CHTB Essentials tuberculosis in children

CHTB Essentials

1. Pediatric TB Management Essentials Based on Childhood TB Guidelines (updated 2021) National TB Elimination programme and Indian Academy of Pediatrics 1

2. Objective of this training module To teach essentials about childhood TB, including: Clinical presentation of the common forms Diagnostic tools Collection of different body specimens for diagnosis ( T eaching Videos) Treatment regimen and dosages for children Monitoring of treatment and adverse events Drug resistant TB management among children HIV TB coinfection Prevention of TB Notification of cases and private sector engagement 2

3. How prevalent is TB in Children ? NTEP annual report 2019 3

4. Clinical presentation of the common forms of TB in a child 4

5. Case What will you ask for ? 5

6. Case Sameer’s symptoms 6

7. Defining cough - duration and pattern Intensity of Cough 1w 2w 3w 4w Duration in weeks 1) Acute with Delayed recovery 2) Recurrent 3) Persistent, non-remittent Prospective study - Cape Town, N= 151, 0-13 yrs; cough of 2 weeks or more; 21 (15.6%) reported symptoms with a persistent, non-remitting character. Tuberculosis diagnosed in 16 (10.5%) children, Arch Dis Child 2005;90:1162–1165 7 Chronic cough – reported in up to 20% of children from poor area Chronic persistent cough is inferred from detailed history by the physician and not merely as reported by the caregiver. Caregivers do not necessarily understand the need for differentiating between persistent or delayed resolution or recurrent cough till probed

8. 8

9. Symptom Characterization for suspecting TB 9

10. Back to Sameer……………………… Mother – PTB, sputum status not known, ATT x 2m What is it’s significance? 10

11. Case What is the risk of infection to the sibs ? 11

12. Source Case Exposure of Contacts No Infection Infection No Disease Primary Disease Persistent “Latent” Infection Mycobacterial Virulence Host Immunity 12 30% 70% Risk of developing disease: 5-10% lifetime, >50% infancy 25% in 1-5 y 90-95%

13. Case What is the risk of infection to the close contacts (sibs) ? What is the risk of progression to disease ? Risk of progression to disease Life time risk – 5 to 10% 1 to 5 years – 25% Infants - >50% 30 % risk of infection 13

14. But her smear status is not known ! What if she has a smear negative PTB ? 14

15. Fraction of cases / infected 0.0 0.2 0.4 0.6 0.8 1.0 Smear- neg Culture-pos Smear-pos Culture- pos Fraction due to smear- neg cases Fraction due to smear- pos cases Grzybowski S, et al. Bull Int Union Tuberc Lung Dis 1975 Cases of pulmonary tuberculosis Infected contacts < 15 yr Infection with TB can occur from contact with a sputum smear-negative source case but it is less common than from smear-positive cases 15

16. And when does the source case become non infectious on treatment ? 16

17. Sameer is a TB suspect Presumptive TB case Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years How should you proceed now ? Back to Sameer The word suspect is not used to describe a patient any more ! He is a presumptive case of TB. 17

18. Pyramid of TB diagnostics Yield of test and robustness of diagnosis can be improved by better characterisation of symptoms and interpretation of radiology!! 18

19. Usual challenges in Diagnosis 19

20. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Initial screening test Errors in radiograph interpretation can lead to both under as well as over diagnosis P enetration R otation I nspiratory M otion Pay attention to Sameer 20

21. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Suggestive of TB LN Fibrocavitary Miliary Initial screening test Beware! Confounders Summation shadows Thymus Overlays e.g. Hair braid seen here 21

22. Lymphadenopathy : Frontal radiographs Direct signs: Sharply demarcated and lobulated density or Ill-defined with vague borders, occupying the hilum & obliterating hilar point Other structures making up the mediastinum & hilum can obscure it Indirect signs: Contour & calibre of trachea Impression on the tracheobronchial tree as well as splaying of carina can be shown with high-kilovolt filtered radiographs 22

23. Lateral Chest films Good to visualise retro-cardiac disease and hila Dough nut sign Lobulated densities posterior to the bronchus intermedius Completes the inferior portion of a ‘doughnut’-shaped density; Upper half is seen in normal individuals as an up-side-down ‘horse-shoe’ made up of the RPA and LPA and the aortic arch Picks up 12-19% additional cases Allows view of the ‘hidden areas’ like left lower lobes which are hidden behind the heart Summation Shadow Better delineation of soft miliary shadows Radiation cost – 3x frontal view 23

24. Source Case Exposure of Contacts No Infection Infection No Disease Primary Disease Persistent “Latent” Infection Mycobacterial Virulence Host Immunity 24 Sameer

25. Three features common to primary infection are Patient may have non-specific mild symptoms which can go un-recognised, Primary lung foci are usually quite small relative to large hilar nodes, and Primary foci may resemble pneumonia & be located within any lobe Radiological picture of a typical Ghon’s Complex 25 What is the fate of the Primary Complex ?

26. Primary Infection (LUNG) Ghon’s Complex Contained Treated Naturally Heal Ghon complex = Ghon focus + hilar lymph nodes Reactivation disease Risk much higher with natural healing as compared to those treated 26 Is the reactivation rates different between naturally healed versus treated cases? Ghon’s Focus Regional LN Airway Involvement Intra Bronchial Spread Bronchopneumonic Consolidation Partial or Complete Obstruction Parenchymal Cavitation with Intra-Bronchial Spread Contiguous rupture Pleural Effusion Pericardial Effusion Miliary TB Progressive Primary TB

27. Lymph Node Disease NO Airway Compression No Obstruction/Collapse Right Para Tracheal LN Right Hilar LN Primary TB Please comment upon the Chest X-ray 27 Lets look at a few images

28. Pulmonary Primary complex Please comment upon the Chest X-ray 28

29. Please comment upon the Chest X-ray Air Way Compression Progressive Primary PTB 29 Right Main Bronchus Rt paratracheal and subcarinal Lymph Node Disease with Airway Compression Hyperinflation right Lower lobe No Collapse

30. Consolidation Cavity with in a Consolidation Parenchymal cavitation with Consolidation Progressive Primary Disease Cavity with in a Consolidation Please comment upon the Chest X-ray 30

31. Miliary TB 31

32. Reactivation or Post Primary tuberculosis 32

33. Fibro-Cavitary pneumonia Rt UL and Lt lung 33 Reactivation or Post Primary tuberculosis Cavitary pneumonia Lt UL

34. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Weight loss of 5% or no weight gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Initial screening test Sameer Is the diagnosis confirmed ? Not really, It is highly suggestive but neither confirmed nor complete Confirmed diagnosis means either showing presence of (smear or NAAT) or growing the pathogen (Microbiological diagnosis) Completeness : means knowing about rifampicin resistance (at least) Back to Sameer ! 34

35. TUBERCULOSIS – CONSEQUENCE OF CONVENTIONAL MANAGEMENT 35

36. NOW Goal POSTS have moved! Mtb detection Mtb AND Rifampicin resistance detection TB DIAGNOSIS Diagnosis of TB needs to be more efficient Microbiological Rapid detection of Rifampicin (and INH Resistance) Rapid molecular test make it easier and better as compared to the past TB DIAGNOSIS 36

37. Strategic shift and tools to achieve the desired change TB DIAGNOSTICS HAVE EVOLVED IT IMPACTS THE WAY YOU MANAGED TB! 37

38. Microbiological Diagnosis There are hurdles There are solutions ! 38

39. Gastric Aspirate (GA) /Lavage (GL) Induced Sputum (IS) How do we access the respiratory specimen when the sputum is not brought up spontaneously? 39

40. Video GA 40

41. Video IS 41

42. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Suggestive of TB Sputum/GA/IS Overnight fasting not required Use GA/IS NAAT – 1 sample 2 samples required for smear May even be on the same day Initial screening test Sameer 42

43. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years NTEP approved NAAT Suggestive of TB Sputum/GA/IS NTEP approved rapid NAAT Country wide network of Xpert and TrueNat machines for free testing ( Mtb and Rif resistance) under NTEP 43

44. NTEP approved NAATs - Newer Rapid Molecular Tests for Tuberculosis Truenat ™ MTB-RIF Dx ™ Xpert MTB/RIF TM 44

45. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Suggestive of TB Sputum/GA/IS NTEP approved rapid NAAT NAAT - ve Sameer Does it mean no TB ? Back to Sameer ! 45

46. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years NTEP approved NAAT Suggestive of TB Sputum/GA/IS NTEP approved rapid NAAT Limitations Is any other molecular test available ? Yes, Line probe assay – discussed later 46

47. We are headed towards a drug sensitivity based therapy! 47

48. New Pyramid of TB diagnostics Yield of test and robustness of diagnosis can be improved by better characterisation of symptoms and interpretation of radiology!! 48

49. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Suggestive of TB Sputum/GA/IS NTEP approved rapid NAAT NAAT - ve Sameer Back to Sameer ! What do we do now ? 49

50. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Suggestive of TB Sputum/GA/IS NTEP approved rapid NAAT NAAT - ve GA was repeated as X ray was highly TB suggestive Bronchoscopic findings like compression of airways or caseation or bronchiectasis with mucosal ulcerations suggest TB pathology Look for and Test alternate site like enlarged peripheral LN Better quality specimen / Alternate specimen like BAL, LN aspirate Review from higher center 50

51. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Suggestive of TB Sputum/GA/IS NTEP approved rapid NAAT NAAT + ve Microbiologically confirmed TB Rif Res detected DRTB pathway Rif Res not detected Treat with 1 st line drugs NAAT - ve Look for and Test alternate site like enlarged peripheral LN Better quality specimen / Alternate specimen like BAL, LN aspirate Review from higher center NAAT + ve NAAT - ve No other likely alternate diagnosis Treat as clinically diagnosed probable TB Check for Rif resistance 51

52. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Suggestive of TB Sputum/GA/IS NTEP approved rapid NAAT Microbiologically confirmed TB Rif Res not detected Treat with 1 st line drugs NAAT - ve NAAT + ve Sameer Sameer has Drug sensitive (Rif res not detected) Pulmonary TB HIV testing should be offered to all children diagnosed with TB Notification a must Back to Sameer ! Look for and Test alternate site like enlarged peripheral LN Better quality specimen / Alternate specimen like BAL, LN aspirate Review from higher center 52

53. Microscopy/NAAT/LPA/C&DST Revised Diagnostic algorithm Sample Transport System Private laboratory Service Microscopy NAAT C & DST Laboratory Technician Free Services to TB patients in private sector (Diagnosis) Programme Provided Purchase of Services 53

54. Incentives Bank account and Aadhar seeding Direct Benefit Transfer Schedule H1 notification Mandatory notification: Laboratories Private practitioners & hospitals Chemists Self-notification Pubic Heath Action by heath staff Counseling, home visit Treatment adherence HIV, DM screening 19 March 2018 19 June 2017 TB Notification from Private Sector Incentives & Regulations IPC 269 – Act of Omission IPC 270 – Act of Commission 54

55. Linkages to access from public health facility Programme provided drugs at private practitioners Programme provided drugs at chemists Empanel Private Chemist & Doctors Subsidize Reimbursements Incentives / Honorarium Free Services to TB patients in private sector (Drugs) Programme Provided Purchase of Services 55

56. Nikshay 56

57. Modalities of notification Submission of hardcopies to DTO Reporting into Nikshay web portal/mobile application Reporting via Nikshay Sampark (1800 11 6666) 57

58. Incentives to Patients for Social Protection “ Nikshay Poshan Yojana ”- Launched from 01 st April 2018 Nutritional support through Direct Benefit Transfer of 500 INR per month For all patients on TB treatment throughout duration of treatment Patient need to be registered in the Nikshay portal Tribal patient incentive 750 INR per patient in tribal areas for transport support 58

59. Incentives to Providers Private Provider Incentive 500 INR at notification & 500 INR on reporting treatment outcome Informant incentive Incentive of 500 INR to informant f or notification of patients in public sector Incentive for Treatment support New Case: 1000 INR at completion of treatment Drug Resistant Case: 2000 INR at completion of intensive phase, 3000 INR at completion of treatment 59

60. Quiz Learning from a different type of case (not Sameer) 5y boy with fever and cough for 2 weeks X ray Non specific shadow Not TB suggestive 60

61. Quiz Learning from a different type of case (not Sameer) 5y boy with fever and cough for 2 weeks X ray Non specific shadow Not TB suggestive 61

62. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Suggestive of TB Sputum/GA/IS NTEP approved rapid NAAT NAAT + ve Microbiologically confirmed TB Rif Res detected DRTB pathway Rif Res not detected Treat with 1 st line drugs Nonspecific shadows Course of appropriate antibiotic Persistent shadow NAAT - ve Look for alt site like peripheral LN & test LN asp Better quality specimen / Alt specimen like BAL, LN aspirate Review from higher center NAAT + ve NAAT - ve No other likely alt diagnosis Treat as clinically diagnosed probable TB Skip this step if already received an appropriate antibiotic course 62

63. Persistent fever for > 2w without a known cause Unremitting cough for > 2w Wt loss of 5% or no wt gain in past 3m despite adequate nutrition or failure of nutritional rehabilitation in babies with SAM With or without contact with patient with pulmonary TB in past 2 years X ray chest Suggestive of TB Sputum/GA/IS NTEP approved rapid NAAT NAAT + ve Microbiologically confirmed TB Rif Res detected DRTB pathway Rif Res not detected Treat with 1 st line drugs Normal Evaluate for EPTB Ref to higher center For invest for alternate causes Nonspecific shadows Course of appropriate antibiotic Persistent shadow NAAT - ve Look for alt site like peripheral LN, asp Alt specimen like BAL, LN aspirate Review from higher center NAAT + ve NAAT - ve No other likely alt diagnosis Treat as clinically diagnosed probable TB 63

64. Challenges with diagnostic tests for TB Direct Smear: positive in only 10-15% of children Commonly performed on sputum and gastric aspirates Use if only rapid NAAT not available or for selecting sputum smear positive cases for direct LPA Culture : slow and requiring sequential procedures for isolation and in-vitro drug sensitivity testing Faster result possible with LPA for Drug sensitivity on the isolate NAAT: Rapid reliable NTEP approved NAAT which also tells about Rif resistance Good “Rule in” test but not a sensitive “Rule out” test Indirect Chest radiography: often non specific findings, inter and intra observer variation TST / IGRA: a positive test is only a marker of infection Can not by itself differentiate infection from disease in an individual 64

65. Role of Smear for Acid Fast Bacilli 65

66. Role of Mtb culture Not routinely available Long TAT Cost, an issue Now available through NTEP lab network and other accredited laboratories Short TAT Under current Universal DST strategy may be used upfront with specimens like IS/ GA/ BAL, if molecular tests are negative In the past Now Diagnostic yield can be improved with MTb culture 66

67. Type of disease affects microbiological diagnosis 67 Smear Culture Over all yield Primary complex 6% 22% 23% Progressive primary 18% 46% 47% Pleural effusion* 5% 28% 32% Pediatr Infect Dis J 2013;32:1313–1317 * The smear or culture yield depicted here is from respiratory specimens like GA/ IS and not from pleural fluid Data from Delhi TB study group ( N=403)

68. Childhood TB: Microbiological confirmation 68

69. Summary 69

70. Other tests for TB not part of the algorithm for lack of diagnostic value for TB disease 70

71. Tuberculin Skin Test (Mantoux’s Test) 71

72. C-Tb Test The next-generation skin test for detection of Tuberculosis 72 as yet not available in our country

73. Interferon  Release Assays [ IGRAs] Quantiferon Gold (TM) and Elispot -TB (TM) Both IGRA and TST tests cannot distinguish between LTBI and active TB disease 73

74. IGRA: Limitations 74

75. TST video 75

76. 76

77. Persistent Fever > 2wk, without a known cause and/or Unremitting Cough for > 2wk and/or Weight loss of 5%; or, no wt gain in past 3 mo despite adequate nutrition; or, failure of nutritional rehabilitation in babies with severe acute malnutrition With or without Contact with patient with Pulmonary TB in past 2 years Chest X-ray 1 Microbiologically confirmed TB Case. CXR highly suggestive 2 Expectorated sputum/ GA/IS for NTEP approved NAAT for Mtb 4 NAAT + ve NAAT - ve CXR Non specific shadows 3 Persistent shadow and symptoms Give course of appropriate antibiotics 5 Skip this step if already received an appropriate antibiotic course NAAT + ve HIV testing should be offered to all children diagnosed with TB CXR Normal Algorithm for Pediatric Intrathoracic TB among children with no risk factors for drug resistance 77 RIF resistance not detected Treat with first line drugs NAAT - ve or repeat test not indicated or feasible RIF resistance detected 4 - follow the DRTB pathway 4 No other likely alternative diagnosis Treat as Clinically Diagnosed Probable TB case @ 6 Check for EPTB Needs detailed investigation for TB or an alternate cause for the symptoms. May require CECT chest or other investigations depending on symptoms. Consider referral to a higher center for further investigations Look for any other site like a significantly enlarged peripheral enlarged lymphnode and test the LN aspirate for Mtb Consider Repeat NAAT from a better quality specimen or alternative specimen like BAL or aspirate depending upon the availability and feasibility May seek review from a higher centre

78. Important Notes to the Algorithm Chest X-ray shall be done upfront in cases who are suspected to have TB. If a recent good quality chest X-ray is available, it need not be repeated. Highly suggestive Chest X-ray refers to Miliary shadows, or Lymphadenopathy (hilar or mediastinal), or Chronic fibro-cavitary shadows. Non Specific Chest X-ray: Refer to patterns other than highly suggestive like consolidations, in-homogenous shadows or bronchopneumonia, etc. 78

79. NTEP approved NAAT shall be preferred over smear examination in all children. Available NTEP approved NAAT include Xpert Rif™, Truenat ™ and LPA. If a specimen is positive by any of these methods, the case is labelled as microbiologically confirmed TB. At the initial step, If self expectorated sputum is available and imaging /NTEP approved NAAT test is not available or delayed, smear may be done (for ease of availability and low cost). Whenever smear is used for diagnosis at least 2 samples should be tested while a single sample is sufficient for more sensitive NTEP approved NAAT. If a specimen is negative by NTEP approved NAAT (or smear), the second aliquot or a fresh good quality specimen should be submitted for a repeat NAAT and liquid culture RR detected in a new case with no risk factors for DRTB needs to be retested if only Mtb detected was very low as that could be false positive. If there is a discordance in Rifampicin resistance between NAAT and LPA, a second NAAT is performed at the C & DST laboratory using the decontaminated deposit Important Notes to the Algorithm 79

80. Important Notes to the Algorithm Antibiotics of choice include amoxycillin or co-amoxyclav. Antibiotics like Linezolid or any quinolone should not be used as they have anti-TB action. In case antibiotic trial has already been done in adequate dose and duration, it may not be repeated. Clinically Diagnosed Probable TB case : Is a patient with a high clinical suspicion for TB disease based on suggestive symptoms, radiology and often supportive circumstances (history of exposure to a TB case) or evidence of infection (positive Skin test for TB or positive IGRA) BUT the rapid microbiological tests are negative. Such a case may be treated as clinically diagnosed patient provided common alternative diagnoses have been ruled out. Where facilities exist, send one aliquot of the specimen for liquid culture, if the NAAT is negative for Mtb . 80

81. Pediatric TB Further Work-up Algorithm under U-DST * LPA may be done directly if smear positive else send for MGIT foll o wed by FLPA to evaluate for H ( inhA and/ or KatG mutn ) and Eto ( inhA ) resistance ** SLLPA may be done directly if smear positive else send for MGIT followed by SLLPA or LC DST ( Mfx 2.0, Km, Cm, Lzd ) $ RR detected in a new case with no risk factors for DRTB needs to be retested if only Mtb detected was very low as it makes Rif resistance detection less reliable 81 Rif resistance not detected Mtb Detected Reinvestigate for non-response including for DRTB Non response in 4 weeks Repeat NAAT H Resistant ( inhA and/or KatG mutation) Eto resistance ( inhA mutation) Rif resistance detected $ FL-LPA SL - LPA** FQ and/or SLI Resistance FL-LPA* Rif resistance not detected H Resistant Not detected All presumed cases of TB NAAT Mtb not Detected Clinically diagnosed case of TB With no risk factors for DRTB Treat with standard regime 2RHZE / 4RHE

82. Some Case studies to review Are you ready? 82

83. Case 12y girl with fever, cough for 2 weeks X ray comments Non specific shadow Not TB suggestive 83

84. Case 2y Fever x 2 weeks Mother on treatment for pulmonary TB 84

85. A B C D Which of the X ray images is NOT highly suggestive of pulmonary tuberculosis? 85

86. A B C D Foreign body with RML collapse Miliary tuberculosis Paratracheal adenopathy Cavitary consolidation Which of the X ray images is NOT highly suggestive of pulmonary tuberculosis? A 86

87. Extra Pulmonary TB 87

88. When should we suspect TB ? 88 When do you suspect TB in a child?

89. Case Summary 10 y boy Fever with chills x 7 days Mild cough Antibiotics on OPD basis No h/o contact with TB Case 89 What can be the possible causes for this effusion? Your comments?

90. Investigations CBC - Hb 10.8, TLC 7980, N68, L22 ESR 85 mm in 1st hr. TST negative Co- amoxy - clav for 7 days 90

91. Follow up Fever persists Pl fluid aspirated 870 cells , L 80 Protein 3.8 g/dl Smear No AFB, Gram’s stain negative ADA 80 u/l 91 Pl fluid interpretation and diagnostic clue What is the role of ADA ? What else could have been done on the pleural fluid sample - Role of Culture / NAAT for Mtb ? Can GA/IS be of help ? Role of CT chest ? High proteins (>3g/l) in absence of pus or cobweb formation ADA is not useful in differentiating TB from other infective causes of effusion. Poor yield on NAAT IN PLEURAL FLUID Definite role for bacteriological studies of the respiratory specimens About 28% - 40% of the children with PE, M tb positive on GA/ IS culture No routine role of CT chest in diagnosis

92. Pleural TB Diagnostics 92

93. LN TB 93

94. LN TB Matted LN / Cold abscess +/- sinus FNA Cytology , NAAT, AFB smear, MGIT Pus from LN/ discharge from sinus improves the yield AFB detected on smear / NAAT + ve / Caseous granuloma Treat as case If no granuloma / non caseous granuloma NO AFB on smear or NAAT neg Excision biopsy LN > 2cms in one or more site 7 day course of antibiotic and review after 2 weeks Non response Yield Smear 10 – 15% Culture 20 -50% NAAT 35% Often the Quality NAAT may be more easily available than cytology. Then one may resort to cytology only in NAAT negative cases No 94

95. How to aspirate pus/ sap from enlarged lymphnodes 95 Insert Video

96. Case 96

97. 97 Forms of Abdominal Tuberculosis Intestinal 39-66% Nodal 4-42% Peritoneal 27-40% Small bowel Large bowel UGI uncommon Ascitic form Dry type Visceral Hepato-splenic Pancreas Disseminated 2.5-12% Ulcerative, ulcerohyperplastic and hyperplastic One third patients had >1site involved GIT, lymph nodes, peritoneum Indian Journal of Medical Sciences.2010; 64: 204-209 J Pediatr Gastroenterol Nutr 2010;50: 634–638. Singapore Med J 2007; 48 (10) : 900-905 Indian Pediatrics 1991;28:1093-1100

98. Clinical features 98 Unpublished Data from SGPGI, India, n=38

99. Imaging studies in abdominal TB 99

100. Recurrent or Chronic Abdominal Pain (RAP) and Mesenteric lymphadenopathy Recurrent abdominal pain without any red flag signs with isolated mesenteric lymphadenopathy and normal abdominal examination is highly unlikely presentation of TB 100

101. Recurrent or Chronic Abdominal Pain and Mesentric lymphadenopathy 101

102. Common errors Insufficient Evidence for ATT Mild grade fever USG abdomen showing sub-centrimetric LN Failure to gain weight Functional abdominal pain Chronic diarrhea without proper evaluation 102 SGPGIMS data 1998-2012 Around 18% received un-necessary ATT Around 19% of Celiac patients receive erroneous ATT

103. TB Meningitis 103

104. 104

105. Divided in three clinical stages Usually progresses over several weeks from stage one to three Infants and young children may progress rapidly over days 105 Stage 1 Typically lasts 1 to 2 weeks. Nonspecific symptoms. Fever, headache, irritability/ drowsiness, malaise, anorexia, inadequate weight gain or weight loss, stagnation or regression of development milestones Stage 2 Begins abruptly. Characterized by increased intracranial pressure, meningeal irritability, and vasculitis without marked changes in sensorium. Clinical constellation lethargy, nuchal rigidity, Kernig and Brudzinski signs, seizures, hypertonia, vomiting, cranial nerve palsies with basal meningitis and other focal neurological deficits Stage 3 Coma, hemiplegia or paraplegia, decerebrate posturing, deterioration in vital signs and finally death The stage at which treatment begins dictates the prognosis : progressively worsening from stage 1 to stage 3

106. Investigations 106

107. Neuroimaging in TBM 107 J Infect 2009; 59: 167–87

108. Neuroimaging in TBM 108 J Infect 2009; 59: 167–87

109. Algorithm for diagnosis of TBM Suspect TBM if: Insidious onset of fever and neurological abnormality with or without Headache/Vomiting Poor feeding/Weight loss Irritability/lethargy Seizures Confusion/Coma Neck Stiffness Cranial Nerve palsy Hemiparesis Immediate investigation CXR, TST Hmg , LFT, Glucose, ESR, CECT cranium HIV Lumbar puncture: Cytology (including AFB staining), Biochemistry, NAAT, MTB and pyogenic culture AFB seen or NAAT + ve in CSF Check for the following three criteria YES NO > 3 Clinico -investigative features strongly suggestive of TBM a)>5 days of symptoms b)WBC in Blood<15x10 9 /Lit c)CSF 10-500 WBC/mm 3 d)CSF Lymphocytes > 50% e)CSF/ plasma gluc < 50% f)Imaging evidence of; Basal meningeal enhancement Hydrocephalus Cerebral Infarct Suggestive of Tuberculoma 2 or more Risk factors for TBM a) HIV or other immunocompromised b) SAM c) Recent contact with active pulmonary TB Evidence of TB elsewhere Criterion 1 Criterion 2 Criterion 3 Start treatment for TBM 2 or more Criterion fulfilled ? YES No Next slide 109

110. Again review criterion 1,2,3. and check if n ow 2 or more Criterion are fulfilled? Does the patient have unexplained meningitis with low CSF glucose, falling GCS or new focal neurology? Continue to investigate Keep low threshold for starting empirical ATT Start treatment for TBM YES Review assessment within 48 to 72 hours Consider repeat LP Expand search for TB elsewhere Consider MRI head (Contrast) particularly if initially CECT head was done NO NO NO YES Continue workup and management for alternative diagnosis (e.g. Antibiotics for PTPM) PTPM: Partially treated pyogenic meningitis 110

111. Treatment ATT x 12 months (2HRZE+10HRE) Study in adult TBM with higher doses of rifampicin & addition of quinolones have not shown higher efficacy ( Heemskerk AD, et al.  N Engl J Med. 2016 Steroids Prednisolone 2 mg/kg/d (or equivalent dose dexamethasone: 0.6 mg/kg/day) )in divided doses, for at least 4 weeks and then tapered over next 4 weeks Decongestive therapy for raised ICT As needed Mannitol, Acetazolamide, Glycerol Antiepileptics As needed Surgical intervention, if hydrocephalus not controlled by medical management Shunt / EVD/ Ventricular tap 111

112. Tuberculoma A manifestation of CNS tuberculosis Presents as intracranial space occupying lesion (ICSOL) 112 Location Size Peri-lesional edema predicate the manifestations Seizures Headache Neurological focal deficits CNS tuberculosis other than TBM

113. Parameters Tuberculoma NCC CECT Appearance >2 cm, irregular thick outline, marked perilesional edema ≤ 2cm, regular, thin, rounded outline with variable edema , Location Infratentorial or supratentorial Predominantly supratentorial Midline shift More likely Less likely Contrast MRI Appearance T2 - usually hypointense core usually T2 hyperintense core, eccentric Dot, scolex best seen on FLAIR or DWI images MRS Lipid peak present Lipid peak absent T2 relaxation time Shorter (83-290 ms ) Longer (305-1365 ms) 113

114. Bone and Joint TB 114 Roughly accounts for 5-15% of all EPTB and 2-5% of all TB in children and adults Clinical Presentations

115. Dactylitis ( spina ventosa ) Tuberculous osteitis , the dactylitis form, often affects children multiple or consecutive bones can be involved 115

116. Clinical features of Pott’s spine 116

117. Imaging findings 117

118. Treatment 118

119. Expert Rev. Anti Infect. Ther . 10(6), 631–635 (2012) Specimen Sensitivity in culture positive specimens 95% CI Tissue biopsies 75% Fine Needle Aspirates 88.3% 82–95 Gastric aspirates 78.7% 68–89 Pus samples 87.3% 67–100 Cerebrospinal fluid 85.7% 67–100 Lower sensitivity for Pleural fluid 44.4% 21–67 Body fluids (Pericardial, peritoneal, Synovial) 50% 19–81 119

120. 120

121. The three type of the populations are in constant dynamic relationship. Different drugs are effective in different metabolic populations, requiring a combination therapy for treatment. (Modified from, Clinics in Chest Medicine 1980;1:231-41) 10 5 Type A: Actively dividing organisms 10 8 - H>>S>>R>>E Type B: Intracellular Slowly multiplying organisms - PZA Type C: Extracellular Slowly multiplying organisms and spurters - RIF, INH. Relapse due to persisters Failure due to selection of resistant organisms 2 6 Time in months Basis of Chemotherapy of Tuberculosis 121

122. Childhood TB is often a primary paucibacillary disease, and thus chances of primary drug resistance are low and reflective of the prevalence of resistance in the pool of infectious cases (adults) (Transmitted resistance) 122

123. Phases of TB Treatment Intensive Phase (IP) Continuation Phase (CP) 123

124. TB Treatment – What’s new ? 124

125. Regimen for TB (RS TB) IAP NTEP guidelines 2019 125 Type of patient a Regimens New microbiologically confirmed RS Pulmonary TB New Clinically diagnosed Pulmonary TB (probable RSTB) New microbiologically confirmed RS extra-pulmonary TB New Clinically Diagnosed extra-pulmonary TB (probable RSTB) Drug sensitive Previously Treated TB c ( Recurrent, Treatment after loss to follow up , Treatment after Failure) 2HRZE+ 4HRE b Molecular testing shall be done in all new cases in children with suspected TB at diagnosis and RSTB (Rifampicin resistance not detected) cases included in this regimen In case of Neuro and spinal TB the continuation phase is extended to 10 months All these category of children shall be evaluated as DR TB suspects and evaluated as per DR TB Algorithm. DST based treatment shall be followed. In case they are found to be Rifampin (and INH) sensitive, they shall be re-started on the regimen as for a new case. This group was earlier treated with CAT II regimen which is now withdrawn from NTEP.

126. What Drug Doses should one use? 126 Recommended Drug Doses have increased Range mg/kg/day Average mg/kg/day Maximum dose(mg) Rifampicin R 10-20 15 600 Isoniazid H 7-15 10 300 Pyrazinamide Z 30-40 35 2000 Ethambutol E 15-25 20 1500 Streptomycin S 15-20 20 1000

127. FDCs incorporating the multi-drug therapy for TB are preferred 127

128. 128 Weight band (kg) Dose from 0-18 years 4-7 1 P + 1E 8- 11 2 P + 2E 12-15 3 P + 3E 16-24 4 P + 4E 25-29 3 P + + 3E + 1 A 30- 39 2 P + + 2E + 2 A Pediatric Drug Formulations and Dosages

129. 129 Pyridoxine: current recommendation

130. Key Points - Treatment of TB 130

131. Writing TB prescription 131

132. 132

133. When, How and What to monitor ? 133

134. Clinical response to therapy Int J TB Lung Ds 2018;22(11, suppl 2):S537-8 134

135. When, How and What to monitor? 135

136. Issues in a child with Non -responding TB Most commonly because of poor regimen, adherence Drug resistance though important but not the only cause 136

137. Fresh radiological lesions 137

138. Paradoxical response 138

139. Also called paradoxical upgrading reactions (PURs) 139 Paradoxical response

140. Causes of symptom persistence or recurrence in a TB patient on therapy 140 Summary:

141. Monitoring and management of treatment adverse effects 141

142. Monitoring and Ensuring Adherence 142

143. Side effects of first line drugs Drug Side effects Isoniazid Skin rash, Hepatotoxicity , Jaundice, Peripheral neuropathy Rare: Toxic psychosis, Generalized epileptic convulsions, Pellagra, Arthralgia , Anaemia, Lupoid reactions (uncommon in children) Rifampicin Orange-red discoloration of secretions (urine, faeces, tears, sweat) Hepatotoxicity Cutaneous syndrome : Flushing and/or pruritus , with or without rash, involving particularly the face and scalp, often with redness and watering of the eyes. Abdominal syndrome: pain, nausea, vomiting or, less commonly, diarrhoea. “Flu” syndrome(uncommon), Purpura , acute haemolytic anaemia, shock, and renal damage with or without impaired kidney function or failure (rare) 143

144. Side effects of first line drugs Drug Side effects Pyrazinamide Hepatotoxicity, Joint pain, Hypersensitivity Rare: Gastrointestinal reactions, Sideroblastic anaemia. Ethambutol Ocular toxicity (dose dependent): (Impairment of vision, Red–green blindness, Central scotomas , and Peripheral field defects. Rare: Generalized cutaneous reactions, Arthralgia , Peripheral neuropathy Streptomycin Vestibular damage and Ototoxicity (Vertigo and ataxia, Tinnitus, and Loss of hearing) Hypersensitivity reactions, Renal damage Pain, rash, induration at injection site 144

145. Monitoring of adverse effects of treatment 145

146. Sameer develops vomiting and anorexia 146

147. ATT Drug induced liver injury (DILI) Definition of Drug induced liver injury (DILI) J Respir Crit Care Med 2002;166:916-9. 147

148. Clinical features Nausea, Vomiting, Anorexia Pain abdomen, Jaundice, Unexplained fatigue New onset hepatomegaly Bleeding manifestation Present in 50-75% Symptoms common to Gastritis – another adverse event 148

149. Symptoms suggesting DILI Nausea, vomiting, abdominal pain or unexplained fatigue ALT 5 X ULN Or ALT 3 X ULN with symptoms Or Jaundice STOP ATT Start Lf, Sm , E if patient sick, particularly during IP Repeat ALT after 7 days ALT <2X ULN Start Rifampicin full dose ALT <2X ULN SE if ADD INH full dose Repeat LFT after 3 days Repeat LFT q 3-7 days ALT <2 X ULN ADD Pyrazinamide full dose IF resurgence of ALT >5 X ULN or recurrence of jaundice Omit the OFFENDING DRUG Modify Regimen 149

150. Further management of Sameer He was put on alternative liver safe regime His viral markers for hepatitis were negative LFTs improved in 10 days and his regimen could be reintroduced after 15 days of interruption Mom is worried that the treatment was interrupted and wishes to know what needs to be done. 150

151. Forced versus unplanned interruptions / alterations of drug regimens Forced interruption due to DILI (or other SAEs) Restart the therapy when feasible For deciding the final duration of therapy; do not take into account the number of days the full complement of original treatment regime was missed and complete full complement. If interruption in first 4 week, restart regimen For unplanned interruptions ….. We continue . 151

152. Managing treatment interruptions (non-adherence) Interruption up to 4 weeks Interruption over 4 weeks Resume therapy (Restart if missed with in 1st 4 wks ) Reinvestigate for DRTB Rif resistance not detected Retreat with 1 st line drugs and Check for INH resistance and treat appropriately Rif resistance detected Treat as MDRTB In case the interruption happens in CP, and on retrieval, the patient has no clinical evidence of active disease and tests for DRTB are negative, the remaining treatment course may be completed Reasons for interruptions should always be evaluated and addressed in all cases (Educate and address myths/ fear or any intolerance) How to do this, follows later 152

153. Drug resistant TB 153

154. DR TB in children - Some Basic aspects 154

155. Definitions 155

156. Some more terms / definitions 156

157. Presumed DRTB Case 157 U-DST strategy requires everyone to be tested upfront for resistance hence the DRTB workup is now not restricted to these presumed DRTB situations

158. Approach to diagnosis of MDR TB in children 158 District and nodal DR-TB centres should be involved In addition, due to U-DST, we will find some of the fresh treatment naïve cases with Rifampicin resistance

159. Recommended Tests for Drug resistance in TB and their lab turn around time (TAT) Usually we need both NAAT and MGIT + LPA DST as direct LPA is only possible if the patient is smear positive (Algorithm Follows) 159

160. What is Line Probe Assay (LPA)? 160

161. Pediatric Drug Resistant TB Diagnostic Algorithm * First Line LPA (FL-LPA) may be done directly if smear positive; else, send for MGIT followed by FL-LPA to evaluate for R and H resistance. ** Second Line LPA (SL-LPA) may be done directly if smear positive; else, send for MGIT followed by SL-LPA or LC DST ( Mfx 2.0, Km, Cm, Lzd ) $ RR detected in a new case with no risk factors for DRTB needs to be retested if only Mtb detected was very low as testing for resistance becomes less reliable All microbiologically diagnosed TB patients NAAT/MGIT culture RR TB RS TB FL-LPA* FL-LPA SL - LPA** FQ and SLI Sensitive FQ and/or SLI Resistance H Sensitive H Resistant ( inhA and/or KatG mutation) Eto resistance ( inhA mutation For discordance on LPA for RR-TB – repeat NAAT at LPA lab RR-TB -New Case$ Source’s sample of contacts subjected to DST, if child’s specimen not available 161 Reflex testing for SL-LPA 6 + LC DST 7 – Mfx , Z, Lzd , Cfz 8

162. If the microbiological tests are not feasible (no access to specimen) or negative for Mtb in a clinically probable case? 162 In view of the prolonged duration and risks of second line drug therapy, decision in such a situation should be made on recommendation of the DR TB Committee and after ruling out other differential diagnoses PROBABLE MDRTB CASE

163. Rifampicin resistance detected All TB patients All presumptive TB 1 or key population 2 Non-responders Rifampicin resistance n ot d etected   DS-TB regimen NAAT 3 FL-LPA 5 + SL-LPA 6 + LC DST 7 – Z, Bdq 8 , Cfz 8 , Mfx , Lzd , Dlm 8 No additional r esistance detected 4   or H resistance detected 4 with KatG or InhA mutation (not both) & FQ resistance not detected 4   H resistance detected 4 with both KatG and InhA mutation or FQ resistance detected 4 Shorter oral Bedaquiline containing MDR/RR-TB regimen 10 Longer oral M/XDR-TB regimen 11 FL-LPA 5 Additional resistance or intolerance or non-availability of any drug in use or emergence of exclusion criteria H mono/poly DR-TB regimen Modify H mono/poly DR-TB regimen as per replacement table H resistance detected 4 Non-responders Additional resistance or intolerance or non-availability of any drug in use or emergence of exclusion criteria Longer oral M/XDR-TB regimen, modified if needed as per replacement table Reflex testing for SL-LPA 6 + LC DST 7 – Mfx , Z, Lzd , Cfz 8 Other exclusion criteria 9 for shorter regimen PRESENT ABSENT After completing PTE, check on Nikshay or with C&DST lab, if LPA results are available NO YES YES Stop DS-TB regimen FIRST SPECIMEN TESTED AT NAAT SITE SECOND SPECIMEN TESTED AT C&DST LAB Yes No Integrated DR-TB diagnosis and treatment algorithm

164. Rifampicin resistance detected All TB patients All presumptive TB 1 or key population 2 Non-responders Rifampicin resistance n ot d etected   DS-TB regimen NAAT 3 FL-LPA 5 + SL-LPA 6 + LC DST 7 – Z, Bdq 8 , Cfz 8 , Mfx , Lzd , Dlm 8 No additional r esistance detected 4   or H resistance detected 4 with KatG or InhA mutation (not both) & FQ resistance not detected 4   H resistance detected 4 with both KatG and InhA mutation or FQ resistance detected 4 Shorter oral Bedaquiline containing MDR/RR-TB regimen 10 Longer oral M/XDR-TB regimen 11 FL-LPA 5 Additional resistance or intolerance or non-availability of any drug in use or emergence of exclusion criteria H mono/poly DR-TB regimen Modify H mono/poly DR-TB regimen as per replacement table H resistance detected 4 Non-responders Additional resistance or intolerance or non-availability of any drug in use or emergence of exclusion criteria Longer oral M/XDR-TB regimen, modified if needed as per replacement table Reflex testing for SL-LPA 6 + LC DST 7 – Mfx , Z, Lzd , Cfz 8 Other exclusion criteria 9 for shorter regimen PRESENT ABSENT After completing PTE, check on Nikshay or with C&DST lab, if LPA results are available NO YES YES Stop DS-TB regimen FIRST SPECIMEN TESTED AT NAAT SITE SECOND SPECIMEN TESTED AT C&DST LAB Yes No Integrated DR-TB diagnosis and treatment algorithm

165. Management of Paediatric Drug Resistance TB Age 5 years or below needs modification Bdq to be replaced with 2 Gp C drugs Age 5 years or below needs modification (4-6 ) Mfx h , Km/Am, Eto , Cfz , Z, H h , E (5) Mfx h , Cfz , Z, E

166. Pretreatment evaluation for MDR TB or RR TB 166

167. Consideration for newer and repurposed drugs in Children 167

168. Dosage of DR-TB drugs for children* (< 18 yrs of age) * as per Companion handbook to the WHO guidelines for the programmatic management of drug-resistant TB 2014 # Children at risk for peripheral neuropathy (e.g. malnutrition or HIV co-infection) should also receive pyridoxine 5–10 mg/day DRUGS Daily Dose (Pediatric till the age of 18 yrs ) Isoniazid 1 7–15 mg/kg for patients less than 30 kg; max dose 300 mg daily ; High dose : 15-20 mg/kg Rifampicin 10–20 mg/kg for patients less than 30 kg; max dose 600 mg daily Pyrazinamide 30–40 mg/kg for patients less than 30 kg; max dose 2000 mg daily Ethambutol 15-25 mg/kg once daily Levofloxacin 5 years and under: 15–20 mg/kg split into two doses (morning and evening) Over 5 years: 10–15 mg/kg once daily Moxifloxacin 7.5–10 mg/kg; High dose : 10-15 mg/kg Bedaquiline 200 mg daily for 2 wks ; then 100 mg thrice weekly for 22 wks for weight bands 16-30 kg. approved only age >12 yrs Delamanid 50 mg twice daily (100 mg) for 24 weeks in 6-11 years of age 100 mg twice daily (200 mg) for 24 weeks for 12-17 years of age. Linezolid <6 years age: 10-12 mg/kg/d; >6 years age: 15 mg/kg/d Cycloserine 15–20 mg/kg Clofazimine 2-5 mg/kg 50 mg capsule: Use thrice a week in children weighing upto 5 kg and every alternate day in children between 5-9 y Ethionamide / Protionamide 15–20 mg/kg p- aminosalicylic acid 200–300 mg/kg for patients less than 30 kg in two divided doses Kanamycin 15–20 mg/kg once daily (Max 1000mg) Amikacin 15–20 mg/kg once daily (Max 1000mg) Capreomycin 15–20 mg/kg once daily (Max 1000mg) Imipenem cilastatin Meropenem is preferred in children. Meropenem  20–40 mg/kg intravenous every eight hours. Meropenem is given with Amoxicillin- clavulanate * 40mg/kg given twice daily based on the amoxicillin component 168

169. Pediatric dosages, formulations and Weight bands for DRTB drugs Drug Child formulation strength Adult formulation strength 4-7 kg 8-11 kg 12-15 kg 16-24 kg 25-29 kg 30-39 kg High dose INH 100 mg 300 mg 1C 1.5C 2.5C 3.5C 1.5A 2A Ethambutol 100 mg 400 mg 1C 2C 3C 4C 1A + 1C 1A + 3C Pyrazinamide (Z) 300 mg 500 mg 0.5C 1C 1.5C 2.5C 2A 2.5A Levofloxacin (Lfx) 100 mg 250 mg 1C 1.5C 2.5C 1A + 1C 1A + 2C Moxifloxacin (Mfx) 100 mg 400 mg 0.75C 1.25C 1.75C 2.5C 0.75A 1A Linezolid (Lzd) (*-<6 yrs) 100 mg 600 mg 0.5C* 1C* 1.5C* 3C 4C 1A Clofazimine (Cfz) 50 mg 100 mg 1C (3/week) 1C (every other day) 1C ( every other day) 1A 1A 1A + 1C Cycloserine (Cs) 125 mg 250 mg 0.75C 1.5C 1A 1.5A 2A 2.5A Ethionamide (Eto) 125 mg 250 mg 0.75C 1.5C 2C 3C 2A 2.5A

170. Possible adverse event due to drugs in MDR/RR-TB regimen Adverse Drug Events Drugs Adverse Drug Events Drugs QT prolongation Bdq , FQ, Cfz Psychotic symptoms H, FQ, Rash, allergic reaction and anaphylaxis Any drug Suicidal ideation H, Eto Gastrointestinal symptoms Eto , Z, E, Bdq , Cfz , FQs, H Seizures H, FQ Diarrhoea and/or flatulence Eto Tendonitis and tendon r upture FQ Hepatitis Z, H, Eto , Bdq Vestibular toxicity (tinnitus and dizziness) FQs, H, Eto Giddiness Eto , FQ, Z Optic neuritis E, Lzd, Eto, Cfz, H Hypothyroidism Eto Metallic taste Eto, FQs Arthralgia Z, FQ, Bdq Gynaecomastia Eto Peripheral neuropathy H, FQ, rarely Eto , E Alopecia H, Eto Headache Bdq Superficial fungal Infection and thrush FQ Depression FQ H, Eto Dysglycaemia and hyperglycaemia Eto 170

171. CLHIV and TB Children living with HIV AIDS and Tuberculosis 171

172. Four-pronged strategy for HIV-TB coordination to reduce mortality 172 National Technical Guidelines on Anti Retroviral Treatment October 2018

173. 4 Symptom Complex for TB screening among CLHIV Adolescents Current cough Fever Weight loss Night sweats Children Current cough Fever Poor weight gain Contact with a TB case 173 In addition, following may also be investigated: Pleuritic chest pain Swelling in the neck, armpits, groin, abdomen, joints etc National Technical Guidelines on Anti Retroviral Treatment October 2018

174. Diagnostic Algorithm of TB in CLHIV 1 NAAT + X-Ray chest Extra Pulmonary TB suspected Any one or more suggestive of TB X-Ray chest and other radiological examinations Cytology Histopathological examination Extra pulmonary TB TB suspected Microbiologically positive TB Clinically diagnosed TB HIV infected child Non TB NAAT positive N AAT negative + X-ray suggestive of TB NAAT negative + X-ray negative for TB Pulmonary TB suspected Intensified TB case finding culture / NAAT positive specimen from extra pulmonary site 174

175. Treatment of TB in CLHIV 175 National Technical Guidelines on Anti Retroviral Treatment October 2018

176. Treatment of TB in CLHIV- Special Considerations 176

177. Treatment of TB in CLHIV- Special Considerations 177 National Technical Guidelines on Anti Retroviral Treatment October 2018

178. TB PREVENTIVE THERAPY (TPT) Screening and Management Earlier referred to as Latent TB infection 178

179. 179 TARGET POPULATION FOR TPT House hold Contacts (any age) of an active case of pulmonary* TB patients (DSTB as well as DRTB) People living with HIV (+ ART) Adults and children >12 months Infants <12 months with HIV in contact with active TB Expanded Target populations A child born to mother who was diagnosed to have TB in pregnancy INH prophylaxis for 6 months, provided congenital TB is ruled out. Children on prolonged immunosuppressive therapy, anti-TNF treatment, dialysis, transplantation, diabetes, who have TB infection

180. POST-TREATMENT TPT FOR PLHIV All CLHIV/PLHIV who had successfully completed treatment for TB disease earlier should receive a course of TPT after completing treatment of TB. 5-7 times higher risk of recurrence of TB among PLHIV and nearly 90% of these due to re-infection. Ensure completion of the initial course of TB treatment and effective infection control measures in clinical and community settings would reduce recurrence of TB. 180 Additional Recommendations for TPT

181. All Household contacts of Pulmonary TB patients Children over 1 yr age living with HIV-AIDS (CLHIV), irrespective of TB exposure Ask for TB symptoms Yes No Investigation for TB disease Ideally TEST AND TREAT. Initiate TB Preventive Therapy (TPT) if LTBI test positive DO NOT WITHHOLD TPT IF TESTING NOT POSSIBLE Age 5-18 years Age <5 years Initiate TB Preventive Therapy (TPT) TB Treat for TB No TB Algorithm for TB screening and TPT 181

182. TB Preventive Therapy 182

183. TPT Regimen for pediatric Household Contacts DRTB ( Pulm ) cases 183

184. Dosage of 6H regimen Regimen Dose by age and weight band 6 months of daily isoniazid monotherapy (6H) Age 10 years & older: 5 mg/kg/ day d Age <10 years: 10 mg/kg/day (range, 7–15 mg) d Maximum dose of H if given daily would be 300 mg/day 184

185. Dosage of 3HP regimen Regimen Dose by age and weight band DOSAGE CHART 3HP Three months of weekly Isoniazid + Rifapentine (12 doses) Age 2-14 years c Medicine, formulation 10–15 kg 16–23 kg 24–30 kg 31–34 kg >34 kg Individual drugs Isoniazid, 100 mg a 3 5 6 7 7 Rifapentine , 150 mg 2 3 4 5 5 FDC Isoniazid + rifapentine (150 mgeach ) d 2 3 4 5 5 Age >14 years c Medicine, formulation 30–35 kg 36–45 kg 46–55 kg 56–70 kg >70 kg Individual drugs Isoniazid, 300 mg 3 3 3 3 3 Rifapentine, 150 mg 6 6 6 6 6 Isoniazid + rifapentine FDC (300 mg/300 mg) b 3 3 3 3 3 a 300 mg formulation can be used to reduce the pill burden b Expected to become available in the near future c Dosage may differ among adults and children in overlapping weight-bands 185

186. TB Prevention Treatment completion Completing therapy as per regimen is desireable . Should there be any interruptions, one may reintroduce therapy with intent to complete therapy with in an additional third of the initial planned duration. Treatment completion may also be considered if a person initiated on TPT who completed at least: 80% of recommended dose (144/180) consumed within 133% of planned TPT duration (239 days) for 6H or 6Lfx or 90% of recommended dose (11/12) consumed within 133% of planned TPT duration (120 days) for 3HP or 80% of recommended dose (96/120) consumed within 133% of planned TPT duration (160 days) for 4R 186

187. Adjuvant Pyridoxine 187

188. Mother has Active TB when baby is born (PTB / EPTB ) Mother has completed treatment but was having disease while carrying this baby Other contact with Pulmonary TB The exposed Newborn Vitals HS megaly RS exam X ray chest USG Abdomen Close Observation No IPT IPT INH 10 mg/kg Pyridoxine 10mg/d 6 months No Active Disease } Neonate born to mother with TB 3 likely situations Isolation if DRTB or Non adherence to treatment EBM may be used Cough etiquette Give BCG vaccine Source DRTB Newborn 188

189. BCG Protection : for Pulmonary and EP TB Pulmonary TB Efficacy variable: Ranged from substantial protection, in UK MRC trial (RR 0.22; 95% CI, .16–.31) to Absence of clinically important benefit ( Chingleput trial) Efficacy better in school age with prior testing (74%) and neonatal vaccination (60%) Estimated efficacy varied according to latitude 189 Protection by BCG Vaccine Against Tuberculosis: A Systematic Review of Randomized Controlled Trials. Clinical Infectious Diseases 2014;58(4):470–80 Overall protection is around 85% with protection around 90% with neonatal vaccinations Meningeal & Miliary TB 189

190. BCG Adenitis 9 m baby Swelling in the left axilla x 2w No other complaints BCG scar seen Firm, nontender LN 190 None of these, BCG is an attenuated Mtb

191. BCG lymphadenopathy Clinical diagnosis based on : T emporal relationship with BCG vaccination (with in weeks to months) on the same side as the vaccination scar Usually axillary Uncommonly can be supraclavicular too, when the BCG is given high on the shoulder Enlarged nodes can be one or more, and, at any or both of these sites Axillary node same side as BCG (Lt) two ulcerated axillary nodes Supraclavicular ruptured node. Note the BCG has been given high up on the same shoulder Axillary and supraclvicular nodes and BCG site abscess on shoulder

192. Case 192

193. BCG Adenitis 193

194. Thank You Questions Please!! 194

195. Thanks to Guidelines Revision Committee 2019 195