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  • 學位論文

卡介苗接種政策─效益與副作用分析

BCG Vaccination Policy: Analysis of Effectiveness and Adverse events

指導教授 : 方啟泰

摘要


背景及目的:卡介苗接種是一項有實證根據的結核病防治政策,為世界衛生組織及世界各國所推薦。然而卡介苗不僅帶來對幼童結核性腦膜炎的保護力,也伴隨著不同程度的不良反應,在近年引發是否應停打的爭議,疾管署在2016年將接種建議時間延後至出生滿5個月。本研究希望藉由文獻回顧、統合分析及資料庫分析, 綜合所有現有科學證據,作為提供卡介苗接種政策的實務參考。 方法:本研究共分為4個面向進行探討: 一、卡介苗接種政策之演變:系統性文獻回顧 以系統性文獻回顧方式蒐集不同卡介苗接種政策之代表性國家,及國際組織對卡介苗之接種建議。 二、新生兒時期接種卡介苗對於嚴重型態結核病保護力之實證研究:統合分析 檢視當代對於卡介苗保護力較具代表性的系統性回顧及統合分析文獻,就其原始文獻僅選取針對新生兒時期接種,計算接種卡介苗者較未接種卡介苗者罹患嚴重型態結核病之勝算比(Odds Ratio, OR)及其95%信賴區間,進而推算接種卡介苗對於嚴重型態結核病之保護力(Vaccine efficacy)。 三、卡介苗不良反應風險管理策略:系統性文獻回顧 透過PubMed、Embase、Web of Science及Scopus等引文系統,以系統性文獻回顧方式,搜尋2005年至2016年6月間發表之文獻。搜尋方式以英文關鍵字於摘要/標題進行檢索,包含:「BCG」或「Bacille Calmette-Guerin」,及「policy」或「policies」或「strategy」或「strategies」,及「side effect」或「side effects」或「adverse event」或「adverse events」或「osteitis」或「osteomyelitis」,共檢視300篇文獻。 四、我國2008-2015年間卡介苗骨炎/骨髓炎發生率與接種月齡之相關性 以預防接種管理系統於2005/1/1至2015/12/31有卡介苗接種紀錄,且在中央傳染病追蹤管理系統於2005/1/1至2015/12/31通報為未滿5歲之疑似結核病個案,且其肺外病灶分子生物學鑑定為Mycobacterium bovis者。將卡介苗不良反應主動監測推動後之出生世代,即2008-2015年出生世代,依接種月齡分為4組,計算各月齡組別之相對危險性(Risk Ratio, RR)及95%信賴區間。 結果: 一、卡介苗接種政策之演變:系統性文獻回顧 國際抗癆聯盟及世界衛生組織對於結核病高發生率之國家,仍建議採行全面性卡介苗接種政策,但WHO建議出生後儘早接種,當時並未針對新生兒時期接種的成效與安全性作實證評估,純粹為希望提升接種率的行政考量。在未曾將卡介苗列為常規疫苗或曾全面性接種卡介苗目前調整為選擇性接種的代表性國家中,高風險族群成為主要的接種對象。 二、新生兒時期接種卡介苗對於嚴重型態結核病保護力之實證研究:統合分析 以Random effect方式進行統合分析,結果顯示接種卡介苗者較未接種卡介苗者罹患嚴重型態結核病之勝算比為21%(95% CI:8%-54%),故新生兒時期接種卡介苗對於嚴重型態結核病之保護力為79%(95% CI:46%-92%),低於包含延後施打在內的整體平均值86%(95% CI:65%-95%)。 三、卡介苗不良反應風險管理策略:系統性文獻回顧 即使符合國際間停止全面性接種卡介苗的標準,在接種政策上仍面臨不同方案的選擇,亦即在幼童罹患嚴重型態結核病及卡介苗不良反應之間作抉擇,若透過數理模式計算,可提供量性數據做為調整卡介苗政策的參考。此外,母親為愛滋病毒感染者其新生兒應延後卡介苗接種時間,以利判定新生兒是否感染愛滋病毒,避免因接種疫苗產生不良反應。 四、我國2008-2015年間卡介苗骨炎/骨髓炎發生率與接種月齡之相關性 以出生滿1個月至未滿2個月(1-2個月)為參考值計算其他接種月齡組別之相對危險性(Risk Ratio, RR),出生未滿1個月之新生兒接種卡介苗發生骨炎/骨髓炎之相對危險性為2.66(95% CI: 1.40-5.48),顯示2016年之前於新生兒時期施打之建議確實有需要調整。 結論:卡介苗問世於醫療科技及衛生環境窘迫的年代,國際性衛生組織亟欲透過此一策略降低嚴重結核病造成嬰幼兒的死亡率。而透過本研究得知,新生兒時期接種卡介苗並未提升對於嚴重型態結核病之保護力,卻增加嚴重不良反應的風險。因此在顧及高風險族群的情形下,透過延後卡介苗接種時間可平衡嚴重型態結核病及嚴重卡介苗不良反應。

並列摘要


Background and purpose: BCG vaccination an evidence-based strategy of tuberculosis prevention which endorsed by WHO. BCG vaccination brings not only advantages such as protect severe illness from tuberculosis but also accompany with severe adverse events. In order to provide practical recommendation, this article will access the following aspects. Recently, discontinuation of BCG vaccination or not trigger a disputation. Since 2016, Centers of Disease Control of Taiwan suggest to postpone BCG vaccination schedule to 5 months after birth. This article will conduct systematic review, meta-analysis and data-base analysis to sum up the available scientific evidence as a practical reference for BCG vaccination policy. Method: This article will discuss 4 aspects: 1. Progress of BCG Vaccination Policy: A Systematic Review Describe the progress of BCG vaccination policy and tuberculous epidemiology profile from countries, never enroll BCG in a routine immunization schedule, ever implement BCG as an universal immunization but shift to selective and adjacent to Taiwan. Recommendation from WHO and IUATLD. 2. Vaccine Efficacy against Severe Form of Tuberculosis while Vaccinated in the Neonatal Period: Meta-Analysis Derived the original articles from the well-knew researches which analyzed the efficacy of BCG vaccination. Select the original articles which participants vaccinated BCG in the neonatal period. Calculate the Odds Ratio(OR)and 95% confidence interval of severe tuberculous diseases comparing vaccinated with unvaccinated participants. Vaccine efficacy is defined as [1 – OR]. 3. Risk Management of BCG Adverse Events: A Systematic Review Subjects retrieved from Pubmed, Embase, Web of Science and Scopus using the terms〔“BCG” or “Bacille Calmette-Guerin”〕and〔“policy” or “policies”〕and〔“strategy” or “strategies”〕and〔“side effect” or “side effects” or “adverse event” or “adverse events” or “osteitis” or “osteomyelitis”〕which published between Jan. 2005 to Jul. 2016, a total of 300 studies were included. 4. Relationship between Incidence of BCG- Osteitis /Osteomyelitis and Month of Vaccinated Age in 2008-2015 Birth Cohort. A retrospective descriptive study design that utilized data through National Immunization Information System(NIIS)and national TB surveillance and management system. Enrolled those notified cases with Mycobacterium bovis molecular findings and age less than 5 whom reported since 2005 to 2015, and ever had a BCG vaccination record. Divide 2008-2015 birth cohorts to 4 groups by immunized month age from within one month, 1-2 months, 2-3months and 3-4 months. Calculate the Risk Ratio(RR)and 95% confidence interval. Result: 1. Progress of BCG Vaccination Policy: A Systematic Review IUATLD and WHO recommend to immunized BCG as soon as possible at birth in TB high burden countries. At that time, vaccinated in the neonatal period seems only an administrative consideration for increasing the BCG coverage rate because there were no evidence-base assessment of vaccine efficacy and safety. In those countries which never enroll BCG in a routine immunization schedule or ever implement BCG as an universal immunization but shift to selective, TB high risk groups were the target population for BCG vaccination. 2. Vaccine Efficacy against Severe Form of Tuberculosis while Vaccinated in the Neonatal Period: Meta-Analysis While comparing vaccinated with unvaccinated participants, the Odds Ratio of severe tuberculous diseases is 21% (95% CI: 8%-54%) calculated by random effect. Namely, vaccine efficacy is 79% (95% CI: 46%-92%) which lower than the overall vaccine Efficacy 86%(95% CI:65%-95%)vaccinated in neonatal and postponed period. 3. Risk Management of BCG Adverse Events: A Systematic Review Even if the countries fit the criteria of BCG discontinuation, the policy makers still need to face the vexed issues between severe form of tuberculosis and BCG related harms. For precluding harm by BCG, infants should postpone BCG vaccination for confirming the HIV status while his/her mother was living with HIV. 4. Relationship between Incidence of BCG-Osteitis /Osteomyelitis and Month of Vaccinated Age in 2008-2015 Birth Cohort. Take the incidence of BCG-osteitis /osteomyelitis of the group immunized 1-2 months as reference, the Risk Ratio(RR)in vaccinated within one month group is 2.66(95% CI: 1.40-5.48). This reveals the recommendation of vaccinated BCG in the neonatal period before 2016 ought to be revised. Conclusion: BCG vaccine were produced and used since 1920`s. That era were lack of effective strategies to control and treat tuberculosis. International health organization eager to decrease the incidence and mortality rate of tuberculosis especially in the young population. According to the meta-analysis result in this article, vaccinated BCG in the neonatal period has the similar vaccine efficacy against severe form of tuberculosis with those vaccinated in whatever age. But vaccinated BCG within one month after birth would increase the RR of BCG-osteitis /osteomyelitis. Therefore, taking into account of the tuberculosis high-risk groups, delaying BCG vaccination would balance the severe form of tuberculosis and severe BCG adverse events.

參考文獻


1. WHO, WHO position paper on BCG vaccination. Weekly Epidemiological Record, 2004. 79(4): p. 25-40.
2. Zwerling, A., et al., The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med, 2011. 8(3): p. e1001012.
3. Borgdorff, M.W., K. Floyd, and J.F. Broekmans, Interventions to reduce tuberculosis mortality and transmission in low- and middle-income countries. Bull World Health Organ, 2002. 80(3): p. 217-27.
4. Tu, H.-A.T., et al., A review of the literature on the economics of vaccination against TB. Expert review of vaccines, 2012. 11(3): p. 303-317.
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