氣喘急性發作時表現型態與預後因子之研究

Abstract

氣喘(Asthma)是一種相當普遍的呼吸道發炎疾病，病人會有不同程度反覆陣發性的呼吸困難、喘鳴、咳嗽、多痰等症狀，嚴重而快速的呼吸道阻塞可引起急性呼吸衰竭而導致病患死亡。氣喘病人的發炎現象和一般人不同，傾向以Th-2淋巴球亞型活化為主軸，引發後續一連串細胞與介質間的反應，一般相信是受到遺傳因子的調控所致。目前已有許多細胞分子陸續被證實與氣喘有關，其中較為重要的如β2-adrenergic receptor、chemokine CC-16、NOS、TNF-α、IL-4、IL-5、IL-13等，這些分子的基因許多多型性(polymorphism)已被找到，並被積極的和臨床上的觀察互相關聯。這些標記分子在氣喘急性發作時的角色為何？可否協助了解氣喘急性發作的致病機轉？可否用來定義氣喘急性發作的不同表現型式？這樣的差異是否有臨床上的意義？是否也是受到不同基因型的調控？是尚未被回答的問題，也是本研究所要探討的主題。本研究的目的可分為二部份，第一在確立氣喘發作時的表現型態，本步驟的研究假說為：「氣喘發作時確實有二種或三種不同的表現型態(phenotype)，這些型態可以從病患對氣喘急性發作標準療法的反應快慢將之區分開來。」第二在探討這樣的型態差異，其機轉為何？可否由周邊血液的血清標記加以測量？此步驟的研究假說為：「前述的表現型態phenotype差異和某些特定的血清標記有關」本研究將分二個階段進行，笫一階段為Retrospective cases review，研究對象為台大醫院急診自2002年1月至2002年12月一年之中所有疾病診斷為氣喘急性發作的病患，以回顧病歷記載方式進行，儘可能蒐集各種數據，加以描述性統計。笫二階段為Prospective case control study，研究對象為台大醫院急診自2003年1月至2004年12月之間，疾病診斷為氣喘急性發作的病患，在排除不適當的個案之後，徵得病患同意後，抽取急性發作期與平時期週邊血液，另選擇相當之其他病患配對成為對照組，取得血清後進行sICAM-1、sE-selectin、Total NO、IL-1b、CD40L、IgE、TNFa以及LTB4的測定。第一部分研究結果發現在臨床上，氣喘急性發作的季節性並不如想像明顯，而急性發作時病患對標準治療流程的反應不一，這樣不同的反應無法用一開始的嚴重度或是肺功能加以預測，可能代表著不同的表現型態。第二部分研究結果發現氣喘急性發作病人之周邊血液的血清中的TNFa、CD40L及IL-1b比對照組為低，反之，sE-selectin與LTB4的表現則較高。其中，若以TNFa＞0.22與Total NO＞110為切點，可以有意義的預測氣喘急性發作病患的預後，具有相當大的臨床意義。

Asthma is a very common airway inflammatory disease. The unique inflammatory process in asthmatic patients tends to activate Th-2 subtype lymphocytes rather than the usual Th-1. Series of reactions and interactions among cytokines, inflammatory cells and other mediator networks starts right after the activation. This tendency to activate Th-2 cells is believed to being modulated by genetic factors. Many candidate genes have been documented to be strongly related to the developments of asthma, such as genes encoding β2-adrenergic receptor, chemokine CC-16, NOS, TNF-α, IL-4, IL-5, IL-13 etc. Various serum markers have been found and studied for their relationships with asthma. What roles are these markers playing in the acute exacerbations of asthma？Could it be helpful to understand the pathogenesis of acute attack？Is there any different presentations or phenotypes in concerning about acute exacerbations of asthma？And how’s the clinical significance of these differences？It deserves to be answered. The studies were divided into two study periods. The first one was a retrospective descriptive review of all the asthma cases from Jan. to Dec. 2002. All cases are reviewed by chart and clinical data collected to clarify the various clinical presentations of acute exacerbations of asthma. The second period was prospective case control study to compare the serum markers level between asthmatic patients and the controls. In the first part we found that the seasonal changes of acute exacerbations are not as dramatic as people think. The clinical responses to the standard treatments of asthma as guidelines depicted differ significantly, which could not be predicted by the initial severity assessments or peak flow measurements. In the second part we found that TNFa, CD40L and IL-1b serum levels were lower than the controls. However, the levels of sE-selectin and LTB4 were contrarily higher. Besides, if we choose TNFa > 0.22 and Total NO as cut points, it will significantly define two groups of different treatment responses and could be used to predict the prognosis of acute exacerbations of asthma.