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系統識別號 U0026-0812200914090634
論文名稱(中文) 孩童諾羅病毒急性腸胃炎之流行病學探討: 1.台灣地區5歲以下孩童諾羅病毒急性腸胃炎之分子流行病學; 2.諾羅病毒是引起孩童急性腸胃炎的病因-統合性分析
論文名稱(英文) Epidemiologic study of norovirus acute gastroenteritis among children: 1.Molecular epidemiology of norvirus acute gastroenteritis among children < 5 years old in Taiwan; 2.Norovirus is a cause of acute gastroenteritis among children-A meta-analysis
校院名稱 成功大學
系所名稱(中) 公共衛生研究所
系所名稱(英) Graduate Institute of Public Health
學年度 96
學期 2
出版年 97
研究生(中文) 鄭晏宗
研究生(英文) Yan-Tzong Cheng
電子信箱 t8694405@mail.ncku.edu.tw
學號 t8694405
學位類別 碩士
語文別 中文
論文頁數 144頁
口試委員 指導教授-陳國東
口試委員-呂宗學
口試委員-王新台
口試委員-黃永豐
中文關鍵字 諾羅病毒  杯狀病毒  統合性分析  急性腸胃炎病原  腹瀉病原 
英文關鍵字 caliciviridae  meta-analysis  norovirus  acute gastroenteritis agent  diarrheal agent 
學科別分類
中文摘要 過去的研究顯示,諾羅病毒可以於急性腸胃炎症狀的病患檢體中被檢出,但是台灣的相關文獻卻甚少將此病原納入探討。除此之外,過去至今的研究中,從未有研究進一步證實諾羅病毒與急性腸胃炎症狀的相關性。
本研究之目的為探討諾羅病毒是否為急性腸胃炎症狀之病因,尤其以孩童為主要探討的對象。先以實驗室診斷方法瞭解諾羅病毒於急性腸胃炎孩童病患之感染情形,再以統合性分析評估諾羅病毒與急性腸胃炎症狀之間的相關性。
研究方法分為兩個部份:實驗室診斷的部份,檢體來自台灣四家公立醫院(台大醫院、台北榮民總醫院、台中榮民總醫院及高雄榮民總醫院),研究時間從2001-2003年,在研究期間內具急性腸胃炎症狀之5歲以下孩童皆為此研究之研究對象。先以反轉錄聚合酶連鎖反應進行檢驗,再由台灣疾病管制局進行核酸定序,定序後之鹼基序列與參考病毒株之基因序列進行比對,以軟體MEGA3.1進行基因樹分析。統合性分析的部份,使用資料庫及搜尋引擎蒐集1972-2007年可以評估諾羅病毒於急性腸胃炎症狀之相關性文獻,並依據條件進一步篩選適合的文獻。選擇OR值(勝算比)作為統合效果量,以統計量 及 探討同質性,依可能會影響整體效果量的變項分層,並以軟體CMA進行統合性分析,除了以Mantel-Haenszel法將各篇研究的結果進行統合之外,亦採用固定效果模式進行所有計算。
研究結果在實驗室診斷的部份,一共取得329份孩童急性腸胃炎症狀檢體,諾羅病毒的檢出率為1.5%(5/329),皆為GII Group。基因序列分析的結果顯示,陽性檢體的基因型包括GII/3(2/5)、GII/4(2/5)及GII/13(1/5)。統合性分析一共搜尋到738文獻(已發表文獻466篇;未發表文獻272篇),符合篩選條件共28篇。結果顯示,整體而言,諾羅病毒與急性腸胃炎症狀的相關性是顯著的(OR=3.3,95%CI:2.9-3.8),但是整體效果量不具同質性( =76.9,p-value=<0.0001),因此進一步以影響變項進行分析。會影響整體效果量的變項包括資料來源( =13.0,p-value<0.001)、研究場所( =15.0,p-value=0.002)、研究對象( =12.9,p-value=0.012)及實驗室診斷方法( =6.3,p-value=0.012);人類發展指數( =0.2,p-value=0.670)及病例定義( =1.2,p-value=0.273)則不會影響整體效果量。進一步將研究對象為孩童的文獻進行交叉分層分析,結果發現,以孩童為研究對象的文獻中,實驗室診斷以基因體RNA為偵測標的的研究,其效果量具有同質性,且諾羅病毒與急性腸胃炎症狀的相關性在此分層是顯著的(OR=2.7,95%CI: 2.2-3.2),資料來源為監測性研究(OR=2.5,95%CI: 2.1-3.0)或疫情爆發研究(OR=4.7,95%CI: 3.2-7.1)以及研究場所為醫院(OR=2.8,95%CI: 2.0-4.1)及社區(OR=2.0,95%CI: 1.2-3.3)的研究亦有相同結果。除此之外,諾羅病毒的GII Group與急性腸胃炎症狀有明顯的相關性(OR=3.7,95%CI: 1.7-8.0)。
本研究實驗室診斷的部份證實:諾羅病毒在2001-2003年於台灣確實可以從產生急性腸胃炎症狀之孩童檢體被檢出。另外,藉由統合性分析可以發現,諾羅病毒是引起孩童急性腸胃炎症狀的病因,而且不同於以往的認知,諾羅病毒在孩童所引起的症狀不只是偶發性,而是全面性的。
因此,臨床醫師應將諾羅病毒列入優先考慮的急性腸胃炎病原之ㄧ,另外,諾羅病毒的疾病負擔以及成本效益研究也可以開始進行,以作為是否發展諾羅病毒疫苗的依據。
英文摘要 Base on the past researches, norovirus can be detected from specimens of the patients with acute gastroenteritis. However, domestic studies rarely discussed this pathogen. Else than this, in the past researches, there was no further proof of the relationship between norovirus and the symptoms of acute gastroenteritis.
The purpose of this study is to explore whether or not norovirus is the pathogen to the symptoms of acute gastroenteritis, especially on children. First, use experimental diagnosis to understand the norovirus infection among children, and then use meta-analysis to evaluate the relation between norovirus and the symptoms of acute gastroenteritis.
The methods are also composed of experimental diagnosis and meta-analysis. In the part of experimental diagnosis, the specimens are children aged <5 with acute gastroenteritis symptoms, and the specimen database were collected from four governmental hospitals during 2001 to 2003. (National Taiwan University Hospital, Taipei Veterans General Hospital, Taichung Veterans General Hospital, and Kaohsiung Veterans General Hospital).Use RT-PCR to detected norovirus and then proceed nucleotide sequences analysis by Taiwan CDC. Compare the outcome with reference strains, and further proceed phalogenetic analysis sequence by MEGA3.1. In the part of meta-analysis, use electronic databank from 1972 to 2007 to collect reference and then use criteria to select the proper reference which can be used to evaluate the correlation between norovirus and the symptoms of acute gastroenteritis. The relation was expressed as an OR with a 95% CI, and used statistics and to evaluate homogeneity. All data was stratified by variables which can influence effect size, and analyzde by CMA.
In the experimental diagnosi 1.5 %( 5/359) of specimens could be identified norovirus, including GII/3(2/5), GII/4(2/5), and GII/13(1/5). In the meta-analysis 28 studies met the selection criteria. Overall, the relation between norovirus and the symptoms of acute gastroenteritis is significant (Odds Ratio [OR], 3.3; 95% confidence interval [CI], 2.9-3.8). However, the effect sizes is heterogeneity ( ,76.9; p-value,<0.0001); therefore further analyze the data by variables. The variables which can influence the effect sizes include data source( ,13.0; p-value,0.001), research setting( ,15.0; p-value,0.002), research population( ,12.9; p-value,0.012), and methods of experimental diagnosis( ,6.3; p-value,0.012). Further proceed intersection analysis and focus on children studies. The result indicates that experimental diagnosis based on RT-PCR, is homogeneity and the relation between norovirus and the symptoms of acute gastroenteritis is significant (OR, 2.7;95%CI, 2.2-3.2). Equally, the surveillance studies (OR, 2.5;95%CI, 2.1-3.0), outbreak studies(OR,4.7; 95%CI, 3.2-7.1), hospital-based studies(OR, 2.8; 95%CI, 2.0-4.1), and community-based studies(OR, 2.0; 95%CI, 1.2-3.3) have the same result as the former. By the way, the correlation between GII Group of norovirus and the symptoms of acute gastroenteritis is significant (OR, 3.7; 95%CI, 1.7-8.0).
The results of the experimental diagnosis confirmed that norovirus can be detected from specimens on children with acute gastroenteritis in Taiwan from 2001 to 2003. Different from the past cognition, norovirus was actually a cause of acute gastroenteritis among children, not only accidentalism but also integral.
In the future, the norovirus souuld be evaluated one of the important acute gastroenteritis agents by clinicians. Moreover, in order to evaluate the development of the norovirus vaccine, the disease burden and cost effectiveness studies can start to process.
論文目次 口試合格證明 I
摘要 II
ABSTRACT IV
致謝 VI
目錄 VII
表目錄 XI
圖目錄 XIV
附錄目錄 XVI
第一章、緒論 1
第一節 前言 1
第二節 研究目的 3
第二章、文獻回顧 4
第一節 急性腸胃炎 4
1.1流行病學 4
1.2疾病負擔 5
1.3急性腸胃炎病因 6
1.4傳染性急性腸胃炎病原分布 7
第二節 諾羅病毒 10
2.1.發現 10
2.2病毒型態 10
2.3分類與命名 11
2.4生物特性 12
2.5基因體組織及病毒專一性蛋白質 13
2.6血清型及抗原性 14
2.7基因型 14
2.8傳播 15
2.9發病原因 17
2.10實驗室診斷 18
2.11臨床症狀 21
2.12預防及治療 22
2.13研究發展情況 23
2.14台灣的研究現況 27
第三節 統合性分析 28
3.1統合性分析簡介 28
3.2統合性分析於觀察性研究 29
3.3統合性分析於急性腸胃炎病原領域的應用 29
3.4統合性分析於諾羅病毒的應用 33
第三章、材料與方法 34
第一節 研究架構 34
第二節 實驗室診斷 35
2.1研究對象 35
2.2檢體保存及選取 35
2.3萃取RNA 35
2.4反轉錄聚合酶連鎖反應 36
2.5核酸序列分析 37
第三節 統合性分析 38
3.1背景分析 38
3.2問題定義 38
3.3文獻搜尋策略 39
3.4資料萃取 42
3.5統計分析 44
第四章、結果 49
第一節 實驗室診斷 49
1.1檢驗結果 49
1.2核酸序列分析 51
第二節 統合性分析 54
2.1搜尋及篩選 54
2.2文獻特性介紹 58
2.3諾羅病毒與急性腸胃炎症狀相關性之影響變項 60
2.4諾羅病毒基因分型與急性腸胃炎症狀相關性 85
第五章、討論 88
第一節 實驗室診斷 88
1.1檢驗結果 88
1.2核酸序列分析 90
第二節 統合性分析 92
2.1文獻搜尋及篩選 92
2.2諾羅病毒與急性腸胃炎症狀相關性與影響變項 95
2.3諾羅病毒基因分型與急性腸胃炎症狀相關性 107
第六章 結論、限制與建議 108
第一節 結論 108
第二節 研究限制 110
第三節 未來研究與建議 112
第七章、參考文獻 113
附錄 125
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