Key Issues In TB Diagnosis In

Children – The Clinician-

Researcher Perspective

Jeffrey R. Starke, M.D.

Professor of Pediatrics
Baylor College of Medicine
Houston, Texas USA
 A Difficult Case
A 7 yo HIV + girl has cough, abdominal pain,
cervical and axillary adenopathy, bilateral
rales and a large liver. A 10 day course of
clarithromycin did not improve her
symptoms. Her CD4 count was 291/20%,
her hemoglobin was 8.9, but other labs
were WNL. After several weeks, her
cough improved, she was sweating a lot
but did not have fever or weight loss. Her
adult cousin had pulmonary tuberculosis
2-3 years ago [household contact].

Her chest xray shows…

 A Difficult Case

Does she have tuberculosis?

• She produces no sputum

• There is no tuberculin
• There is no culture available
 Another Difficult Case
A 19 mo old child presents acutely to an OSH with a
several day history of fever, agitation and
lethargy, and a possible generalized seizure. His
emergency head CT shows:

An emergent EVD is placed, he is

transferred to TCH. CXR is WNL, no
family hx of TB. He is started on
broad spectrum antibiotics
 Another Difficult Case
 The ventricular CSF has 15 WBC [88% mononuclear],
protein of 58 and a glucose of 39
 The spinal CSF has 111 WBC [82% mononuclear],
protein of 512, and a glucose < 20
 All AFB stains of CSF and gastric aspirates were
negative, and the CSF and gastric cultures were
ultimately negative
 The tuberculin skin test yielded 0 mm of induration,
and the QuantiFERON was indeterminate
 The T.Spot TB IGRA was “wicked positive”
 3 weeks later, the mother’s boyfriend was found to
have pulmonary TB
 The child had a typical course for TB meningitis and
improved slowly on anti-TB medications
Tuberculosis: A Low Tech
Disease Even In 2011

 ~ 400 BC: Hippocrates [H&P]

 1882: Koch [TB culture]
 1895: Rontgen [x-ray]
 1907: Mantoux [TST]
 1983: Mullis [PCR]
 Late 1990’s: IGRAs
 TRANSITIONS IN TUBERCULOSIS

Susceptible

Exposed

Infected
Diseased

Sick

Diagnosed

Treated

Cured
 TRANSITIONS IN TUBERCULOSIS

Susceptible

Exposed

Infected
Diseased

Sick

Diagnosed

Treated

Cured
 TRANSITIONS IN TUBERCULOSIS

Susceptible

Exposed

Infected
Diseased

Sick

Diagnosed

Treated

Cured
HOW IS TUBERCULOSIS DIAGNOSED?

Adults – Mycobacterial-based diagnosis

 positive sputum AFB smear - 60% - 75%

 positive sputum culture - 90%

 positive tuberculin skin test - 80% [HIV < 50%]

Children
 positive sputum or gastric AFB smear - 10%

 positive sputum or gastric culture - 10% - 40%

 positive tuberculin skin test - 50% - 80%

DIAGNOSIS OF TUBERCULOSIS

Even in developed countries, the

“gold standard” for the clinical
diagnosis of tuberculosis in
children is the triad of:
1. a positive TST
2. an abnormal CXR and/or
physical exam
3. a history of recent contact to an
infectious adult case of TB
 Sensitivity = Specificity = 95%

90% prevalence 1% prevalence

PPV= 99% (1% false+) PPV=15% (85% false+)
Passive Case-Finding Of
Childhood Tuberculosis
 The child is exhibiting signs and
symptoms and/or has an
abnormal chest xray
 The major question is, “Does this
child have tuberculosis or some
other disease?”
 The major issue for tests is
usually their sensitivity
Active Case-Finding for Childhood
Tuberculosis [“Texas TB”]
 The child has had exposure to a
person with proven or suspected
tuberculosis and may have no or
minor signs and symptoms
 The major question is, “Does this
child have tuberculosis infection
or tuberculosis disease?”
 The major issue for tests is their
specificity
 Points To Ponder
What is the real difference between TB
infection and TB disease?
 The organism is present in both cases
 We can sometimes culture the organism from children
with recent infection but no clinical disease
 We treat infection with 1 drug, disease with 3-4 drugs
 The functional difference is the burden of organisms
 Infection and disease are on a continuum – when
does “infection” turn into “disease”? [Symptoms?
Abnormal chest radiograph or exam?]
No test to detect M. tuberculosis can
be considered independently of the
clinical/epidemiologic presentation
Impact Of HIV On The Diagnosis
Of Pulmonary Tuberculosis
Diagnostic feature Impact of HIV
 chronic symptoms  less specific

 positive TB contact  less specific

 malnutrition
 less specific

 positive tuberculin test

 less sensitive
 “typical” CXR findings
 less specific
 satisfactory response
 less sensitive
to TB treatment
 New TB Tests Are Not
Applied to Children
Test # of published
studies in children
FNA 140
Fluorescent microscopy 1
LED-FM 0
MODS 2
Line-probe assays 1
LAMP 0
GeneXpert 0
 Clinician vs. Researcher
Clinician
Preserve/improve patient health
Care for all patients
Comfort with current methods
Risk:Benefit for decisions
Accept consistent bias
All results observable
Emphasis on sensitivity
Resources from programs
Reseacher
Develop new knowledge
Select patients for study
Innovation
Accuracy and certainty
Eliminate bias
Blinded to study results
Emphasis on specificity
Resources from grants