all children with a positive
TST should include:
– A careful history
• Household investigation
– Physical examination
– Chest radiographs (PA & lateral)
Childhood TB diagnosed by:
Combination of :
 Contact with infectious adult case
 Symptoms and signs
 Positive tuberculin skin test
 Suspicious CXR
 Bacteriological confirmation
 Serology
Symptom-based Criteria*
Pulmonary Disease
• Persistent cough x ≥ 2 weeks
• Failure to thrive x 3m
• Fatigue
• Sensitivity: 82%
• Specificity: 90%
• In HIV(-) children > 3 yrs old
Lymphadenopathy
• > 4 wks of adenopathy
• > 2 x 2 cm
• No response to antibiotics
• Sensitivity: 89%
• Specificity: 98%
• In HIV(-) children > 1 yr old
Pediatrics 2006;118:e1350
*: all performed in TB endemic regions
Pediatr Infect Dis J 2006;25:142
CXR Findings in Pediatric TB
• Hilar or mediastinal adenopathy
• Segmental/lobar infiltrates
• Calcifications (seen in 75-80% of children with
pulmonary TB)
• Miliary disease
• Pleural effusions
• 15% of patients with TB disease will have normal
CXRs
Common Pediatric Finding in TB
CXR vs. CT
• How to interpret a newer technology that is
more sensitive, but less specific than the gold
standard?
• Not routinely recommended, but may be
helpful in immunocompromised patients
• Difficult to know the significance of findings
that are only apparent on CT
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 don’t 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)
PCR for Childhood TB
• Primary use in adults has been for determining if
patients with positive acid-fast smears have TB or
environmental mycobacteria
• Limited utility in children
– Much decreased sensitivity in extrapulmonary TB cases
• A negative test does not exclude TB
• As false positive tests can be seen due to laboratory
contamination, a positive assay alone should not call
off the search for alternative diagnoses (especially if
the story doesn’t fit with TB)
Clin Infect Dis 2009;49:46
Specimen Collection
Induced Sputum:
Gastric Aspirates:
 Outpatient procedure
 Inpatient procedure
 2-3h fasting period
 Overnight fasting
 Lavage with NS if volume < 20cc  Pretreated with salmeterol;
nebulized saline, then CPT
given
 Nasopharynx suctioned




Generally done qAM x3
Inpatient costs substantial
AFB smear yield: minimal
AFB Culture yield: 20-30%




One specimen sufficient
Minimal costs
AFB smear yield: 50%
AFB Culture yield: 25-30%
Lancet. 2005;365:130
Gastric Aspirates
• Inpatient procedure
• Overnight fasting
• Lavage with NS if volume <
20cc
•
•
•
•
Generally done qAM x3
Inpatient costs substantial
AFB smear yield: minimal
AFB Culture yield: 20-30%
Sputum collection in young children by
nebulization procedure
Induced Sputum
• Outpatient procedure
• 2-3h fasting period
• Pretreated with salmeterol;
nebulized saline, then CPT
given
• Nasopharynx suctioned
•
•
•
•
One specimen sufficient
Minimal costs
AFB smear yield: 50%
AFB Culture yield: 25-30%
Lancet. 2005;365:130
Microscopic-observation drugsusceptibilty assay
Traditional
MODS
6-8 weeks
7-10 days
Cost per specimen
High
$3
Separate step for
identifying species?
Separate step for
susceptibility testing?
Feasible in developing
countries?
Yes
No
Yes
No
No
Yes
Total Time
Field Trial of Rapid Xpert System
Xpert compared to microscpy
Therapy for TB Disease
• Start 4-drug therapy (a change from 2006 Red Book)
– INH, rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB)
• Use PZA only during 1st 2 months for susceptible TB
• Stop EMB once culture results known, if have pan-susceptible
TB
• Anticipate minimum 6 month therapy, and we often extend it
to longer periods, especially for extrapulmonary disease
• Always administered by directly observed therapy (DOT)
XDR-TB Outbreak S Africa
History of Drug-Resistant TB
Streptomycin
1944
Year, 1st
Documented
Resistance
1948
Isoniazid
1952
1952
Pyrazinamide
1952
1964
Ethambutol
1960
1965
Rifampin
1966
1968
Fluoroquinolones
1988
1992
Drug
Year
Introduced
Multi-Drug Resistant TB Worldwide
Multiple Drug Resistant Tuberculosis
Treatment of MDR-TB in Children
Conclusions
• Screen all children for TB risk factors via questionnaire
• Children with risk factors should be evaluated by either PPD
or IGRA
– Immunocompetent children > 4 years old can have IGRAs performed
• IGRAs offer improved specificity, not sensitivity, compared to
PPDs
• Children < 4 years old are at high risk for progressing from TB
exposure to disease, and therefore need prophylaxis in
window period
• Children with TB infection should receive a course of therapy
to prevent future disease
• Children with TB disease need multidrug therapy coordinated
by an infectious disease specialist through the health
department to ensure adherence and decrease the risk of
developing drug-resistant TB
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
Drugs for MDR TB in Pediatrics
Targeted Tuberculin Testing
Risk-Assessment Questionnaire
• Was your child born outside the United
States?
– Africa, Asia, Eastern Europe, Latin America
• Has your child traveled outside the United
States? >1 week
• Has your child been exposed to anyone with
TB disease? TB or LTBI, nature of contact
• Does your child have close contact with a
person who has a positive TB skin test?
Pediatrics 2004;114:1175, supplement
AAP Recommendations:
Tuberculin Skin Testing
• Children for whom immediate TST is indicated:
– Contacts of persons with confirmed or suspected
infectious tuberculosis (contact investigation)
– Children with CXR or clinical findings suggesting TB
– Children immigrating from endemic countries (e.g.,
Asia, Middle East, Africa, Latin America)
– Children with histories of travel to endemic countries
and/or significant contact with indigenous persons
from such countries
Red Book
AAP Recommendations:
Tuberculin Skin Testing
• Children who should be considered for TST at
4-6 and 11-16 years of age:
– Children whose parents immigrated (with
unknown TST status) from regions of the world
with high prevalence of tuberculosis
– Children with continued potential exposure by
travel to endemic areas and/or household contact
with persons from endemic areas (with unknown
TST status)
Validated Questions to Determine LTBI
Risk
•
•
•
•
Has a relative or contact had TB disease?
Has a family member had a positive TB skin test?
Was the child born in a high-risk country?
Has your child traveled to a high-risk country for > 1
week?
• Should consider screening for risk factors at the initial
visit and every 6 months thereafter in first 2 years of
life
Pediatrics 2001;107:e54; Red Book 2009
What Does an Indeterminate Mean?
• Indeterminate can occur as a result of low mitogen
response (due to patient immunocompromise,
poor specimen handling or storage, lab error, etc.)
or high nil response (due to patient illness, recent
vaccinations, etc.)
• Estimated rate of indeterminates for QGT-G:
approximately 1-2% among HCW, about 5-10%
among patients
• Upon retesting, approximately ½ of the
indeterminates come out with a definitive result
(unpublished data)
• Retesting indeterminates once, and if
indeterminate again, stop
• Indeterminate rate much higher among children
What Does the Red Book Say?
• “The correct interpretation of a negative IGRA test
result in a child with a positive PPD result remains
challenging because of the current absence of
longitudinal studies.”
• “At this time, neither an IGRA nor the PPD can be
considered a ‘gold standard’ for diagnosis of LTBI.”
Red Book 2009, p687
Conclusions
• Screen all children for TB risk factors via questionnaire
• Children with risk factors should be evaluated by either PPD
or IGRA
– Immunocompetent children > 4 years old can have IGRAs performed
• IGRAs offer improved specificity, not sensitivity, compared to
PPDs
• Children < 4 years old are at high risk for progressing from TB
exposure to disease, and therefore need prophylaxis in
window period
• Children with TB infection should receive a course of therapy
to prevent future disease
• Children with TB disease need multidrug therapy coordinated
by an infectious disease specialist through the health
department to ensure adherence and decrease the risk of
developing drug-resistant TB
Red Book Statement on LTBI
• “All infants, children, and adolescents who
have a positive PPD result but no evidence of
TB disease and who have never received
antituberculosis therapy should be considered
for INH unless resistance to INH is suspected
or a specific contraindication exists”
Red Book 2009, p691
LTBI Treatment Pearls
• Use INH suspension only in children < 5 kg
• Compliance with 9 months of INH averages a bit over
50%; be skeptical
• Use health department to administer medications to
high-risk patients: infants, immunocompromised
children, recent contacts
• When children aren’t tolerating INH, the problem is
more often with the parent than the child
• Routine LFTs not indicated unless: concomitant
administration of other hepatotoxic drugs; pre-existing
liver disease; or signs/symptoms of hepatitis
Tuberculosis
A Global Emergency
• One third of the world’s population is infected
• TB kills 5,000 people a day – 2-3 million each year
• HIV and TB co-infection is producing explosive
epidemics
• Hundreds of thousands of children will become TB
orphans this year
• MDR threatens global TB control
Notes on TB Drugs*
Side Effects
INH
Peripheral neuropathy; seizures in overdose
RIF
Orange discoloration of secretions;
inactivates oral contraceptives; many drug
interactions
Can increase uric acid  gout symptoms;
rash
Optic neuritis, red-green color blindness
PZA
EMB
*All primarily hepatically metabolized, except EMB, which is also renally excreted
Positive TST Results:
Infants, Children, and Adolescents
• TST considered positive at >5 mm induration when:
– In close contact with known or suspected contagious
cases of tuberculosis
– Suspected to have tuberculosis disease:
• CXR consistent with active or previously active tuberculosis
• Clinical evidence of tuberculosis
– Receiving immunosuppressive therapy
– With immunosuppressive conditions
– With HIV infection
Treatment Required
Tuberculosis in Children
Pediatric TB Algorithm
Treatment of TB
BCG and TST (1)
• General teaching is that reactivity from BCG wanes
after a few years and is unlikely to persist > 10 years,
but may be boosted by PPD.
• Study done in Switzerland* suggests that false
positives due to BCG may be much more common
than we thought:
– 40% of 5000 HCW had positive TST
– Prior BCG strongest risk factor for positive TST among
those less than age 40 with TSTs <18 mm (was not as
strong a risk factor for those > 40 years old and those with
TSTs > 20 mm)
*CID 2005; 40:211 – 217.
QuantiFERON® (QFT) History
• First generation (QuantiFERON ® – TB) test FDAapproved in 2001
• 2003 CDC guidelines advise use of test in selected
groups only
• Second generation test (QuantiFERON® - TB Gold)
FDA-approved March 2005
• CDC guidelines December 2005* allow use of
QuantiFERON® - TB Gold (QFT-G) in any situation
in which a TST would be used; however, points
out lack of data in many groups (pediatrics,
immunocompromised, etc.)
*MMWR 2005, 54 (RR-15): 49-55
TB Epidemiology: US
• As of 2009, TB rates have dropped significantly in
the US
• TB cases with HIV co infection 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
AAP Recommendations:
Tuberculin Skin Testing
• Children for whom immediate TST is indicated:
– Contacts of persons with confirmed or suspected
infectious tuberculosis (contact investigation)
– Children with CXR or clinical findings suggesting TB
– Children immigrating from endemic countries (e.g.,
Asia, Middle East, Africa, Latin America)
– Children with histories of travel to endemic countries
and/or significant contact with indigenous persons
from such countries
Red Book
Childhood TB
•
Why neglected?
– Not considered important in global program or
contributing to immediate transmission
– Not regarded as public health risk
– Difficult to diagnose
•
Why is it important?
– Health problem in children
– May later contribute to epidemic
Newer Regimens (NOT Yet AAP
Recommended)
• 3 months of INH +
Rifampin
• 4 months of Rifampin
• 3 months of INH +
weekly Rifapentine
Advantages:
• Improved adherence
• More effective if have
high rates of INH
resistance in the
community
• Cost effective
Pediatrics 2009;123:816
Clin Infect Dis 2007;45:715
Semin Resp Crit Care Med 2008;29:532