老年族群使用statins對季節性流感疫苗降低需就醫急性呼吸道疾病效果的影響

Influence of statins use on the effectiveness of seasonal influenza vaccine against medically attended acute respiratory illness in elderly

邱賢宗(Hsien-Tsung Chiu)

指導教授 ： 沈麗娟 ； 王繼娟

國立臺灣大學/醫學院/臨床藥學研究所/碩士(2016年)

https://doi.org/10.6342/NTU201601653

摘要

研究背景 Statins的免疫抑制作用可能降低施打疫苗所引起的免疫反應，且可依是否與statins抑制HMG-CoA reductase相關分成數個機轉，如抑制GTPases protein isoprenylation、負調控major histocompatibility complex (MHC)分子的表現等。其中，對於抑制T細胞上的lymphocyte function-associated antigen-1 (LFA-1)與其抑制HMG-CoA reductase無關，且不同statins因結構不同而抑制效果有所差異。不過目前仍尚未有文獻考量不同statins對免疫系統作用的差異，且探討老年族群statins的使用對季節性流感疫苗降低需就醫急性呼吸道疾病效果的影響。
研究目的 利用全民健康保險研究資料庫探討老年族群statins的使用是否會對季節性流感疫苗在需就醫急性呼吸道疾病的發生風險造成影響，並希望進一步探討statins的使用時間點、強度、種類是否與此相關。
研究材料與方法 本研究為回溯性世代研究，以2007-2013年全民健康保險資料庫老人檔為資料來源，疫苗相符或不相符年度各包含3個年度，將各年度10月1日至次年5月31日施打季節性流感疫苗的日期作為index date，以index date前後14天為暴露期間，若暴露期間有使用任何一劑statins則視為有statins的使用，比較兩組在觀察期間發生需就醫急性呼吸道疾病的風險是否有差異。資料分析利用propensity score配對平衡兩組間的基本特性，並以conditional logistic regression進行勝算比(OR)的預測。
研究結果 本研究總樣本數為440,180，2007-2008至2012-2013的6個年度依序分析76,330人、85,545人、34,725人、74,680人、82,560人及86,340人。結果顯示6個年度合併後，老年族群statins的使用會使觀察期間發生需就醫急性呼吸道疾病的風險上升1.03倍(95% CI: 1.02-1.05)，在疫苗相符年度或不相符年度結果一致。在次族群分析中，依statins使用時間點分組，僅有疫苗相符年度在施打季節性流感疫苗之後使用statins會使發生需就醫急性呼吸道疾病的風險上升1.06倍(95% CI: 1.02-1.09)，而疫苗不相符年度則沒有影響。所有statins中，僅有simvastatin及lovastatin會使發生需就醫急性呼吸道疾病的風險上升，分別為1.14倍(95% CI: 1.10-1.18)及1.18倍(95% CI: 1.12-1.25)。不同年齡層或降血脂強度則未有一致性的趨勢。
結論 本研究發現無論是在疫苗相符或不相符年度，老年族群statins的使用都會降低季節性流感疫苗的效果而使發生需就醫急性呼吸道疾病的風險上升3%，尤其是在疫苗相符年度施打疫苗之後使用statins，所有statins中，simvastatin及lovastatin最有可能影響到季節性流感疫苗的效果，影響程度高達14%及18%。建議臨床上仍應考量使用statins的利益及風險，若為了避免此影響，可選擇pravastatin或不含hexahydronaphthalene的statins，如atorvastatin、fluvastatin或rosuvastatin，或在施打流感疫苗後短暫停用statins數天，而未來也需要更進一步的研究，了解不同statins對免疫系統作用的差異或採用經實驗室確認的流感作為結果。

關鍵字

季節性流感疫苗 ； 需就醫急性呼吸道疾病 ； statin ； 老年族群 ； 全民健保資料庫

並列摘要

Background: The immunomodulatory effects of statins may reduce the immune response induced by vaccines, which could be divided into several mechanisms depends on the inhibition of HMG-CoA reductase, such as GTPases protein isoprenylation inhibition, down-regulation of major histocompatibility complex (MHC) molecules expression. For the inhibition of lymphocyte function-associated antigen-1 (LFA-1), different statins do not have equal inhibitory effects because of the structural differences and the effects are independent of HMG-CoA reductase. However, there is lack of studies considering the immunomodulatory effects of different statins and focusing on the influence of statins use on the effectiveness of seasonal influenza vaccine against medically attended acute respiratory illness (MAARI) in the elderly.
Objective: To investigate whether statins use influenced the effectiveness of seasonal influenza vaccine on the incidence of MAARI in the elderly and timing of statins exposure, and different potency or types of statins by using the National Health Insurance Research Database in Taiwan.
Materials and Methods: We conducted a retrospective cohort study by using the 2007-2013 elderly database from Taiwan’s National Health Insurance Research Database. Vaccine match years and vaccine mismatch years each contained three years. All elderly who were vaccinated with seasonal influenza vaccine during October 1 to May 31 in the next year were enrolled for analysis, and the date of vaccination was defined as index date. People who had any statin use in the exposure period defined as before and after 14 days of index date were statin users, others were statin non-users. We compared the risk of MAARI in the observational period between statin users and statins non-users. Propensity score matching was used to make the two groups comparable. Conditional logistic regression models were used to estimate odds ratios.
Results: After matching, total sample size was 440,180. There were 76,330, 85,545, 34,725, 74,680, 82,560 and 86,340 people being analyzed during 2007-2008 to 2012-2013 influenza seasons. In general, the risk of MAARI in the observational period was higher in the elderly who used statins in the exposure period in six years combined data (OR: 1.03, 95% CI: 1.02-1.05). Vaccine match years and vaccine mismatch years both had similar results. In the subgroup analysis, statins use after vaccination in the vaccine match years was associated with higher risk of MAARI in the observational period (OR: 1.06, 95% CI: 1.02-1.09) rather than in the vaccine mismatch years. Among all statins, only simvastatin and lovastatin use in the exposure period had higher risk of MAARI (OR: 1.14, 95% CI: 1.10-1.18; OR: 1.18, 95% CI: 1.12-1.25). No consistent relationships were found in different age groups or lipid-lowering potency groups.
Conclusions: Statins use was associated with the 3% reduced effectiveness of seasonal influenza vaccine against MAARI in the elderly, especially statins use after vaccination in the vaccine match years. Simvastatin and lovastatin had 14%-18% higher risk to reduce the effectiveness of seasonal influenza vaccine. We recommended choosing pravastatin or other statins not containing hexahydronaphthalene, such as atorvastatin, fluvastatin, rosuvastatin, or stopping taking statins after vaccination for several days after evaluating the benefit and risk in clinical. In the future, other studies exploring the differences of the statins on the immunomodulatory effects or using the laboratory-confirmed influenza as outcome are needed.

並列關鍵字

seasonal influenza vaccine ； medically attended acute respiratory illness (MAARI) ； statin ； elderly ； National Health Insurance Research Database (NHIRD)

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