多價肺炎鏈球菌結合型疫苗對預防台灣兒童肺炎住院的成效：以全國人口為基礎的時間序列分析

Abstract

背景： 國內多價肺炎鏈球菌結合型疫苗的研究多著重於對侵襲性肺炎鏈球菌感染症的影響，對兒童肺炎的影響很少有實證數據探討。本研究的目的為觀察歷年國內五歲以下兒童肺炎住院趨勢，並分析肺炎鏈球菌結合型疫苗上市，及肺炎鏈球菌結合型疫苗之全國性政策介入，與兒童肺炎住院趨勢的關係。 方法： 本研究以ICD代碼自衛生福利資料科學中心資料庫之全民健保資料庫，及內政部的公開人口學數據估計每年五歲以下(60個月以下)，及以施打疫苗期程分成三個月齡層(2至12個月、12至24個月和24至60個月)的肺炎、嚴重肺炎、敗血性肺炎及膿胸住院率。同年齡泌尿道感染住院率為陰性對照組。事前事後分析呈現不同疫苗上市時期或政策時期與無疫苗時期的住院率比及住院率差，並藉此估計多價肺炎鏈球菌疫苗保護力。分段時間序列分析則是在控制流感疫苗及全國流感疫情下，分析不同月齡層在疫苗上市時期及不同政策時期的月住院率變化，及圖像化呈現變化的淨趨勢。 結果： 觀察發現台灣五歲以下兒童的肺炎住院率在2005年及2011年分別出現峰值，於2011年後下降並在2017年達到最低點。事前事後分析顯示，與無疫苗時期相比，在全國施打政策期間，疫苗保護效果為14% (95%信賴區間為0.05, 0.78; p=0.0026)。同一期間，疫苗對嚴重肺炎的保護效果則為50% (95%信賴區間0.32, 0.78; p=0.0024)。與無疫苗時期相比，全國施打政策後的肺炎住院率差約為每十萬人減少236人(95% 信賴區間為-257, -216, p<0.0001)，約等於減少2400位五歲以下兒童因肺炎住院。分段時間序列分析在控制流感疫苗及全國流感重症人數的第一個分齡分段線性回歸模式顯示，調整後的月住院率趨勢(線性斜率)在七價疫苗上市後每個月齡組的斜率降幅都達到統計顯著，並以低月齡組減少最多(β=-1.17, p=0.0113)。十三價疫苗上市後則是高月齡組降幅最大(β＝-1.28, p=0.0001)。第二個分段線性回歸模式則顯示，全國施打政策開始後，高月齡組肺炎及嚴重肺炎月住院率呈現逐月下降，且嚴重肺炎月住院率的斜率較追加接種時期顯著降低(β＝-0.088, p=0.0158)。 結論：研究觀察期間的五歲以下兒童肺炎住院率下降，應可歸因於七價肺炎鏈球菌結合型疫苗及十三價肺炎鏈球菌結合型疫苗的影響。全國施打政策有效地降低五歲以下兒童肺炎及嚴重肺炎住院率。

Background To date there is limited data to demonstrate the effectiveness of pneumococcal conjugate vaccine (PCV) against childhood pneumonia after the introduction of PCVs or the national policy of stepwise immunization program. Our study is aimed to observe the impact of multivalent PCVs against hospitalized pneumonia among Taiwanese children less than 60 months of age. Methods We estimated annual rates of hospitalization for pneumonia, severe pneumonia, septic pneumonia and empyema from the National Health Insurance Research Database and online source of Ministry of the Interior. Three age groups (2 to 12 months, 12 to24 months, and 24 to 60 months) were defined according to current vaccine schedules. Hospitalization rate of urinary tract infection was designed as a negative control. Two individual year preceding the introduction of PCV7 (2002 and 2004) were selected as pre-vaccination baseline years. Rate ratio and rate difference of pneumonia or severe pneumonia were compared between pre-vaccination period, and three post-vaccine periods to estimate increases or declines in hospitalizations due to pneumonia. Segmented regression analysis was applied in each of three age groups to graphically define the trend of hospitalized pneumonia and severe pneumonia. Results The annual rate of hospitalized pneumonia and severe pneumonia among children younger than 60 months demonstrated two peaks, was higher at 2005 and 2011, appeared to decline thereafter and reached the lowest level in 2017. Hospitalization rates before vaccine introduction and after the national immunization program showed significant reduction which demonstrated a vaccine effectiveness for 14% (95% CI: 0.05, 0.22; p=0.0026). Meanwhile, vaccine effectiveness against severe pneumonia was 50% (95% CI: 0.32, 0.78; p=0.0024). After the implantation of national immunization program, the annual hospitalization rate for pneumonia declined by 236.0 per 100,000 children (95% CI, 216.0 to 257.0, p<0.0001), which translates to 2400 fewer hospitalizations annually than expected on the basis of the rates before any of PCV was introduced. Age-specific, segmented regression showed the adjusted monthly rate reacted to the introduction of PCV7 and PCV13. In children less than 12 months of age, trend (slop) after the year of PCV7 introduction decreased soon and significantly (β=-1.17, p=0.0113). In contrast, trend after the year of PCV13 introduction has significant decline in the older age group (β=-1.28, p<0.0001). In children aged between 24 to 60 months, the monthly hospitalization rates for pneumonia and severe pneumonia showed a monthly decline after the nation immunization program implemented, and the slope of the monthly rate for severe pneumonia was significantly lower than the slop in the catch-up policy period (β=-0.088, p=0.0158). Conclusion Decline of hospitalized pneumonia in Taiwanese children less than 5 years of age could be attributed to the introduction of multivalent pneumococcal conjugate vaccine. National immunization program is effective in reducing the incidence of hospitalized pneumonia and severe pneumonia in children aged less than 5 years.