1. LATENT TB IN ADULTS by Assoc. Prof. Pang Yong Kek 1

2. LEARNING OBJECTIVES To learn about the definition & diagnosis of LTBI To learn about the investigations & algorithm of investigations of LTBI To learn about the treatment target groups & treatment regimens of LTBI 2

3. 3 ESTIMATED INCIDENCE OF ACTIVE TB WHO, Global TB Report, 2011

4. INTRODUCTION In high TB prevalence areas, many have been exposed to infectious TB through: o a direct contact with a known index case or o inadvertent exposure to an unsuspected active TB patient. 4

5. INTRODUCTION  Some will acquire the infection.  But, many of those infected will develop adequate immunity to keep the infection at bay.  Hence, only a small number will eventually develop active disease.  Those infected but remain asymptomatic are said to have Latent TB Infection (LTBI). 5

6. Charles Bryan MD. Infectious Disease. Chapter Five. Mycobacterial Diseases. http://pathmicro.med.sc.e du PATHOGENESIS OF TB 6

7. WHAT IS LTBI? 7

8. LTBI LTBI is diagnosed when an individual:  shows positive reaction to the TST/IGRA but  does not have any clinical, bacteriological (if done), or radiographic evidence of active TB 8

9. DIAGNOSTIC CRITERIA  No symptoms to suggest active disease  Normal CXR (usually)  Negative sputum smear for AFB (if collected)  “Positive” TST (Mantoux Test)/IGRA 9

10. If the CXR is abnormal, ensure no changes are seen on repeat CXR (≥ 6 months apart) repeat sputum induction or BAL for AFB smear & culture should be considered, even if no changes are seen on repeat CXR DIAGNOSTIC CRITERIA 10

11. Remark: Calcified nodular lesions (calcified granulomas) & apical or basal pleural thickening pose a lower risk for future progression to active TB → Hence, does not require treatment DIAGNOSTIC CRITERIA 11

12. WHY TREATMENT OF LTBI IS NECESSARY? 12

13. TB CONTROL PROGRAMME  We know that: early detection & prompt treatment of active TB (esp. infectious TB), constitute one of the most important strategies to control TB 13

14. UNIQUE FEATURES OF TB  However, the signs & symptoms of active TB, are usually quite subtle in early stage.  Consequently, it will not alert the victims to seek early medical attention.  The lack of florid symptoms & signs often elude early detection by the health care providers. 14

15. UNIQUE FEATURES OF TB  Besides, MTB does not immediately debilitate the host.  This allows the hosts to remain active & mobile spreading the infection. Animation taken from: http://www.fw-ac- deptofhealth.com/images/tbanim2.gif 15

16. UNIQUE FEATURES OF TB  Once infected, many could mount sufficient immune response & control the disease.  Only about 5 - 10% developed reactivation in later part of their lives. 16

17. SO, WHY BOTHER? 17

18. TREATMENT OF LTBI  When LTBI reactivated, it will spread the disease in the community.  LTBI Rx prevents this sporadic reactivation & dissemination of TB. Thus, it is certainly an essential component of TB control in the community. 18

19. Diagnosis of Active TB Symptoms SignsCXR Sputum AFB CulturePCRBiopsy 19

20. Diagnosis of LTBI TSTIGRA Dependent on the demonstration of host immune response toward tuberculous proteins. 20

21. TUBERCULIN SKIN TEST (TST) Robert Koch 1843 -1910 Pioneered the Tuberculin Skin Test 21

22. PRINCIPLE OF TST  TST is based on the principle of delayed-type hypersensitivity response to intradermal inoculation of PPD, or tuberculin. 22

23. TUBERCULIN SKIN TEST (TST) However, interpretation of TST posts a big challenge to the healthcare professionals. 23

24. THE SHORTCOMINGS OF TST Tuberculin contains >200 proteins, widely shared among the mycobacteria. TB NTMBCG 24

25. THE SHORTCOMINGS OF TST Due to this cross-reactivity, it has a poor specificity in population which have been extensively vaccinated with BCG. Furthermore, NTM infection is relatively common in tropical countries - further compound the diagnosis. 25

26. NEW TESTS - IGRA  Recently, with the invention of 2 new tests, collectively known as IGRA QuantiFERON-Gold-In-Tube (QFT-GIT) test Elispot test (T-SPOT)  the prospect of differentiating LTBI from BCG vaccination/NTM infection has becoming promising. 26

27. PRINCIPLE OF IGRA 2 to 3 specific antigens are utilised, 1. ESAT-6 (early secretory antigenic target-6) 2. CFP-10 (culture-filtrate protein-10) 3. TB 7.7 (only in QFT test) expressed in M. tuberculosis complex, absent from all strains of BCG & majority of NTM 27

28. PRINCIPLE OF IGRA  Because ESAT-6 & CFP-10 is not shared by BCG & most NTM, T-cells of individuals with BCG vaccination or NTM infection alone, will not be stimulated to produce interferon-γ. TB NTM BCG 28

29. PRINCIPLE OF IGRA  Circulating T-cells of infected individuals are sensitised to TB antigens (which include ESAT-6 & CFP-10).  When the T-cells are incubated with these 2 antigens in the lab, they are stimulated to secrete interferon- γ.  The interferon- γ could be measured by:- ELISA technique (Quantiferon Test) ELISPOT technique (T-SPOT) 29

30. QUANTIFERON TEST 30

31. T-SPOT 31

32. SENSITIVITY & SPECIFICITY OF IGRA  Although this test is more specific, it still cannot overcome the limitation that the test result is dependent on the immune status of the tested individuals 32

33.  Only individuals who are at high risk of acquiring LTBI or developing TB reactivation should be investigated.  Treatment might be considered for those who are positive for LTBI. WHO SHOULD BE TESTED? 33

34. POSITIVE TST FOR LTBI Positive TST (Measurement) Type of Individuals ≥5 mmHIV-infected persons Organ transplant recipients Persons who are immunosuppressed for other reasons (such as those taking the equivalent of >15 mg/day of prednisolone for ≥1 month or taking TNF-α antagonists) 34

35. POSITIVE TST FOR LTBI Positive TST (Measurement) Type of Individuals ≥10 mmClose contacts Recent immigrants (< 2 years) Injecting drug users Residents & employees of high risk congregate settings(such as correctional facilities, nursing homes, homeless shelters, hospitals & other healthcare facilities) Persons with fibrotic changes on CXR 35

36. POSITIVE TST FOR LTBI Positive TST (Measurement) Type of Individuals ≥15 mmIndividuals from countries with low incidence of TB 36

37. WHO SHOULD BE TESTED? The goal of testing – to identify persons who are going to benefit most from treatment. A pre-test evaluation should be made to identify these individuals. There are two broad categories of individuals 1. Persons who have recent close contact 2. Immunocompromised individuals 37

38. WHO ELSE SHOULD BE SCREENED? 1.Individuals who are at increased risk of acquiring TB infection ( e.g. prison-warden, nursing home residents/workers, intravenous drug users & healthcare workers ) 2.Immunocompromised individuals who are at increased risk of reactivation ( e.g. HIV infection, patients on immunosuppresants, patients with advanced organ failure ) 38

39. ALGORITHM FOR SCREENING & TREATMENT Target individuals - screen for symptoms of active TB If active TB suspected - CXR & sputum direct smear & Mantoux test If otherwise – TST (Mantoux test) TST <5 mm – no further test TST ≥5 mm, may proceed with IGRA test 39

40. Close contacts Immune competent individuals TST < 5 mm TST 5 – 9 mm IGRA test negative IGRA Test positive S&S / CXR / sputum positive Active TB Active TB Rx S&S / CXR / sputum negative Latent TB LTBI Rx TST ≥ 10 mm Immune compromised individuals Work-up for active TB Active TB confirmed Active TB ruled out Consider prophylactic Rx irrespective of LTBI status PROPOSED ALGORITHM OF SCREENING & TREATMENT OF LTBI 40

41. SHORTCOMING OF THIS ALGORITHM  Lack of longitudinal study that treatment of LTBI using TST/IGRA is effective in preventing disease reactivation in high burden countries.  A study of this nature is desperately required. 41

42. WHAT IS THE ADVANTAGE OF TARGETED SCREENING? Active TB Latent TB 42

43. THE OCCULT TARGETS ARE FLAGGED! 43

44. ADVANTAGES OF TARGETED CONTACT SCREENING 1. A positive TST is more likely to indicate LTBI - less false positive result. 2. They are likely to benefit most from the treatment - reactivation risk is higher in recent contact. 3. Besides, they may be more likely to accept therapy & adhere to it. 44

45. ANTITB REGIMENS FOR LTBI 45 DrugsDurationIntervalCompletion criteria Isoniazid 6 - 9 months Daily  180 doses in 9 months (6- month regimen)  270 doses in 12 months (9- month regimen) Isoniazid + rifampicin 4 monthsDaily  120 doses within 6 months Rifampicin4 monthsDaily  120 doses within 6 months Isoniazid & rifapentine* 3 monthsOnce weekly  12 doses *Rifapentine is not currently registered in Malaysia. *Its use should be restricted to those on DOT

46. TAKE HOME MESSAGES 1.Sporadic reactivation is a cause of continuous dissemination of TB in Malaysia. 2.Treatment of LTBI may be incorporated into TB elimination programme. 3.Nonetheless, longitudinal study is needed to prove the long-term effectiveness of this strategy. 46

47.  ykpang@ummc.edu.my ykpang@ummc.edu.my THANK YOU 47