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1 DOI: /trd ISSN: (Print)/ (Online) Tuberc Respir Dis 2010;68: CopyrightC2010. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 제주시중고등학생의잠복결핵감염진단을위한체외인터페론감마검사의유용성 1 제주대학교의과대학예방의학교실, 2 제주보건소배종면 1, 김은희 1, 왕옥보 2 Original Article An Usefulness of In Vitro Interferon Gamma Assay for the Diagnosis of Latent Tuberculosis Infection in Middle- and High-School Students in Jeju-Shi, Korea Jong-Myon Bae, M.D., Ph.D. 1, Eun Hee Kim, M.S. 1, Ok Bo Wang, M.P.H. 2 1 Department of Preventive Medicine, Jeju National University School of Medicine, 2 Jeju Public Health Center, Jeju Special Self-Governing Province, Jeju, Korea Background: The tuberculin skin test (TST) has limitations in diagnosing a latent tuberculosis infection (LTBI). The interferon-gamma release assay (IGRA) was introduced to middle- and high-school students since 2009 by the Korea Centers for Disease Control and Prevention. The aim was to evaluate the utility of IGRA in diagnosing LTBI in middle- and high-school students. Methods: From August 2007 to July 2009, among suspected LTBI students showing TST induration with a 10 mm diameter and over with a normal chest x-ray in school students of Jeju city, 341 students underwent a Quanti FERON-TB Gold In-Tube (QFT-IT) test to confirm LTBI. Results: From 348 students showing a positive TST, a QFT-IT test was carried out on 341 students. The positive QFT-IT rate was 52.8% (=180/341). The positive QFT-IT rate was higher in high-school boys with a mm diameter of induration in TST. Conclusion: With the introduction of IGRA for diagnosing LTBI in middle- and high-school students, approximately 47% of students who show a TST induration with a 10 mm diameter and over can avoid taking unnecessary preventive chemotherapy. These results suggest that IGRA is useful for diagnosing and controlling LTBI in Korean students. Key Words: Interferon-gamma Release Assay; Latent Tuberculosis; Student Health Services; Tuberculin skin test; Disease Outbreaks 서 2007 년도한국의폐결핵발생률은인구십만명당 90명으로 OECD 가입 30개국가중수위를차지하고있다 1. 연 Address for correspondence: Jong-Myon Bae, M.D., Ph.D. Department of Preventive Medicine, Jeju National University School of Medicine, 1, Ara 1-dong, Jeju , Korea Phone: , Fax: jmbae@jejunu.ac.kr Received: Jan. 25, 2010 Accepted: Feb. 17, 2010 론 령별로볼때 세청소년의신환자신고율은 2004 년도십만명당 33.8, 2005년도 34.5, 2006년도 38.3, 2007년도 39.3 으로증가하는추세를보여주었다 2. 중고등학생인결핵신환자는그동안매일시간을같이보내는사람, 특히동급생에게결핵균을전파할수있다는점에서, 동급생의잠복결핵감염 (latent tuberculosis infection, LTBI) 을조기에진단하는것은결핵관리에서중요한의미를갖는다 3. 질병관리본부는결핵관리지침을통해, 무증상의동급생을 LTBI 의심자로간주하고, 지역보건소가주축이되어이들에게 LTBI에대한검사를시행토록하고있다

2 JM Bae et al: Interferon gamma assay for latent tuberculosis infection diagnosis Figure 1. The guideline for diagnosis of latent tuberculosis infection in school students, Korea. BCG: bacilli Chalmette-Guerin vaccine; TST: tuberculin skin test; IGRA: Interferon gamma release assay) [cited from Reference 2]. 2008년도결핵관리지침에서는접촉자에대하여흉부 X- 선촬영검사 (chest X-ray, CXR) 와함께결핵피부반응검사 (tuberculin skin test, TST) 를시행하여 10 mm 이상의경결을보인대상자를 LTBI 로진단하고예방화학요법을시작하여왔다. 그러나 2009년도지침에서는 CXR와함께 TST를시행하여 10 mm 이상의경결을보인대상자에게그다음으로실험실인터페론감마검사 (interferon-gamma release assay, IGRA) 를시행하며, 그결과양성일경우에 LTBI 감염자로판정하고예방화학치료를시작토록변경되었다 (Figure 1). 이처럼 2009년도결핵관리지침에서처음도입된 IGRA 검사는 LTBI 진단에서 TST 검사의여러한계를극복하기위해개발된것이다 4-9. 그동안 bacilli Chalmette-Guerin vaccine (BCG) 접종이한국소아의기본예방접종항목이란점에서 TST 검사의위양성이많았던상황에서 10,11, Menzies 등 12 이수행한메타분석에서는 IGRA 가 TST에비해특이도가높으면서 BCG 접종에영향을받지않는것으로나왔다. 특히 IGRA 는결핵균노출과상관성이높아서 4, BCG 접종을시행한대상자에서의 LTBI 진단에유익한것으로알려지고있다 13,14. 따라서 IGRA 가도입되면그동안 TST 위양성으로예방화학치료를불필요하게받게될대상자를줄일수있을것으로기대할수있다. 즉, TST 검사양성자로예방화학치료적용이될대상자에서, IGRA 검사를수행할경우얼마만큼줄일수있는가를알아내는것이본연구의목적이다. 대상및방법제주특별자치도제주시보건소는지역사회의예산지원과행정협조속에 2007 년 8월이후부터중고등학교결핵관리에서접촉자조사로 IGRA 검사를시행하여운영해오고있다. 본연구대상자료원 (source population) 은 2007년 8 월부터 2009년 7월까지질병관리본부결핵관리지침에따라제주시소재중고등학생에서 LTBI 진단을위해수행한역학조사대상자이다. 즉, 질병관리본부의결핵관리지침중잠복결핵감염진단흐름도에따라활동성결핵환자와밀접접촉자인같은반학생을대상으로설문조사, CXR 촬영과함께 TST 검사를수행하였으며, CXR 촬영에서정상소견을보였으나 시간후경결크기가 10 mm 이상으로나온학생에한하여 IGRA 검사를수행하였다. IGRA 검사는혈액이나조직속의자극받은 T 세포가만들어내는인터페론감마를측정하는것으로 4,9,15-17, 상용검사로는 1980년호주에서개발된 QuantiFERON-TB 와 1990 년영국에서개발된 TSPOT.TB test 가있다 9,14. 이중 QuantiFERON-TB 는미국, 일본식약청의승인을받은가운데 15, 본연구에서도 cellestis 회사가제공하는 Quanti- FERON-TB Gold In-Tube (QFT-IT) 검사법 (Cellestis, Melbourne, Australia) 을이용하기위해대상자의동의하에전혈 3 ml를채혈하였다. 검사결과 early secreted antigenic target 6 (ESAT-6) 과 culture filtrate protein 10 (CFP- 10) 이 0.35 IU/mL 이상이될때양성으로판정하며 16,18, 이를위해 QuantiFERON-TB Gold In-Tube Analysis Software를적용하였다. 156

3 Tuberculosis and Respiratory Diseases Vol. 68. No. 3, Mar Table 1. Proportional rate of postive tuberculin skin test (TST) and in vitro interferon-gamma assay (QFT-IT) in subjects by events of outbreaks Events of outbreaks 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th Total Potential LTBI cases (a) ,467 No. of TST positive (b) % of TST positive (=b/a) No. of QFT-IT test (d) No. of QFT-IT positive (e) % of QFT-IT positive (f=e/d) % CI of (f) 75.7, 21.5, 64.4, 48.2, 48.2, 0.5, 11.7, 31.8, 47.3, LTBI: latent tuberculosis infection; CI: confidence interval. QFT-IT 검사결과에미치는변수들을분석하기위하여설문조사로수집한변수중연령, 성별, 가족내결핵력, BCG 접종반흔여부, TST 경결크기 (mm) 의분포를 chi-square 법으로살펴보았다. 검사양성률의 95% 신뢰구간은이항분포에따라산출하였고중복성여부에따라통계적유의성을평가하였다. 단변수분석에서유의하게나온변수들은범위를재분류한다음로지스틱회귀법을적용하여다변량분석을시행하였다. 결과 2007 년 8월부터 2009 년 7월현재결핵관리지침에따라중고등학생잠복결핵감염을진단하기위한역학조사를총 12번수행하였으며, 총대상자 2,467명중 TST 검사에서 10 mm 이상의경결을보여양성반응을한대상자는 348명 (14.1%) 이었다. 이중 QFT-IT 검사시행을거부한 7명을제외하고나머지동의한 341명의학생에대하여 QFT-IT 검사를수행한결과, 양성판정자는 180명 (52.8%) 으로나왔다 (Table 1). 보건당국은이들양성자에게예방화학치료를시작하였다. 나머지 47.2% 에해당하는음성자 161명은예방화학치료를하지않고관찰하였다. Table 1에서총 12번수행한역학조사건별로 TST 양성률, QFT-IT 양성률의차이를보이고있는가운데, Table 2처럼조사를중복하여수행하게된세고등학교를따로뽑아보았을때, TST 양성률과 QFT-IT 양성률에서학교별로차이를여전히보였다. QFT-IT 검사유무와관련한변수의분포를살펴보았을때중학생보다는고등학생에서, 여학생보다는남학생에서, TST 반응경결크기에따라 QFT-IT 양성률이높은 Table 2. The proportional rate of positive tuberculin skin test (TST) and in vitro interferon-gamma assay (QFT-IT) in subjects in 3 high schools High schools A B C Events of 1st/10th 6th/8th 3rd/12th outbreaks Potential LTBI cases (a) No. of TST positive (b) % of TST positive (=b/a) No. of QFT-IT test (d) No. of QFT-IT positive (e) % of QFT-IT positive (f=e/d) 95% CI of (f) 56.1, 43.4, LTBI: latent tuberculosis infection; CI: confidence interval. 것으로나왔다 (Table 3). 특히크기가 15 mm 이상일경우양성률은 73.3% (=96/131) 이었다. 이에, 연령, 성별, 경결크기를모두보정해보았다. 그결과 TST 양성반응자에서남자고등학생이면서, 경결크기가 mm 범위를보일때 QFT-IT 검사양성일가능성이높은것으로나왔다 (Table 4). 고찰 전세계인구의 1/3 이결핵균에노출된적이있는 LTBI 라고간주하고있으며 4,19, 이중 10% 에서활성화된다

4 JM Bae et al: Interferon gamma assay for latent tuberculosis infection diagnosis TST는 1910년결핵감염진단을위해사용되기시작한이후 15, 그동안결핵진단과유병조사에활용하고있다 21. TST에사용하는 purified-protein derivative (PPD) 는 BCG 이외에도비결핵항산균 (non tuberculosis mycobacteria, NTM) 에서가지고있는 200 여가지항원을활용하기때문에, TST 특이도가낮을뿐만아니라 LTBI 를구별하는데제한을가지고있다 14,22,23. 특히 BCG 백신접종에의한위양성, 반복검사에의한증폭효과, 결과해석의어려움등많은한계들 4,5,9,24,25 로인해결핵관리에어려움이많았다 6. LTBI 진단에서 TST 검사의여러한계를극복하기위해 Table 3. Characteristics of subjects (n=341) in positive tuberculin skin test (TST) by results of in vitro interferon-gamma assay (QFT-IT) QFT-IT, No. (%) Negative (n=161) Positive (n=180) p-value* Age 15 2 (1.2) 7 (3.9) (18.0) 50 (27.8) (64.0) 89 (49.4) (16.8) 34 (18.9) Sex Girl 35 (21.7) 67 (37.2) Boy 126 (78.3) 113 (62.8) Family history No 158 (98.1) 176 (97.8) of PTB Yes 3 (1.9) 4 (2.2) BCG scar No 8 (5.0) 14 (7.8) Yes 153 (95.0) 166 (92.2) Size of indura (78.3) 84 (46.7) <0.001 tion, mm (21.3) 96 (53.3) PTB: pulmonary tuberculosis infection; BCG: bacilli Chalmette- Guerin vaccine. *p-value by chi-square test. 개발된 IGRA 검사와 TST 검사간의일치도연구에서 60 80% 로제시하고있다 9,26. 이수준은불일치가많다는것으로해석할수있으며, BCG 접종이큰교란변수로작용하는것으로알려져있다 14. 또한인터페론수치는최근의결핵균노출을의미하는반면 TST 양성은이전의노출을의미한다고주장하고있는바 27 이주장이맞다면불일치현상을일부해석해낼수있겠다. 그리고 IGRA 수치와 TST 경결크기간의상관성은통계적으로차이가없다고보고하고있다 13. 본연구에사용한 QFT-IT 는 LTBI 진단에있어 TST 검사보다민감도가높으면서위양성이적고, 대상자를한번방문으로해결할수있다는장점이있다 6,28,29. 이에, 미국은결핵진단을위해 TST 검사대신으로사용할수있다고밝히고있으며 30, 캐나다, 영국을포함한유럽일부에서도 IGRA 사용을승인하였다 15,31. 결핵유병률이높고 BCG 접종을하고있는인도의보건의료종사자들을대상으로 TST 검사에서 10 mm 이상을양성으로할때, IGRA 양성은 226명 (75.8%), 음성은 72명 (24.2%) 으로보고하였다 8. 이를본연구결과와비교해볼때, 우리자료에서음성이더많이나왔다. 이점은우리학생들에게적용할때비용경제적측면에서우리학생들에게더유리하다고해석해볼수있겠다. 이렇게인도연구결과와차이를보이는것은결핵유병률이다르고, 대상자연령이달라서생긴것으로해석할수있겠다 8,29. 특히연령증가에따른 QFT-IT 양성률관련성은결핵균폭로기회가누적된것이반영된것으로보고있다 4,8, 한편본연구대상들은같은지역에서유사한연령대이므로, 그유병률이비슷하여 QFT-IT 양성률이역학조사시점별로차이가없어야할것이다. 그러나 Table 1처럼역학조사건별로 TST 양성률과 QFT-IT 양성률에차이를보였으며, 학교별로묶어보았지만여전히차이가있었다. Table 4. Adjusted odds ratios (aor) in results of in vitro interferon-gamma assay (QFT-IT) for age, sex and size of induration Negative (n=161) QFT-IT, No. (%) Positive (n=180) aor 95% CI School Middle 31 (19.3) 57 (31.7) 1.0 High 130 (80.7) 123 (68.3) , 3.94 Sex Girl 35 (21.7) 67 (37.2) 1.0 Boy 126 (78.3) 113 (62.8) , 3.61 Induration size, mm <15, 19< 133 (82.6) 101 (56.1) ~19 28 (17.4) 79 (43.9) , 5.88 CI: confidence interval. 158

5 Tuberculosis and Respiratory Diseases Vol. 68. No. 3, Mar 이런사실은동일지역이라고해도역학조사를하게된상황변수들, 즉 index case 발견경로등에좌우되는것으로해석할수있다. 본연구에서는 index case의도말양성정도, 증상시작후조사시작시점까지의기간의차이등의분석을할수있도록진행되지못함에따라상황변수들을추가로분석하지못하는한계를가지고있다. 향후잠복감염의 QFT-IT 검사의타당성조사에이상의내용을반영한추가적인연구가필요할것이다. IGRA 가잠복결핵진단에서높은민감도와특이도를가진것으로보고하고있는가운데 32,35,36, 사전에시행한 TST 검사가 interferon-gamma 수치에영향을주어 IGRA 검사에영향을준다는주장이제기되었다 37,38. 본대상자들은 TST 검사후 48 72시간을지난뒤경결크기를측정한다음 IGRA 검사를수행하였기때문에, 본연구결과의해석은 QFT-IT 결과에 TST 검사가영향을준것을감안해야할것이다. 그러나세포면역체계상기억은수주의시간이필요하다는점에서 TST 검사의증폭효과에대하여는현재논란중에있다 4,37,39. 또한결핵유병률, AIDS 등면역저하여부, 인종등에따라 IGRA 검사결과에영향을주는것으로알려져있다 29,40. 이런가운데 TST 경결크기가 20 mm 이상인경우보다 mm인경우에 QFT-IT 양성률이유의하게높게나온점은본연구를통해새롭게도출된결과이다. 본연구내용만으로는새로운해석을할수없는한계가있으며, 향후이에대한가설제시와규명연구가필요할것으로본다. 또한본연구에서는빠져있지만 TST 검사음성인학생에서 QFT-IT 검사를수행하여서 TST 검사의위음성이얼마인가를알아내는것도시급히연구될주제이다. 본연구결과에따르면, 2008년도관리지침에따를때예방화학치료적용이될대상자 341명에서, QFT-IT 를수행할경우 180명 (52.8%) 만이예방화학치료를받게되며, 나머지 161명 (47.2%) 은추구관찰대상자로재분류되었다. 따라서 QFT-IT 를수행하여예방화학치료대상자를 47.2% 줄일수있는것으로나왔다. 그러나 QFT-IT 의한계가제기되고있는상황에서, 본연구의음성자뿐만아니라양성자에있어추가적인추적연구가필요하다. 또한 TST 검사에비하여 IGRA 검사비용이높다는점에서경제성분석도필요하다 7. 즉, 2009년결핵관리지침개정에맞추어, 추적연구전략을세워서정책수립에필요한다양한근거를만들어야할것이다. 감사의글 We thank Young-Shin Song in Jeju Public Health Center for assistance in data collection, and technologists in Korean Institute of Tuberculosis for testing Quanti FERON-TB Gold In-Tube. 참고문헌 1. World Health Organization. Global tuberculosis control: epidemiology, strategy, financing. Global report 2009 [Internet]. Geneva: World Health Organization; 2009 [cited 2010 Feb 15]. Available from: who.int/tb/publications/global_report/2009/en/index. html. 2. Korea Centers for Diseases Control and Prevention. Tuberculosis [Internet]. Seoul: Korea Centers for Diseases Control and Prevention; 2010 [cited 2010 Feb 15]. Available from: 3. Shim TS, Koh WJ, Yim JJ, Lew WJ. Diagnosis and treatment of latent tuberculosis infection in Korea. Tuberc Respir Dis 2004;57: Swindells JE, Aliyu SH, Enoch DA, Abubakar I. Role of interferon-gamma release assays in healthcare workers. J Hosp Infect 2009;73: Lee JY, Shim TS. Diagnosis of Mycobacterium tuberculosis infection using ex-vivo interferon-gamma assay. Tuberc Respir Dis 2006;60: Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: part I. Latent tuberculosis. Expert Rev Mol Diagn 2006;6: Madariaga MG, Jalali Z, Swindells S. Clinical utility of interferon gamma assay in the diagnosis of tuberculosis. J Am Board Fam Med 2007;20: Pai M, Gokhale K, Joshi R, Dogra S, Kalantri S, Mendiratta DK, et al. Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood interferon gamma assay with tuberculin skin testing. JAMA 2005;293: Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4: Fine PE. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 1995;346: Brock I, Weldingh K, Lillebaek T, Follmann F, Andersen P. Comparison of tuberculin skin test and 159

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untitled ORIGINAL ARTICLE Korean J Clin Lab Sci. 2016, 48(3):225-229 http://dx.doi.org/10.15324/kjcls.2016.48.3.225 pissn 1738-3544 eissn 2288-1662 Korean J Clin Lab Sci. Vol. 48, No. 3, September 2016 225 Diagnosis