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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.

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Paediatric tuberculosis

Paediatrictuberculosis

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
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


Paediatric tuberculosis

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),


Paediatric tuberculosis

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


Paediatric tuberculosis

Not included or not reporting to EuroTB

0% – 4%

5% – 19%

20% – 49%

> 49%

Andorra

Malta

Monaco

San Marino

Percentage of TB cases of foreign origin, 2006

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
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;


Paediatric tuberculosis

Children with TB at Imperial HCT:

Ethnicity and country of birth:


Children acquire tb from household contacts
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


Paediatric tuberculosis

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 tuberculosis

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 tuberculosis

PAEDIATRIC TB

Case 1

1 day before bronchoscopy:

- afebrile, less cough, looking well

-continued improvement,

- discharged home, no ∆


Paediatric tuberculosis

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 tuberculosis

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

- F/H is often the clue to diagnosis


Paediatric tuberculosis

CHILDHOOD EXPOSURE

PRIMARY

PULMONARY

INFECTION

Successful

immune

response

FORMS

CAVITY

WELL

ADULT

IMMUNITY

(live MTB)

LATE REACTIVATION OF PULMONARY DISEASE


Paediatric tuberculosis

CHILDHOOD EXPOSURE

PRIMARY

PULMONARY

INFECTION

Inadequate

immune

response

PROGRESSIVE

PULMONARY

DISEASE

Lympho/

haematogenous

spread

MILIARY TB or

EXTRA-PULMONARY

DISEASE

Self healing??


Paediatric tuberculosis

CHILDHOOD EXPOSURE

PRIMARY

PULMONARY

INFECTION

Inadequate

immune

response

PROGRESSIVE

PULMONARY

DISEASE

-most serious form of TB, fatal if untreated

-most common in < 2 year-olds

-worst prognosis in < 2 year-olds

-insidious onset;

Lympho/

haematogenous

spread

MILLIARY,

EXTRA-PULMONARY

DISEASE

TB MENINGITIS


Paediatric tuberculosis

TB MENINGITIS

Primary focus

in lung

Brain focus

(Rich focus)

Meninges

CSF

Severe granulomatous

inflammatory response

VI NERVE

PALSY

BRAIN

INFARCTION

CSF protein 

 ICP

Thick gelatinous

exudate forms,

envelopes base

of brain

Cranial nerve palsies

Vascular occlusions

Hydrocephalus


Paediatric tuberculosis

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


Paediatric tuberculosis

CT scan; enhanced

Ring enhancing

tuberculomata


Paediatric tuberculosis

MRI > SENSITIVITY THAN CT

ENHANCED CT SCAN GADALLINIUM ENHANCED MRI



Paediatric tuberculosis

TB MENINGITIS

SUCCESS of Rx DEPENDS ON

EARLY DIAGNOSIS


Paediatric tuberculosis

TB MENINGITIS

TREATMENT with quadruple therapy

Drugs:

-? CSF penetration

- duration

- sensitivity

Adjunctive therapy:

- steroids

- SIADH

- acetazolamide

- surgery


Paediatric tuberculosis

Diagnostic tests

Microbiological

Organism

smear culture DNA


Paediatric tuberculosis

The “gold-standard”

Appearance in sputum

Appearance in culture

‘cording’


Paediatric tuberculosis

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


Paediatric tuberculosis

Diagnostic tests

Microbiological

Organism

smear culture DNA

Immunological

Host response

skin test antigen-specific

production of IFNγ


Paediatric tuberculosis

IGRA and the diagnosis of active TB

Acknowledgement & Thanks

Signs and

symptoms

Travel

Contact history

Active TB

Microbiology

Radiology

IGRA

TST


Paediatric tuberculosis

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


Paediatric tuberculosis

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


  • Paediatric tuberculosis

    major antigens

    ESAT6 and CFP10

    RD1 region

    T cell tests (interferon-g)

    that distinguish M. tuberculosis

    infection from BCG vaccination

    Gene deletions and the origin of BCG

    M. tuberculosis

    10 deletions

    64 genes

    M. bovis

    4/5 deletions

    30/40 genes

    BCG substrains


    Ifn responses to specific antigens by elispot or whole blood assay
    IFN-γ 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


    Paediatric tuberculosis

    IGRA and National TB guidelines

    UK: NICE Guidelines 2006

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


    Paediatric tuberculosis

    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



    Paediatric tuberculosis

    ELISPOT assay

    In vitro blood test:

    Coating antibody

    PBMC+antigen

    IFN-γ production

    Biotinylated 2nd antibody

    Avidin-peroxidase

    Each spot is an individual T cell that has released IFNγ


    Spot the difference

    IGRA versus TST: our own research

    Spot the Difference

    Interferon-γ 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


    Paediatric tuberculosis

    IGRA and the diagnosis of active TB

    Acknowledgement & Thanks

    IGRA missed between 20-40% of definite active TB


    Paediatric tuberculosis

    Combining IGRA and TST in the diagnosis of active TB

    Acknowledgement & Thanks

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


    Paediatric tuberculosis

    IGRA and the diagnosis of active TB- other studies

    Acknowledgement & Thanks

    • 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.


    Paediatric tuberculosis

    IGRA and the diagnosis of active TB

    Acknowledgement & Thanks

    A negative IGRA does not exclude active TB

    IGRA is not a “rule-out”- test,

    but can add value to additional investigations


    Paediatric tuberculosis

    IGRA and the diagnosis of latent TB

    Acknowledgement & Thanks

    Contact history

    Travel/Immigration

    Absence of clinical

    signs and symptoms

    Latent TB

    negative

    Radiology

    IGRA

    TST


    Paediatric tuberculosis

    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
    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


    Paediatric tuberculosis

    Conclusions

    • IGRA should not currently replace the TST in children

    • we should not forget the many additional challenging question in childhood TB

    • 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

    better microbiological diagnostics

    better biomarkers than IFNγ

    better vaccines

    improved understanding of primary TB


    Tb treatment in children
    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


    Paediatric tuberculosis

    Drugs and ADHERENCE

    IF YOU DON’T TAKE THE DRUGS,

    THEY WON’T WORK


    Paediatric tuberculosis

    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
    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


    Paediatric tuberculosis

    • 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
    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


    Paediatric tuberculosis

    Thank you

    Any questions?

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

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