1. TB in Children Oscar Roberto Santos Punla Medical Clerk

2. Etiology Mycobacteria acid-fast bacilli, obligate aerobes, slow-growing Contain high molecular weight mycolic acids in their cell walls (lipid- rich cell wall (resistant to bactericidal action of antibiotics) Classified into: M. tuberculosis complex M. tuberculosis M. bovis Nontuberculous mycobacteria (M. avium-intracellulare; M. kansasii) Mycobacterium bovis – causes primary pulmonary as well as primary GI TB

3. Epidemiology One third of the world’s population is infected TB kills 5,000 people a day – 2-3 million each year HIV and TB co-infection is producing explosive epidemics Hundreds of thousands of children will become TB orphans this year MDR threatens global TB control

4. TB Global Burden 2006 9.2 M new cases 4.1 M  new smear (+) cases 0.7 M HIV (+) 14.4 M prevalent cases 1 M children < 15 years 0.5 M MDR-TB cases 1.5 M deaths WHO Global TB Control 2008

5. Background Tuberculosis (TB) is increasing among adults in many areas TB is major cause of childhood morbidity and mortality worldwide Limited information on epidemiology of TB in children

6. TB in Children WHO estimate of TB in children – 1.3 million annual cases – 450,000 deaths 15% of TB in low-income countries children vs. 6% in United States

7. Childhood TB… Why is it neglected? Difficulty confirming the diagnosis by microbiology Lack of family-centered approach internationally Children rarely contagious – public health “dead- end” Perceived lack of scientific study Disinterest of pediatricians Misplaced faith in BCG vaccines

8. Childhood TB Why is it important? – Health problem in children – May later contribute to epidemic

9. Childhood TB as Sentinel Event Indicates recent transmission in a community Rapid progression from infection to disease “A deterioration in the control of TB thus immediately hurts the youngest generation” (Rieder, 1997) Children are future reservoir of disease

11. Childhood TB diagnosed by: Combination of : Contact with infectious adult case Symptoms and signs Positive tuberculin skin test Suspicious CXR Bacteriological confirmation Serology

13. Transmission

15. Incubation Period 2-12 weeks from infection to development of a (+) skin test risk of developing TB disease is highest during the 6 months after infection and remains high for 2 years many years may elapse between latent TB and disease

16. Pathogenesis of Tuberculosis Organisms contained in droplet nuclei land in the alveoli Infectious dose probably < 10 organisms Organisms ingested by macrophages, transported to regional [hilar, mediastinal, cervical] lymph nodes Lymphohematogenous dissemination of organisms occurs early – meninges, apices of lungs, lymph nodes, other organs

18. Predisposing Factors chronic illness malnutrition fatigue

19. Risk of Progression to Disease Age – 43% in infants (children < 1 yr) – 25% in children aged one to five years – 15% in adolescents – 10% in adults Recent Infection Malnutrition Immunosuppression, particularly HIV

20. Timetable of Pediatric Tuberculosis Miliary and Meningeal 2 – 6 months Pulmonary 2 – 12 months Lymph node 2 – 12 months Pleural effusion 3 – 12 months Skeletal 6 months – 2 years Renal 1 – 5 years

21. Transmission marker of contagiousness: (+) bacilli in sputum children <12 years old with 1° PTB are not contagious: 1.pulmonary lesions are small 2.cough is minimal or nonexistent 3.little or no expulsion of bacilli Bacilli in sputum

22. Features of Contagious Pediatric Tuberculosis Cavitary lung lesion Sputum production Positive acid-fast stain of sputum smear Bronchoscopy Draining lesions or surgical drainage of an abscess

23. Are Children With Tuberculosis Ever Contagious? Difficult to answer in the community Orphanages – caretaker with TB led to transmission; a child with TB did not Schools – only 2 reported “epidemics” caused by children <13 years old Children’s Hospitals – rare case reports of transmission, all with special circumstances, none has been patient -to -patient

24. Genetics of Pediatric Tuberculosis Houston study of 184 families with 1(143) or multiple (41) cases of tuberculosis diseases Examined 3 genes : NRAMP1 (protective in adults), VDR (vitamin D receptor), MBL (mannose binding ligand) Compared genetic and standard epidemiologic information to determine influences on expressions of tuberculosis in children

25. NRAMP1 Genetics And Pediatric Tuberculosis 1. The attributable risk of NRAMP1 gene variation was 85% among tuberculosis-infected children. [high frequency of the risk allele] 2. NRAMP1 and VDR genes acted as “progressor” alleles, mediating the development of tuberculosis infection to disease 3. The NRAMP1 effect was minimal in families with more than one case of disease, negating the common technique of general scanning in multiplex families to determine the effect of genes on host response.

26. Challenges for Surveillance Difficult diagnosis of childhood TB Lack of standard case definition Increased extrapulmonary disease Low public health priority of childhood TB

27. We’re All in the Same Boat “Successful TB control in the U.S. …depends on the development of effective strategies to control and prevent disease among foreign-born persons.” Source: CDC. Controlling TB in the United States, 2005

28. Tuberculosis Cases by Race/Ethnicity: California, 2006 Asian/Pacific Islander 1,223 (44.0%) Hispanic 1,068 (38.4%) Unknown 4 (0.1%) Black 208 (7.5%) American Indian/ Alaska Native 9 (0.3%) White 267 (9.6%)

29. The Paradox of Tuberculosis By use of drugs and BCG vaccines, we can: cure tuberculosis disease prevent progression of infection to disease prevent a high proportion of life-threatening childhood tuberculosis Yet, tuberculosis remains one of the three biggest scourges of humans, and our inability to control it remains our biggest health failure.

34. DIRECTLY OBSERVED THERAPY FOR PEDIATRIC TUBERCULOSIS Means a “dispassionate” 3rd party is Physically present when medications are taken Standard of care for tuberculosis disease Encouraged for high risk LTBI: contacts of cases, infants, HIV-infected or immune compromised

37. Clinical Forms of PTB (PPS Consensus) Pulmonary/Endothoracic TB Extrapulmonary TB

38. Clinical Forms  Pulmonary Tuberculosis (PTB) -refers to disease involving the lung parenchyma

39. Clinical Forms-Pulmonary Asymptomatic or Latent TB Infection (LTBI) Primary Pulmonary TB Progressive Primary Tuberculosis Reactivation Tuberculosis Endobronchial TB Miliary TB Pleurisy with effusion Asymptomatic or Latent TB Infection (LTBI) Primary Pulmonary TB Progressive Primary Tuberculosis Reactivation Tuberculosis Endobronchial TB Miliary TB Pleurisy with effusion

40. Latent Tuberculosis Infection (LTBI) M. tuberculosis infection in a person who has a positive TST result, no physical findings of disease and chest radiograph findings that are normal or reveal evidence of healed infection (e.g. granulomas or calcification in the lung, hilar lymph nodes or both). such patients are non-infectious Clinical Forms of TB Report of the Committee on Infectious Diseases, AAP 2003 Latent Tuberculosis Infection (LTBI) M. tuberculosis infection in a person who has a positive TST result, no physical findings of disease and chest radiograph findings that are normal or reveal evidence of healed infection (e.g. granulomas or calcification in the lung, hilar lymph nodes or both). such patients are non-infectious Clinical Forms of TB Report of the Committee on Infectious Diseases, AAP 2003

41. Primary Pulmonary TB involves a primary complex and its progression most frequent: presence of enlarged lymph nodes without primary focus visible radiographically involves a primary complex and its progression most frequent: presence of enlarged lymph nodes without primary focus visible radiographically

42. Primary Pulmonary Tuberculosis

43. Progressive Primary Tuberculosis with local progression of the primary complex  caseation enlarges, liquefies and disseminates its contents into the bronchi  new foci pneumonia, atelectasis, air trapping, stenosis, bronchiectasis retractions, wheezes, crackles, localized decreased breath sounds with local progression of the primary complex  caseation enlarges, liquefies and disseminates its contents into the bronchi  new foci pneumonia, atelectasis, air trapping, stenosis, bronchiectasis retractions, wheezes, crackles, localized decreased breath sounds

44. Progressive Pulmonary TB

45. Reactivation Tuberculosis Rare in childhood; may occur in adolescents More common in children who acquire the initial infection after 7 yrs of age CXR: extensive infiltrates or thick walled cavities Hx: fever, cough, hemoptysis, weight loss PE: minor or absent

46. Extensive Cavitary Disease

47. Endobronchial TB Extrabronchial or Extraluminal hyperemic and edematous lymph nodes impinge upon the wall of a bronchus  occlude the lumen usually RML bronchus Extrabronchial or Extraluminal hyperemic and edematous lymph nodes impinge upon the wall of a bronchus  occlude the lumen usually RML bronchus

48. Endobronchial TB occurs more frequently adherence of LN’s with spread of the disease through the airway wall  ulceration of mucosa  granulation tissue  obstruct lumen usually the RML or RUL bronchus Treatment: add Prednisone 1-2 mg/kg/day for 6-12 weeks Endobronchial TB occurs more frequently adherence of LN’s with spread of the disease through the airway wall  ulceration of mucosa  granulation tissue  obstruct lumen usually the RML or RUL bronchus Treatment: add Prednisone 1-2 mg/kg/day for 6-12 weeks

49. Miliary TB infants and young children affected as a complication of primary TB bacilli spreads via lymphatics to capillaries of most organ system (oxygenated: liver, spleen, marrow and brain ) mandatory tests include lumbar tap and funduscopy size of millet lesions varies with the host’s immune status, the larger lesions are found in immunocompromised patients infants and young children affected as a complication of primary TB bacilli spreads via lymphatics to capillaries of most organ system (oxygenated: liver, spleen, marrow and brain ) mandatory tests include lumbar tap and funduscopy size of millet lesions varies with the host’s immune status, the larger lesions are found in immunocompromised patients

50. Miliary TB death occurs in 4-12 weeks if untreated usually 2° to meningitis fever resolves in 2-3 weeks of chemotherapy X-ray lesions improve in 5-10 weeks Treatment: add prednisone to mitigate alveolocapillary block death occurs in 4-12 weeks if untreated usually 2° to meningitis fever resolves in 2-3 weeks of chemotherapy X-ray lesions improve in 5-10 weeks Treatment: add prednisone to mitigate alveolocapillary block

51. Miliary TB

52. Pleural Effusion older children, unilateral either as a hypersensitivity reaction or as an extension of subpleural focus or TB of the spine onset is acute with high fever and chest pain serous pleural effusion and a (+) PPD older children, unilateral either as a hypersensitivity reaction or as an extension of subpleural focus or TB of the spine onset is acute with high fever and chest pain serous pleural effusion and a (+) PPD

53. Clinical Forms-Extrapulmonary Extrapulmonary -refers to tuberculosis of other organs other than the lungs e.g. pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones, meninges -If patient has both pulmonary and extrapulmonary TB, it should be classified as Pulmonary TB e.g. Miliary TB Treatment of TB: Guidelines for National Programmes, WHO, 2003

54. Classification (Stages) TB Exposure (+) exposure to an adult or adolescent with active TB TB Infection (+) Mantoux test with or without exposure, normal CXR, no signs and symptoms TB Exposure (+) exposure to an adult or adolescent with active TB TB Infection (+) Mantoux test with or without exposure, normal CXR, no signs and symptoms

55. TB Disease 3 or more of the following – exposure to an adult/adolescent with active TB – (+) Mantoux test – signs and symptoms suggestive of TB – abnormal CXR suggestive of TB – laboratory findings suggestive of TB (histological, cytological, biochemical, immunological and/or molecular) TB Disease 3 or more of the following – exposure to an adult/adolescent with active TB – (+) Mantoux test – signs and symptoms suggestive of TB – abnormal CXR suggestive of TB – laboratory findings suggestive of TB (histological, cytological, biochemical, immunological and/or molecular)

56. Clinical Signs/Symptoms (any 1 or 2 or more are considered positive) Cough of more than 2 weeks duration

57. Clinical Signs/Symptoms (any 1 or 2 or more are considered positive) Fever of more than 2 weeks duration

58. Clinical Signs/Symptoms (any 1 or 2 or more are considered positive) painless cervical and/or other lymphadenopathies

59. Clinical Signs/Symptoms (any 1 or 2 or more are considered positive) poor weight gain

60. Clinical Signs/Symptoms (any 1 or 2 or more are considered positive) failure to make a quick return to normal health after an infection (measles, tonsillitis, whooping cough) failure to respond to appropriate antibiotic therapy (pneumonia, otitis media)

61. Tuberculin Skin Test Most widely used method to determine – Latent TB infection – Infected persons – Those who do not have the disease A measure of a person’s cellular immune responsiveness Features include: – Delayed course – Indurated character – Occasional vesiculation and necrosis

62. Tuberculin Skin Test based on a delayed type of hypersensitivity reaction (DTH), manifested as an indurated area at the site of the intradermal injection which usually begins within 5 to 6 hours of administration, as previously sensitized lymphocytes, monocytes and macrophages infiltrate the site. an immediate wheal and flare reaction may occur but usually disappears by 24 hours and should not be interpreted as a positive reaction. only the area of induration should be measured. Menzier, RI. Tuberculin Skin Testing. Tuberculosis: A Comprehensive International Approach 2000:279-322

63. Tuberculin Skin Test In most children, tuberculin reaction first appear 3-6 weeks, and occasionally up to 3 months, after initial infection

64. Tuberculin Skin Test PPD-RT23 – 2-TU (tuberculin unit), the WHO standardized dose for Mantoux tuberculin testing – Most widely used tuberculin skin test in the world – bioequivalent 5 TU of PPD-S PPD-S – Standard tuberculin preparation

65. Tuberculin Skin Test As a rule of thumb, 0.1 ml of the 2-TU of RT-23 will have a tuberculin reactivity similar to 0.1 ml of the 5 TU PPD-S.

66. Method of Mantoux Testing

67. Interpretation of PPD WHO Consensus –  10mm is considered positive in high risk individuals

68. Mantoux Test Interpretation False Negative Reactions False Positive Reactions 1. Viral, Bacterial, Fungal, Early TB Infection, Severe TB disease 1. Exposure to NTM 2. Live virus vaccines 2. BCG vaccine 3. Metabolic, Malignancies 3. Transfusion with whole blood from donors with known positive TST 4. Corticosteroids, Immunosuppressive drugs 4. Inexperienced or biased reader 5. Technical factors and interpretation 5. Increasing mm induration

69. Phenomena related to TST Anergy – Absence of reaction does NOT rule out TB – A decrease or disappearance of the DTH (delayed type hypersensitivity) responses to TST in immunosuppressed individuals Skin test conversion – Indicative of recent infection – An increase in reaction size of ≥10mm induration within 2 years with previously negative TST reaction Boosted reaction

70. Boosting Effect Overtime the effect of DTH to mycobacterial antigens may wane and thus a TST could be negative. However, with subsequent TSTs, the DTH response may be stimulated by PPD and result in a positive reaction – boosting phenomenon. Increase in TST size caused by repetitive TSTs in an individual previously sensitized to mycobacterial antigens, particularly BCG & NTM. Boosting is minimized if TSTs are placed <1 week apart. No boosting occurs if person has not been infected with mycobacterial antigens. Overtime the effect of DTH to mycobacterial antigens may wane and thus a TST could be negative. However, with subsequent TSTs, the DTH response may be stimulated by PPD and result in a positive reaction – boosting phenomenon. Increase in TST size caused by repetitive TSTs in an individual previously sensitized to mycobacterial antigens, particularly BCG & NTM. Boosting is minimized if TSTs are placed <1 week apart. No boosting occurs if person has not been infected with mycobacterial antigens.

71. Radiologic Findings in Tuberculosis

72. “ A clear chest x-ray does not rule out the existence of a small focus of progressive tuberculosis; nor are there pathognomonic roentgen features in a fresh primary tuberculous complex. Moreover, not all shadows are tuberculous infiltrates.” Mita Pardo de Tavera (1975)

73. CHEST X-RAYS considered essential to assess children and adolescents with positive TST for pulmonary TB LTBI. Chest x-rays are usually normal but findings may include dense nodules with calcifications (i.e. a ghon complex) calcified non-enlarged regional lymph nodes or both or pleural thickening (i.e. scarring) ATS targeted tuberculin testing and treatment of LTBI. Am J Respi Care Med. 2000;161 AAP Tuberculosis Red Book: 2003 Report of the Committee on Infectious Diseases 2003:642-660

74. Radiologic Findings in PTB In its complete form, the primary complex is composed of the following; however, NOT ALL features are necessary to make the diagnosis. – Size and shape in the radiolucent lung – Enlarged regional nodes – Lymphangitis – A localized pleural effusion

75. Lateral chest x-rays improved the accuracy of detecting hilar adenopathy in children 1 month - 12 years of age. 176 culture confirmed cases of TB disease 46% (81 of 176) had adenopathy visible on CXR 49% (40 of 81) visible on both frontal & lateral views 24% (19 of 81) only on frontal view 27% (22 of 81) only on lateral view Imuts KJA et al. Value of Adolescent Chest Radiographs in Tuberculosis in Children. Pediatr Radiol 1994;24:478-480 Lateral chest x-rays improved the accuracy of detecting hilar adenopathy in children 1 month - 12 years of age. 176 culture confirmed cases of TB disease 46% (81 of 176) had adenopathy visible on CXR 49% (40 of 81) visible on both frontal & lateral views 24% (19 of 81) only on frontal view 27% (22 of 81) only on lateral view Imuts KJA et al. Value of Adolescent Chest Radiographs in Tuberculosis in Children. Pediatr Radiol 1994;24:478-480

76. Radiologic Findings in PTB Parenchymal involvement Lymph node involvement Airway involvement Pleural involvement

77. Parenchymal involvement Acinar consolidation – Typical – Homogenous density with ill defined margins – Predominantly in the upper lobes Atelectasis – In the anterior segments of the RU and RM lobes due to bronchial compression of the enlarged lymph nodes – An entire lobe, often the RML, may be affected

78. Lymph Node involvement Hilar or paratracheal lymph node enlargement is the radiologic finding that clearly differentiates primary from post-primary tuberculosis Usually unilateral Highly suggestive is the large size of the adenitis relative to the insignificant size of the primary lung focus

79. Lymph Node involvement Radiologic Findings in TB

80. Airway Involvement Tracheobronchial involvement is common Bronchial obstruction due to tuberculous LN may present radiographically as – Hyperaeration – Segmental atelectasis – usually in the RML – Collapse-consolidation lesions

81. Pleural involvement Very common Usually localized, contiguous to the primary foci May also be generalized, as seen in progressive types of PTB

82. Resolution of Radiographic Changes Pulmonary infiltrates Usually clears in 2-9 months Hilar adenopathy Usually clears in 2-3 years Pleural effusion Complete resorption in about 6-12 weeks Hyperaeration in endobroncial TB Improve as early as 3 weeks Miliary TB After several months

83. CT Scans Chest CT Scan may show enlarged or prominent mediastinal or hilar adenopathy not demonstrable on chest x-ray. Can demonstrate endobronchial disease, pericardial invasion, early cavitation or bronchiectasis. Neri N et al. Diagnosis of Pediatric Tuberculosis in the Modern Era. Pediatr Infect Dis J. 1999;18:122-126

84. Mycobacteriology and New Diagnostic Tests for TB

85. Mycobacteriology of Childhood TB Obtain cultures Lowenstein – Jensen Bactec Method sputum, gastric lavage, bronchoalveolar lavage, body fluid

86. New diagnostic tests for TB 1.Immunoassays for mycobacterial antibodies and myobacterial antigens (ELISA)

87. 2. Polymerase Chain Reaction (PCR) New diagnostic tests for TB

88. 3. DNA Probes New diagnostic tests for TB

89. Skin Test Chest X-ray CT Scan Culture New Tests

90. FIRST LINE ANTI-TB DRUGS Isoniazid (H) Rifampicin (R) Pyrazinamide (Z) Streptomycin (S) Ethambutol (E) MANAGEMENT

91. SECOND LINE ANTI-TB DRUGS 1. Kanamycin 2. Capreomycin 3. Viomycin 4. Thiacetazone 5. Ethionamide 6. Cycloserine 7. Para-aminocalicyclic acid (PAS) 8. Terizodone 9. Ofloxacin 10. Ciprofloxacin 11. Amikacin 12. Rifabutin

92. MAIN PROPERTIES OF ANTI-TB DRUGS 1. Bactericidal activity 2. Sterilizing activity 3. Ability to prevent or delay emergence of resistance

93. RELATIVE BACTERICIDAL ACTIVITY OF FIRST LINE ANTI- TUBERCULOSIS DRUGS +/-0+/-E 0+/-+++S +++00Z ++++R ++/-++H Slowly growing intracellular organisms (acid pH) (acid pH) Slowly growing extracellular organisms (neutral pH) Rapidly growing extracellular organisms (neutral pH) DRUGS

94. PRINCIPLES OF CHEMOTHERAPY OF TUBERCULOSIS S, H, R Z, R, H S, H, R Z, R, H rapidly growing slowly growing intracellular and in rapidly growing slowly growing intracellular and in extracellular bacilli closed caseous lesions extracellular bacilli closed caseous lesions InadequateAdequate Adequate Inadequate treatment TreatmentBactericidal sterilizing late growth of Action action persisters Action action persisters Treatment Elimination of elimination of Relapse Failure extracellular persisters Failure extracellular persisters bacilli bacilli LASTING CURE OF TUBERCULOSIS LASTING CURE OF TUBERCULOSIS

95. Preventive Therapy of Childhood Tuberculosis TB Exposure Start H Repeat MTX after 3 months (+) CXR &/or S/Sx suggestive of TB PTB III- multiple drug therapy D/C INH,If no BCG scar, Give BCG TB Infection II cont H for 6 months Yes (+) (-) No

96. Interruptions in Therapy Interruption in initial phase yes no 14 days % planned doses in continuation phase completed Continue tx, restart 80% if total not completed in 3 mos, duration of additional tx may not restartinterruption be necessary 3 months continue tx, if not restart completed in 6 mos, start from beginning American Thoracic Society: Treatment of Tuberculosis 2003

97. Indication for Baseline Liver Function Test and Monthly Interval Monitoring concurrent and recent liver disease clinical evidence of hepatotoxicity pregnancy or within 6 weeks postpartum if more than 3-5x elevated, D/C INH concurrent and recent liver disease clinical evidence of hepatotoxicity pregnancy or within 6 weeks postpartum if more than 3-5x elevated, D/C INH

99. Pathogenesis of Tuberculosis

100. TB in Children