- KSLM Spring Symposium / ASCPaLM Congress - Clinical application of IGRA tests in the diagnosis of TB infection 2014.4.5. University of Ulsan College of Medicine, Asan Medical Center Tae Sun Shim, MD 목차 Clinical application of IGRA tests in the diagnosis of TB infection TB infection Diagnosis IGRA Clinical application TB infection 결핵의 자연 경과 노출 감염 Infection 감염 잠복결핵감염 발병(결핵) 예방치료 TB infection 잠복결핵감염(LTBI) = Latent TuBerculosis Infection • 결핵균에 감염되어 체내에 소수의 살아있는 균이 존재하나 • 외부로 배출되지 않아 타인에게 전파되지 않으며, • 증상이 없고, • 항산균 검사와 흉부 X선 검사에서 정상인 경우 Dx of TB infection 잠복결핵감염 vs. 활동성 결핵 Dx of TB infection Contact investigation in a high school TST (+) No subjective symptoms Normal CXR => LTBI Chest CT: suggestive of active TB => R/O Active TB Burden of bacilli Latent TB vs active TB Dx of TB infection Symptoms Simple CXR Sputum AFB S/C Chest CT LTBI 치료는 어떻게 ? Active TB Dx of TB infection Diagnosis of LTBI 결핵감염의 진단 + 활동성 결핵의 배제 Dx of TB infection 소수의 생존해 있는 균 Dx of TB infection Dx of TB infection 결핵 감염의 진단: 면역학적 진단방법 Tuberculin skin test (TST) Interferon-gamma releasing assay (IGRA) QuantiFERON-TB Gold In Tube (QFT-GIT) T-SPOT.TB assay (T-SPOT) TST Mantoux 법(PPD 주사) 48-72 시간 후 Dx of TB infection TST의 단점 Dx of TB infection • 위양성 – BCG 접종 – Nontuberculous mycobacteria (NTM); 비결핵 항산균 • Inaccuracy of measuring induration – Subjective interpretation – Interobserver variation • Hospital visit (two times) • Booster 효과 • 면역억제자에서 민감도의 저하(위음성) IGRA IGRA 말초혈액을 채취하여 체외에서 검사 (boosting 효과 없음) 결핵균 특이 항원 (ESAT-6 & CFP-10 ± B7.7) 사용 (특이도가 높다) 한 번의 채혈로 검사 완료 검사자간의 차이 적음 QFT-GIT & T-SPOT 검사가 상업화 됨 TST에 비하여 고비용 QuanTIFERON-TB Gold In Tube 양성 ≥ 0.35 IU/ml IGRA IGRA Representative case of (+) T-SPOT.TB assay (-) Control Spot counts 0 (+) Control 149 ESAT-6 19 (19-0) or (96-0) ≥ 6 spots CFP-10 96 국내 QFT-G 결과 IGRA (JAMA, Kang et al, 2005) IGRA 국내 IGRA 검사 결과 활동성 결핵 (n=79) All (+) in 46 patient (58.2%) All (-) in one patient (1.3%) 결핵 저위험군 (n=78) All (+) in 2 patient (1.5%) All (-) in 85 patient (64.9%) (Lee et al., ERJ, 2006) IGRA & TST 결과 요약 IGRA Both are acceptable but imperfect tests in LTBI detection Sensitivity - T-SPOT (90%) > QFT-GIT (80%) = TST (80%) - IGRA: low sensitivity in children - Both reduced sensitivity in immunocompromised patients Specificity IGRA: > 95% in settings with a low TB incidence TST: much less in BCG-vaccinated subjects Both have low predictive value for progression to active TB (Pai M et al., CMR 2014; 27:3-20) 국내 IGRA & TST 결과 IGRA (Lee et al., Eur Respir J 2006; 28:24-30) IGRA 검사의 임상적 적용 LTBI 의 진단(TST 보다 IGRA가 선호되는 경우) - Targeted diagnosis and treatment Repeated tests Treatment response 판정 Active TB 의 진단(disease site 검체 이용) Indeterminate results Diagnosis of NTM (nontuberculous mycobacterial) diseases LTBI 의 진단: IGRA IGRA 검사가 TST 보다 선호되는 경우 Low rates of returning to have TSTs read BCG vaccinated subjects 두 검사 병합사용을 고려할 수 있는 경우 Either test positive strategy: when the risk for infection, the risk for progression, and the risk for a poor outcome are increased To confirm positive TST result When the initial IGRA result is indeterminate (CDC MMWR Recomm Rep. 2010 ; 59(RR-5): 1-25) LTBI 의 진단: 정상면역 성인 (2014 국내 지침안) LTBI 의 진단: 면역저하 성인 (2014 국내 지침안) Target population for LTBI diagnosis Targeted TST (미국흉부학회, 2000) 발병의 위험이 높은 high-risk group 만을 대상으로 TST 시행 즉 TST 시행하여 양성인 경우 잠복결핵의 치료를 시행할 사 람만을 대상으로 시행(치료를 염두에 두고) - 전염성 결핵환자의 접촉자(접촉자 조사) - 결핵발병 고위험 조건을 가진 자 - 결핵환자 진료하는 의료인 접촉자조사(2014 국내 지침안) 접촉자조사 접촉자조사 Contact investigation in school TB outbreaks (Song S et al., Chest 2012; 141:983-8) A retrospective observational study 5 school TB outbreaks in Korea (age range 17 – 18) Baseline TST & QFT-GIT 2 year F/U Active TB developed in 1.2% (21/1826) 6.1% (6/99) in TST(+) and 0.6% (10/1556) in TST(-) 18.8% (6/32) in TST(+)/QFT-GIT(+) 0% (0/67) in TST(+)/QFT-GIT(-) “TST(+) -> IGRA(+) -> LTBI treatment” strategy maybe effective 접촉자조사 (AJRCCM 2008; 177:1164–70) Germany 601 close contact of Mtb confirmed TB patients 2 year F/U with baseline TST & QFT-GIT tests TB developed in 14.6% (6/41) among those who were QFT-GIT (+), 2.3% (5/219) among those who were TST (+). (p<0.003) 접촉자조사 (AJRCCM 2011; 183:88-95) Germany 4 year F/U with baseline TST & QFT-GIT tests TB developed in 12.9% (19/147) among those who were QFT-GIT (+), - 28.6% (6/21) for children - 10.3% (13/126) for adults 4.8% (10/207) among those who were TST (+)*. * Induration ≥10 mm High-risk group Incidence of TB in anti-TNF-α agents users 1998.1. – 2002.9. US FDA, Adverse Event Reporting System Anti-TNF-a Ab (infliximab): 129/100,000 Soluble TNF-R (etanercept): 60/100,000 General US population 5/100,000 (Wallis RS et al., CID, 2004) ‘Anti-TNF therapy’ should also be included in the high-risk group. High-risk group 2001 – 2006, Asan Medical Center 8,433 employee -> 61 TB patients develop 의료인 (Cho K-W et al., Int J Tuberc Respir Dis 2008;12: 436-40) 의료인 결핵연구원 Kim SJ et al., Int J Tuberc Respir Dis 2007;11: 138-42) Monthly F/U of QFT-GIT among HCWs in contacts with TB patients (Park et al., Chest 2012) (Park et al., Chest 2012) (van Zyl-Smit RN et al., AJRCCM 2009; 180:49-58) QFT-GIT T-SPOT Serial IGRA: 66 면역억제제 사용자 Seiral QFT-G(IT) Median interval: 9.2 Mos (1-38) Mean test No.: 3.1 (2-7) (Kim et al., Korean J Lab Med 2011;31:271-278) (van Zyl-Smit RN et al., AJRCCM 2009; 180:49-58) Effect of TB treatment on ELISPOT responses (Carrara S et al., Clin Infect Dis 2004; 38: 754-6) 18 patients with bacteriologically confirmed TB Initial (T0) and 3 montha after (T1) ESAT-6 ELISPOT assay Effect of LTBI treatment on QFT-GIT responses (Johnson JL et al., Chest 2014; 145: 612-7) Prospective controlled study High TB-burden area Adults with TST (+): 39 LTBI Treatment vs. 39 Observation Effect of LTBI treatment on QFT-GIT results (Bartalesi F et al., J Infect 2013; 66:346-56) Italy LTBI treatment (3HR) in 166 subjects Either test positive strategy: TST & QFT-GIT QFT-GIT change between T0 and T1* - Reversion rate: 24% (27/111) - Conversion rate: 18% (10/55) * T0 = baseline, T1 = at completion of 3HR (AJRCCM 2006; 174: 1048-54) 12 smear-negative TBp vs. 25 Non-TB, Germany 말초혈액 BAL fluid Active TB 의 진단: IGRA at disease sites 12 CNS TB vs. 25 Non-TB, South Korea 말초혈액 CSF (Kim S-H et al., Clin Vaccine Immunol 2008;15:1356-62) Active TB 의 진단: IGRA at disease sites CSF MC ELISPOT / PBMC ELISPOT > 2 => Sensitivity 50%, Specificity 100% (Kim S-H et al., Clin Vaccine Immunol 2008;15:1356-62) Indeterminate results QFT-G: 21.4% (68/318) (Ferrara al., AJRCCM 2005;172: 631-5 ) - More common in immunocompromised HIV positive subjects (Brock al., Respir Res 2006;7: 56 ) - QFT-GIT: CD4 ≦100/uL vs others = 24% vs 2.8% (p<0.05) Indeterminate results (Metcalfe et al., AJRCCM 2013;187: 206-11 ) Repeatability (using leftover stimulated plasma) - In USA (low-risk setting), using QFT-GIT - 93.8% (166/177) = indeterminate result - 6.2% (11/177) = negative Reproducibility (Kobashi et al., ERJ 2009;33:812-5) - In Japan, using QFT-G - 72 indeterminate result: 64 TST (-) vs. 8 TST (+) - Repeated test: 60/72 (83.3%) indeterminate result 2/72 (2.8%) positive result 10/72 (13.9%) negative result TB vs. NTM (Kobashi Y et al., Clin Infect Dis 2006; 43: 1540-6) Prospective controlled study Low TB-burden country, Japan 50 TB, 100 NTM (96 MAC), 50 HC QFT-G used Ra SW et al., Ra SW et al., 국내 일반 성인에서의 감염률 Summary Two commercialized IGRAs: QFT-GIT & T-SPOT assay Diagnosis of TB infection using IGRA IGRA preferred over TST - BCG vaccinated subjects - Immunocompromisde subjects Higher predictive value of IGRA for developing TB than TST in TB contacts No differentiation between LTBI and active TB No differentiation between TB and NTM disease Not useful in the evaulation of anti-TB treatment response 끝 경청해 주셔서 감사합니다.
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