dr. I Made Bagiada, SpPD, K-P Tempat/Tgll Lahir :Singaraja, 25 Januari 1956 Email : madebagiada@yahoo.com Alamat Institusi : RS Sanglah Denpasar Riwayat Pendidikan : FK UNUD Tahun 1985 Spesialis FK UNUD Tahun 1998 Konsultan FK UNUD Tahun 2006

Update diagnosis LTBI, TB, and MDR TB I MADE BAGIADA DIVISI PARU BAGIAN/SMF PENYAKIT DALAM FK UNUD/RSUP SANGLAH DENPASAR

Introduction Latent tuberculosis infection (LTBI) is a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifested active TB. A direct measurement tool for M. tuberculosis infection in humans is currently unavailable. The signs & symptoms of active TB, are usually quite subtle in early stage. We need fastest diagnostic tool for MDR TB

Introduction “Earlier and faster diagnosis of all forms of TB is vital,” “It improves the chances of people getting the right treatment and being cured, and it helps stop spread of TB disease.”

The early diagnosis of TB, including drug-susceptibility testing of universal and systematic screening of contacts and high-risk groups Ensure early detection of tuberculosis Detect all cases of drug-resistant TB Improving the introduction of new diagnostic Carry out systematic TB screening among high-risk groups

Epidemiology Latent TB infection (LTBI): One-third of the world’s population is estimated to have LTBI: they do not have active TB disease but may develop it in the near or remote future, a process called “TB reactivation”. The lifetime risk of reactivation for a person with documented LTBI is estimated to be 5–10%, with the majority developing TB disease within the first five years after initial infection. However, the risk is considerably higher in the presence of predisposing factors.

Epidemiology Active TB: Still with various problems (clinical, diagnostic, treatment, adherence, ect.) Required a more sensitive diagnostic tools Improving the introduction of new diagnostic

Epidemiology MDR TB: MDR-TB is a form of TB that responds poorly to standard treatment because of resistance to the first-line drugs isoniazid and rifampicin. At present it is estimated that only 2% of MDR-TB cases worldwide are being diagnosed and treated appropriately, mainly because of inadequate laboratory services. The initiatives announced today should increase that proportion at least seven-fold over the next four years, to 15% or more.

Epidemiology In developing countries most TB patients are tested for MDR-TB only after they fail to respond to standard treatments. Even then, it takes two months or more to confirm the diagnosis. Patients have to wait for the test results before they can receive life-saving second-line drugs. During this period, they can spread the multidrug-resistant disease to others. Often the patients die before results are known, especially if they are HIV-infected in addition to having MDR-TB. http://www.who.int/mediacentre/news/releases/2008/pr21/en/

" WHO renewed its call to make MDR-TB an urgent public health priority,"

CLINICALLY FICTURES LTBI: Asymptomatic medical history and physical examination: Asymptomatic and no abnormal found on physical examination Normal chest radiograph Negative sputum examination for AFB smear and culture

CLINICALLY FICTURES TB DISEASE Positive clinical TB: Systemic symptom: Respiratory symptom: Coughing more than 2 weeks Systemic symptom: Low grade fever Night sweat Decrease body weight Loss of appetite

Diagnostic criteria Early detection & prompt treatment of active TB (esp. infectious TB), constitute one of the most important strategies to control TB Ensure early detection of LTBI Ensure early detection of TB Detect all cases of drug-resistant TB WHO – THE END TB STRATEGY, 2014

Ensure early detection of LTBI Diagnosis and treatment of LTBI is one of the strategies recommended by the WHO to control and eliminate TB disease worldwide, and is one of the elements of the WHO End TB Strategy Eur Respir J 2016; 47: 704–706

Ensure early detection of TB Although the current most frequently used test for tuberculosis – sputum-smear microscopy – is a low-cost option providing specific diagnosis, it significantly lacks sensitivity. As a result, health services miss many tuberculosis patients or identify them only at advanced stages of the disease. Screening for symptoms alone may not suffice; additional screening tools such as a chest radiograph may facilitate referral for diagnosis of bacteriologically negative tuberculosis, extrapulmonary tuberculosis and tuberculosis in children. WHO – THE END TB STRATEGY, 2014

Detect all cases of drug-resistant tuberculosis. Diagnosis of drug resistance remains a particular challenge for laboratory systems in many low- and middle-income countries. Capacity to diagnose drugresistant TB is limited in most places where it is sorely needed. Only a fraction of the estimated cases of multi drugresistant Tuberculosis receive a laboratory test to confirm the disease. Adequate capacity to diagnose all cases of drugresistant tuberculosis is essential to make further progress in global TB care and control. WHO – THE END TB STRATEGY, 2014

Diagnostic criteria 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.

Diagnostic criteria 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

DIAGNOSTIC TEST LTBI: TB, MDR-TB TST and IGRA AFB sputum and others C-Tb Diaskintest TB, MDR-TB AFB sputum and others PCR TB GeneXpert Culture

TST and IGRA TST IGRA PLUS ACCEPTABLE IMPERFECT DIAGNOSTIC TEST

TST and IGRA They are indirect markers of Mycobacterium tuberculosis exposure and neither test is able to accurately differentiate between LTBI and active TB, or resolve the various stages within the spectrum of M. tuberculosis infection

http://www.cdc.gov/tb/publications/ltbi/pdf/targetedltbi.pdf

RISK FACTORS FOR LTBI AND TB REACTIVATION High-risk factors HIV/AIDS Close contacts Organ-transplantation recipients Chronic renal failure requiring dialysis TNF-alpha blockers Silicosis Moderate-risk factors Fibronodular disease on chest x-ray Health-care workers Prisoners, homeless persons, illicit drug users Low-risk factors Diabetes mellitus Smoking Use of corticosteroids Underweight Emerging Microbes and Infections (2016) http://www.cdc.gov/tb/publications/ltbi/pdf/targetedltbi.pdf

Tuberculin Skin Test (TST) The TST is used to determine if a person is infected with M. tuberculosis. If a person is infected, a delayed-type hypersensitivity reaction is detectable 2 to 8 weeks after infection. The skin test is administered intradermally using the Mantoux technique by injecting 0.1ml of 5 TU purified protein derivative (PPD) solution. The reading and interpretation of TST reactions should be conducted within 48 to 72 hours of administration. http://www.cdc.gov/tb/publications/ltbi/pdf/targetedltbi.pdf

CLASSIFICATION OF TST REACTIONS http://www.cdc.gov/tb/publications/ltbi/pdf/targetedltbi.pdf

http://www.cdc.gov/tb/publications/ltbi/pdf/targetedltbi.pdf

http://www.cdc.gov/tb/publications/ltbi/pdf/targetedltbi.pdf

Interferon–Gamma Release Assays (IGRAs) IGRAs are used to determine if a person is infected with M. tuberculosis by measuring the immune response to TB proteins in whole blood. Specimens are mixed with peptides that simulate antigens derived from M. tuberculosis and controls. In a person infected with M. tuberculosis, the white blood cells recognize the simulated antigens and release interferon-gamma (IFN- γ); results are based on the amount of IFN- γ released. IGRAs commercially available as: QuantiFERON®-TB Gold-in-Tube test (QFT-GIT) T-SPOT® TB test http://www.cdc.gov/tb/publications/ltbi/pdf/targetedltbi.pdf

TST TEST ADVANTAGES: LIMITATION: Low reagent cost No equipment cost Limited skill requirement and No requirement for laboratory LIMITATION: Required a second patient visit to conduct the test The reading and interpretation of TST result affected by health care worker perception or bias Affected by BCG and most environmental mycobacteria (NTM)

IGRA TEST ADVANTAGES: Required a single patient visit to conduct the test Does not cause booster phenomenon Laboratory test not affected by health care worker perception or bias Result can be available within 24 hours Unaffected by BCG and most environmental mycobacteria (NTM)

IGRA TEST LIMITATION: Blood sample must be processed within 8 – 30 hour after collection Limited data exist on use in groups such as children younger than 5 years of age, persons exposed to TB, immunocompromised persons, and those who will be tested repeatedly (serial testing)

LIMITATION OF TST AND IGRA Cannot distinguish individuals who have successfully cleared M. tuberculosis infection from those who have true infection (that is amenable to therapy This inability to differentiate can favour the administration of LTBI treatment in those without the infection and, thereby, increase costs and adverse events. Reduced sensitivity in immunocompromised patients, particularly in those with a severe immune depression, and have a low predictive value for progression to active TB A majority of individuals with positive results do not progress to active TB disease.

New rapid tests for drug-resistant TB for developing countries People in high burden TB and with low-resource countries who are ill with multidrug-resistant TB (MDR-TB) will get a faster diagnosis -- in two days, not the standard two to three months Genxpert / Xpert MTB/RIF The MeltPro TB assay, developed by Zeesan Biotecheh (Xiamen, China), is an innovative molecular test for detection of resistance to the main first-line and second-line anti-TB drugs http://www.who.int/mediacentre/news/releases/2008/pr21/en/

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