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
hous ehold
black african
afro-caribbean
caucasian
SE asian
mixed race
arab
no
south asian
caucasian
7%
39%
vis itor
yes
56%
afro-caribbean
2%
no
Country of Birth
28%
UK
38%
dk
4%
household
62%
dk
dk
5%
mixed race
4%
SE asianvisitor
6%
6%
no
non- UK
62%
UK
non-U K
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 IFNγ
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 s tin 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)
Pos s ible
(N=28)
>15
6-15
<6
+
-
Ind
+
-
TF
43
19
38
46
45
9
38
53
9
83
8
8
80
12
8
58
38
4
45
30
26
52
42
5
45
45
10
60
21
19
64
29
6
50
42
8
7
14
79
7
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 DON’T TAKE THE DRUGS,
THEY WON’T 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/