Pediatr Infect Vaccine. 2019 Aug;26(2):89-98 pissn 2384-1079 eissn 2384-1087 Original Article 국내소아청소년결핵관련논문의연구영역과동향 임호윤, 1 이정현, 1,2 정유진, 1,2 오지은 1,2 1 고신대학교복음병원소아청소년과 2 고신대학교의과대학소아과학교실 Research Areas and Trends in Articles on Pediatric and Adolescent Tuberculosis in Korea Ho Yoon Lim, 1 Jung Hyun Lee, 1,2 Yu Jin Jung, 1,2 Chi Eun Oh 1,2 1 Department of Pediatrics, Kosin University Gospel Hospital, Busan, the Republic of Korea 2 Department of Pediatrics, Kosin University College of Medicine, Busan, the Republic of Korea Received: Apr 5, 2019 Revised: Apr 30, 2019 Accepted: May 16, 2019 Correspondence to Chi Eun Oh Department of Pediatrics, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, the Republic of Korea. E-mail: chieunoh@kosin.ac.kr Copyright 2019 The Korean Society of Pediatric Infectious Diseases This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https:// 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. ORCID ids Ho Yoon Lim https://orcid.org/0000-0001-5608-6198 Jung Hyun Lee https://orcid.org/0000-0002-0496-9826 Yu Jin Jung https://orcid.org/0000-0001-7945-0511 Chi Eun Oh https://orcid.org/0000-0002-0439-8170 ABSTRACT Purpose: Despite the decline in tuberculosis (TB) incidence and mortality rates in the Republic of Korea through a national TB control program, TB remains one of the most critical infectious diseases in Korean children. We investigated the trends and research areas of published articles on TB in Korean children and adolescents. Methods: In 6 Korean and overseas databases, we searched titles and abstracts including tuberculo* or TB, child* or adolescen* or neonat* or infant* or pediatric*, and korea*. The publication type, publication year, research areas, journal title, and research subjects were analyzed. Results: Out of the 257 searched documents, 120 papers were included in the analysis. Of these, 82 were original articles (68.3%), 33 case reports (27.5%), 4 review articles (3.3%), and 1 guideline (0.8%). In the original articles, the most common subject of studies was the clinical characteristics of patients with TB (36.6%), followed by diagnostics (29.3%), contact investigations (9.8%), epidemiology (6.1%), treatment (4.9%), vaccine (3.6%), latent TB infection (3.6%), complications (3.6%), and surveys on perception of TB (2.4%). From 1962, 4 articles were published in the 1960s, 10 articles in the 1970s, 11 articles in the 1980s, 22 articles in the 1990s, 26 articles in the 2000s, and 47 articles since 2010. Conclusions: The amount of research on TB in Korean children has increased over the past 5 decades; however, it has mainly focused on the clinical characteristics and diagnostics. Research in different areas, such as treatment and vaccine, is needed in the future. Keywords: Tuberculosis; Research; Child; Adolescent; Republic of Korea 89
Conflict of Interest No potential conflict of interest relevant to this article was reported. Author Contributions Conceptualization: Oh CE; Data curation: Lim HY; Formal analysis: Oh CE, Lim HY; Investigation: Oh CE, Lim HY, Lee JH, Jung YJ; Methodology: Oh CE; Project administration: Oh CE; Validation: Oh CE, Lim HY; Writing - original draft: Lim HY; Writing - review & editing: Lim HY, Oh CE, Lee JH, Jung YJ. 서론 2017년한해동안전세계적으로천만명 ( 범위 : 9 11백만명 ) 의결핵환자가발생했고그중백만명은소아였다. 1) 소아결핵은비특이적인증상으로나타날수있고, 진단이힘들기때문에소아에서의결핵역학을정확하게파악하기힘들다는특징이있으므로추정한수치보다소아결핵환자가더욱많을것이라는의견도있다. 소아결핵환자의수는성인과비교할때상대적으로적지만, 소아연령층에서발생하는결핵의특성때문에따로연구가필요하다. 소아에서는폐결핵이있는경우에도균수가적고객담채취가어려운경우가많아서성인과는진단적접근을다르게해야하며, 청소년의경우일차감염이후질병으로진행하는위험이상대적으로높아지면서성인과같이공동형폐결핵으로발현할가능성이높은데이러한연령별특성을보이는기전을규명하기위한연구도필요하다. 2) 소아에서결핵으로인한질병이환과합병증의발생, 그리고사망을감소시키기위해서는소아에서결핵을진단할수있는효과적인검사와아이들이먹기편한약물제형의개발, 결핵질환을가진소아나결핵환자와접촉한소아에대해적절한도움을주는것과새로운진단법이나약물에대한임상시험에서소아를반드시포함하는것이필요하다. 3) 국내결핵발병률은 2016년도에인구 10만명당 77명으로 Organization for Economic Cooperation and Development (OECD) 국가중가장높다. 4) 하지만 2010년이후국가결핵관리민간-공공협력사업과가족혹은학교등에서의결핵접촉자검진을강화하면서 10대청소년에서의결핵발병률이 10년전과비교할때상당히감소했다. 4) 결핵관리를위한전략을세우고수행하는것도중요하지만, 근본적으로결핵발병과사망률을감소시키려면질병을이해하기위한기초연구에서부터진단과치료, 예방에대한연구가필수적이다. 본연구는국내소아청소년을대상으로한결핵관련연구의동향을분석하여이미연구가 이루어진분야를확인하고향후연구가더필요한영역에대해알아보기위해시행되었다. 방법 1. 연구대상국내외데이터베이스에서국내소아와청소년을대상으로한결핵관련문헌을검색한후원저, 증례, 종설그리고지침에해당하는문헌을선택하였다. 검색된문헌중국외자료이거나성인을대상으로한경우, 결핵이주제가아닌경우, 문헌의종류가학회초록, 뉴스, perspectives, 보고서인경우는제외하였다. 본연구의계획서는고신대학교복음병원임상시험및의학연구윤리심사위원회의심의후심사면제승인을받았다 (IRB file No. 2018-11-024). 2. 검색방법국외데이터베이스중에서는 EMBASE, PubMed, Scopus, ProQuest Medical Library 그리고 ScienceDirect를, 국내데이터베이스로는 KoreaMed를활용하여 2018년 12월 7일에검색을시행했다. 각데이터베이스에서논문검색시사용한검색어는논문의제목에서 tuberculo* 또는 TB, 제목또는초록에서 child* 또는 adolescen* 또는 neonat* 또는 newborn* 또는 student* 또는 infant* 또는 pediatric* 그리고제목또는초록에서 Korea 였다 ((tuberculo*[title] OR 90
TB[Title]) AND (child*[title/abstract] OR adolescen*[title/abstract] OR neonat*[title/abstract] OR newborn*[title/abstract] OR student*[title/abstract] OR infant*[title/abstract] OR pediatric*[title/abstract]) AND korea*[title/abstract]). Scopus의경우다른데이터베이스와검색방법이달랐으므로, 논문의제목에서 tuberculo* 또는 TB, 초록에서 child* 또는 adolescen* 또는 neonat* 또는 newborn* 또는 student* 또는 infant* 또는 pediatric* 그리고초록에서 Korea 를검색했다 ((tuberculo*[ti] or TB[TI]) AND (child*[ab] or adolescen*[ab] or neonat*[ab] or newborn*[ab] or student*[ab] or infant*[ab] or pediatric*[ab]) AND (korea[ab])). 각데이터베이스별로검색된논문에서중복된것을제외한후논문의종류, 발행연도, 연구영역, 투고된학술지, 연구대상을분석했다. 논문의종류는원저, 증례, 종설, 체계적문헌고찰과메타분석, 지침을포함하였고, 검색된문헌중이에해당하지않는문헌은제외했다. 발행연도는 10년단위로나누어 1960년대 (1960 1969년 ) 부터 2010년대 (2010 2018년) 로분류했다. 원저의경우연구영역을역학, 진단, 백신, 치료, 공중보건, 잠복결핵감염, 접촉자조사, 합병증, 결핵에대한인식그리고임상적특징을기술한연구로분류했다. 학술지의경우국내와국외출판여부를구별하였고, 학술지명이변경된경우현재사용중인학술지명으로통합했다. 결과 1. 국내소아청소년을대상으로출판된결핵관련문헌의수와논문의종류 1962년에출판된논문을시작으로 2018년 12월까지검색된국내소아청소년결핵관련문헌은각데이터베이스별로 EMBASE 62편, PubMed 39편, Scopus 60편, ProQuest Medical Library 37편, ScienceDirect 0편, KoreaMed 146편이었다. 각데이터베이스별로검색된모든논문에서중복을제외한논문의수는 257편이었다. 그중소아나청소년대상이아닌논문 69 편, 주제가결핵이아닌논문 38 편, 내용이확인되지 않은논문 6 편, 연구대상이한국인이아닌논문 18 편, 원저, 증례, 종설, 지침에해당하지않 는문헌 6 편을제외한논문의수는 120 편이었다 (Fig. 1). 분석에포함된 120 편의논문을종류에따라분류했을때, 원저는 82 편 (68.3%), 증례 33 편 (27.5%), 종설 4 편 (3.3%), 지침 1 편 (0.8%) 이었다. 2. 원저의연구영역연구에포함된 82편원저의연구영역을분류했을때임상적특징을기술한논문이 30편으로 36.6% 를차지했고, 진단방법에대한연구가 24편으로 29.3% 를차지하여두가지영역이전체의 65.9% 를차지했다. 접촉자조사 (9.8%), 역학 (6.1%), 치료 (4.9%), 백신 (3.6%), 잠복결핵감염 (3.6%), 합병증 (3.6%), 결핵에대한인식 (2.4%) 에대한연구가뒤를이었다. 각영역에포함된논문들의주제를 Table 1에정리하였다. 91
EMBASE PubMed Scopus ProQuest Medical Library KoreaMed ScienceDirect (n=62) (n=39) (n=60) (n=37) (n=146) (n=0) Excluded searched duplicates 257 searched articles No. of excluded articles (n=137) Not intended for children or adolescents (n=69) Non-tuberculous (n=38) Unconfirmed (n=6) Non-domestic (n=18) Other type (n=6) 120 included articles Fig. 1. Flow chart of article selection. Table 1. Research areas and subject details of 82 original articles Research areas Subject of articles No. of related articles Clinical characteristics Pulmonary TB 8 Miliary TB 6 Tuberculous meningitis 6 Childhood cancer patients 3 Spinal TB 2 Genitourinary TB 2 Endobronchial TB 1 Intracranial TB 1 Fundus findings in TB 1 Diagnosis IGRA 11 Comparison of IGRA and TST 4 Adenosine deaminase 2 Bronchoscopy 2 TST 2 Bacteriologic examination 1 Peripheral-blood-based PCR assay 1 Mass miniature radiography 1 Contact investigation 8 Epidemiology Drug-resistant TB 3 Prevalence 1 Molecular epidemiology 1 Treatment Rifampin effects 2 Plaster-of-paris jackets 1 Effects of chemoprophylaxis 1 Complication Spinal TB 2 Growth change after knee joint TB 1 LTBI Risk factors 2 Relationship between asthma 1 Knowledge and attitudes toward TB 2 Abbreviations: TB, tuberculosis; IGRA, interferon-gamma release assay; TST, tuberculin skin test; PCR, polymerase chain reaction; LTBI, latent tuberculosis infection. 92
No. of published article 50 Korean journal Overseas journal 45 40 12 35 30 25 2 20 1 35 15 10 24 1 1 21 5 3 1 9 10 0 1962 1969 1970 1979 1980 1989 1990 1999 2000 2009 2010 2018 Fig. 2. Number of articles regarding pediatric and adolescent tuberculosis in Korea by time period. 3. 증례보고의주제 33편증례의주제를분류했을때, 선천결핵이 7편, 장결핵이 3편, 원발폐결핵, 역설반응으로인한흉막삼출그리고림프절결핵이각각 2편이었다. 그외청소년결핵, 근이영양증으로오인된척추결핵, 기관지내시경세침흡인으로진단된흉강내결핵, 약물탈감작, 결핵연관혈구탐식성림프조직구증, 결핵성심낭염, 이식후파종결핵, 결핵성비장농양, 결핵성복막염, 결핵종, Bacille Calmette-Guérin (BCG) 골수염, 동맥염과관계, 속립결핵합병증, 비뇨기결핵, 편도결핵, 후인두농양영아결핵, 종격동덩이로발견된영아결핵이각각 1편이었다. 대상환아가 3명인증례 2편을포함하여각증례의환아 1명씩총 37명의증례대상자들을나이기준으로분류했을때신생아 ( 생후 1 27일 ) 7명, 영유아 (28일 23개월) 6명, 아동 (2 11 세 ) 12명그리고청소년 (12 18세) 이 12명이었다. 4. 시대별논문수 1962 년에출판된논문을시작으로 1960 년대 4 편, 1970 년대 10 편, 1980 년대 11 편, 1990 년대 22 편, 2000 년대 26 편, 2010 년이후 47 편의문헌이발표되었다 (Fig. 2). 5. 학술지별논문수단일학술지로서국내소아와청소년의결핵관련문헌이가장많이게재된학술지는대한소아청소년과학회학술지인 Korean Journal of Pediatrics로 34편 (28.3%) 의문헌이포함되었다. 다음으로는대한소아감염학회학술지인 Pediatric Infection and Vaccine에 16편 (13.3%) 의논문이게재되었다. 총 24개의국내학술지에국내소아청소년결핵관련논문이게재되었다. 국외학술지중 The International Journal of Tuberculosis and Lung Disease 에가장많은 4 편의문헌이 게재되었다. 국내소아청소년대상의결핵관련논문이출판된국외학술지의개수는총 14 개였다 (Fig. 3). 93
Korean Journal of Pediatrics Pediatric Infection and Vaccine Pediatric Allergy and Respiratory Disease Tuberculosis and Respiratory Diseases The International Journal of Tuberculosis and Lung Disease Yonsei Medical Journal Korean Journal of Radiology Investigative and Clinical Urology Allergy, Asthma & Respiratory Disease Clinical Pediatric Hematology-Oncology Pediatric Gastroenterology, Hepatology & Nutrition Journal of the Korean Orthopaedic Association Journal of Korean Medical Science Tuberculosis American Journal of Infection Control Archives of Pediatric Infectious Diseases Asian Spine Journal Chest International Journal of Infectious Diseases Journal of Allergy and Clinical Immunology Pediatric Radiology Pediatrics PLOS One Postgraduate Medicine Respirology Vaccine Annals of Clinical Microbiology Journal of Korean Academy of Community Health Nursing Journal of Preventive Medicine and Public Health Journal of the Korean Ophthalmological Society Journal of the Korean Society of Radiology Korean Association of Pediatric Surgeons Korean Journal of Asthma, Allergy and Clinical Immunology Korean Journal of Family Medicine Korean Journal of Otorhinolaryngology-Head and Neck Surgery Neonatal Medicine Perinatology The Korean Journal of Thoracic and Cardiovascular Surgery Fig. 3. Number of articles regarding pediatric and adolescent tuberculosis in Korea by journals. Korean journal Overseas journal 0 5 10 15 20 25 30 35 고찰 본연구는국내소아청소년을대상으로한결핵관련논문의동향을분석하여, 이미연구가이루어진분야를확인하고향후연구가더필요한영역을알아보기위해시행되었다. 출판된원저중임상적특징과진단에관련된논문이전체의반이상을차지했고, 국내소아청소년결핵관련논문수는시간에따라증가하는추세였다. 결핵관련연구는 World Health Organization (WHO) 의 International Roadmap for TB Research 에따르면 6가지영역, 즉, 기초과학, 역학, 진단, 치료, 백신, 운용과학 (operational research) 그리고공중보건으로나눌수있다. 5) 본연구는국내소아청소년을대상으로한연구만을선택했으므로기초과학연구는포함되지않았고, 역학, 진단, 치료, 백신에대한연구가포함되었다. 또한선택된원저의영역을분석했을때, WHO 자료에서분류한영역외에연령대별혹은장기계통별국내소아결핵환자들의임상적특징을기술한논문과전염성이있는결핵환자들과접촉한소아에대한조사혹은전염성이있는소아결핵환자로인한접촉자조사, 잠복결핵위험요인에대한분석, 결핵합병증에대한연구와결핵에대한소아청소년의인식조사연구가추가로확인되었다. 94
소아청소년의결핵이환위험과사망률을감소시키기위해연구가필요한핵심과제는효과적인백신, 더좋은진단법, 보다짧은기간의치료법의개발이다. 2) 본연구에서는검색키워드를결핵으로한정했으므로국내소아청소년을대상으로한결핵백신에대한연구의수와연구영역에대해파악할수는없었다. 본연구에포함된결핵백신연구는 3편으로, 1980년대에출판된 BCG 백신의효능을분석한연구와국내에서사용하는두가지종류의 BCG 백신사용현황과각백신을접종한소아에서세포매개면역반응을측정한연구가있었다. 6-8) 현재소아에서사용가능한유일한결핵백신인 BCG는속립결핵과결핵성수막염에대한방어효과가있지만일차결핵과잠복결핵의활성화에대한예방효과는불확실하므로, 이를대체하여영아및청소년과성인에서결핵을예방하기위한백신개발이이루어지고있다. 9) 신생아혹은영아를대상으로임상시험을시행중인백신은 VPM1002와 MTBVAC이있으며, 그중 VPM1002는 3상임상시험을진행하기에이르렀다. 9,10) 본연구에서결핵치료에대한논문은 4편이확인되었고, 모두 1981년도이전에출판된것으로리팜핀치료가간기능에미치는영향과결핵성수막염에서리팜핀의효과에대한연구, 활동성폐결핵환자와접촉한소아에서이소니아지드복용과결핵질환발병률에대한연구, 척추결핵환자에서보장구착용의효과에대한연구가보고되었다. 11-14) 과거에소아결핵에대한진단이나치료법혹은치료약제의개발은전체적으로볼때우선순위에서밀려나있었지만, 2000년도후반부터결핵종식을위해서소아결핵에대한문제들을결핵관리의주된과제중하나로포함시키고자하는노력이진행되고있다. 15,16) 이러한노력의결과, 소아에서일차결핵치료약제들의약동학과내성결핵치료약제로사용되는퀴놀론계약물의약동학과안전성에대한연구와소아에투여하기위해개발된리팜피신용액의생체이용률에대한연구등이최근발표되었다. 17-20) 또한소아결핵치료에서약제복용기간을단축시키기위한연구와신약인델라마니드 (delamanid) 와베다퀼린 (bedaquillin) 을내성결핵소아에서사용하기위한연구가진행중이며이러한연구들은주로결핵발병률이매우높은개발도상국에서이루어지고있다. 21) 국내소아결핵의발병률을고려할때신약임상시험은국내에서이루어지기어렵겠지만, 결핵치료약제에대한국내소아들의약동학혹은생체이용률에대한연구가향후필요할것으로생각된다. 소아결핵은증상이비특이적이고소아기에흔한다른질환과의감별이어려운경우가있어진단이어렵다. 하지만감염이있는경우질병으로급속히진행할수있고, 특히어린소아에서는중증감염으로진행할수있으므로조기에정확한진단을할수있는진단법이개발된다면합병증의발생이나사망률을줄일수있을것이다. 22) 본연구에포함된진단관련논문 24편중 15편 (62.5%) 은 2000년도후반에국내에도입된인터페론감마분비검사에관한것이었고 2008년도이후발표된진단관련논문 20편중 75% 를차지하였다. 새로도입된검사법에대해국내소아청소년을대상으로활발한연구가이루어졌음을확인할수있었다. 국외에서진행중인소아결핵진단관련연구로는 Xpert MTB/RIF 검사를대변이나비인두흡인액검체로시행하거나, 23-25) 소변 (lipoarabinomannan 항원검사 ) 혹은혈액검체 (T-cell activation markers-tb 검사 ) 를이용한새로운진단법, 26,27) 그리고분자진단법을이용하여결핵감염과질환을구분하는것이있다. 28) 이미국내에서사용중인 Xpert MTB/RIF 검사도구를활용하여소아에서도채취가쉬운검체를이용한연구및새로운분자진단법을개발하는연구등이국내에서도가능하리라고생각된다. 95
1960년대부터 10년간격으로시대를나누어보았을때, 국내소아결핵관련논문수는계속증가해왔다. 국내연구자들및의학학술지의발전과함께논문출판의질적및양적증가가이루어져왔으므로이러한양적증가는소아결핵관련논문에국한된것은아닐것으로보인다. 29) 전세계적으로도결핵관련출판물은지속적으로증가하고있다. 30) 본연구에포함된 120편의논문중 18편 (15%) 의논문이국외학술지에출판되었고, 국내소아청소년결핵데이터가국내뿐아니라국외학술지에도꾸준히보고되고있음을알수있었다. 본연구를통해 1962년부터 2018년까지의국내소아청소년결핵관련논문을분석함으로써, 그동안국내연구자들에의해여러영역의결핵연구가이루지고있었으며결핵증례보고역시활발하게이루어져왔음을확인할수있었다. 향후에는치료약제에대한국내소아청소년의데이터를마련하고새로운진단기법과백신을국내소아청소년에적용하는연구가필요할것으로생각된다. 전세계적으로결핵으로인한소아의질병이환과사망을줄이기위한노력이이루어지고있는가운데, 국내소아청소년고유의데이터마련을위한연구들이더욱활성화되어야할것이다. ACKNOWLEDGEMENT The authors are grateful to Yohwan Oh, a librarian at Pusan National University, for data retrieval and collection. REFERENCES 1. World Health Organization. Global tuberculosis report: exclusive summary [Internet]. Geneva: World Health Organization; 2018 [cited 2019 Mar 21]. Available from: https://www.who.int/tb/publications/ global_report/tb18_execsum_web_4oct18.pdf. 2. Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med 2012;367:348-61. 3. World Health Organization. Roadmap for childhood tuberculosis: towards zero deaths [Internet]. Geneva: World Health Organization; 2013 [cited 2019 Mar 21]. Available from: https://apps.who.int/iris/bitstream/handle/10665/89506/9789241506137_eng.pdf. 4. Cho KS. Tuberculosis control in the Republic of Korea. Epidemiol Health 2018;40:e2018036. 5. Stop TB Partnership; World Health Organization. An international roadmap for tuberculosis research: towards a world free of tuberculosis [Internet]. Geneva: World Health Organization; 2011 [cited 2019 Mar 21]. Available from: http://www.stoptb.org/assets/documents/resources/publications/technical/ tbresearchroadmap.pdf. 6. Kang PS, Lee SK. A study on the effects of BCG vaccination against tuberculosis. Korean J Prev Med 1982;15:33-46. 7. Lee H, Cho SN, Kim HJ, Anh YM, Choi JE, Kim CH, et al. Evaluation of cell-mediated immune responses to two BCG vaccination regimes in young children in South Korea. Vaccine 2011;29:6564-71. 8. Lee H, Dockrell HM, Kim DR, Floyd S, Oh SY, Lee JB, et al. The current status of BCG vaccination in young children in South Korea. Tuberc Respir Dis (Seoul) 2012;72:374-80. 9. Schrager LK, Harris RC, Vekemans J. Research and development of new tuberculosis vaccines: a review. F1000Res 2018;7:1732. 96
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