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Paediatric tuberculosis Beate Kampmann FRCPCH PhD A/Professor in Paediatric Infection & Immunity Consultant Paediatrician Imperial College London, UK.

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Presentation on theme: "Paediatric tuberculosis Beate Kampmann FRCPCH PhD A/Professor in Paediatric Infection & Immunity Consultant Paediatrician Imperial College London, UK."— Presentation transcript:

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2 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

3 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

4 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),

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:

6 Percentage of TB cases of foreign origin, 2006 Andorra Malta Monaco San Marino Not included or not reporting to EuroTB 0% – 4% 5% – 19% 20% – 49% > 49% Trends in incidence of TB in children under 15 years by ethnic group in London,

7 UK: Tuberculosis rates in persons born abroad by age Sources: Enhanced Tuberculosis Surveillance, Labour Force Survey population estimates, Abubakar et al Arch. Dis. Child. 2008;93; ; Development of TB in immigrant children

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

9 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

10 Presentation of PAEDIATRIC TB Case 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?

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

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

14 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

15 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

16 CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELLADULT IMMUNITY (live MTB) Successfulimmuneresponse LATE REACTIVATION OF PULMONARY DISEASE FORMSCAVITY

17 CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION PROGRESSIVEPULMONARYDISEASE MILIARY TB or EXTRA-PULMONARYDISEASE Inadequateimmuneresponse Lympho/haematogenousspread Self healing??

18 CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION PROGRESSIVEPULMONARYDISEASE MILLIARY,EXTRA-PULMONARYDISEASE TB MENINGITIS Inadequateimmuneresponse Lympho/haematogenousspread -most serious form of TB, fatal if untreated -most common in < 2 year-olds -worst prognosis in < 2 year-olds -insidious onset;

19 TB MENINGITIS Primary focus in lung Brain focus (Rich focus) MeningesCSF Severe granulomatous inflammatory response CSF protein  Thick gelatinous exudate forms, envelopes base of brain Cranial nerve palsies Vascular occlusions BRAININFARCTION Hydrocephalus  ICP VI NERVE PALSY

20 TB MENINGITIS CSF -lymphocytes, low sugar, high protein, AFB may be visible -but often-polymorphs initially -protein normal initially -protein normal initially -no visible organisms -sugar normal initially So: repeat LP, neuro-imaging, CXR, contacts

21 Ring enhancing tuberculomata CT scan; enhanced

22 ENHANCED CT SCAN GADALLINIUM ENHANCED MRI ENHANCED CT SCAN GADALLINIUM ENHANCED MRI MRI > SENSITIVITY THAN CT

23 HYDROCEPHALUS

24 TB MENINGITIS SUCCESS of Rx DEPENDS ON EARLY DIAGNOSIS

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

26 Diagnostic tests Microbiological Organism smear culture DNA

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

28 Paediatric TB: 10 6 bacteria Adult TB: >10 9 bacteria - children less infectious - difficulty in confirming diagnosis (< 30%) - difficulty in detecting resistance PAEDIATRIC TB: Implications of bacterial load

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

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

31 -technically difficult in children -UK : 2 units of SSI tuberculin (PPD) - > 200 antigens, Read-out: -degree of hypersensitivity to PPD TUBERCULIN SKIN TEST (used since 1890)

32 -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 Problems with the TST:

33 M. tuberculosis M. bovis 4/5 deletions 30/40 genes 10 deletions 64 genes BCG substrains Gene deletions and the origin of BCG RD1 region major antigens ESAT6 and CFP10 T cell tests (interferon-  ) that distinguish M. tuberculosis infection from BCG vaccination

34 IFN-  responses to specific antigens by ELISPOT or Whole Blood Assay Van Pinxteren Clin Diagn Lab Immunol 2000 Unable to distinguish between TB and BCG effect Clear difference between acute TB and BCG vaccination

35 UK: NICE Guidelines IGRA and National TB guidelines

36 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 2 commercially available assays

37 Principal of Quantiferon Gold

38 Coating antibody PBMC+antigen IFN-  production Biotinylated 2 nd antibody Avidin-peroxidase In vitro blood test: ELISPOT assay Each spot is an individual T cell that has released IFN 

39 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 Jun;33(6): IGRA versus TST: our own research

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

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

42 Acknowledgement & Thanks IGRA and the 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. Connell et al, Thorax 2006, Jul;61(7): The whole blood IFN-gamma assay was positive in all 9 children (100%) with TB disease. Bianchi et al, PIDJ 2009, Jun;28(6):510-4 IGRA was positive in 15 of 16 (93.8%) children with active pulmonary TB Nicol et al; Pediatrics 2009,Jan; 123(1): 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).

43 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 active TB

44 Acknowledgement & Thanks IGRA and the diagnosis of latent TB Travel/Immig ration Latent TB negative Radiology TST Contact history Absence of clinical signs and symptoms IGRA

45 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 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 and the diagnosis of latent TB

46 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

47 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 TB Conclusions better microbiological diagnostics better biomarkers than IFN  better vaccines improved understanding of primary TB

48 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 mg/kg, rapid acetylators (1) - Ethambutol 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

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

50 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

51 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

52 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

53 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

54 Thank you Any questions? Website: www1.imperial.ac.uk/medicine/people/b.kampmann/


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