Approach to pediatric 2-TUBERCULOSIS(tb)

Tuberculosis updates

1. TUBERCULOSIS IN CHILDREN Workie S(MD) 1

2. Distribution of tuberculosis in the world in 2008.  (From Dye C: Global epidemiology of tuberculosis. Lancet 2009;367:938–940.) 2

3. Introduction: Currently, 95% of tuberculosis cases occur in developing countries: where HIV/AIDS epidemics have the greatest impact & where resources are often unavailable for proper identification & Rx of these diseases. 3

4. Introduction: The WHO estimates: >8 million new cases of tuberculosis each year. ~ 3 million people die of the disease worldwide each yr. ~ 1.3 million cases & 450,000 deaths in children each yr. > ⅓ of the world's population is infected with M.tb. 4

5. National burden of tuberculosis: According to the 2007 WHO estimates, incidence of TB all forms = 341/ 100,000 & smear positive TB = 152 per 100,000 population. The prevalence of all forms = 546/100,000 & mortality of all forms = 73 per 100,000 population. Ethiopia stands 7 th in the list of High Burden Countries . 5

6. Etiology. There are 5 closely related mycobacteria M. tuberculosis M. bovis M. africanum M. microti M. canetti. 6

7. Etiology………. M. tb is the most important cause of tb. disease in humans. The tubercle bacilli are: non-spore-forming non-motile pleomorphic weakly gram-positive curved rods 2–4 μ m long. obligate aerobes 7

8. Etiology…………… Grow best at 37–41°C Produce niacin & lack pigmentation. A lipid-rich cell wall accounts for resistance to the bactericidal actions of antibody & complement. A hallmark of all mycobacteria is acid fastness Once stained, they resist decoloration with ethanol & HCl or other acids. 8

9. Etiology………. Mycobacteria grow slowly, generation time = 12–24 hr . Isolation from clinical specimens usually takes 3–6 wk & Drug susceptibility testing requires additional 4 wk. Growth can be detected in: 1–3 wk in selective liquid medium using radiolabeled nutrients ( the BACTEC radiometric system) Drug susceptibilities can be determined in 3–5 days. 9

10. Etiology……. High-pressure liquid chromatography analysis. Species of mycobacteria can be determined within hrs. Each species has a unique fingerprint of mycolic acids. nucleic acid amplification (NAA) tests: M. tuberculosis in clinical specimens sometimes can be detected directly within hours. 10

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13. Epidemiology Latent tuberculosis infection (LTBI) occurs after inhalation of infective droplet nuclei containing M.tb. A reactive TST & the absence of clinical & radiographic abnormalities are the hallmark of this stage. The word tuberculosis refers to disease. 13

14. Epidemiology………… Untreated infants with LTBI have: up to a 40 % likelihood of developing tuberculosis The risk for progression ↓ing gradually through childhood to adult lifetime rates of 5–10%. The greatest risk for progression occurs in the 1 st 2 yr after infection 14

15. Epidemiology………… The WHO estimates that ⅓ of the world's population—2 billion people—are infected with M. tuberculosis. Infection rates are highest in: Africa Asia & Latin America. 15

16. Epidemiology…………. Global burden of TB continues to ↑ due to several factors: the impact of HIV epidemics population migration patterns increasing poverty & social upheaval crowded living conditions in developing countries & in inner city populations in developed countries inadequate health coverage poor access to health services & inefficient tuberculosis control programs. 16

17. Children at greater risk of developing TB Contacts of newly diagnosed smear-positive case Children < 5 years of age HIV-infected children Severely malnourished children. 17

18. Children at ↑ ed risk for progression of LTBI to tb.disease : diabetes mellitus chronic renal failure malnutrition congenital or acquired immunodeficiency Infants & children ≤4 yr of age, especially < 2 yrs Persons co-infected with HIV Persons with skin test conversion in the past 1–2 yr Persons who are immunocompromised 18

19. Transmission. Transmission of M. tuberculosis is: person to person usually by airborne mucus droplet nuclei Transmission rarely occurs by direct contact with: Infected discharge or Contaminated fomite . 19

20. Transmission. The chance of transmission ↑ es when the patient has : acid-fast smear of sputum extensive upper lobe infiltrate or cavity copious production of thin sputum severe and forceful cough. Environmental factors, especially poor air circulation 20

21. Transmission……………… Most adults no longer transmit the organism: Several days to 2 wks after beginning of chemotherapy. but some patients remain infectious for many weeks. Young children with tb. rarely infect other children/adults. 21

22. Pathogenesis……. The lung is the portal of entry in >98% of cases . The tubercle bacilli multiply initially within alveoli & alveolar ducts. The primary complex of tuberculosis includes: local infection at the portal of entry & the regional lymph nodes that drain the area 22

23. Pathogenesis…………… Most of the bacilli are killed. some survive within non activated macrophages, which carry them through lymphatic vessels to the regional LNs. When the 1 infection is in the lung, the hilar LNs usually are involved, although an upper lobe focus may drain into para-tracheal LNs. 23

24. Pathogenesis……. The tissue reaction in the lung parenchyma & LNs intensifies over the next 2–12 wk. The parenchymal portion of the primary complex often heals completely by: fibrosis or calcification after undergoing caseous necrosis & encapsulation. 24

25. Pathogenesis…………. Occasionally, this portion continues to enlarge, resulting in: focal pneumonitis & pleuritis . If caseation is intense, the center of the lesion liquefies & empties into the associated bronchus leaving a residual cavity. 25

26. Pathogenesis……………. Partial obstruction of the bronchus caused by external compression may cause hyperinflation in the distal lung segment. Complete obstruction results in atelectasis . Inflamed caseous LNs can attach to the bronchial wall & erode through it, causing endobronchial tuberculosis or fistula tract . 26

27. Pathogenesis The caseum causes complete obstruction of the bronchus. The resulting lesion is, a combination of pneumonitis & atelectasis. called collapse-consolidation or segmental lesion . 27

28. Pathogenesis………….. During the development of the 1 complex ( Ghon complex ), the combination of: parenchymal pulmonary lesion & corresponding lymph node site tubercle bacilli are carried to most tissues through the blood & lymphatic vessels . 28

29. Pathogenesis…………….. Although seeding of the organs of the RES is common, bacterial replication is more likely to occur in organs with conditions that favour their growth: the lung apices brain kidneys & bones. 29

30. Pathogenesis…………. Disseminated tuberculosis occurs if: the number of circulating bacilli is large & the host cellular immune response is inadequate . 30

31. Pregnancy and the Newborn. Pulmonary & EPTB other than lymphadenitis in a pregnant woman is associated with ↑ ed risk for: prematurity IUGR LBW & perinatal mortality. 31

32. Pregnancy and the Newborn . Congenital tuberculosis is rare b/c the most common result of female GUT tuberculosis is infertility. Congenital transmission : Usu. from a lesion in the placenta through umbilical vein. 1 infection in the mother just before or during pregnancy . by aspiration or ingestion of infected amniotic fluid . 32

33. Pregnancy and the Newborn. The tubercle bacilli first reach the fetal liver Organisms pass through the liver into the main fetal circulation & infect many organs. The bacilli in the lung usually remain dormant until after birth, when oxygenation & pulmonary circulation increase. The most common route of infection for the neonate is postnatal airborne transmission from an adult with infectious PTB. 33

34. Clinical manifestation: Tuberculosis presents in children in various clinical forms : Primary pulmonary tuberculosis Acute disseminated tuberculosis: meningitis & miliary. Post -primary pulmonary tuberculosis Extra -pulmonary tuberculosis . 34

35. Clinical manifestation: Primary pulmonary tuberculosis Occurs most often in children < 5 years of age. 1 infection is asymptomatic in the majority of cases, and goes unnoticed. In 10% of cases primary infection has clinical Mxs & presents with certain Sxs & radiographic abnormalities . 35

36. Clinical manifestation: Generalized symptoms are often minor: slight fever Profuse night sweating loss of weight apathy and listlessness. Sometimes the Sxs are more obvious (e.g. a high fever of 39–40 °C & profound lethargy) 36

37. Clinical manifestation: Mucocutaneous Mxs: infrequent, are highly Xstic Erythema nodosum painful nodules under the skin in 2-3 bursts: on the shins (legs) sometimes on back of the arms & rarely on the front. Painful, red, raised lesions that may turn purple & take on the appearance of a bruise. 37

38. Clinical manifestation: Phlyctenular conjunctivitis begins with: generalized pain & irritation in one eye accompanied by watering & photophobia . On examination, grey or yellow lesions can be observed where the cornea joins the white of the eye 38

39. Clinical manifestation: a number of blood vessels enter the lesions, giving an appearance of vascular engorgement of the conjunctiva. Each lesion persists for about a week , then disappears, to be replaced by others. In severe cases the cornea may ulcerate. 39

40. Clinical manifestation: Local complications of primary tuberculosis while unusual, are well recognized: 1.Fistulation of the lymph node into the bronchi : the LN swells & erodes into the bronchus. Small infants: acute bronchial obstruction in older children it usually causes cough 40

41. Clinical manifestation: The formation of a primary tuberculous cavity at the site of infiltration is a more unusual complication. Delayed local complications can occur. Without Rx, LAP can compress a lobar or segmental bronchus, creating breathing difficulties . 41

42. Clinical manifestation: Bronchiectasis may develop in the poorly ventilated area of the lung, creating: bronchial super infections & repeated episodes of haemoptysis. The most Xstic feature of this type of sequelae is “ hilar disease ” or “ right middle lobe syndrome” 42

43. Clinical manifestation: Acute disseminated tuberculosis Early CPxs of primary infection Occurs within 2–10 mths Caused by dissemination of bacilli from the primary infection through the bloodstream They can occur: At all ages, ( most often in <2 years of age) Not vaccinated with BCG. Are very serious & often fatal if late diagnosed & treatment 43

44. Clinical manifestation: Tuberculous (TB) meningitis Often occurs in children < 5 yrs . Start initially with non specific complaint ; irritability, headache or vomiting. Later on Changes in state of consciousness Strabismus Possibly neck rigidity. 44

45. The Dx is obvious at a later stage When the disease progresses to such an advanced stage: There is almost no chance of cure. If survives, major neurological sequelae are expected: Paralysis Deafness or Blindness 45

46. Clinical…………… 3 stages of tuberculous meningitis Stage one: Typically lasts 1–2 wk Is Xzed by nonspecific Sxs: fever, headache, irritability, drowsiness & malaise. Focal neurologic signs are absent Stagnation or loss of developmental milestones. 46

47. Clinical…………… Stage two Usually begins more abruptly Lethargy, nuchal rigidity, seizures Positive Kernig or Brudzinski signs, hypertonia Vomiting , cranial nerve palsies & other focal neurologic signs . 47

48. Clinical…………… The accelerating clinical illness usually correlates with the development of Hydrocephalus Increased ICP Vasculitis Some children have no evidence of meningeal irritation but may have signs of encephalitis. Disorientation Movement disorders Speech impairment 48

49. Clinical…………… Stage three: Is marked by coma Hemiplegia /paraplegia HTN Decerebrate posturing Deterioration of vital signs & eventually death. 49

50. Prognosis ( stage ,age, time of rx ) Stage of the illness Patients in the 1st stage have an excellent outcome Most patients in the 3rd stage who survive have permanent disabilities blindness, deafness, paraplegia, diabetes insipidus mental retardation . Age of the patient The prognosis for young infants is generally worse than for older children Time of initiation of Rx 50

51. It is imperative that anti-tuberculosis Rx be considered for any child who develops Basilar meningitis & hydrocephalus Cranial nerve palsy Stroke with no other apparent etiology. 51

52. Clinical………….. Acute miliary tuberculosis   Generalized dissemination through bloodstream Caseous focus ruptures into blood vessel Growth of tubercle within the blood vessel Usually occurs in the first 4 months after primary infection Can occurs within the first weeks after primary infection 52

53. Clinical…………… Is common in late HIV/AIDS disease. It’s often accompanied with TB meningitis. It is a severe condition with high fever at 39–40°C Uniformly fatal if no treatment Characteristic spoted shadows on X Ray. In HIV-infected child, difficult to differentiate from LIP. 53

54. MILIARY Disease

55. Clinical……………. The Dx rests on strong clinical suspicion If Rx is delayed, the prognosis will be badly affected. 56

56. Clinical manifestation: Post-primary pulmonary tuberculosis A delayed result of primary infection Usually occurs in adults but may appear in Older children & adolescents Particularly in the presence of malnutrition or other immunosuppressant . 57

57. Clinical manifestation: Sxs of childhood TB Children with TB develop chronic Sxs in most cases TB may be a more acute disease in the presence of HIV. The commonest symptoms are : Chronic cough : Is a persistent cough Present for > 2 wks & that is not improving . 58

58. Clinical………….. Fever: Fever of > 38 C for 14 days After common causes like malaria, pneumonia have been excluded . Weight loss: Documented weight loss Failure to gain weight, Even after being treated in a nutritional Rx. 59

59. Clinical……………. Signs of childhood TB The clinical picture is similar to that of the adults.   60

60. Clinical……………. Physical signs requiring Ix for TB: Meningitis not responding to Rx with antibiotics, with sub-acute onset Pleural effusion or pericardial effusion Distended abdomen with ascites Non-painful enlarged joints 61

61. Clinical…………….. Extra-pulmonary tuberculosis in children Tuberculous lymphadenitis The most common form. Often referred to as scrofula Most cases occur within 6-9 mo of initial infection Disease is most often unilateral 62

62. Systemic signs and symptoms other than a low-grade fever are usually absent TST is usually reactive, but the CXR is normal in 70 % of cases. Lymph node tuberculosis can resolve if left untreated but more often progresses to caseation and necro sis 63

63. 2 . Tuberculosis of the spine or joints: Is the 2 nd most common form of childhood EPTB May occur within the 1 st few yrs following primary infection The classic manifestation is tuberculous spondylitis with progression to Pott disease 64

64. Clinical ……………. 3 .Tuberculosis of the serous membranes TB pleurisy & peritonitis are rare in small children, although frequent in adolescents. Peritonitis with ascites is relatively more common, particularly in girls aged 10–14 years 65

65. Diagnosis of Paediatric TB Criteria for the diagnosis of childhood tuberculosis Categories Supportive evidence Diagnostic confirmation 1 pulmonary tb. Mediastinal LAP with/ out infiltration TST - positive Positive sputum culture - rare Post-1 pulmonary tb. infiltration affecting upper zones with cavities AFB on smear and culture of sputa/gastric aspiration Tuberculous meningitis Meningeal syndrome, strabismus, sometimes miliary pattern and choroid tubercles Clear CSF: high protein levels and lymphocytosis Positive CSF culture Miliary tuberculosis General deterioration Typical miliary image on X Ray Culture (pleural fluid, CSF, etc.) or biopsy of another lesion (liver, pleura, etc.) Other tuberculosis X-ray & clinical signs TST positive Cytochemical exam. of effusions high protein level & lymphocytosis Positive - culture - Tissue biopsy 66

66. Diagnosis of Paediatric TB To make the Dx of childhood TB with a fair degree of accuracy the following tests are useful: Tuberculin skin test (TST) Chest radiograph Sputum smear microscopy HIV testing . 67

67. Diagnosis of Paediatric TB These tests, coupled with: The history of contact with a smear-positive case & The presence of Sxs suggestive of TB Are used to make the diagnosis . 68

68. TST Recommendations for Infants, Children & Adolescents Children for whom immediate TST is indicated Contacts of people with confirmed or suspected contagious tuberculosis Children with radiographic or clinical findings suggesting tuberculosis disease Children immigrating from countries with endemic infection Children who should have annual TST: Children infected with HIV 69

69. Definitions of Positive TST Results in Infants, Children & Adolescents INDURATION ≥5 MM Close contact with known/suspected contagious people. Children suspected to have tuberculosis disease: Findings on CXR consistent with active or previously tuberculosis disease Clinical evidence of tuberculosis disease Children receiving immunosuppressive therapy or with immunosuppressive conditions, including HIV infection 70

70. Definitions of Positive….. INDURATION ≥10 MM Children at ↑ ed risk of disseminated tuberculosis disease: Children < 4 yr of age Children with medical conditions: lymphoma, DM, CRF Malnutrition Children with ↑ ed exposure to tuberculosis disease: Children born in high-prevalence regions of the world Children who travelled to high-prevalence regions 71

71. Definitions of Positive….. INDURATION ≥15 MM Children 4 yr of age or older without any risk factors. 72

72. Dx of Tuberculosis in HIV-positive children PTB is the most common Mx of TB in HIV-positive children. Presence of ≥ 3 of the following strongly suggest the Dx : Chronic symptoms suggestive of TB Physical signs highly suggestive of TB Positive TST (diameter of indurations >5 mm) CXR suggestive of TB. 73

73. Diagnosis of Paediatric TB 74

74. Diagnosis of Paediatric TB 75

75. Drug-resistant TB ??? Drug-resistant TB is a laboratory diagnosis. Drug-resistant TB should be suspected if: Features in the source case suggestive of drug-resistant: Contact with a known case of drug-resistant TB Remains sputum smear-positive after 3 months of Rx History of previously treated TB History of Rx interruption 76

76. Drug-resistant TB Features of child suspected of having drug-resistant TB: Contact with a known case of drug-resistant TB Not responding to the anti-TB regimen Recurrence of TB after adherence to Rx 77

77. Drug-resistant TB Mono-resistant TB Resistant in vitro to one first-line anti-TB drug. Poly-resistant TB: Resistant in vitro to > 1 first-line drug, other than both INH & RIF MDR : Resistant to at least both INH & RIF . 78

78. Drug-resistant TB Extensive-drug resistant TB (XDR) : Resistance to at least RIF & INH , in addition to: Any Fluoroquinolone & At least one of the 3 following injectables used in anti-TB Rx: Capreomycin kanamycin Amikacin. 79

79. Principles of tuberculosis treatment Chemotherapy Nutritional rehabilitation Health education Family screening Follow up 80

80. Treatment of tuberculosis in children Should be Rxed with the 4-drug initial phase regimen. 3 times weekly Rx is not recommended for children . DOT should be used for all children with tuberculosis . Parents should not be relied on to supervise DOT. EPTB can be Rxed with the same regimens as pul.disease . Exceptions are the disseminated TB disease & meningitis for which the recommended duration is 9 to 12 months . 81

81. Treatment of tuberculosis in children Pyridoxine is recommended for children who are being treated with INH & who have: Nutritional deficiencies Symptomatic HIV infection Who are breastfeeding . 82

82. Treatment of tuberculosis in children TB Dxic category TB cases Regimen Intensive phase Continuation phase I New smear-positive pul.TB New smear-negative pul.TB with extensive parenchymal involvement Severe forms of EPTB (other than TB meningitis) Severe concomitant HIV disease 2HRZE 4RH I TB meningitis 2HRZS 7-10RH II Relapse Treatment after interruption Treatment failure 2HRZES/ 1HRZE 5HRE III New smear-negative pul.TB (other than in cat. I) Less severe forms of EPTB 2HRZE 4RH IV Chronic and MDR-TB Specially designed standardized or individualized regimens 83

83. Recommended doses of paediatric treatment: DRUG RECOMMENDED DOSAGE Daily Three times weekly Mg/kg Max. dose Mg/kg Max. dose Isoniazid 5 (4-6) 300 10 (8-12) - Rifampicin 10 (8-12) 600 10 (8-12) 600 Pyrazinamide 25 (20-30) - 35 (30-40 - Ethambutol 20 (15-25) - 30 (25-35) - Streptomycin 15 (12-18) - 15 (12-18) - 84

84. Indications for treatment with steroids TB meningitis ↓ ed consciousness Neurological defects or Spinal block . TB pericarditis (with effusion or constriction). TB pleural effusion (when large with severe symptoms). Hypoadrenalism (TB of adrenal glands). TB laryngitis (with life-threatening airway obstruction). Severe hypersensitivity reactions to anti-TB drugs. Renal tract TB (to prevent ureteric scarring). Massive lymph node enlargement with pressure effects. 85

85. Prednisolone Treatment Indication Prednisolone treatment Initial dose Tapering dose TB meningitis 60mg(1–2 mg/kg/)day in 1–2 ÷ doses PO for 4–6 wk Taper over 1 – 2 wks TB pericarditis 60 mg (1–2 mg/kg) daily for wks 1–4 30 mg (0.5–1 mg/kg) daily for wks 5–8, then ↓ over several wks TB pleural effusion 30 mg (0.5–1 mg/kg) daily for 1–2 wks 86

86. Management of patients initially smear positive, who interrupted TB Rx for < 8 consecutive weeks Duration of Rx before interruption Duration of interruption  Smear result at return Treatment < 4 weeks < 2 consecutive wks No smear Same Rx. 2 - 8 consecutive wks No smear Re-start same Rx 4 - 8 weeks < 2 consecutive wks Negative Same Rx. Positive Re-start same Rx 2 - 8 consecutive wks Negative One-month extra intensive phase. Positive re-Rx regimen. > 8weeks < 8 consecutive wks Negative Same Rx. Positive re-Rx regimen. 87

87. STANDARDIZED CASE DEFINITIONS Note from wHO guide line 2004 A TB suspect is any person who presents with symptoms and signs suggestive of TB, in particular cough of long duration. A case of TB is a patient in whom TB has been bacteriologically confirmed , or who has been diagnosed by a clinician . 88

88. A definite TB case is a patient who is culture-positive for the M. tuberculosis complex. ( In countries where culture is not routinely available , a patient with two sputum smears positive for AFB is also considered a “definite case”.) 89

89. Pulmonary TB – sputum smear-positive (PTB+) Two or more initial sputum smear examinations positive for AFB or 1 sputum smear positive for AFB, and CXR abnormalities consistent with active pulmonary TB as determined by a clinician or 1 sputum smear positive for AFB, which is also culture positive for M. tuberculosis 90

90. Pulmonary TB – sputum smear-negative (PTB-) A case of pulmonary TB that does not meet the above definition for smear-positive TB. In keeping with good clinical and public health practices, diagnostic criteria should include: at least three sputum smears negative for AFB and no response to a course of broad-spectrum antibiotics and CXR abnormalities consistent with active TB and decision by a clinician to treat with a full course of anti-TB treatment 91

91. Extrapulmonary TB TB of organs other than the lungs: E .g . pleura , lymph nodes, abdomen, genitourinary tract, skin, joints, bones, meninges . Diagnosis is based on one culture -positive specimen, or histological or strong clinical evidence consistent with active extrapulmonary TB, followed by a decision by a clinician to treat with a full course of anti-TB treatment. A patient diagnosed with both pulmonary and extrapulmonary TB should be classified as a case of pulmonary TB. 92

92. The following are forms of extrapulmonary TB: pleural effusion (the pleurae are outside the lungs); miliary (TB is widespread throughout the body and not limited to the lungs). 93

93. Category of TB patient for registration on diagnosis New A patient who has definitely never taken anti-TB drugs or who has taken anti-TB drugs for less than one month . Relapse A TB patient who: a) previously received treatment and was declared cured or treatment completed; and b) has once again developed bacteriologically positive (by smear or culture ) TB. 94

94. Treatment after failure A patient who is started on a re-treatment regimen after having failed previous treatment. Treatment after default A TB patient who returns to treatment, bacteriologically positive, following interruption of treatment for 2 months or more. 95

95. Transfer in A TB patient who has been transferred from another TB register to continue treatment. Other All TB patients who do not fit the above definitions . This group includes chronic cases (TB patients who are sputum smear-positive at the end of a re-treatment regimen ). 96

96. TB diagnostic category Patients Category I new sputum smear-positive PTB º new sputum smear-negative PTB with extensive parenchymal involvement º new cases of extrapulmonary TB (more severe forms) º severely ill TB patients with concomitant HIV infection Category II º previously treated sputum smear-positive PTB: relapse, treatment after default, treatment after failure Category III º new sputum smear-negative PTB with limited parenchymal involvement and known HIV-negative º extrapulmonary TB (less severe forms) and known HIV-negative Category IV º chronic and MDR-TB cases 97

97. The table below shows the severe and less severe forms of extrapulmonary TB. Severe extrapulmonary TB meningitis miliary pericarditis peritonitis bilateral or extensive pleural effusion spinal intestinal genitourinary 98

98. Less severe extrapulmonary TB lymph node pleural effusion (unilateral) bone (excluding spine) peripheral joint adrenal gland 99

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