TB in children: still a difficult task for the clinician?

Beate Kampmann MD FRCPCH PhD

A/Professor in Paediatric Infection & ImmunityConsultant PaediatricianImperial College London, UKand Themeleader VaccinologyMRC-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 Mortality1.4 million cases annually (95% developing countries) 450,000 Deathsestimated 10-15% of global burden related to childhood TB Different clinical spectrum of disease5-10% < 2 yr meningitis disseminated disease more common Co infection with HIV- clinically very difficult to distinguish Remains a diagnostic challengepaucibacillary, rarely culture confirmed :Sputum smear positive in 10.3% (10-14yr), 1.8% (5-9) and1.6% (

Tuberculosis in Children differs from adults Immune responses areAge-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 reactivationmight 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

ca. 9000 cases in 200939% in London

Percentage of TB cases of foreign origin, 2006Trends in incidence of TB in children under 15 years by ethnic group in London, 2001-2006

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

Development of TB in immigrant children

Is the general population at risk of disease from affected migrants?

Little evidence to suggest that the wider population are at significant riskSource, Enhanced Tuberculosis SurveillanceTuberculosis rates by place of birth: 2000-2005

Children acquire TB from (household) contactsIf 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 examinationWHAT INVESTIGATIONS WOULD YOU DO?

PAEDIATRIC TBCase 1Mantoux test: 2mmGastric washings; - microscopy and (later) culture negative

-Rx.Erythromycin and Augmentin-no improvement on antibiotics-bronchoscopy planned

PAEDIATRIC TBCase 11 day before bronchoscopy: - afebrile, less cough, looking well-continued improvement, - discharged home, no

PAEDIATRIC TBCase 1out-patient review 6 weeks later: -completely well, thriving, no coughGrandfather admitted to local hospital with pulmonary TB-repeat Mantoux: now 25mm-TB treatment commenced

PAEDIATRIC TB

Case 1

Discussion PointsPrimary TB in children:- spontaneous recovery is possible- diagnosis is difficult- no visible AFB- cultures usually negative- tuberculin test negative- F/H is often the clue to diagnosis

Self healing??

L Wyld Aug 2010Miliary TB

L Wyld Aug 2010

Diagnostic testsMicrobiological

Organism

smear culture DNA

Appearance in sputumAppearance in culturecordingThe gold-standard

Diagnostic testsImmunological

Host response

skin test antigen-specific production of IFN

What are IGRA and why do we need them

How do they work

What do they contribute to the diagnosis ofactive or latent TB

Performance in the immunocompromised

Remaining research questions

Conclusions

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

Antigens used: ESAT-6CFP10 +/- TB7.7mitogennegative controlIn principal: can both distinguish between BCG vaccination and M.tuberculosis infection

but: Paucity of data in children Confusion about use of IGRA

M. tuberculosisM. bovis4/5 deletions30/40 genes10 deletions64 genesBCG substrains

AG presentation(ESAT-6, CFP-10, TB7.7)Ag-specificcytokinesecretionCytokine quantificationby ELISA Principal of Quantiferon-Gold in tube assay

each spot is an antigen-specific T cell that has released IFN Principal of ELISPOT assay

UK: NICE Guidelines 2006http://guidance.nice.org.uk/CG33 IGRA and National TB guidelines

Contact history

IGRA

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 identifymore children with active TB than TST.

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

IGRA versus TST: our own research

IGRA missed between 20-40% of definite active TB

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

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. Connell et al, Thorax 2006, Jul;61(7):616-20The whole blood IFN-gamma assay was positive in all 9 children (100%) with TB disease. Bianchi et al, PIDJ 2009, Jun;28(6):510-4IGRA was positive in 15 of 16 (93.8%) children with active pulmonary TB Nicol et al; Pediatrics 2009,Jan; 123(1): 38-43Comparison of T-SPOT.TB assay and TST for the evaluation of young children at high risk for tuberculosisSensitivity 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).

A negative IGRA does not exclude active TB

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

Contact history

Absence of clinicalsigns and symptomsIGRA

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 paediatriciansbut: 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 and the diagnosis of latent TB

Detection of tuberculosis in HIV-infected children using an ElispotDavies et al, AIDS. 2009 May 15;23(8):961-9.

ELISPOT was positive in 14/21 (66%) with definite TBELISPOT 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.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.Active TBLatent TBHIV+ve children (n=23): tests yielded discordant results61% of individuals testing positive with T-SPOT.TB, 41% with TST and 28% with QuantiFERON TB Gold (QTF)- older versionIGRA in the immuno-compromised host

Newly diagnosed HIV or new immigrant with HIVIGRA at baselinepositivenegativeInvestigate for active TBActive TBTB TxLatent TBchemopro? Immune system check PHA

? Lack of exposure/no infectionRepeat IGRA when immune reconstituted

Use as baseline result if concerns of active TB arise later

Algorithm for use of IGRA in HIV+ve patients

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 responsesCurrent 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

Should we abandon the TST in screening for LTBI ?

Remaining questions and further research

IGRA detect immune memory but do not confirm the presence or absence of M. tuberculosis- active or latent

higher specificity than the TST

designed to test for evidence of TB infection, not TB disease

can be used as a rule-in test for active TB in children, but not as a rule-out test

higher sensitivity in immunocompromised patients compared to TST

IGRA should not currently replace the TST in children

we should not forget the many additional challenging question in childhood TBConclusionsbetter microbiological diagnosticsbetter biomarkers than IFNbetter vaccines

improved understanding of primary TB

Diagnosis of TB in children

Poor microbiology

Suspicion ratherthan 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; 90:6142: Donald et al, Int J Tuberc Lung Dis 2006; 10:1318

IF YOU DONT TAKE THE DRUGS,THEY WONT WORKDrugs and ADHERENCE

PAEDIATRIC TBPOOR ADHERENCESupport-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

L Wyld Aug 2010

New vaccines on the horizonFour main types of vaccines are currently under development:Vaccines based on BCGSubunit (protein and peptide) vaccinesDNA vaccines4. Live attenuated and inactivated wholecell 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 supportComprehensive 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

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

www.ptbnet.org

Thank you

Any questions?

Contact details:

b.kampmann@imperial.ac.uk

*******************************So, Children with evidence of TB infection should receive chemoprophylaxis

But how do we establish this?

We used to do it with the TST which can diagnose infection with mycobacteria.Unfortunately, the TST lacks specificity, as BCG vaccination can give a false-positive result

We now have blood based assays, which appear specific for infection with M.TB and measure the immunological footprint of M.Tb infection in the form of secreted interferon-gamma- the so-called IGRA.

The Nice guidelines in 2006 recommended the use of IGRA to guide the assignment of chemoprophylaxis, as seen in this algorithm.Only children with positive IGRA should now receive prophylaxis

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