Paediatric tuberculosis

Beate Kampmann FRCPCH PhD

A/Professor in Paediatric Infection & Immunity
Consultant Paediatrician
Imperial College London, UK
and
Institute of Infectious Diseases and Molecular Medicine
University of Cape Town, RSA

Overview
What is special about TB in children?
Epidemiology- who are our patients?
Clinical presentations
How can we make the diagnosis?
New Immunological Tools-how helpful are they?
Issues in TB therapy in children
Future research topics

Tuberculosis in Children. the problem

Significant Morbidity and Mortality
1.4 million cases annually (95% developing countries)
450,000 Deaths
estimated 10-15% of global burden related to childhood TB
Different clinical spectrum of disease
5-10% < 2 yr meningitis
disseminated disease more common
Co infection with HIV- clinically very difficult to distinguish
Remains a diagnostic challenge
paucibacillary, rarely culture confirmed :
Sputum smear positive in 10.3% (10-14yr), 1.8% (5-9) and1.6% (<5)
Cultures positive 21% (10-14), 5% (5-9) and 4.2% (<5),

Tuberculosis in Children differs from adults

Immune responses are

Age-dependent: Following infection 40% < 2 yr, 25% 2-5 yr and

5-15% of older children will develop disease within 2 years

Majority of disease results from progression of primary infection

rather than reactivation
might affect detectable immune responses
More likely to be extrapulmonary and disseminated,
particularly in infants

Newton, Kampmann The Lancet Infectious Diseases, August 2008; Vol 8: 498-510

Percentage of TB cases of foreign origin, 2006

Not included or not reporting to EuroTB

0% 4%
5% 19%
20% 49%
> 49%

Andorra
Malta
Monaco
San Marino

Trends in incidence of TB in children under 15 years

by ethnic group in London, 2001-2006

UK: Tuberculosis rates in persons

born abroad by age

Development of TB
in immigrant children

Sources: Enhanced Tuberculosis Surveillance, Labour Force Survey population estimates, Abubakar et al Arch. Dis. Child. 2008;93;1017-1021;

Children with TB at Imperial HCT:

Ethnicity and country of birth:

south asian
29%

Travel to TB endemic countries

yes

black african
47%

arab
5%

no

dk

household

black african
afro-caribbean
caucasian
SE asian
mixed race
arab
no
south asian

caucasian
7%

39%

visitor

yes
56%
afro-caribbean
2%

no
28%

Country of Birt h

UK
38%

dk
4%
household
62%

dk

dk
5%

mixed race
4%
SE asian
visitor
6% 6%

no

non-UK
62%

UK
non-UK

Children acquire TB from

(household) contacts

If you ask yourself, does this child have TB,

ask yourself:

is there TB in this family?

Or: if you see adults with TB, ask yourself if they have children

Presentation of PAEDIATRIC TB
Case 1
-14

month Asian girl

-previously well, no F/H of TB

-3 weeks cough and unwell
-admitted to local hospital
-low grade fever
-normal chest examination

WHAT INVESTIGATIONS WOULD YOU DO?

PAEDIATRIC TB
Case 1

Mantoux test: 2mm

Gastric washings;
- microscopy and (later) culture negative

-Rx.

Erythromycin and Augmentin

-no improvement on antibiotics

-bronchoscopy planned

PAEDIATRIC TB
Case 1

1 day before bronchoscopy:

- afebrile, less cough, looking well

-continued improvement,

- discharged home, no

PAEDIATRIC TB
Case 1

out-patient review 6 weeks later:

-completely well, thriving, no cough

Grandfather admitted to local hospital with pulmonary TB

-repeat Mantoux: now 25mm

-TB treatment commenced

PAEDIATRIC TB
Case 1

Discussion Points

Primary TB in children:
- spontaneous recovery is possible

- diagnosis is difficult
- no visible AFB

- cultures usually negative

- tuberculin test negative

CHILDHOOD EXPOSURE

PRIMARY
PULMONARY
INFECTION
Successful
immune
response

WELL
ADULT

IMMUNITY
(live MTB)

LATE REACTIVATION
OF PULMONARY
DISEASE

FORMS
CAVITY

CHILDHOOD EXPOSURE

PRIMARY
PULMONARY
INFECTION

Self healing??

Inadequate
immune
response

PROGRESSIVE
PULMONARY
DISEASE
Lympho/
haematogenous
spread
MILIARY TB or
EXTRA-PULMONARY
DISEASE

CHILDHOOD EXPOSURE

PRIMARY
PULMONARY
INFECTION
Inadequate
immune
response

-most serious form of TB, fatal if untreated

-most common in < 2 year-olds

-worst prognosis in < 2 year-olds

-insidious onset;

PROGRESSIVE
PULMONARY
DISEASE
Lympho/
haematogenous
spread
MILLIARY,
EXTRA-PULMONARY
DISEASE
TB MENINGITIS

TB MENINGITIS
Primary focus
in lung

VI NERVE
PALSY

Brain focus
(Rich focus)

Meninges
CSF

Severe granulomatous
inflammatory response

BRAIN
INFARCTION

CSF protein

ICP

Cranial nerve palsies

Vascular occlusions
Hydrocephalus

Thick gelatinous
exudate forms,
envelopes base
of brain

TB MENINGITIS
CSF
-lymphocytes, low sugar, high protein, AFB may be visible
-but often

-polymorphs initially
-protein normal initially
-no visible organisms
-sugar normal initially

So: repeat LP, neuro-imaging, CXR, contacts

CT scan; enhanced

Ring enhancing
tuberculomata

MRI > SENSITIVITY THAN CT

ENHANCED CT SCAN

GADALLINIUM ENHANCED MRI

HYDROCEPHALUS

TB MENINGITIS
SUCCESS of Rx DEPENDS ON

EARLY DIAGNOSIS

TB MENINGITIS
TREATMENT with quadruple therapy
Drugs:
-? CSF penetration
- duration
- sensitivity
Adjunctive therapy:
- steroids
- SIADH
- acetazolamide
- surgery

Diagnostic tests

Microbiological

Organism

smear

culture

DNA

The gold-standard
Appearance in sputum

Appearance in culture
cording

PAEDIATRIC TB: Implications of bacterial load

Paediatric TB: 106 bacteria

Adult TB: >109 bacteria

- children less infectious

- difficulty in confirming diagnosis (< 30%)
- difficulty in detecting resistance

Diagnostic tests

Immunological

Host response

skin test

antigen-specific
production of IFN

Acknowledgement
& Thanks
IGRA and
the diagnosis
of active TB

Signs and
symptoms

Contact history

Travel

Active TB

Radiology

Microbiology

TST

IGRA

TUBERCULIN SKIN TEST (used since 1890)

-technically difficult in children
-UK : 2 units of SSI tuberculin (PPD)
- > 200 antigens,
Read-out:
-degree of hypersensitivity to PPD

Problems with the TST:

-poor specificity,does not distinguish between;
-TB disease
-TB infection
-BCG
-non-typical mycobacteria
poor sensitivity, can be falsely negative in;
-early infection
-disseminated disease
-severe malnutrition
-other acute infections (measles, pertussis)
-live vaccines
-immunocompromised (HIV)

*In children a negative TST does not exclude TB

Gene deletions and the origin of BCG

major antigens
ESAT6 and CFP10

M. tuberculosis
10 deletions
64 genes

M. bovis
4/5 deletions

RD1 region

30/40 genes

BCG substrains

T cell tests (interferon-g)

that distinguish M. tuberculosis
infection from BCG vaccination

IFN- responses to specific antigens by ELISPOT or Whole

Blood Assay
Unable to distinguish
between TB and BCG effect

Clear difference between acute

TB and BCG vaccination

Van Pinxteren Clin Diagn Lab

Immunol 2000

IGRA and National TB guidelines

UK: NICE Guidelines 2006

http://guidance.nice.org.uk/CG33

2 commercially available assays

Antigens used:
ESAT-6
CFP10 +/- TB7.7
mitogen
negative control

In principal: can both distinguish

between BCG vaccination and
M.tuberculosis infection
But:
Paucity of data in children
Confusion about use of IGRA

Principal of Quantiferon Gold

In vitro blood test:

Coating antibody

Biotinylated 2nd

ELISPOT assay

PBMC+antigen

antibody

IFN- production

Avidin-peroxidase
Each spot is an individual T cell
that has released IFN

IGRA versus TST: our own research

Spot the Difference

Interferon- release assays (IGRA)
in paediatric active and latent
tuberculosis in London
- a side-by-side comparison with TST
Kampmann B, Whittaker E, Williams A, Walters S,
Gordon A, Martinez-Alier N, Williams B, Crook AM,
Hutton AM, Anderson ST.
Interferon- gamma release assays do not identify
more children with active TB than TST.

Eur Respir J. 2009 Jun;33(6):1374-8

Acknowledgement
& Thanks
IGRA and
the diagnosis
of active TB

Re sults (%) of all thre e te st in the diffe rent sub-groupsof

Active TB
TST
QFG-IT
Tspot.TB

All active
TB
(N=91)
De finite
(N=25)
Probable
(N=38)
De finite &
Probable
(N=63)
Possible
(N=28)

>15

6-15

<6

Ind

TF

43

19

38

46

45

38

53

83

80

12

58

38

45

30

26

52

42

45

45

10

60

21

19

64

29

50

42

14

79

79

14

11

79

11

IGRA missed between 20-40% of definite active TB

Thanks
Combining IGRAAcknowledgement
and TST in the&diagnosis
of active TB

A combination of TST and IGRA increases sensitivity to above 93%

& Thanks
IGRA and the Acknowledgement
diagnosis of active
TB- other studies
Bamford et al, Arch Dis Child 2009 Oct 8 (Epub ahead of print)
UK-wide study of 333 children from 6 large UK centers, 49 with culture-confirmed TB:
TST had a sensitivity of 82%, Quantiferon-Gold in tube (QFT-IT) had a sensitivity of 78%
and T-Spot.TB of 66%.
Neither IGRA performed significantly better than a TST with a cut-off of 15 mm.
Combining results of TST and IGRA increased the sensitivity to 96% for TST plus T-Spot.TB
and 91% for TST plus QFG-IT in the definite TB cohort.
Nicol et al; Pediatrics 2009,Jan; 123(1): 38-43
Comparison of T-SPOT.TB assay and TST for the evaluation of young children at high risk
for tuberculosis
Sensitivity of the T-SPOT.TB was no better than that of the tuberculin skin test (>10mm) for
culture-confirmed tuberculosis (n=10) (50% T-Spot and 80% TST) and was poorer for the
combined group of culture-confirmed and clinically probable tuberculosis (n=58)
(40% T-Spot and 52% TST).
Bianchi et al, PIDJ 2009, Jun;28(6):510-4
IGRA was positive in 15 of 16 (93.8%) children with active pulmonary TB
Connell et al, Thorax 2006, Jul;61(7):616-20
The whole blood IFN-gamma assay was positive in all 9 children (100%) with TB disease.

Acknowledgement
& Thanks
IGRA and
the diagnosis
of active TB

A negative IGRA does not exclude active TB

IGRA is not a rule-out- test,
but can add value to additional investigations

Acknowledgement
& Thanks
IGRA and
the diagnosis
of latent TB

Contact history
Travel/Immig
ration

Absence of clinical
signs and symptoms
Latent TB

negative
Radiology

TST

IGRA

IGRA and the diagnosis of latent TB

No gold standard for LTBI

Acknowledged discrepancy of TST and IGRA results

- due to poor specificity of TST
(Kampmann ERJ 2009, Connell PlosOne 2008, Bianchi PIDJ 2009)

Which IGRA is better?

- Good agreement between 2 IGRAS (92%, k=0.82)
(similar to Connell et al, PLoS One. 2008 Jul:
agreement between QFT-IT and T-SPOT.TB 93%, k=0.83).

Currently: ? over-treatment by paediatricians

-

but: to date no studies of negative predictive value of IGRA in children

Performance in very young children- conflicting messages

Increased sensitivity in immuno-compromised hosts

Conclusion 2:
Latent TB
Good agreement between 2 IGRAS
(92%, k=0.82)
over-treatment by Paediatricians,
compared to NICE recommendations
How many children will develop TB if TST> 15, but
untreated with chemopro as IGRA negative?
How many children have neg TST but would have
had pos IGRA at screening
Longitudinal survey required

Conclusions

IGRA should not currently replace the

IGRA detect immune memory
do not confirm the
TSTbut
in children
presence or absence of M. tuberculosis- active or latent
higher specificity than
TST not forget the many
we the
should
additional challenging question in
designed to test for evidence
of TB infection,
not TB disease
childhood
TB
can be used as a rule-in
testmicrobiological
for active TB
in children,
better
diagnostics
better biomarkers than IFN
but not as a rule-out test
better vaccines

higher sensitivity in immunocompromised patients compared to TST

improved understanding of primary TB

TB treatment in children
Treatment regimens are adopted from adult schemes
Children respond very well to treatment, incl DOTS

Dosages need to be adjusted for weight:

Pharmakokinetics in children differ from adults
- INH- 5-10 mg/kg, rapid acetylators (1)
- Ethambutol 15-25 mg/kg (2)
Problems with treating TB in the HIV-infected child on ART
1: Schaaf et al, Arch Dis Child 2005; 90:614
2: Donald et al, Int J Tuberc Lung Dis 2006; 10:1318

Drugs and ADHERENCE

IF YOU DONT TAKE THE DRUGS,

THEY WONT WORK

PAEDIATRIC TB
POOR ADHERENCE
Support
-hospital TB clinic
-community
-health care workers
-social services
-DOT (Directly Observed Therapy)
-accurate record of treatment
-successful treatment
-prevention of resistance
-different adult

-different location

Take Home messages:

Think of the diagnosis, especially in the epidemiological
context
TB is a family disease

The diagnosis of active TB in children is based on a jigsaw of

findings
IGRA can be an additional piece in the jigsaw, but a negative
IGRA does not exclude active TB
TB therapy needs a lot of support for families

 founded in April 2009, branch of TBNET

to date: members from 15 European
countries, incl. Eastern Europe
includes clinicians, epidemiologists and
laboratory scientists

Aims
enhance the understanding of the pediatric aspects of tuberculosis
facilitate collaborative research studies
for childhood TB in Europe

provide expert opinion through excellence in science and teaching

establish a better evidence base for diagnosis and treatment of TB
in children

Research questions
- immunological mechanisms of age related susceptibility to TB
- Epidemiology of childhood TB
- MDR /XDR TB in children
- Performance/evaluation of new diagnostics
- New drugs
- New vaccines

Thank you
Any questions?

E-mail: b.kampmann@imperial.ac.uk

Website: www1.imperial.ac.uk/medicine/people/b.kampmann/