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1 LATENT TB infection Prof. Mohamed Awad Tag El Din Incidence 2 One third of world population is infected by mycobacterium Tuberculosis Only 5% can develop the disease LEARNING OBJECTIVES 3 • 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 INTRODUCTION 4 • 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. INTRODUCTION 5 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). PATHOGENESIS OF TB 6 Charles Bryan MD. Infectious Disease. Chapter Five. Mycobacterial Diseases. http://pathmicro.med.sc.e du 7 WHAT IS LTBI? LTBI 8 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 DIAGNOSTIC CRITERIA 9 No symptoms to suggest active disease Normal CXR (usually) Negative sputum smear for AFB (if collected) “Positive” TST (Mantoux Test)/IGRA DIAGNOSTIC CRITERIA 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 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 12 WHY TREATMENT OF LTBI IS NECESSARY? TB CONTROL PROGRAMME 13 • We know that: early detection & prompt treatment of active TB (esp. infectious TB), constitute one of the most important strategies to control TB UNIQUE FEATURES OF TB 14 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. UNIQUE FEATURES OF TB 15 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-acdeptofhealth.com/images/tbanim2.gif UNIQUE FEATURES OF TB 16 Once infected, many could mount sufficient immune response & control the disease. Only about 5 - 10% developed reactivation in later part of their lives. 17 SO, WHY BOTHER? TREATMENT OF LTBI 18 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. Symptoms Biopsy GeneXpert Signs Diagnosis of Active TB Culture 19 Sputum AFB CXR TST • Dependent on the demonstration of host immune response toward tuberculous proteins. 20 Diagnosis of LTBI IGRA TUBERCULIN SKIN TEST (TST) 21 Robert Koch 1843 -1910 Pioneered the Tuberculin Skin Test PRINCIPLE OF TST 22 TST is based on the principle of delayed-type hypersensitivity response to intradermal inoculation of PPD, or tuberculin. TUBERCULIN SKIN TEST (TST) 23 • However, interpretation of TST posts a big challenge to the healthcare professionals. THE SHORTCOMINGS OF TST 24 Tuberculin contains >200 proteins, widely shared among the mycobacteria. TB BCG NTM THE SHORTCOMINGS OF TST 25 • 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. NEW TESTS - IGRA 26 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. PRINCIPLE OF IGRA 27 2 to 3 specific antigens are utilised, 1. 2. 3. • • ESAT-6 (early secretory antigenic target-6) CFP-10 (culture-filtrate protein-10) TB 7.7 (only in QFT test) expressed in M. tuberculosis complex, absent from all strains of BCG & majority of NTM PRINCIPLE OF IGRA 28 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 BCG NTM PRINCIPLE OF IGRA 29 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) QUANTIFERON TEST 30 T-SPOT 31 SENSITIVITY & SPECIFICITY OF IGRA 32 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 WHO SHOULD BE TESTED? 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. POSITIVE TST FOR LTBI 34 Positive TST (Measurement) ≥5 mm Type of Individuals • HIV-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) POSITIVE TST FOR LTBI 35 Positive TST (Measurement) ≥10 mm Type of Individuals • Close 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 POSITIVE TST FOR LTBI 36 Positive TST (Measurement) ≥15 mm Type of Individuals • Individuals from countries with low incidence of TB WHO SHOULD BE TESTED? 37 • 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 WHO ELSE SHOULD BE SCREENED? 38 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) ALGORITHM FOR SCREENING & TREATMENT 39 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 PROPOSED ALGORITHM OF SCREENING & TREATMENT OF LTBI Close contacts Immune compromised individuals Immune competent individuals TST < 5 mm TST 5 – 9 mm TST ≥ 10 mm IGRA Test positive IGRA test negative S&S / CXR / sputum positive Active TB Active TB Rx 40 Work-up for active TB Active TB confirmed S&S / CXR / sputum negative Latent TB LTBI Rx Active TB ruled out Consider prophylactic Rx irrespective of LTBI status SHORTCOMING OF THIS ALGORITHM 41 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. 42 WHAT IS THE ADVANTAGE OF TARGETED SCREENING? Active TB Latent TB THE OCCULT TARGETS ARE FLAGGED! 43 ADVANTAGES OF TARGETED CONTACT SCREENING 44 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. ANTITB REGIMENS FOR LTBI 45 Drugs Isoniazid Duration Interval 6-9 months Daily Completion criteria 180 doses in 9 months month regimen) 270 doses in 12 months month regimen) Isoniazid + rifampicin Rifampicin 4 months Daily 120 doses within 6 months 4 months Daily 120 doses within 6 months Isoniazid & rifapentine* 3 months Once weekly 12 doses • *Rifapentine is not currently registered in Malaysia. • *Its use should be restricted to those on DOT (6(9- TAKE HOME MESSAGES 46 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. 47 THANK YOU