台灣川崎病流行病學之研究與免疫球蛋白治療方式之比較分析

Abstract

背景與目標 川崎病是目前大多數工業化國家造成兒童後天性心臟病最常見的原因。目前國內外流行病學研究大多是以次級資料庫為主，但少有研究對於診斷的正確性予以評估。對於以免疫球蛋白治療川崎病，目前僅有少數研究針對不同製程免疫球蛋白療效進行評估，但都受限於有限的病例數以及缺乏長時間的追蹤。本研究之目的為：(1)台灣川崎病之流行病學分析，比較兩種疾病定義標準，估算急性川崎病ICD診斷申報的準確性。(2)台灣川崎病的臨床流行病學分析，與免疫球蛋白在急性川崎病的資源耗用（utilization）分析。(3)比較不同製程成分之免疫球蛋白，在療效以及預後是否有所不同。 方法 本研究主要分為三大部分：(1)以兩種定義包括傳統定義組（住院主診斷碼ICD9 446.1）以及新定義組（住院主診斷碼ICD9 446.1，同時曾接受免疫球蛋白治療）來估算年發生率、季節分佈以及復發率並比較之。(2)針對第一次因川崎病接受免疫球蛋白治療的病人，分析急性冠狀動脈瘤，慢性冠狀動脈瘤以及復發的臨床危險因子。(3)針對不同製程的免疫球蛋白（丙酸化，儲存的酸鹼值，或是IgA濃度）的比較性效果評估（comparative effectiveness）。 結果 (1) 1997到2008，傳統定義組，平均發生率為65.3每十萬五歲以下小孩人年。新定義組，平均發生率為41.2。季節高峰新定義組為春天，傳統定義組為春夏。五年累積再發生率傳統定義組為3.2％，新定義組為1.1％。(2)在慢性冠狀動脈血管瘤方面，年齡小於1歲或年齡大於5歲、男性、有先天性心臟病、發燒天數較長以及醫學中心治療都是顯著的危險因子。發燒天數較短顯著的有較高的復發比率（hazard ratio 1.99）。(3)需要兩次以上療程的風險，丙酸化的免疫球蛋白的相對危險值為1.45，而酸性的保存環境與含有IgA則不顯著。對於急性冠狀動脈血管瘤，丙酸化則則不顯著，但是酸性的保存環境，卻有顯著不良影響，相對危險值為1.49，含有IgA則不顯著。在慢性冠狀動脈血管瘤，丙酸化是也有顯著不良影響，相對危險值為1.44。而酸性的保存環境則有保護效果，相對危險值為0.82，含有IgA不顯著。 結論 台灣地區川崎病的盛行率先前有可能稍被高估，而本研究的數據可能略為低估，真正的發生率可能介於兩者之間。台灣川崎病盛行的高峰季節為春季。男性、發燒天數長、年齡大於五歲或小於1歲為慢性冠狀動脈血管瘤的危險因子。治療前發燒天數較短者，可能有較高的復發率。丙酸化製程之免疫球蛋白，有較高的治療失敗機率，同時有較高比率的慢性冠狀動脈病變。酸性儲存的免疫球蛋白，可能會造成急性冠狀動脈血管瘤的機率增加。

Background and Objectives: Kawasaki disease is the leading cause of acquired heart disease among children in most industrialized countries. Most of the epidemiological studies use secondary database. However, the validity in the secondary database has seldom been evaluated. For using immunoglobulin to treat Kawasaki disease, only few studies have ever evaluated the comparative effectiveness among immunoglobulin from different manufacturing processes. Moreover, those studies were limited by small case numbers and lack of longitudinal follow up. The aims of this study were: (1) Epidemiological study of Kawasaki disease in Taiwan, comparing two different case definitions and evaluating the validity of ICD coding in clams data; (2) Clinical epidemiological analysis of Kawasaki disease and the utilization of immunoglobulin for Kawasaki disease in Taiwan; (3) Comparative effectiveness evaluation of immunoglobulin from different manufacturing processes. Methods: This research are mainly divided into 3 parts: (1) Using two case definitions including classical (main diagnosis ICD9 446.1) and new definition group (main diagnosis ICD9 446.1 plus receiving immunoglobulin therapy) to evaluate and compare annual incidences, seasonal distributions and recurrence rates; (2) For patients who received immunoglobulin therapy for the first time, analyzing the clinical risk factors of acute coronary aneurysm, chronic coronary aneurysm and recurrence rate; (3)Evaluating the comparative effectiveness among immunoglobulin from different manufacturing processes (β-propiolactonation, acidification and containing IgA) Results: (1) From 1997 to 2008, the average incidence in the classical definition group was 65.3 per 100,000 person-years under 5 years. It is 41.2 in the new definition group. The peak season is spring in the new definition group and spring-summer in the classical group. The five-year cumulative recurrence rate is 3.2% in classical group and 1.1% in new group. (2) Risk factors for chronic aneurysm include age younger than 1 or older than 5 years, male, congenital heart disease, longer febrile duration and medical centers. Patients with shorter fever duration have higher recurrence rate (hazard ratio 1.99); (3) For needing two or more courses of immunoglobulin therapy, β-propiolactonation has the relative risk of 1.45. acidification and containing IgA were non-significant. For acute aneurysms, acidification has the relative risk of 1.49. β-propiolactonation and containing IgA were non-significant. and For chronic aneurysm, β-propiolactonation, has the relative risk of 1.44 and acidification could protect it with the relative risk of 0.82. Containing IgA was non-significant. Conclusions: The incidence of Kawasaki disease in Taiwan might be overestimated previously. The data in this study might underestimate. The truth may lie between. The peak seasons of Kawasaki disease in Taiwan is spring. Male, longer fever duration and age less than 1 or older than 5 years were risk factors for chronic coronary aneurysms. Patients with shorter fever duration before therapy might have higher recurrence rates. β-propiolactonation immunoglobulin has higher risk for treatment failure and chronic coronary aneurysm. Acidification might increase the risk for acute coronary aneurysm.