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PAEDIATRIC TUBERCULOSIS

PAEDIATRIC TUBERCULOSIS. Sam Walters Imperial NHS Trust LONDON. 2011 ESTIMATED TB CASES 12 MILLION. 8.7 million new cases: 500,000 children (6-8%). * Up to 40% of cases in high incidence countries are children. DEATHS: 1.43 million 60,000 children (4.2%)

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PAEDIATRIC TUBERCULOSIS

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  1. PAEDIATRICTUBERCULOSIS • Sam Walters • Imperial NHS Trust • LONDON

  2. 2011 ESTIMATED TB CASES 12 MILLION 8.7 million new cases: 500,000 children (6-8%) * Up to 40% of cases in high incidence countries are children DEATHS: 1.43 million 60,000 children (4.2%) [2012; 74,000 children (5.2%)]

  3. 2011 500,000 children (6-10%) non-HIV DEATHS: 2011 60,000 children (4.2%) 2012 74,000 children (5.2%)

  4. ? 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 2011 500,000 children (6-10%) non-HIV DEATHS: 201160,000 children (4.2%) 201274,000 children (5.2%)

  5. ? 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 2011 500,000 children (6-10%) Children now firmly placed on global TB agenda non-HIV DEATHS: 201160,000 children (4.2%) 201274,000 children (5.2%)

  6. PAEDIATRIC TUBERCULOSIS • Clinical Presentation

  7. Clinical Presentation -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;

  8. -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

  9. -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

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

  11. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION INFECTION ≠ DISEASE NATURAL HISTORY

  12. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION Successful immune response WELL CHILD ‘LIFELONG’ IMMUNITY (live MTB)

  13. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION Successful immune response 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 WELL CHILD or ADULT IMMUNITY (live MTB)

  14. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION Successful immune response WELL CHILD or ADULT IMMUNITY (live MTB) LATE REACTIVATION, RE-INFECTION ‘Immunosuppression’; age, malnutrition, infection, HIV

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

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

  17. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION Inadequate immune response PROGRESSIVE PULMONARY DISEASE Lympho/ haematogenous spread DEATH MILLIARY, EXTRA-PULMONARY DISEASE DEATH

  18. PAUCI-BACILLARY TB Implications of bacterial load: Paediatric TB: Adult TB: 104-106 bacteria >109 bacteria -difficulty in confirming diagnosis -difficulty in detecting resistance -? emergence of resistance

  19. PAUCI-BACILLARY TB Implications of bacterial load: Paediatric TB: Adult TB: 104-106 bacteria >109 bacteria -difficulty in confirming diagnosis -difficulty in detecting resistance -? emergence of resistance -  infectivity

  20. PAUCI-BACILLARY TB Implications of bacterial load: Paediatric TB: Adult TB: 104-106 bacteria >109 bacteria -difficulty in confirming diagnosis -difficulty in detecting resistance -? emergence of resistance -  infectivity -not part of immediate public health problem

  21. PAUCI-BACILLARY TB Implications of bacterial load: Paediatric TB: Adult TB: 104-106 bacteria >109 bacteria -difficulty in confirming diagnosis -difficulty in detecting resistance -? emergence of resistance -  infectivity -not part of immediate public health problem

  22. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION Inadequate immune response PROGRESSIVE PULMONARY DISEASE WELL CHILD Successful immune response Lympho/ haematogenous spread IMMUNITY ( live MTB) LATE REACTIVATION Any Organ e.g. Bone, Kidney MILLIARY, EXTRAPULMONARY DISEASE

  23. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION Inadequate immune response WELL CHILD PROGRESSIVE PULMONARY DISEASE Successful immune response Lympho/ haematogenous spread ‘LIFELONG’ IMMUNITY (lesions sterilised) MILLIARY, EXTRAPULMONARY DISEASE Treatment Treatment

  24. CHILDHOOD EXPOSURE HOST Immunosuppression Genetics ? Age esp. young children ORGANISM Infecting dose -smear +ve, log phase -smear -ve / culture +ve, ? dormant MTB strain differences PRIMARY PULMONARY INFECTION Inadequate immune response Successful immune response PROGRESSIVE PULMONARY DISEASE WELL CHILD Lympho/ haematogenous spread DEATH LIFELONG IMMUNITY (live MTB) MILLIARY, EXTRA-PULMONARY DISEASE DEATH ? WHICH PATHWAY

  25. 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

  26. CHILDHOOD EXPOSURE PRIMARY PULMONARY INFECTION Inadequate immune response WELL CHILD PROGRESSIVE PULMONARY DISEASE Successful immune response, Lympho/ haematogenous spread IMMUNITY Sterile lesions MILLIARY, EXTRAPULMONARY DISEASE Treatment Successful immune response Treatment

  27. Triple therapy: the Big Three (+ one) ISONIAZID RIFAMPICIN PYRAZINAMIDE (Ethambutol)

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

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

  30. TREATMENT: HOW LONG? • ‘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

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

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

  33. 2008-2011: % CONFIRMED MDR-TB from ISOLATES Resistance to at least INAH and Rifampicin (2010 global prevalence; 650,000 cases) Very few children

  34. 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

  35. TUGELA FERRY (KZN, SOUTH AFRICA)

  36. TUGELA FERRY (KZN, SOUTH AFRICA) 2005 - 2006 -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!

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

  38. 2nd line drugs with anti-TB activity Streptomycin Cycloserine Amikacin Rifabutin Capreomycin Rifapentine Ciprofloxacin Ethionamide Ofloxacin Prothionamide Sparfloxacin Clofazamine Thiacetazone Linezolid PAS Clarithromycin IFN  TNF  2nd line for good reasons - limited paediatric data - complex drug interactions -↑toxicities,↓tolerability Promising new drugs; Moxifloxacin PA 824 (Nitroimidazol-oxazine) TMC-207 (Bedaquiline) Sirturo™(metronidazole class)

  39. TREATMENT sensitive MTB: HOW LONG? • 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 extrapulmonarylesions? • HIV • -?12 months (relapse with same organism: SA children treated for 6/12)

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

  41. DRUG TOXICITY 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

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

  43. 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

  44. CSF ABNORMALITIES IN MENINGITIS (%) Donald et al. 1987; J Trop Ped; 33: 213-216 Viral Neisseria Haemophilus StreptococcusTuberculous Investigation meningitis meningitidisinfluenzaepneumomiaemeningitis Cell count >500x106/l 12 81 74 70 3 Protein >0.8 g/l 7 83 84 97 76 Glucose < 2.2mmol/l 1 76 73 75 64 CSF/blood glucose : <0.4 7 79 74 91 79 Organisms seen on microscopy 0 65 47 85 8 Number of cases 108 140 47 34 62

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

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

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