三軍總醫院實證醫學競賽

三軍總醫院實證醫學應用骨科部

Scenario 一名學齡前男童將赴大陸旅遊, 但正值腸病毒 71 型大流行, 父親考慮是否至大陸當地醫院施打疫苗, 但對疫苗相關保護效果有疑慮

Asking an answerable question

以病人為中心提出問題施打腸病毒 71 型疫苗是否有保護效果?

臨床問題 Children EV71 vaccine Placebo Prevention of enterovirus 71 infection Healthy children inactivated enterovirus 71 vaccine Placebo Decrease the incidence of enterovirus 71 infection

Background Knowledge 腸病毒屬於小 RNA 病毒科 (Picornaviridae), 分為人類腸病毒 A B C D(Human enterovirus A B C D) 型, 其中腸病毒 71 型被歸類於人類腸病毒 A 型所有腸病毒中, 除了小兒麻痺病毒之外, 以腸病毒 71 型 (Enterovirus Type 71) 最容易引起神經系統的併發症腸病毒適合在濕熱的環境下生存與傳播, 人類是腸病毒唯一的傳染來源, 主要經由腸胃道 ( 糞 - 口水或食物污染 ) 或呼吸道 ( 飛沫咳嗽或打噴嚏 ) 傳染病後一週內傳染力最強 ; 而患者可持續經由腸道釋出病毒, 時間長達 8 到 12 週之久

腸病毒可以引發多種疾病, 其中很多是沒有症狀的感染, 或只出現類似一般感冒的輕微症狀一般腸病毒感染主要常見症狀為手足口病或泡疹性咽峽炎, 以年齡層分析, 患者以 5 歲以下幼童居多, 約佔所有重症病例 90%; 在死亡病例方面, 以 5 歲以下幼童最多手足口病 : 主要由 A 族克沙奇病毒及腸病毒 71 型引起, 特徵為發燒及身體出現小水泡, 主要分布於口腔黏膜及舌頭, 其次為軟顎牙齦和嘴唇, 四肢則是手掌及腳掌手指及腳趾常因口腔潰瘍而無法進食, 病程為 7-10 天

Tracking down the best evidence

檢索策略系統 Systems 綜結Summaries 精要 Synopses 統整 Syntheses 研究 Studies The "5S" levels of organisation of evidence from healthcare research Brian Haynes, R Evid Based Med 2006;11:162-164 Secondary database Step1. Background review from textbook Step 2. Background review from evidence base journal Step 3. Systemic review articles and meta-analysis Primary database Step 4. Original articles with critical appraisal Step 5. Conclusion 11

資料庫搜尋 Secondary database UptoDate Primary database PubMed 12

13 搜尋到的篇數符合 PICO 的篇數 47 2

Primary database - Pubmed 14 搜尋到的篇數符合 PICO 的篇數 40 2

15 搜尋到的篇數符合 PICO 的篇數 3 1

資料庫搜尋篇數符合 PICO 數 40 2 47 1 3 1 16

Flowchart for selection of articles Search for potential relevant articles (n=90) Articles retrieved for further evaluation (n=14) Article selected for inclusion (n=3) Studies excluded (n=76) Not fitting with our PICO Studies excluded (n=11) Not systematic review or RCT Repeated article 17

嚴格評讀 Critical Appraisal 這篇文獻納入理由符合臨床問題發表年份較新較佳的研究設計有全文可供評讀 22

Integrating the appraisal

Critical appraisal 26

Did the trial address a clearly focused issue? 此研究是否問了一個清楚明確的問題? With considerable associated mortality, including thousands of deaths in China, To reduce morbidity, an EV71 vaccine is needed. A human diploid-cell based inactivated EV71 C4 genotype vaccine is being developed and has shown evidence of safety and immunogenicity in phase 1 and 2 studies. We conducted a double-blind, randomized, placebo-controlled, phase 3 clinical trial to evaluate the protection induced by this vaccine against EV71-associated hand, foot, and mouth disease in children 6 to 71 months of age. This paper: Yes No Unclear

Was the assignment of patients to treatments randomised? 此研究是否適當的隨機分派病患? 原文 : We conducted a double-blind, randomized, placebo-controlled, phase 3 clinical trial to evaluate the protection induced by this vaccine against EV71-associated hand, foot, and mouth disease in children 6 to 71 months of age. This paper: Yes No Unclear

Were all of the patients who entered the trial properly accounted for at its conclusion? 是否所有的病患被適當納入結果中去分析? 原文 : This paper: Yes No Unclear 29

4. Were patients, health workers and study personnel blind to treatment? 病患 ( 給藥測量結果的 ) 醫療照護者分析數據人員是否都是盲性的? Protocol: This paper: Yes No Unclear 30

5. Were the groups similar at the start of the trial? 隨機分派後的兩組病患是否具有可比性? This paper: Yes No Unclear 31

6.Aside from the experimental intervention, were the groups treated equally 除了研究介入 (intervention) 的差別, 兩組間其他的治療是否相等? This paper: Yes No Unclear 32

7. How large was the treatment effect? 介入的治療效果有多大? 33

如果 paper 有給我們兩組病患事件的發生率 : 實驗組事件發生率 (EER, experimental event rate) 對照組事件發生率 (CER, control event rate), 我們可以進一步計算 : (4 cases in the vaccine group and 151 in the placebo group) EER:2/3500=0.00057 CER: 94/3500=0.02685 ARR or ARI = EER CER =0.00057-0.02685=0.02628 NNT=1/0.02628=38 This paper: Yes No Unclear

8. Can the results be applied in your context? 此研究是否可應用到你的病患? This paper : Yes No Unclear 35

9. Were all clinically important outcomes considered? 是否所有重要的臨床結果都被考量到? This paper: Yes No Unclear 36

11. Are the benefits worth the harms and costs? 這些好處隨之而來的傷害和花費是否值得? 37

建議分級 (GRADES OF RECOMMENDATION) 建議等級 A B C D 說明有好的證據支持此建議 (level 1 研究有一致結論 ) 有相當的證據支持此建議 (level 2 或 3 研究有一致結論, 或根據 level 1 研究之推論 ) 沒有充分證據支持或反對此建議 (level 4 研究, 或根據 level 2 或 3 研究之推論 ) 有 level 5 的證據, 或研究沒有一致結論 38

Conclusion Our systematic review results do not indicate any increased risk of fetal death or preterm birth associated with maternal influenza vaccination 39

Evaluate effectiveness & efficacy Integrate with clinical expertise & patient values

臨床回覆林爸爸你好, 根據目前實證醫學證據顯示, 學齡前孩童施打腸病毒 71 型疫苗可於人體產生經由人體試驗發現, 可以誘發對抗目前在亞洲流行的腸病毒 71 型足量的中和抗體, 並且證實相當安全在中國, 由三個針對 6~60 個月的小孩且已經進入第三期人體試驗的研究指出,FI-EV71 疫苗所誘發的抗體足以保護大於 90% 的小孩免於得到腸病毒 71 型感染, 大於 80% 的小孩免於因腸病毒 71 型感染後造成嚴重疾病, 但目前台灣尚未進行第 3 期試驗, 而大陸已有相關研究並已發表於新英格蘭期刊, 建議可到大陸地區醫院進一步諮詢 41

感謝聆聽 Thanks for your attention!! 42

三軍總醫院 實證醫學競賽

三軍總醫院實證醫學競賽