Tuberculosis in

children
Part One

By
Malak Shaheen
(MD, PhD Pediatrics)
TB…..The Early Beginning!
Typical skeletal
abnormalities of Pott’s
deformities, were found in
Egyptian mummies
(5000 years ago)

Leão and Portaels;Tuberculosis Textbook, 2007

 TB…..The Early Beginning!
In 1890, about eight years after the discovery of
the tubercle bacillus, Robert Koch (1843-1910)
announced a cure for TB.

He obtained a heat-inactivated filtrate from

cultures of M. tuberculosis.

This product, known as “Koch's Old Tuberculin”,

 However,TB patients who received tuberculin
had generalized systemic reactions ,
in contrast to people without TB, who did not
develop this violent reaction.

These observations were the basis for the

proposal of the use of tuberculin as a
diagnostic test
In 1934, Florence Siebert made a simple
protein precipitate of the old tuberculin
and named it purified protein derivative
(PPD)
 Childhood Tuberculosis
The Invisible Enemy

Part 2

By
Malak Shaheen
(MD, PhD Pediatrics)
Why invisible ?
Corrigan DL and Paton JY: Tuberculosis in children.
Breathe 2007; (3);4;pp 351-363.
Natural history of TB in children
No signs/symptoms
Exposure
Exposure
TST -

Months
Infection No signs/symptoms
to
years TST +

Disease Signs/symptoms or
radiographic
evidence of TB
TST +
More challenges …….
HIV Children
MDR
Invisible – How to tackle ?
 Diagnosis of TB in Children
WHO recommendations

1. Careful History (?? TB scores)

2. Clinical Examination (including
growth)
3. Immunological tests: TST/IGRAs
4. Bacteriological confirmation (if
possible)
5. Investigations relevant for pulm. or
extrapulm. TB (including radiology)
6. HIV testing
 1. Careful History
Contact history
Chronic Symptoms: chronic cough,
chronic fever, failure to thrive

2. Clinical Examination
Growth retardation
Pulmonary and extrapulmonary organ
affection
 3. TST
Standardized as either:
5 tuberculin units (TU) of PPD-S
Or 2 TU of PPD RT 23
Problems with Skin Testing
False negative
10% of culture proven TB will have negative
skin test , immunodeficiency
False positive
Environmental mycobacteria, BCG
immunisation
Cellular immune responce
 TST: How to perform in children?

Standardized as either:
5 tuberculin units (TU) of PPD-S
Or 2 TU of PPD RT 23

Techniques with Skin Testing

Heaf gun test

Mantoux intradermal test
+ve TST
 Challenges with T. Skin
Testing
False negative
10% of culture proven TB will have
negative skin test , immunodeficiency
False positive
Environmental mycobacteria, BCG
immunization
Difficult Technique and Interpretation
Novel Vision – TST Update
Interferon - - Release Assays (IGRAs)

T-cell sensitization to TB antigens

Use PPD, early secretory antigenic target
(ESAT) 6, culture filtrate protein (CFP)
10 and TB 7.7 antigen
ELISA-based (QuantiFERON-TB) OR
T Spot TB (Elispot and Elispot plus)
 Applications
1. Diagnosis of active TB disease
2. Distinguish between M tuberculosis
and NTM
3. Differentiate M tuberculosis from
BCG
4. Latent infection TB infection
5. Monitor treatment
 4. Bacteriological Confirmation
First:
Obtain appropriate samples for smear
microscopy, culture and histopathology
if possible.
Samples could be;
Sputum, gastric lavage, induced sputum,
peripheral LN, pleural fluid, CSF,
ascitic tap, joint tap, pericardial tap
…..etc
 Microscopic Smear

Easy, inexpensive and fast

Ziehl-Neelsen (ZN) stain
Fluorochrome stains (auramine-rhodamine)
better than ZN
Ba et al Int J Tuberc Lung Dis 1999;3:1101-05

Sputum induction with nebulised 3% saline

showed a better yield
Zar et al Lancet 2005 365:130-4
 Conventional Cultures

Lowenstein-Jensen media
Up to 3 weeks for positive growth
Yield from extra-pulmonary sites lower
(<50%)
Recent!
Automated Liquid Media
Various automated liquid media
available (BACTEC 460, MGIT)

Have faster turn around times (1-2

weeks vs 3-4 weeks) and higher recovery
rates than solid media
 Mean Detection Times (days)
Conventional BACTEC Other
culture 460 Systems

Smear + 20-25 9-13 9-20

Smear - 21-33 15-22 18-36

NTM 22-40 13-17 12-25

 5. Investigations relevant for
suspected TB
Flexible Bronchoscopy

Endobronchial disease
Luminal obstruction
Sample collection
Bronchoscopy samples have lower yield than
3 gastric aspirates
Nucleic Acid Amplification Techniques

Sensitivity 40% and specificity 80% in

children.
False positives (NTM) and false negative
(pauci-bacillary disease)
Lower sensitivity with extrapulmonary
samples
Molecular probes for rifampicin
resistance (mutations rpoB gene)
Molecular typing (RFLP, VNTR, MIRU)
for epidemiological investigation
 Diagnostic Accuracy of
Chest X-rays
Sensitivity of 60% in adults with culture
confirmed TB
Sensitivity of 40% and specificity of
74% in children
De Villliers 2004 Australasian Radiology
2004;48:148-153
Lower sensitivity in HIV positive adults
(and children?)
 CT Scan

• Helpful in identifying hilar lymphadenopathy

(more than 50% of children with normal chest
x-ray)
• Inter observer variability especially in
differentiating thymus
• Andronikou et al Pediatr Radiol 2005;35:425-28

• High resolution and spiral CT imaging

Magnetic Resonance Imaging

Useful in distinguishing different tissue

characteristics e.g. fibrosis versus
inflammation
Useful for extrapulmonary disease
especially bone/joint
Treatment
 Treatment of MBT
Latent
(Single drug regimen) 6-9 H or 6R
(Double drug regimen) 2 RZ or 3RH

Active (consider susceptibility test if possible)

- Categ I: 2HRZE Or 2SHRZ + 4HR
- Categ II: 2SHRZE + 1HRZE + 5HRE
- Categ III: 2HRZ + 4HR

Consider injectable forms of the 2nd line ttt.

 Special
Considerations
 TB in HIV infected child

HIV assessment (for all proved +ve TB)

TB Diagnosis; (TST > 5mm)
In treatment, consider longer duration!
Higher incidence of MDR and XDR
Interactions between antiretroviral therapy
and rifampicin!
Immune reconstitution inflammatory
syndrome (IRIS) continue TB ttt
Prophylaxis
 For HIV children (if CD4 < 100/mm)

Azithromycin or clarithromycin (3-6 Months)

For TB contact (if < 5 years or immuno-

suppressed) 6-9H or 6R or 9-12EFq
 Hospital infection control measures
(isolation, sterilization, physical barriers, …..)

Index case findings

Managing contacts (chemoprophylaxis)
Family survey
Negative pressure rooms
Care giver with particulate respirators
Better treatment of TB in Children

Criteria of
drug
resistant TB
in Children
(?)
WHO (2014)
 What do we want to achieve in TB
care?
Targets
“TB elimination by 2050”

44
START:
Better Diagnosis of TB in Children

Optimal sample collection

Improved laboratory procedures
Better imaging techniques
Immune-based diagnostics
46
TB or not TB; that is the question !
 Evidence
of TBNET consensus 2009 report

1) Children are more likely to develop

tuberculosis than adults after exposure to an
active case, hence contact screening and
chemoprophylaxis are particularly important
(evidence B).
2) The diagnosis of latent infection with M.
tuberculosis in children relies on history of
exposure, positivity of the tuberculin skin
test and exclusion of clinical symptoms
and radiological findings consistent with
active tuberculosis (evidence B).
3) The positive and negative predictive
value of IGRAs remains to be established
in children (evidence D).

4) Latency, as assayed by the tuberculin skin

test and IGRA, is a state of persistent
mycobacteria-specific T-cell responses in
the absence of clinical evidence for
tuberculosis disease (evidence A).
5) Whether latent tuberculosis infection
depends on the presence of living
mycobacteria is presently unclear (evidence
A).

6) The tuberculin skin test and IGRAs measure

‘‘lasting tuberculosis immune responses’’
and not ‘‘latent tuberculosis infection’’
(evidence A).
7) The tuberculin skin test and IGRAs
cannot discriminate active from latent
infection (evidence A).

8) In general, tuberculin skin test and IGRA

results correlate poorly, mainly because of
positive tuberculin skin test results in
individuals vaccinated with BCG
(evidence A).
9) IGRAs may be superior to the tuberculin
skin test in identifying contacts at risk of
developing tuberculosis (evidence C).
10) Contact children aged less than 5 yrs in
particular should be started on
chemoprophylaxis, independent of their
tuberculin skin test result (evidence B).

11) Chemoprophylactic or preventive regimes

are identical in adults and children, but the
dose needs to be adjusted according to
weight (evidence B).
Further Practice ….

Pediatric TB cases
Further Readings ….

www.TuberculosisTextbook.com
Further Readings ….

WHO 2014
Further Readings ….

First edition - 2008

Summary of TB in
Children
2014
Thank You

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