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1 <Brief Communication> 여행자설사에있어활생제의예방효과 : 무작위대조임상시험에관한개작메타분석 Prophylactic Efficacy of Probiotics on Travelers Diarrhea: An Adaptive Meta-analysis of Randomized Controlled Trials Jong-Myon Bae Department of Preventive Medicine, Jeju National University School of Medicine, Jejudo, Korea Corresponding author: Jong-Myon Bae jmbae@jejunu.ac.kr

2 Abstract Objectives: The 2017 guideline for the prevention of travelers diarrhea (TD) by International Society of Travel Medicine suggested that there is insufficient evidence to recommend the use of commercially available prebiotics or probiotics to prevent or treat TD. However, a meta-analysis published in 2007 reported significant efficacy of probiotics in the prevention of TD (summary relative risk [srr] =0.85, 95% confidence interval: ). This study aimed to synthesize the efficacy of probiotics on TD by updating the metaanalysis of double-blind, placebo-controlled, randomized human trials. Methods: The searching process was conducted by the adaptive meta-analysis method using cited by and similar articles options provided by PubMed. The inclusion criteria were double-blind, placebo-controlled, randomized human trials with hypotheses of probiotics as intervention and TD as outcome. The adaptive meta-analysis was conducted by Stata software using csi, metan, metafunnel, and metabias options. Results: Eleven articles were selected for the meta-analysis. The srr was 0.85 (95% confidence interval: ) and showed statistical significance. There was no heterogeneity (I-squared=28.4%) and no publication bias. Conclusion: Probiotics had statistically significant efficacy for the prevention of TD. Keyword: Probiotics, Diarrhea, Randomized controlled trials, Meta-analysis 2

3 Introduction 과거에비하여위생환경이좋아졌다고하지만, 전세계적인인구이동이많아지면서 여행자설사 (Travelers diarrhea, TD) 는여전히국제사회의주요보건문제이다 [1]. TD 을일 으키는병원균으로는박테리아가 80% 이상을차지한다는점에서 [2], TD 발생을사전에예 방하기위한항생제투여를고려할수있지만항생제내성의문제가야기된다 [3]. 국제여 행자의학회 (International Society of Travel Medicine, ISTM) 의 2017 년지침 [1] 에따르면, 일 반인에있어서 TD 예방목적의항생제투여를금지하고있다. 해당지침은또한활생제 (probiotics) 의 TD 예방효과에대하여근거가부족하다고 밝히고있다 (There is insufficient evidence to recommend the use of commercially available prebiotics or probiotics to prevent or treat travelers diarrhea.). 이와관련한근거로인용한 두메타분석논문 [4,5] 중 2006 년도발표된 Sazawal et al [4] 은무작위배정위약대조군임 상시험결과를발표한논문 4 편을선정하였으며 [6-9], 예방효과에있어서통계적으로유의 한차이가없다고발표하였다 (summary relative risk, srr =0.92, 95% Confidence intervals, CI: ). 그러나 1 년늦은 2007 년에발표한 McFarland [5] 는앞서의 4 편에 3 편을추가 한 7 편을선정한결과 [6-12], 활생제가 TD 예방효과가있다고보고하였다 (srr =0.85, 95% 3

4 CI: ). 그리고 2012 년에발표된메타분석 [13] 은 Sazawal et al [4] 이선정한 4 편만을 포함하여서, 체계적고찰에대한불완전성을확인하게되었다. 따라서활생제의 TD 예방효과에대한메타분석결과와지침간의이러한괴리에대 하여우선적으로고려할것은체계적고찰의개작이필요하다는점이다. 본연구의목적은, 활생제의 TD 예방효과에대하여재검색을통해메타분석을재수행하는것이다. Methods 기존의메타분석을개작한다는점에서, adaptive meta-analysis 를적용하였다 [14]. 이는 2 편의메타분석논문 [4,5] 과, 선정된총 7 편의무작위임상시험논문 [6-12] 각각에 있어 PubMed ( 에서제공하는 cited by 와 similar articles 의문헌목록을수합하여검색된리스트를만드는것이다. 수합된목록에서선정을위한제외기준들은다음과같다. (1) 대상자가건강한성 인이아닌경우 (2) 연구설계가무작위배정위약대조임상시험연구가아닌경우 (3) 처치개 입이활생제가아닌경우 (4) 성과가 TD 예방효과가아닌경우. 4

5 최종선정된논문에있어서처치군과비교군의총대상자수와 TD 발생자수의자 료를추출하였다. Stata SE 14 통계프로그램 ( 의 <csi> 명령어를적용하여논 문각각의 RR 과 95% CI 를구하고, <metan> 명령어로 summary RR (srr) 을산출하는메타 분석을수행하였다 [15]. 논문들의이질성은 I-squared value (%) 로평가하였고, 이질성이없 을경우 fixed effect model 을적용하였다. 출판오류 (publication bias) 를알아보기위하여 <metafunnel> 과 <metabias> 옵션을적용하였다 Results 2018 년 7 월 27 일현재, 검색을통해총 1,227 편의문헌리스트가만들어졌으며, 4 가지제외기준을적용하였을때최종 11 편이선정되었다 [3, 6-10,12,16-19] (Fig 1). 이는기 존의두메타분석논문에서선정한 7 편이외에 4 편이추가로선정되었다. 또한 2007 년에 발표한 McFarland [5] 가선정한 7 편중 Kollaritsch [11] 은보다자세한정보가담긴 Kollaritsch [19] 로대치하였다. 11 편에서추출한분석정보에따라산출한 RR 과 95% CI 은 Table 1 과같다. 11 편중 intention-to-treat (ITT) 와 per-protocol(pp) 을구별해서제시한것은 2006 년 5

6 이후발표된 2 편 [16,18] 이었다. 이에우선적으로 PP 에의해구한 RR 들을적용하였을때, 동질성을확보한가운데 (I-squared =28.4%) TD 보호효과가있는것으로나왔다 (srr =0.85; 95% CI: ) (Fig 2). ITT 값으로치환하였을때도통계적유의성은확보되었다 (srr =0.86; 95% CI: ) (not shown). 그리고 funnel plot, Begg t test, Egger s test 결 과상출판오류는없는것으로확인되었다 (Fig 3). Discussion ISTM 의 2017 년지침 [1] 에서, 활생제의 TD 예방효과에대하여근거가부족하다고 밝힌가운데, 본연구결과는활생제는 TD 예방효과가있다는근거를추가하게되었다. 7 편 에대한 McFarland [5] 의효과크기가 0.85 (95% CI: ) 에비교하여, 4 편을추가한본 연구의효과크기는동일수준을보였다 (srr =0.85; 95% CI: ). 추가된 4 편중두 편 [3, 16] 에서 RR 의통계적유의성이없음에도불구하고같은효과크기가산출되었다는점 에서, 활생제의 TD 예방효과에대한근거를지지한다. 활생제는급성감염설사 (acute infectious diarrhea), 항생제투여로인한설사 (antibiotic-associated diarrhea) 등에효과적이라고이미알려져있어 [20], 이번메타분석으 6

7 로 TD 에대하여도활생제가예방효과가있다는점은향후추후연구의필요성이대두된다. 그러나활생제의종류와투여법이다양하고, 관찰기간등이연구마다다르며, 결과제시에서 PP 와 ITT 를구별하지않다는점등에서임상시험연구수행의통일성을기할필요가있겠다.. 7

8 References 1. Riddle MS, Connor BA, Beeching NJ, DuPont HL, Hamer DH, Kozarsky P, et al. Guidelines for the prevention and treatment of travelers' diarrhea: a graded expert panel report. J Travel Med. 2017;24(suppl_1):S57-S Gascón J. Epidemiology, etiology and pathophysiology of traveler's diarrhea. Digestion. 2006;73 Suppl 1: Virk A, Mandrekar J, Berbari EF, Boyce TG, Fischer PR, Kasten MJ, et al. A randomized, double blind, placebo-controlled trial of an oral synbiotic (AKSB) for prevention of travelers' diarrhea. J Travel Med. 2013;20(2): Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis. 2006;6(6): McFarland LV. Meta-analysis of probiotics for the prevention of traveler's diarrhea. Travel Med Infect Dis. 2007;5(2): de dios Pozo-Olano J, Warram JH Jr, Gómez RG, Cavazos MG. Effect of a lactobacilli preparation on traveler's diarrhea. A randomized, double blind clinical trial. Gastroenterology. 1978;74(5 Pt 1): Oksanen PJ, Salminen S, Saxelin M, Hämäläinen P, Ihantola-Vormisto A, Muurasniemi-Isoviita L, et al. Prevention of travellers' diarrhoea by Lactobacillus GG. Ann Med. 1990;22(1): Katelaris PH, Salam I, Farthing MJ. Lactobacilli to prevent traveler's diarrhea? N Engl J Med. 1995;333(20):

9 9. Hilton E, Kolakowski P, Singer C, Smith M. Efficacy of Lactobacillus GG as a Diarrheal Preventive in Travelers. J Travel Med. 1997;4(1): Black FT, Anderson PL, Orskov J, Orskov F, Gaarslev K. Laulund S. Prophylactic efficacy of Lactobacilli on traveler s diarrhea. Travel Med. 1989;7: Kollaritsch H, Kremsner P, Wiedermann G, Scheiner O. Prevention of traveller s diarrhea: comparison of different nonantibiotic preparations. Travel Med Int. 1989:6: Kollaritsch H, Holst H, Grobara P, Wiedermann G. Prophylaxe der reisediarrhoe mit Saccharomyces boulardii [Prevention of traveler s diarrhea with Saccharomyces boulardii. Results of a placebo controlled double-blind study]. Fortschr Med. 1993;111: Ritchie ML, Romanuk TN. A meta-analysis of probiotic efficacy for gastrointestinal diseases. PLoS One. 2012;7(4):e Bae JM, Kim EH. Citation discovery tools for conducting adaptive meta-analyses to update systematic reviews. J Prev Med Public Health. 2016;49: Shim SR, Shin IS, Bae JM. Intervention meta-analysis using STATA software. J Health Info Stat. 2016;41(1): (korean) 16. Briand V, Buffet P, Genty S, Lacombe K, Godineau N, Salomon J, et al. Absence of efficacy of nonviable Lactobacillus acidophilus for the prevention of traveler's diarrhea: a randomized, double-blind, controlled study. Clin Infect Dis. 2006;43(9): Drakoularakou A, Tzortzis G, Rastall RA, Gibson GR. A double-blind, placebo-controlled, randomized human study assessing the capacity of a novel galacto-oligosaccharide mixture in reducing travellers' diarrhoea. Eur J Clin Nutr. 2010;64(2): Hasle G, Raastad R, Bjune G, Jenum PA, Heier L. Can a galacto-oligosaccharide reduce the 9

10 risk of traveller's diarrhoea? A placebo-controlled, randomized, double-blind study. J Travel Med. 2017;24(5). 19. Kollaritsch HH, Wiedermann G. Prevention of traveler s diarrhea: a double-blind randomized trial with Saccharomyces cerevisiae Hansen CBS Travel Med. 1989:7; Wilkins T, Sequoia J. Probiotics for Gastrointestinal Conditions: A Summary of the Evidence. Am Fam Physician. 2017;96(3):

11 Table 1. Summaries of 11 selected articles for adaptive meta-analysis* Reference number First Author Publication Year Treatment group Placebo group N TD N TD RR [95% CI] Probiotics 6 Pozo-Olano [0.52, 2.69] 10 Black [0.41, 0.89] 19 Kollaritsch [0.76, 0.94] 7 Oksanen [0.75, 1.04] 12 Kollaritsch [0.69, 0.96] 8 Katelaris [0.68, 1.61] 9 Hilton [0.18, 1.52] 16 Briand [0.79, 1.95] 17 Drakoularakou [0.38, 0.99] 3 Virk [0.79, 1.32] 18 Hasle [0.45, 0.99] L. acidophilus & L. bulgaricus mixed S. boulardii L. rhamnosus GG S. boulardii L. acidophilus & L. fermentum L. rhamnosus GG L. acidophilus GO mixed GO 11

12 * CI: confidence interval; GO: galacto-ologisaccharide; L.: Lactobacillus; RR: relative risk; S.: Saccaromyces; TD : travelers diarrhea 12

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<B0A3C3DFB0E828C0DBBEF7292E687770> 초청연자특강 대구가톨릭의대의학통계학교실 Meta analysis ( 메타분석 ) 예1) The effect of interferon on development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection?? -:> 1998.1 ~2007.12.31 / RCT(2),