1. PAEDIATRIC TUBERCULOSIS Sam Walters Imperial NHS Trust LONDON

3. 2011 ESTIMATED TB CASES 12 MILLION ESTIMATED TB CASES 12 MILLION 8.7 million new cases: 500,000 children (6-8%) DEATHS: 1.43 million 60,000 children (4.2%) 60,000 children (4.2%) [2012; 74,000 children (5.2%)] * Up to 40% of cases in high incidence countries are children

4. 2011 500,000 children (6-10%) non-HIV DEATHS: 2011 60,000 children (4.2%) 201274,000 children (5.2%)

5. 2011 500,000 children (6-10%) non-HIV DEATHS: 2011 60,000 children (4.2%) 201274,000 children (5.2%) ? PAEDIATRIC DEATHS Unreliable estimates; not that bad in 2009 or, just as bad in 2011/2012; how many HIV deaths due to TB Reliable estimates; huge improvement; fixed dose tabs, management guidelines, linked TB/HIV care, roll-out of ARVs for children

6. 2011 500,000 children (6-10%) non-HIV DEATHS: 2011 60,000 children (4.2%) 201274,000 children (5.2%) ? PAEDIATRIC DEATHS Unreliable estimates; not that bad in 2009 or, just as bad in 2011/2012; how many HIV deaths due to TB Reliable estimates; huge improvement; fixed dose tabs, management guidelines, linked TB/HIV care, roll-out of ARVs for children Children now firmly placed on global TB agenda

7. PAEDIATRIC TUBERCULOSIS Clinical Presentation

8. -18 month girl -18 month girl -previously well, no family history of TB -3 weeks cough and unwell -admitted to hospital -low grade fever, normal examination -appropriate investigations: all negative, Mantoux; 2mm -gastric aspirates x 3; negative AFB -X-ray patchy consolidation;

10. -Rx.3 different antibiotic courses over 3 weeks -gradual improvement; afebrile, less cough, looking well -discharged home, no ∆ -6 weeks later out-patient review -completely well, thriving, no cough -gastric aspirates x 3; negative culture

11. -Rx.3 different antibiotic courses over 3 weeks -gradual improvement; afebrile, less cough, looking well -continued improvement, discharged home, no ∆ -6 weeks later out-patient review -completely well, thriving, no cough -gastric aspirates x 3; negative culture “Grandfather admitted to local hospital with pulmonary TB” -repeat Mantoux; now 22 mm -TB treatment commenced

12. PAEDIATRIC TB Primary TB in children; -spontaneous recovery is usual

13. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION INFECTION ≠ DISEASE NATURALHISTORY

14. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELLCHILD ‘LIFELONG’IMMUNITY (live MTB) Successfulimmuneresponse

15. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELL CHILD or ADULT IMMUNITY (live MTB) Successfulimmuneresponse 1/3 of population of planet have been infected  2.3 billion people 1/3 of population of planet have live MTB in them: = 2,300,000,000 Tuberculosis cases: = 12,000,000

16. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELL CHILD or ADULT IMMUNITY (live MTB) Successfulimmuneresponse LATE REACTIVATION, RE-INFECTION‘Immunosuppression’; age, malnutrition, infection, HIV

17. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELLADULT IMMUNITY (live MTB) Successfulimmuneresponse LATE REACTIVATION OF ADULT CAVITATING PULMONARY DISEASE FORMS CAVITY

18. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELLADULT IMMUNITY (live MTB) Successfulimmuneresponse LATE REACTIVATION OF PULMONARY DISEASE ADULT DISEASE FORMS CAVITY TRANSMISSION

19. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION PROGRESSIVEPULMONARYDISEASE MILLIARY,EXTRA-PULMONARYDISEASE DEATH DEATH Inadequateimmuneresponse Lympho/haematogenousspread

20. Paediatric TB: Adult TB: Paediatric TB: Adult TB: 10 4 -10 6 bacteria >10 9 bacteria 10 4 -10 6 bacteria >10 9 bacteria -difficulty in confirming diagnosis -difficulty in detecting resistance -?  emergence of resistance PAUCI-BACILLARY TB Implications of bacterial load:

21. Paediatric TB: Adult TB: Paediatric TB: Adult TB: 10 4 -10 6 bacteria >10 9 bacteria 10 4 -10 6 bacteria >10 9 bacteria -difficulty in confirming diagnosis -difficulty in detecting resistance -?  emergence of resistance -  infectivity PAUCI-BACILLARY TB Implications of bacterial load:

22. Paediatric TB: Adult TB: Paediatric TB: Adult TB: 10 4 -10 6 bacteria >10 9 bacteria 10 4 -10 6 bacteria >10 9 bacteria -difficulty in confirming diagnosis -difficulty in detecting resistance -?  emergence of resistance -  infectivity -not part of immediate public health problem PAUCI-BACILLARY TB Implications of bacterial load:

23. Paediatric TB: Adult TB: Paediatric TB: Adult TB: 10 4 -10 6 bacteria >10 9 bacteria 10 4 -10 6 bacteria >10 9 bacteria -difficulty in confirming diagnosis -difficulty in detecting resistance -?  emergence of resistance -  infectivity -not part of immediate public health problem PAUCI-BACILLARY TB Implications of bacterial load:

24. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELL CHILD IMMUNITY ( live MTB) LATEREACTIVATION Any Organ e.g. Bone, Kidney PROGRESSIVEPULMONARYDISEASE MILLIARY,EXTRAPULMONARYDISEASE Inadequateimmuneresponse Successful immune response Lympho/haematogenousspread

25. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELLCHILD ‘LIFELONG’ IMMUNITY (lesions sterilised) PROGRESSIVEPULMONARYDISEASE MILLIARY,EXTRAPULMONARYDISEASE Inadequateimmuneresponse Successful immune response Lympho/haematogenousspread Treatment Treatment

26. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELLCHILD LIFELONGIMMUNITY (live MTB) Successfulimmuneresponse PROGRESSIVEPULMONARYDISEASE MILLIARY,EXTRA-PULMONARYDISEASE DEATH DEATH Inadequateimmuneresponse Lympho/haematogenousspread HOSTImmunosuppression Genetics ? Age esp. young children ORGANISM Infecting dose -smear +ve, log phase -smear +ve, log phase -smear -ve / culture +ve, -smear -ve / culture +ve, ? dormant ? dormant MTB strain differences ? WHICH PATHWAY

27. AGE WHEN INFECTED PUERTO RICAN dataSOUTH AFRICAN data ADOLESCENT15%5 – 10% 5 yr - ADOLESCENT5 – 10% 5 – 10 yr2% 3 – 5yr5% 1 – 5 yr24% 1 – 2 yr30% < 1 yr43%50% Age related risk of progression to disease: Adult 5 – 10%/lifetime (HIV 10%/yr) Risk is life long, but concentrated in first 12-24 months after infection (approximately 80% of risk) Undisputed↑risk Disputed↑risk

28. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELLCHILD IMMUNITY Sterile lesions PROGRESSIVEPULMONARYDISEASE MILLIARY,EXTRAPULMONARYDISEASE Inadequateimmuneresponse Successful immune response, Lympho/haematogenousspread Treatment Treatment Treatment Successfulimmuneresponse

29. ISONIAZIDRIFAMPICINPYRAZINAMIDE(Ethambutol) Triple therapy: the Big Three (+ one)

30. September 2009 Probably correct dose but taken 40 yrs!

31. PAEDIATRIC DRUG DOSES ISONIAZID 10-15 mg/kg/day RIFAMPICIN15 mg/kg/day PYRAZINAMIDE 30-40 mg/kg/day ETHAMBUTOL ?20 mg/kg/day * Not CNS

32. ‘SHORT COURSE’ 6 months chemotherapy; -Pyrazinamide 2 months, Ethambutol 2 months -INAH 6 months, Rifampicin 6 months Good data in adults -East African/British MRC studies 1970s -Singapore Tuberculosis Service/British MRC 1970s & 1980s -Hong Kong Chest Service/British MRC 1970s & 1980s Criteria -pulmonary disease (TB adenopathy) -fully sensitive organism TREATMENT: HOW LONG?

33. ‘SHORT COURSE’ Criteria -pulmonary disease (TB adenopathy) -fully sensitive organism (usually unknown in paediatrics) - mostly adult data HOW LONG TO TREAT CHILDREN?

34. RESISTANT TB MDR TB (2-3 decades) - resistant to rifampicin + isoniazid XDR TB (2006) – resistant to -Rifampicin + -Isoniazid + -any 2 nd line anti-TB injectable + -any fluoroquinolone

35. 2008-2011: % CONFIRMED MDR-TB from ISOLATES Resistance to at least INAH and Rifampicin (2010 global prevalence; 650,000 cases) Very few children

36. XDR-TB: EXTENSIVE DRUG RESISTANT TB -resistance to INAH and Rifampicin, any fluoroquinolone and 1 of the injectable drugs (amikacin, capreomycin, kanamycin) Countries that had reported at least one XDR-TB case by Oct 2012 KWAZULU NATAL

37. TUGELA FERRY (KZN, SOUTH AFRICA)

38. -544 TB patients -221 MDR TB -53 XDR TB (55% primary infection) -44 HIV tested; ALL +ve -52 died within 25 days diagnosis  transmission  mortality  association with HIV Must have spread to children but no data; culture negative or not public health threat! Must have spread to children but no data; culture negative or not public health threat! TUGELA FERRY (KZN, SOUTH AFRICA) 2005 - 2006

39. MDR and XDR TB HOW MANY ARE CHILDREN? Not an immediate public health threat but many will be infectious in the future.

40. 2 nd line drugs with anti-TB activity StreptomycinCycloserine AmikacinRifabutin CapreomycinRifapentine CiprofloxacinEthionamide OfloxacinProthionamide SparfloxacinClofazamine ThiacetazoneLinezolid PASClarithromycin IFN  TNF  2 nd line for good reasons 2 nd line for good reasons - limited paediatric data - complex drug interactions -↑toxicities,↓tolerability Promising new drugs; Promising new drugs; MoxifloxacinPA 824 (Nitroimidazol-oxazine) (metronidazole class) TMC-207 (Bedaquiline) Sirturo™ (metronidazole class)

41. EXTRA PULMONARY DISEASE (paucity of data) (2 months intensive treatment) Joint / bone -? 9-12 months CNS -12 months at least, ? 18-24 months if tuberculomata -steroids for 1 month -4th drug initially ethambutol But why should it take longer to sterilise extrapulmonary lesions? HIV -?12 months (relapse with same organism: SA children treated for 6/12) TREATMENT sensitive MTB: HOW LONG?

42. PAEDIATRIC TB ADHERENCE If you don’t take the drugs, the drugs won’t work.

44. HEPATITIS -rare in children -usually with predisposing co-morbidity e.g. HIV, viral hepatitis ? Only routinely measure LFTs at start of therapy BUT with newer ↑in recommended doses need to be vigilant DRUG TOXICITY

45. -insidious onset; -headaches, subtle behaviour change -progresses to convulsions, cranial nerve palsies, hemiplegia, coma, DEATH

46. TB MENINGITIS DIAGNOSIS CSF (textbook description) -lymphocytes, low sugar, high protein, AFB visible But, Mycobacteria don’t read textbooks Early disease; -often polymorphs -protein can be normal initially -sugar can be normal initially Usually-no visible organisms

47. CSF ABNORMALITIES IN MENINGITIS (%) Donald et al. 1987; J Trop Ped; 33: 213-216 Viral Neisseria Haemophilus StreptococcusTuberculous Investigation meningitis meningitidis influenzae pneumomiae meningitis Cell count >500x10 6 /l 12 8174 70 3 Protein >0.8 g/l 7 8384 97 76 Glucose < 2.2mmol/l 1 7673 75 64 CSF/blood glucose : <0.4 7 7974 91 79 Organisms seen on microscopy 0 6547 85 8 Number of cases 108 14047 34 62

48. ENHANCED CT SCAN GADALLINIUM ENHANCED MRI ENHANCED CT SCAN GADALLINIUM ENHANCED MRI MRI > SENSITIVITY THAN CT TB Meningitis

50. MRI > SENSITIVITY THAN CT ENHANCED CT SCAN GADALLINIUM ENHANCED MRI ENHANCED CT SCAN GADALLINIUM ENHANCED MRI Miliary TB, no meningitis

51. TB MENINGITIS TREATMENT TREATMENT Anti TB drugs; -duration-sensitivity -? CSF penetration Adjunctive therapy; -steroids-SIADH-acetazolamide-surgery HYDROCEPHALUS

52. DRUG TYPICAL MIC mg/ml PEAK LEVELS SERUM mg/ml PEAK LEVELS CSF mg/ml % PENETRATION INAH0.025-0.54.43.280 RIFAMPICIN0.006-0.211.50.786.8 PYRAZINAMIDE12.550 100 ETHAMBUTOL*11.2-80.9-4.252-75 STREPTOMYCIN2.1-103026.6 MOXIFLOXACIN**0.375.494.0774 poor penetration of ethambutol across non-inflamed meninges * poor penetration of ethambutol across non-inflamed meninges **Kanellakopoulou k et al. J Anti microb Chemo. 2008 61; 1328-31 CSF penetration of anti-TB drugs

53. ? PAEDIATRIC CNS DRUG DOSES ISONIAZID 15 mg/kg/day?20 if < 10kg RIFAMPICIN 15 mg/kg/day?20 if < 10kg PYRAZINAMIDE 30-40 mg/kg/day40 if < 10kg ETHAMBUTOL 20 mg/kg/day

54. PROGNOSIS Coma divided into 3 stages (MRC 1948); Stage I-early signs of meningeal irritation -no focal neurology -complete recovery if treated Stage II-focal neurology; CN palsies, hemiparesis, confusion -if treated recover but majority have physical or intellectual handicap Stage III-comatose, unable to localise pain -30% mortality, most survivors have severe physical or intellectual handicap EARLY TREATMENT: EARLY DIAGNOSIS

55. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION WELL CHILD or ADULT IMMUNITY (? live MTB) LATEREACTIVATION Any Organ PROGRESSIVEPULMONARYDISEASE MILLIARY,EXTRAPULMONARYDISEASE Inadequateimmuneresponse Successful immune response, Lympho/haematogenousspread Diagnosis Diagnosis

56. Difficulty in diagnosis –Primary TB Non-specific symptomsNon-specific symptoms Tuberculin reaction -veTuberculin reaction -ve X-ray changes non-specificX-ray changes non-specific –Progressive primary Non-specific symptomsNon-specific symptoms Pauci-bacillaryPauci-bacillary Tuberculin reaction  veTuberculin reaction  ve X-ray changes non-specificX-ray changes non-specific –Post-Primary, late reactivation (Adult) Cavitating pulmonary disease (any organ involved)Cavitating pulmonary disease (any organ involved) Tuberculin reaction +ve (usually)Tuberculin reaction +ve (usually) PAEDIATRIC TUBERCULOSIS

57. Difficulty in diagnosis –Primary TB Non-specific symptomsNon-specific symptoms Tuberculin reaction -veTuberculin reaction -ve X-ray changes non-specificX-ray changes non-specific –Progressive primary Non-specific symptomsNon-specific symptoms Pauci-bacillaryPauci-bacillary Tuberculin reaction  veTuberculin reaction  ve X-ray changes non-specificX-ray changes non-specific –Post-Primary, late reactivation (Adult) Cavitating pulmonary disease (any organ involved)Cavitating pulmonary disease (any organ involved) Tuberculin reaction +ve (usually)Tuberculin reaction +ve (usually) PAEDIATRIC TUBERCULOSIS

58. DIAGNOSIS OF TB IN CHILDREN Microscopy / culture ‘gold standard’ (pauci-bacillary, prolonged culture) -respiratory secretions -sputum (need > 5000/ ml to see AFB) -gastric washings > BAL -?induced sputum vs gastric washings** -CSF, bone marrow, lymphoid tissue, etc. Paediatric TB: 10 4 -10 6 bacteria **Induced sputum >> gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. H J Zar et al. Lancet, 2005; 365:130-134 ** Showed equivalence. M Hatherill, H J Zar et al. Arch Dis Child, 2009;94:195-201 **Induced sputum or gastric lavage for community-based diagnosis of childhood pulmonary tuberculosis? Showed equivalence. M Hatherill, H J Zar et al. Arch Dis Child, 2009;94:195-201

59. Diagnostic tests Immunology Host response Tuberculin antigen-specific skin test (TST) production of IFN Microbiology Organism smear culture DNA Histology

60. TUBERCULIN SKIN TEST (used since 1890) -measures; -degree of hypersensitivity to PPD -does not measure; -immunity to tuberculosis -time of infection -presence or extent of disease -poor specificity, does not distinguish between; -TB disease and TB infection -BCG -atypical mycobacteria -poor sensitivity, can be falsely negative in; -early infection, disseminated disease -other acute infections (measles, pertussis), live vaccines -severe malnutrition -immunocompromised In children negative test does not exclude TB Problems with Specificity Low Sensitivity in young kids

61. IGRAs

62. Arch Dis Child 2010:95: 180-186 Conclusions: -TST more sensitive for culture proven TB -a -a negative IGRA does not exclude active TB -a combination of -a combination of IGRA + TST increases sensitivity of diagnosis - -negative IGRAs should not deter treating presumed active TB - -IGRAs would significantly reduce treatment of LTBI in UK -but would it be safe? → NIKS (NIHR IGRA Kids Study) - to assess predictive value of IGRA for LTBI

63. Aims of the project 1.To determine if it is safe to withhold chemoprophylaxis from children exposed to TB with negative IGRA but positive TST Prospective cohort study 2. To link TB exposure, infection and outcome in children via a national contact tracing module, linked to TB register Contact module PI: Prof B Kampmann, Imperial College; study involves 11 NHS sites in the UK

64. Design TB house-hold-exposed children TST and IGRA at screening and 2 months later TST+ve/IGRA-ve followed for 1-2 years Primary endpoint: Development of active TB (? NICE: how safe are the guidelines) Secondary endpoint: how concordant are TST and IGRA (? NICE: is the step-wise screening approach justified) Target: 500, Currently: 489 Results for secondary endpoint available in early 2014, primary endpoint: 2015

65. Clinical; but TB can do anything!

66. DIAGNOSIS OF TB IN CHILDREN Family history Epidemiology Trial of treatment

67. DIAGNOSIS OF TB IN CHILDREN HIGH LEVEL OF SUSPICION Ask yourself “WHY ISN’T THIS TB?”

68. CHILDHOOD EXPOSURE PRIMARYPULMONARYINFECTION Only validated effect- protection against overt primary TB if given to un-infected (tuberculin negative) infants, children or young adults -? prevents dissemination of bacilli from initial site of infection -? protects against TBM and disseminated disease -does not prevent post-primary disease if given to already infected (tuberculin reactive) people -can produce severe necrotising lesions BCG AvoidcontactPREVENTION Screening high risk groups -contact with open TB -recent immigrants from hyper-endemic areas hyper-endemic areas INAH INAHRIF

69. WISH-LIST Better diagnostic tests - differentiate between infection and disease - global application - cheap, robust and simple - monitor success of therapy Better immunisation Better treatments - drugs/regimens - ? immunotherapy - ? other Better delivery of healthcare PAEDIATRIC TUBERCULOSIS

70. WISH-LIST More data; better understanding Better diagnostic tests - differentiate between infection and disease - global application - cheap, robust and simple - monitor success of therapy Better immunisation Better treatments - drugs - ? immunotherapy - ? other Better delivery of healthcare PAEDIATRIC TUBERCULOSIS Better understanding More data More research