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Paediatric tuberculosis

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

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  1. 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

  2. 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

  3. 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),

  4. 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

  5. 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

  6. 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;

  7. Children with TB at Imperial HCT: Ethnicity and country of birth:

  8. 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

  9. 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?

  10. PAEDIATRIC TB Case 1 Mantoux test: 2mm Gastric washings; - microscopy and (later) culture negative -Rx. Erythromycin and Augmentin -no improvement on antibiotics -bronchoscopy planned

  11. PAEDIATRIC TB Case 1 1 day before bronchoscopy: - afebrile, less cough, looking well -continued improvement, - discharged home, no ∆

  12. 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

  13. 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

  14. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION Successful immune response FORMS CAVITY WELL ADULT IMMUNITY (live MTB) LATE REACTIVATION OF PULMONARY DISEASE

  15. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION Inadequate immune response PROGRESSIVE PULMONARY DISEASE Lympho/ haematogenous spread MILIARY TB or EXTRA-PULMONARY DISEASE Self healing??

  16. 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

  17. 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

  18. 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

  19. CT scan; enhanced Ring enhancing tuberculomata

  20. MRI > SENSITIVITY THAN CT ENHANCED CT SCAN GADALLINIUM ENHANCED MRI

  21. HYDROCEPHALUS

  22. TB MENINGITIS SUCCESS of Rx DEPENDS ON EARLY DIAGNOSIS

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

  24. Diagnostic tests Microbiological Organism smear culture DNA

  25. The “gold-standard” Appearance in sputum Appearance in culture ‘cording’

  26. 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

  27. Diagnostic tests Microbiological Organism smear culture DNA Immunological Host response skin test antigen-specific production of IFNγ

  28. IGRA and the diagnosis of active TB Acknowledgement & Thanks Signs and symptoms Travel Contact history Active TB Microbiology Radiology IGRA TST

  29. 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

  30. 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

  31. 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

  32. 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

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

  34. 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

  35. Principal of Quantiferon Gold

  36. 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

  37. 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

  38. IGRA and the diagnosis of active TB Acknowledgement & Thanks IGRA missed between 20-40% of definite active TB

  39. Combining IGRA and TST in the diagnosis of active TB Acknowledgement & Thanks A combination of TST and IGRA increases sensitivity to above 93%

  40. 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.

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. 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

  47. Drugs and ADHERENCE IF YOU DON’T TAKE THE DRUGS, THEY WON’T WORK

  48. 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

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