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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 for Latent Tuberculosis Infection in College Students Keun-Dol Yook 1, Byoung-Seon Yang 2 1 Department of Clinical Laboratory Science, Daejeon Health Institute of Technology, Daejeon 34504, Korea 2 Department of Medical Laboratory Science, Jinju Health College, Jinju 52655, Korea 대학생잠복결핵감염의진단 육근돌 1, 양병선 2 1 대전보건대학교임상병리과, 2 진주보건대학교임상병리과 Tuberculosis (TB) is caused by a chronic infectious agent known as Mycobacterium tuberculosis. It is transmitted in airborne particles, called droplet nuclei which was generated by cough, sneeze, shout, or sing of persons who have TB disease. Most infections of TB do not have symptoms, well known as latent tuberculosis infection (LTBI). However, about 10% of LTBI progress to active disease a one or two years after infection. To investigate the LTBI rate of college students who were in contacted with TB patients, we performed chest X-ray, tuberculin skin test (TST) and Interferon-gamma release assay (IGRA) to 74 college students. At a results, 65 students were showed negative and 9 students positive results at chest X-ray and 1st TST test. When confirmed the 65 students who were showed negative by 2st TST, the results showed correctly. But, 9 students who were showed positive results on chest X-ray and 1st TST by IGRA, the only 3 students (4.05%) showed positive results. In conclusion, the LTBI rate in this study showed 4.05% (3/74) and we suggest to investigate other students LTBI rate for decreasing tuberculosis. Key words: Mycobacterium tuberculosis, latent tuberculosis infection, Tuberculin skin test, Interferon-gamma release assay Corresponding author: Keun-Dol Yook Department of Clinical Laboratory Science, Daejeon Health Institute of Technology, 21 Chungjeong-ro, Dong-gu, Daejeon 34504 Korea Tel: 82-42-670-9169 Fax: 82-42-670-9582 E-mail: yook1090@hanmail.net This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2016 The Korean Society for Clinical Laboratory Science. All rights reserved. Received: April 23, 2016 Revised 1 st : May 25, 2016 Revised 2 nd : July 10, 2016 Revised 3 rd : July 18, 2016 Accepted: July 18, 2016 서론결핵이란결핵균 (Mycobacterium tuberculosis complex) 에의한만성감염질환으로결핵균이포함된비말액을통해공기감염을일으킨다. 이때 90% 의감염자는전염력이없는잠복감염상태만유지, 나머지 10% 의감염자중절반은감염후 1 2 년안에, 다른절반은면역력이감소할때발병하게된다. 세계보건기구 (World Health Organization, WHO) 의 2015 세계결핵현황보고서 (2015 Global Tuberculosis Report) 발표에따르면우리나라의 2014년결핵발생률은인구 10만명기준 86명으로경제협력개발 기구 (Organization for Economic Cooperation and Development, OECD) 국가중 1위에달하고있다. 이는 OECD 결핵평균발생률이 10.5명 (2015년기준 ) 이라는사실을감안하면무려 8배에달한다. 이러한결핵의퇴치를위해서는조기에결핵환자를발견, 진단및치료를통해전파를차단하고, 예방접종및잠복결핵감염치료등을통한발병을예방해야한다 [1]. 이중잠복결핵감염 (latent tuberculosis infection, LTBI) 의경우체내에일부살아있는균이존재하나외부로의배출이없어타인에게전파되지않으며, 무증상으로일반적인항산성균검사와흉부 X선검사에서정상으로나타난다 [2]. 국가결핵관리에서 LTBI

226 Keun-Dol Yook and Byoung-Seon Yang. Diagnosis of Latent Tuberculosis 의치료중요성은그나라의결핵역학상황및가용자원에따라달라진다할수있다. 국내에서 LTBI 의치료가국가결핵사업에추가된것은 1995년부터이며, 결핵관리지침에서활동성결핵환자의접촉자에대하여흉부 X-선검사와, tuberculin skin test (TST) 검사를권고하고있으며, 2009년이후부터는 Interferon-gamma release assay (IGRA) 의사용에대해언급하고있다. 2009년부터는결핵발병고위험군을지정하여 LTBI를치료대상자로권고하고있으며, 점차 LTBI 에대한진단및치료가강조되고있는실정이다 [3]. LTBI 의치료를위해서는지속적인접촉자조사실시, 결핵발병고위험군에대한잠복결핵감염검사및감염치료체계확립이필요하다할수있다. 국내에서결핵의치료에관한지침은매년보건복지부와질병관리본부가발간한국가결핵관리지침에따르고있는데, 결핵관리지침으로는보건소등록결핵환자의동거가족및접촉자는 TST, 객담검사및흉부 X-선검진을하여야하며, 모든 HIV 감염자대상으로흉부 X-선검사를시행하며, 중학교및고등학교에서결핵집단발병시동일학급에서도말양성환자 1명또는도말음성환자 2명이상이면해당학급생을대상으로 TST 및흉부 X-선촬영을시행하며, 학급에관계없이동일학년에서도말양성환자 2명이상또는활동성환자 3명이상이면동일학년전원에서 TST 및흉부방사선촬영을시행하여야한다. 또한 IGRA 검사를시행하며, 그결과양성일경우 LTBI 감염으로판정하고예방치료를시작한다 (Fig. 1). 본연구는결핵감염자와접촉이있는 J 대학교학생 74명을대상으로잠복결핵감염에대한진단을실시하였다. 재료및방법 1. 연구대상본연구는결핵감염자와접촉이있었던 J 대학교학생 74명을대상으로 2015년 4월부터 12월까지잠복결핵감염에대한진단을실시하였다. 결핵감염자와접촉이있었던 J 대학교학생을대상으로잠복결핵감염에대한진단를실시하였다. 접촉자는기존가족력, 과거력, bacille de Calmette-Guerin vaccine (BCG) 접종및반흔유무, 기타위험요소에대한문진을실시하였다. 흉부 X-선검사실시한후 TST의경우 2차에걸쳐실시하였으며, 1차 TST검사에서 10 mm 이하음성으로판정된경우 2차 TST 검사를실시하였다. 1차 TST 검사에서 10 mm 이상양성판정자의경우 IGRA 검사를확진검사로실시하였다. 2. 흉부 X-선및 Tuberculin 검사흉부 X-선촬영으로가슴부위의 X선사진을촬영해폐결핵을진단하였다. TST는주로팔의팔꿈치 10 cm 아래전박안쪽의정맥에서멀리떨어진피부에피내주사하였다. 검사부위를알코올소독후 purified protein derivatives (PPD) RT 23 2TU / Tween 80 0.1 ml을 25 G 주사기에주입후주사침의각도를 15도각도로주입하였다. PPD 주사후 48 72 시간사이에판독하였으며, 전박장축의수직방향으로경결 (induration) 의가장긴직경을촉지해 mm로표시하였다. 이때환자의조건에따라양성기준이달라질수있으므로실제크기를기록하였다. 또한 2단계 TST는 1차 TST에서음성으로나타난경우 8 10 주후에 2차 TST를실시하였다. 3. IGRA (Interferon-gamma release assay) IGRA검사는 Quanti FERON-TB Gold In-Tube (QFT-IT) 검사법 (Cellestis, Melbourne, Australia) 을이용하기위해전혈 3 ml을채혈하였다. 검사결과 early secreted antigenic target 6 (ESAT-6) 과 culture filtrate protein 10 (CFP-10) 이 0.35 IU/mL 이상이면양성을판정하였고이를위해 QFT-IT 분석프로그램을사용하였다. 결과 Fig. 1. Diagnosis of LTBI for normal immune adults. Abbreviation: TST, tuberculin skin test; IGRA, Interferon-gamma release assay; LTBI, latent tuberculosis infection. 결핵감염자와접촉이있었던 J 대학교학생 74명을대상으로잠복결핵감염에대한스크리닝검사로흉부 X-선촬영과 1차 TST 검사를실시하였으며흉부 X-선촬영결과결핵의증과 TST의피부구진판독으로 10 mm 이상인양성피검자가 9명으로 12.2% 를나타내었고모두음성자는 65명으로 87.8% 를나타내었다 (Table 1).

Korean J Clin Lab Sci. Vol. 48, No. 3, September 2016 227 Table 1. The results of latent tuberculosis infection for screening test Methods Screening tests for latent tuberculosis (n=74) Chest X-ray (%) 74 (100.0) 65 (87.8) 9 (12.2) 1st TST (%) 74 (100.0) 65 (87.8) 9 (12.2) Table 2. The results of rechecked 2st TST for 1st screening TST negative Method Rechecked tests for latent tuberculosis (n=65) 2st TST (%) 65 (100) 65 (100) 0 (0) 잠복결핵자에대한스크리닝 1차 TST 음성자 65명에대하여 2 차 TST 검사를 8 10 주후에실시하였는데 1차 TST와동일한 65 명모두에서음성결과를나타내었다 (Table 2). 검사자총 74명중흉부 X-선촬영에서양성을보이며 1차 TST 검사에서양성반응을보인 9명을대상으로 IGRA 검사를실시하여그중 3명 (33.3%) 이양성으로나타내었고 6명 (66.7%) 은음성으로나타났다 (Table 3). 고찰 잠복결핵이란살아있는일부결핵균이체내에존재하나균이외부로배출되지않으며, 증상도없고, 방사선학적검사로도정상인경우를의미한다. 최근결핵의발병률이낮은선진국의경우결핵을근절하기위하여잠복결핵의조절이필수적인요소인만큼잠복결핵의치료에초점을맞추고감염예방에힘쓰고있다. 결핵은결핵균이포함된비말핵을통해공기감염후발병하여, 발병한환자는다시다른사람에게감염을일으키는순환을반복하면서전파된다. 결핵발병위험도는환자의전염력, 접촉자의연령과면역력, 접촉기간이문제가된다 [4]. 그러나결핵환자접촉자가성인인경우잠복결핵의치료시행여부는다른여타의감염자보다필요성이명확하지않으며, 국내의경우와같이성인의 TST 양성율이 50% 이상인경우에는새로운감염여부를확인할수없는단점이있다. 이러한환자에서는결핵발병의고위험질환이없고, 흉부 X-선사진촬영에서정상인경우별도의치료없이경과를관찰하는것을고려할수있다. 그러나영국흉부학회 (British Thoracic Society, BTS) 지침에의하면성인이라도최근 TST 양성이확인된경우라면잠복결핵치료의대상이된다고기술하고있다 [5]. X-선사진촬영 Table 3. The results of IGRA for chest X-ray and TST positive Confirmed test for latent tuberculosis (n=9) Method IGRA (%) 9 (100) 6 (66.7) 3 (33.3) 에서다만활동성결핵환자에서위음성이거나병변유무를정확히판별하기어려운경우가종종있고 [6], 다른질환과의구분이어려운경우가많다. 또한다른폐질환도이방법을통해진단하기때문에보조적인방법으로진단방법에사용된다. TST는결핵균의배양액으로부터분리한 PPD라는물질을피내에주사하여 T-Lymphocyte에의한지연과민반응유무를확인하여결핵감염여부를진단하는검사법이다. 결핵균에감염된후최소 2주 최대 10주이내에지연피부과민반응이나타나며, 일단양성반응을보인경우적절한치료후에도대부분평생지속된다. TST 양성기준은대부분의국가에서경결의크기 10 mm를양성기준으로적용하고있으나 [7], 우리나라의결핵발생빈도가중증도임을감안, 10 mm이상을기준으로하는것이권장된다. 경결이 15 mm이상인경우강양성으로결핵균감염으로간주될수있다 [8,9]. TST는체내검사결과로검사자와검사환경에따른결과오류가능성이적으나, 위양성문제, 재검사시증폭효과및체내검사로써의이상반응과같은단점도가지고있다. 이경우 8 10주후에두번째 TST를시행하면첫번째검사로인해기억면역반응이자극되어양성으로나타날수있는데이를증폭효과라고한다 [10]. 2단계 TST로증폭효과가확인된경우에는이후주기적인 TST는검사가무의미하다할수있다. 과거활동성결핵이나잠복결핵감염에대한치료력이있는경우, 과거 TST 검사상양성이확인되었던경우에는 TST를반복하는것은의미없으므로시행하지않는다. 접촉자조사에서는첫 TST가음성인경우 8 10주후에 TST를반복하게되므로첫검사시 2단계 TST 검사는권고하지않는다 [12]. IGRA는 2000년대이후결핵균감염을진단하는방법으로개발되었고, 과거결핵균에감작된 T세포에결핵균항원을자극하여분비되는인터페론감마를측정하여결핵의감염유무를진단한다 [13]. TST에비해 IGRA의장점은한번의방문으로진단이가능하며, TST는 BCG백신이나비결핵항산균에위양성을나타내지만, IGRA의경우결핵균항원만을이용하므로위양성률이낮다. 그러나 IGRA는비교적최근에개발된검사방법이라연구자료가부족하고가격이 TST에비해고가인것이단점이다. 그러나 IGRA는 BCG접종에의한위양성가능성이낮고또한높은민감도와특이도로인하여잠복결핵감염의진단에있어서 TST를대치할수있는검사로사용되고있다 [14,15].

228 Keun-Dol Yook and Byoung-Seon Yang. Diagnosis of Latent Tuberculosis 항결핵제제 Isoniazid (INH) 는활발히증식하는결핵균에가장강력한살균작용을보이는항생제로, 1950년대에 INH 치료의결핵예방효과가밝혀진이후주요 LTBI 치료제로사용되고있으며, 주로잠복결핵치료초기에많이이용된다. 그러나 INH는 Pyridoxine (Vit B6) 의부족을초래하여말초신경병증을일으킬수있고, 장기간복용으로인한간독성을일으키는단점을가지고있다. 그래서 INH의치료기간은미국에서시행된여러연구결과를종합하여볼때 12개월 INH 치료가 6개월보다는결핵예방에효과적이고, 12개월이상치료할때추가적이득은없어최적의 INH 치료기간은 9 10개월이라고결론내렸다 [16,17]. 일반적으로 9개월치료가권장되고있으나 6개월치료도상당한치료효과가입증되었고비용및효과면에서도우수하여 6개월치료를고려할수있다 [18]. INH의투여량은 5 mg/kg/ 일로최대 300 mg/ 일까지투여한다 [19,20]. 결핵감염자와접촉이있었던 J 대학교학생 74명을대상으로잠복결핵감염에대한진단검사를실시하였다. 그결과접촉자총 74 명중 1차 TST 검사에서양성을보인 9명을대상으로 IGRA 검사를실시하였다. IGRA를통한확진자는 3명으로 4.05% 의감염률을보였다. 현재에있어결핵환자접촉자가성인인경우잠복결핵의치료시행여부의필요성은명확하지않은상황이다. 본연구의접촉자의경우 INH는 5 mg/kg/ 일로최대 300 mg/ 일까지투여하였으며, 치료기간은 6개월간실시하였다. 국내결핵감염율이 OECD 평균의 8배에달하는지금의시점에서는활동성결핵뿐아니라잠복결핵의진단이중요하다할수있다. 즉결핵의퇴치를위해서는조기에결핵환자를발견, 진단및치료를통한결핵의전파차단뿐만아니라예방접종및잠복결핵감염의진단과치료등을통한발병을예방해야한다고사료된다. 요약결핵이란결핵균에의한만성감염질환으로결핵균이포함된비말액을통해공기감염을일으킨다. 대부분의결핵감염자는전염력이없는잠복감염상태만유지하나 10% 의감염자중절반은감염후 1 2 년안에발병하게된다. 결핵감염자와접촉이있는학생 74명을대상으로결핵감염자접촉관련사전조사및흉부 X-선검사, TST 검사및 IGRA 검사를실시하였다. 1차 TST 검사에서양성자는 9명, 음성은 65명으로나타났으며, 음성판독자는 2차 TST검사를, 양성판독자는 IGRA 검사를실시하였다. 1차 TST 양성자 9명중 IGRA 검사에서 3명이양성자로나와잠복결핵감염치료를실시하였다. 1차 TST결과음성자에대한재확인 TST 검사는 1차와차이가없었다. 결론적으로잠복결핵감염율은 74명중 3명으로 4.05% 로나타났고, 잠복결핵감염자색출을위해서다른그룹에대 한조사도필요하다. Acknowledgements: None Funding: None Conflict of interest: None References 1. World Health Organization. Global tuberculosis report 2015 [cited 2016 Apr 5]. Available from: http://www.who.int/tb/ publications/global_report/en/ 2. Mazurek M, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection United States, 2010. MMWR Recomm Rep. 2010;59:1-25. 3. Zachary Taylor, Charles M. Nolan, Henry M. Blumberg. Controlling tuberculosis in the United States: recommendations from American Thoracic Society, CDC, and the Infectious Disease Society of America. MMWR Recomm Rep. 2005;54: 1-81. 4. Shim TS, Koh WJ, Yim JJ, Lew WJ. Treatment of latent tuberculosis infection in Korea. Tuberc Respir Dis. 2008;65:79-90. 5. Control and prevention of tuberculosis in the United Kingdom: code of practice 2000. Joint Tuberculosis Committee of the British Thoracic Society. Thorax. 2000;55:887 901. 6. Kim SJ, Bai GH, Lee H, Kim HJ, Lew WJ, Park YK, et al. Transmission of Mycobacterium tuberculosis among high school students in Korea. Int J Tuberc Lung Dis. 2001;5: 824-830. 7. Woodring JH, Vandiviere HM, Fried AM, Dillon ML, Williams TD, Melvin IG. Update: the radiographic features of pulmonary tuberculosis. AJR Am J Roentgenol. 1986;146:497-506. 8. Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria. Int J Tuberc Lung Dis. 2006; 10:1192-1204. 9. American academy of pediatrics. Tuberculosis. In: Pickering LK, Baker CJ, Long SS, McMillan JA, editors. 2009. Red Book: 2009 Report of the Committee on Infectious Disease. Elk Grove Village, IL: American Academy of Pediatrics; 2009. p680-701. 10. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax. 1998;53:536-548. 11. National Institute for Health and Clinical Excellence. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: Royal College of Physicians; 2006. p105-116. 12. Shim TS. Diagnosis and treatment of latent tuberculosis infection. Korean J Med. 2012;82(3):284-290. 13. Sokal JE. Editorial: Measurement of delayed skin test responses. N Engl J Med. 1975;293:501-502. 14. Mazurek GH, LoBue PA, Oaley CL, Bernardo J, Lardizabal AA, Bishai WR, et al. Comparison of a whole blood interferon gamma assay with tuberculin skin testing for detecting latent

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