질병관리본부가 전국의 고 1학년생을 대상으로 잠재결핵을 검사하고

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1 <Perspective> 고등학생의잠복결핵활성화억제를위한비타민 D 보충제투여 Vitamin D supplementation as a Control Program against Latent Tuberculosis Infection in Korean High School Students 김은희 1), 배종면 1) 1) 제주대학교의학전문대학원예방의학교실 Eun Hee Kim 1), Jong-Myon Bae 1) 1) Department of Preventive Medicine, Jeju National University School of Medicine, Jejudo, Korea

2 Abstract The prevalence of latent tuberculosis infection (LTBI) in the first-grade high school students in Korea was 2.1%, which was the lowest level at congregated settings in For LTBI cases refusing anti-tb medication or having poor compliance, additional support should be considered. Eight systematic reviews concluded that vitamin D (VD) deficiency is a risk factor for TB. While three of four Korean adolescents were VD deficiency, VD supplementation could be a practical remedy to protect LTBI students of refusing anti-tb medication or having poor compliance. Key Words: Latent tuberculosis, Disease Management, Vitamin D, Antitubercular agents, Prevention and control

3 서론 질병관리본부가결핵안심국가를만들기위하여, 잠복결핵감염 (latent mycobacterium tuberculosis infection, 이하 LTBI) 여부를검사한뒤양성자에게는 항결핵제를예방투여한다는사업을 2017 년도부터착수하였다 [1]. 그런데정부가 선정한사업대상군중에서고등학교 1 학년생은 2015 년에발표된세계보건기구 (World Health Organization, WHO) 의 LTBI 관리지침 [2] 에서해당되지않아서, 사업 대상으로의선정에대한의학적근거가부족하다는점이지적되었다 [3]. 그럼에도질병관리본부는 2017 년사업을추진하여그결과를발표하였는데 [4], 전체대상군의 LTBI 양성률 11.6% 이며, 고교 1 학년생은사업대상군들중에서 가장낮은양성률 (2.1%) 을보였다. 해당논문에서이들검사양성자중얼마가항결 핵제를복용하였는가에대한정보가없지만, 항결핵제의부작용을우려하는여론 [5] 을감안하면복용수용률뿐만아니라순응률도낮을것으로예상된다. 따라서 고교 1 학년생에대한잠복결핵검진사업의사업비용대비예방효과는사업대상군 들중가장낮다고추론할수있다. 따라서국내고교 1 년생에대한국가단위의잠 복결핵검진사업을추진할근거가미약하다는결론에도달한다.

4 한편질병관리본부는잠복결핵검진양성자중약물복용을거부한학생들에 대한사후대응조치에대한고려가없다. 학생당사자뿐만아니라학부모에게불 필요한심적압박을줄수있다는점도감안해야한다. 따라서본원고의목적은 잠복결핵양성자중항결핵제복용을거부한대상자에게, 향후활동성결핵으로의 전이를막을수있는방안을모색하는것이다. 본론 인체내침입한결핵균은대식세포 (macrophages) 내의포식소체 (phagosomes) 에서용해 (lysis) 되는데, 만약세포내칼슘이온의농도가올라가지않 으면포식소체내포획된결핵균이용해되지않고체류하게되면서 LTBI 가된다 [6]. 따라서칼슘대사에관여하는비타민 D 는인체면역에직간접으로관여한다 [7,8]. 이와관련하여비타민 D 결핍은결핵감염의위험요인이란근거들이축적되 어왔다 [9,10]. 항결핵제가개발되기전부터간유 (cod liver oil), 일광욕, 경구용 / 주사제비

5 타민 D 투여를활동성결핵의치료법으로사용하였다 [11]. 또한, 연중결핵발생이 계절성변동 (seasonal variation) 을보이는역학적현상도일조량의차이에따른비 타민 D 결핍과관련이있는것으로해석하고있다 [12,13] 2017 년 12 월말현재까지결핵과비타민 D 간의관련성에대하체계적고 찰 (systematic reviews) 이총 8 건이발표되었다 (Table 1). 주요결과들을정리하면 다음과같다. 첫째, 결핵발생자의비타민 D 수준이유의하게낮아서, 결핵발생의 위험요소이다 [14-17,19,21]. 둘째, 비타민 D 보충제투여는활동성결핵의치료에는 도움이되지않는다 [18]. 셋째, 비타민 D 보충제는안전하다 [20]. 그런데비타민 D 보충제를복용하면잠복결핵의활성화를막는다는가설에 대한체계적고찰은아직없다. 이에대한연구결과들이부족하기때문이다. 지금까 지발표된결과들로는잠복결핵자의비타민 D 수준이건강인에비해유의하게낮 으며 [22], 일반인에게비타민 D 를복용하였을때위약군에비하여항결핵면역력이 증강되었고 [23], 비타민 D 를복용한학동기아동에서 tuberculin skin test 양전률이 더낮으면서키는더성장했다 [24]. 이상의결과들에근거할때, LTBI 에서활동성

6 결핵으로의진행을억제한다는가설을제기할수있겠다 [12,25]. 결론및제언 앞서의연구결과들을살펴보았을때, 결핵의초기감염이된이후잠복결핵, 그리고활동성결핵으로진행하는단계에서비타민 D 가관여한다는결론을도출할 수있다 [8]. 따라서비타민 D 보충제투여는결핵발생을억제할수있다는추론 또한가능하다 [14]. 한편국민건강영양조사에따르면한국청소년의 73.3% 가비타민 D 결핍 (<20 ng/ml) 이며 [26], 겨울과봄철에는약 90% 에서 10 ng/ml 미만인것으로 [27] 발표되었다. 따라서한국청소년들에게비타민 D 보충제투여는면역력증강뿐 만아니라근골격계대사를위해서라도필요하다 [28]. 비타민 D 보충제는비용이낮기때문에, 잠복결핵검진사업의일환으로잠 복결핵발생고위험군에게학교단위의지역시험 (community trial) 을수행하여그

7 효과의근거를확보하는것을고려해볼수있겠다 [29]. 만약사업및연구비가부 담이된다면, 일조량이적은겨울과봄계절에집중적으로비타민 D 보충제를제공 하는것도고려할수있겠다. 특히잠복결핵양성자중항결핵제복용을거부한학 생에게우선적으로비타민 D 보충제를제공하여서, 향후추적을통해활동성결핵 의전환률에서항결핵제복용군과비교하는무작위배정비교임상시험을수행할것 을제안한다. 참고문헌 1. Centers for Disease Control and Prevention in Korea. Tuberculosis is progressing now. [cited 2017 March 25]. Available from: MNU2557-MNU2487&fid=7947&cid= (korean) 2. Getahun H, Matteelli A, Abubakar I, Aziz MA, Baddeley A, Barreira D, et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J 2015;46: Bae JM. An opposing view on including high school students in a latent tuberculosis infection control program in Korea. Epidemiol Health 2017;39:e

8 4. Cho SK, Park WS, Jeong HR, Kim MJ, Park SJ, Park AY, et al. Prevalence of latent tuberculosis infection at congregated settings in the Republic of Korea, Public Health Weekly Report 2018;11(12): (korean) 5. Medical Today. Urgent suggestion for stopping the control program of latent tuberculosis infection in high school students. [cited 2017 March 25]. Available from: (korean). 6. Trimble WS, Grinstein S. TB or not TB: calcium regulation in mycobacterial survival. Cell 2007;130(1): Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311(5768): Zittermann A, Pilz S, Hoffmann H, März W. Vitamin D and airway infections: a European perspective. Eur J Med Res 2016;21: Kearns MD, Tangpricha V. The role of vitamin D in tuberculosis. J Clin Transl Endocrinol 2014;1(4): Talat N, Perry S, Parsonnet J, Dawood G, Hussain R. Vitamin d deficiency and tuberculosis progression. Emerg Infect Dis 2010;16(5): McCullough PJ, Lehrer DS. Vitamin D, cod liver oil, sunshine, and phototherapy: Safe, effective and forgotten tools for treating and curing tuberculosis infections - A comprehensive review. J Steroid Biochem Mol Biol 2018;177:21-29.

9 12. Balcells ME, García P, Tiznado C, Villarroel L, Scioscia N, Carvajal C, et al. Association of vitamin D deficiency, season of the year, and latent tuberculosis infection among household contacts. PLoS One 2017;12(4):e Koh GC, Hawthorne G, Turner AM, Kunst H, Dedicoat M. Tuberculosis incidence correlates with sunshine: an ecological 28-year time series study. PLoS One 2013;8(3):e Huang SJ, Wang XH, Liu ZD, Cao WL, Han Y, Ma AG, et al. Vitamin D deficiency and the risk of tuberculosis: a meta-analysis. Drug Des Devel Ther 2016;11: Wallis RS, Zumla A. Vitamin D as Adjunctive Host-Directed Therapy in Tuberculosis: A Systematic Review. Open Forum Infect Dis 2016;3(3):ofw Keflie TS, Nölle N, Lambert C, Nohr D, Biesalski HK. Vitamin D deficiencies among tuberculosis patients in Africa: A systematic review. Nutrition 2015;31(10): Zeng J, Wu G, Yang W, Gu X, Liang W, Yao Y, et al. A serum vitamin D level <25nmol/l pose high tuberculosis risk: a meta-analysis. PLoS One 2015;10(5):e Sutaria N, Liu CT, Chen TC. Vitamin D Status, Receptor Gene Polymorphisms, and Supplementation on Tuberculosis: A Systematic Review of Case-Control Studies and Randomized Controlled Trials. J Clin Transl Endocrinol 2014;1(4):

10 19. Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 2008;37(1): Xia J, Shi L, Zhao L, Xu F. Impact of vitamin D supplementation on the outcome of tuberculosis treatment: a systematic review and meta-analysis of randomized controlled trials. Chin Med J (Engl) 2014;127(17): Yamshchikov AV, Desai NS, Blumberg HM, Ziegler TR, Tangpricha V. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract 2009;15(5): Gibney KB, MacGregor L, Leder K, Torresi J, Marshall C, Ebeling PR, et al. Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-saharan Africa. Clin Infect Dis 2008;46(3): Martineau AR, Wilkinson RJ, Wilkinson KA, Newton SM, Kampmann B, Hall BM, et al. A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med 2007;176(2): Ganmaa D, Giovannucci E, Bloom BR, Fawzi W, Burr W, Batbaatar D, et al. Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial. Am J Clin Nutr 2012;96(2): Arnedo-Pena A, Juan-Cerdán JV, Romeu-García A, García-Ferrer D, Holguín- Gómez R, Iborra-Millet J, et al. Vitamin D status and incidence of tuberculosis

11 among contacts of pulmonary tuberculosis patients. Int J Tuberc Lung Dis 2015;19(1): Byun EJ, Heo J, Cho SH, Lee JD, Kim HS. Suboptimal vitamin D status in Korean adolescents: a nationwide study on its prevalence, risk factors including cotinine-verified smoking status and association with atopic dermatitis and asthma. BMJ Open 2017;7(7):e Lee YA, Kim HY, Hong H, Kim JY, Kwon HJ, Shin CH, et al. Risk factors for low vitamin D status in Korean adolescents: the Korea National Health and Nutrition Examination Survey (KNHANES) Public Health Nutr 2014;17(4): Hong JY, Kim SY, Chung KS, Kim EY, Jung JY, Park MS, et al. Association between vitamin D deficiency and tuberculosis in a Korean population. Int J Tuberc Lung Dis 2014;18(1): Dini C, Bianchi A. The potential role of vitamin D for prevention and treatment of tuberculosis and infectious diseases. Ann Ist Super Sanita 2012;48(3):

12 Table 1. Main conclusions of systematic reviews associated with vitamin D (VD) level and activation of tuberculosis (TB) First author (year) No of selected Main conclusions [Reference number] articles Huang (2016) [14] 38 VD deficiency is a risk factor for TB Wallis (2016) [15] 8 VD is thought to have anti-inflammatory effects. Keflie (2015) [16] % of TB patients had VD deficiency Zeng (2015) [17] 15 VD level less than 25 nmol/l was significantly associated with an increased risk of TB Sutaria (2014) [18] 7 TB patients have lower VD status. Supplementation with VD leads to improved clinical outcomes Nnoaham (2008) [19] 7 Low serum VD levels are associated with high risk of active TB. Xia (2014) [20] 5 VD supplementation have not any beneficial effect in TB treatment Yamshchikov (2009) [21] 13 Serious adverse events attributable to VD supplementation were rare.

한국성인에서초기황반변성질환과 연관된위험요인연구

한국성인에서초기황반변성질환과 연관된위험요인연구 한국성인에서초기황반변성질환과 연관된위험요인연구 - - i - - i - - ii - - iii - - iv - χ - v - - vi - - 1 - - 2 - - 3 - - 4 - 그림 1. 연구대상자선정도표 - 5 - - 6 - - 7 - - 8 - 그림 2. 연구의틀 χ - 9 - - 10 - - 11 -