Transcript Slide 1

TB in children:
still a difficult task for the clinician?
Beate Kampmann MD FRCPCH PhD
A/Professor in Paediatric Infection & Immunity
Consultant Paediatrician
Imperial College London, UK
and
Themeleader Vaccinology
MRC-The Gambia
Overview
• What is special about TB in children?
• Epidemiology- who are our patients?
• Diagnostic challenges:
- Differences between adults and children
- New Immunological Tools-how helpful are they?
• Therapy: Drugs in kids- any differences?
• Prevention: new TB vaccines on the horizon
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
Tuberculosis in the UK:
ca. 9000 cases in 2009
39% in London
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 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;
Is the general population at risk of
disease from affected migrants?
Tuberculosis rates by place of birth: 2000-2005
• Little evidence to suggest
that the wider population
are at significant risk
Source, Enhanced Tuberculosis Surveillance
Children acquire TB from
(household) contacts
If you ask yourself, does this child have TB,
ask yourself:
is there TB in this family?
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
Miliary TB
L Wyld Aug 2010
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
- difficulty in detecting resistance
Diagnostic tests
Immunological
Host response
skin test
antigen-specific
production of IFNγ
Acknowledgement
& Thanks
IGRA in children
What are IGRA and why do we need them
How do they work
What do they contribute to the diagnosis of
active or latent TB
Performance in the immunocompromised
Remaining research questions
Conclusions
Acknowledgement
& Thanks
Paediatric TB: Diagnostic
challenges
due to low bacillary load
Paediatric TB: 106 bacteria
Adult TB: >109 bacteria
• children less infectious
• lack of “gold standard”: microbiological confirmation exceptional
• difficulty in detecting resistance
Acknowledgement
& Thanks
Tuberculin
skin test
(TST)
• technically difficult in children
• UK: 2 units of SSI tuberculin (PPD)
> 200 antigens, incl. BCG Ag
• Read-out: degree of hypersensitivity
• Problem:
lacks specificity and sensitivity
Acknowledgement
& Thanks
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
Thanksof BCG
Gene Acknowledgement
deletions and the& origin
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-γ)
that distinguish M. tuberculosis
infection from BCG vaccination
Principal of Quantiferon-Gold in tube assay
AG presentation
(ESAT-6, CFP-10, TB7.7)
Ag-specific
cytokine
secretion
Cytokine
quantification
by ELISA
Principal of ELISPOT assay
Coating antibody
Biotinylated 2nd
PBMC+antigen
antibody
Avidin-peroxidase
IFN-production
each spot is an antigen-specific
T cell that has released IFN
IGRA and National TB guidelines
UK: NICE Guidelines 2006
http://guidance.nice.org.uk/CG33
& Thanks
IGRA Acknowledgement
and the diagnosis
of active TB
Signs and
symptoms
Contact history
Travel
Active TB
Radiology
Microbiology
TST
IGRA
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
& Thanks
IGRA Acknowledgement
and the diagnosis
of active TB
IGRA missed between 20-40% of definite active TB
Acknowledgement
Thanks of active TB
Combining IGRA
and TST in the&diagnosis
A combination of TST and IGRA increases sensitivity to above 93%
& Thanks
IGRA and theAcknowledgement
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.
& Thanks
IGRA Acknowledgement
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
& Thanks
IGRA Acknowledgement
and the diagnosis
of latent TB
Contact history
Travel/Immi
gration
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
IGRA in the immuno-compromised host
Active TB
Detection of tuberculosis in HIV-infected children using an Elispot
Davies et al, AIDS. 2009 May 15;23(8):961-9.
ELISPOT was positive in 14/21 (66%) with definite TB
ELISPOT was more sensitive than TST for the detection of active TB in HIV-infected children:
positive ELISPOT compared with a positive TST [25/39 (64%) vs. 10/34 (29%), P = 0.005]
“However, the sensitivity of current ELISPOT assays is not sufficiently high
to be used as a rule out test for TB.”
Latent TB
High level of discordant IGRA results in HIV-infected adults and children
Mandalakas et al: Int J Tuberc Lung Dis. 2008 Apr;12(4):417-23.
HIV+ve children (n=23): tests yielded discordant results
61% of individuals testing positive with T-SPOT.TB, 41% with TST and
28% with QuantiFERON TB Gold (QTF)- older version
Algorithm for use of IGRA in HIV+ve patients
Newly diagnosed HIV or new immigrant with HIV
IGRA at baseline
negative
? Immune system
- check PHA
positive
? Lack of exposure
/no infection
Investigate for active TB
Repeat IGRA when “immune reconstituted”
Latent TB
Active TB
Use as baseline result
if concerns of active TB arise later
chemopro
TB Tx
Remaining questions and further research
Should we abandon the TST in screening for LTBI ?
• Reliability of performance of IGRA in very young children
• How do we interpret indeterminate results
• Negative predictive value, i.e.
How many children will develop active TB if TST > 15 mm, but untreated
with chemoprophylaxis as IGRA negative, according to current guidelines
• Is the step-wise approach of TST first, IGRA second justified?
How many children with negative TST would have a positive IGRA at screening
• Does the TST boost the IGRA responses
Current evidence suggests that boosting occurs, but not within first 72 hours
• (Short-term) reproducibility of the commercial IGRA
Can IGRA be used to monitor therapy or to predict development of active TB
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
Diagnosis of TB in children
•
Poor microbiology
•
Suspicion rather
than confirmation
•
Treatment dilemma
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)
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
L Wyld Aug 2010
New vaccines on the horizon
• Four main types of vaccines are currently
under development:
1.Vaccines based on BCG
2.Subunit (protein and peptide) vaccines
3.DNA vaccines
4. Live attenuated and inactivated whole
cell vaccines
E.Whittaker & B.Kampmann, Vaccines in Practice, 2011
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
Comprehensive review of childhood TB in Paediatric Resp Rev 2010
• founded in April 2009
• to date: 35 members from 16 European
countries, incl. Eastern Europe
• includes clinicians, epidemiologists and
laboratory scientists
www.ptbnet.org
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
Thank you
Any questions?
Contact details:
[email protected]