摘要:背景右心房同位症又稱為無脾症,常會伴隨複雜性先天性心臟病。這些病人需要多階段單一心室手術才能達到長期存活,右心房同位症盛行率在東方人明顯較高,其中在台灣的研究更是在世界中首屈一指,可以算是我們的特色疾病之一。然而這些病人五年存活率仍只有55%,除了開刀的風險外,這些病人因為脾臟功能低下容易嚴重細菌感染甚至造成致命性的敗血症。通常感染風險在五歲前最高,而在我們之前的研究顯示,23%右心房同位症病人是死於感染相關問題,因此感染預防及高危險群偵測便是相當重要課題。脾臟是一重要免疫器官,然而脾臟功能的評估相當困難。最近M 型免疫球蛋白記憶性B 細胞被發現與脾臟功能有好的相關性,然而目前在臨床應用性仍未知。肺炎鏈球菌疫苗對於嚴重肺炎鏈球菌感染不只在一般群眾,也在高危險群病人有相當好的預防效果。結合型肺炎鏈球菌疫苗可誘發T 細胞依賴的免疫功能,因此即使在年輕族群(小於兩歲)也有好的預防效果。然而疫苗效力在這些脾臟功能低下的右心房同位症病人仍未知。目標首先評估右心房同位症細菌感染的風險,其次檢測M 型免疫球蛋白記憶性B 細胞對於感染高危險群的預測度,並且我們也將測試肺炎鏈球菌疫苗在這些脾臟功能低下者的效力及M 型免疫球蛋白記憶性B 細胞的預測度,最後,我們將給予以M 型免疫球蛋白記憶性B 細胞偵測出的高危險群病人,分組給予預防性抗生素,來檢測對於嚴重感染的預防效果。方法臨床研究所有在2005 年至2011 在台大醫院及雲林及新竹分院規則追蹤的右心房同位症病人將列入我們的研究,我們對病歷做系統性研究,並以複雜性先天性心臟病病人做為對照組。評估並比較兩組社區感染及住院細菌感染率,及致病菌的差別。免疫功能我們並請這些病人回來接受抽血檢驗,我們以流氏細胞儀免疫法標定來偵測M 型免疫球蛋白記憶性B 細胞,並與之前感染作關連性研究,以評估其是否為感染高危險群的重要指標。其次,我們也將檢驗這些病人的肺炎鏈球菌七種血清型抗體效價(包括在疫苗內的血清型),來瞭解疫苗在這些病人的保護效力。臨床試驗對於上述檢驗出脾臟功能低下的病人,我們會將進行前瞻性研究,一組給予長期抗生素預防(Amoxicillin 20mg/kg/day 一天兩次),另一組則依照目前發燒後再給予的方式,追蹤二年,觀察其嚴重細菌感染情形。初步結果我們測試五位右心房同位症病人,記憶性B 細胞平均為5.54±4.77%,M 型免疫球蛋白記憶性B 細胞平均為0.24±0.18%,而在11 位同年齡的兒童記憶性B 細胞平均為23.6±15.8%,M 型免疫球蛋白記憶性B 細胞平均為5.1±3.9%,可以發現在右心房同位症病童,記憶性B 細胞及M 型免疫球蛋白記憶性B 細胞都明顯較對照組來的低,也因此顯示在這些無脾症患者M 型免疫球蛋白記憶性B 細胞可以做為好的脾臟功能指標。創新及預期成果M 型免疫球蛋白記憶性B 細胞目前在臨床上應用仍未知,藉由此研究,我們可以偵測出感染高危險群病人,並檢測這些病人疫苗效力,及預防性抗生素所扮演角色,有相當重要臨床意義。
Abstract: Introduction:Right atrial isomerism (RAI), which is a form of heterotaxysyndrome and also called asplenia, is commonly associated with complex congenitalheart disease. The prevalence of RAI is significantly higher in Asian population, andis a featured disease in Taiwan. Most of important papers about RAI patientsincluding surgical results, risk factors of mortality, and impact of infection onunexpected death were from Taiwan. Palliative multistage surgery with singleventricle physiology (Fontan type operation) is requisite for long term survival.However, the long term survival is still not optimistic as 5 year survival in our seriesis around 55% in Taiwan.In addition to the risk of operation, patients with RAI also suffered from risk offulminant infection and sepsis due to hyposplenism. The risk of infection is highestduring the first five years of life, which account for 23% of unexpected death in RAIpatients in our previous study. Therefore, infection prevention and high risk patientidentification are important issues in these asplenia patients.As an important immunologic organ, splenic function is still hard to evaluate evenat nowadays. Traditionally, Howelly-Jolly body count was suggested as a marker ofhyposplenism. Neither is the sensitivity optimal nor is the count objective whichlimits its clinical use. IgM memory B cell represents the potential counterpart of Blymphocyte in the marginal zone of the spleen, and has good correlation with splenicfunction. However, its clinical use is still limited, and its role in the risk assessment ofsevere bacterial infection in these RAI patients is still unknown.Pneumococcal vaccine, since its introduction, has changed the disease pattern andincidence of invasive pneumococcal disease not only in general population but also inhigh risk patients. Pneumococcal conjugated vaccine can induce T cell dependentimmune reaction, and was documented to have high protective efficacy even in youngpopulation. However, its protective function in these RAI patients is still unknown.Objective:First, we try to define the risks of bacterial infection in these RAIpatients. Then we will delineate the clinical implication of IgM memory B cellcounts in predicting those with high risk of severe bacterial infection. Besides,we will test the efficacy of pneumococcal vaccine in these hyposplenism patients.Third, we will conduct a clinical trial to delineate the role of antibioticsprophylaxis in the prevention of sepsis in these asplenism patients.Methods:Clinical Study All RAI patients born between Jan 2005 to Dec 2011 and diagnosed inNational Taiwan University Hospital and YunLin and HsinChu branch will beenrolled. Only those patients received regular follow-up at our hospital will beincluded in our study. The charts will be reviewed, and using patients of complexcongenital heart disease at the same period as control group, the communityacquired and nosocomial infection rates, causal bacteria and drug sensitivity, andinfection foci will be compared between these two groups.Immune FunctionWe will then invite all the RAI patients back to evaluate IgMmemory B cell function. Ten milliliter fresh blood will be sampled, and IgMmemory B cell in the peripheral blood will be checked usingimmunophenotyping flow cytometry.We will then correlate previous infectionepisodes to the IgM memory B cell counts and compare those in RAI and controlpatients to see if it can be used as an indicator of high risk group in RAI patients.Second, we will also check the antibody titers of the seven serotypes ofpneumococcus (contained in conjugated vaccine) to see the protective effect inRAI patientsClinical Trial For those with hyposplenism documented by low IgM memory B cellcount, we will arrange prospective study.We will divide these patients into twogroups. Study group will receive daily prophylactic antibiotics with Amoxicillin20mg/kg/day twice daily, and the control group will not. They will be followedup for 2 years to define the difference of incidence of severe bacterial infectionin these two groups.Preliminary DataWe have tested five of RAI patients in our patient cohort. The mean percentage ofmemory B cell count was 5.54±4.77% and mean percentage of IgM memory B cellcount was 0.24±0.18%. The mean memory B cell and IgM memory B cell count in theage, sex-adjusted normal control was 23.6±15.8% and 5.1±3.9%.We can found thememory B cell and IgM memory B cell count were significantly lower in theseasplenic RAI patients. This result suggests that memory B cell or IgM memory B cellmay be an important marker of splenic function and can be used as an indicator ofhigh risk patients.What is New or Innovative in this study?IgM memory B cell in the peripheral blood was found to correlate with splenicfunction, but its clinical use is still unknown. Through the study, we can define thehigh risk group in these RAI patients. Besides, we can see the preventive effect ofconjugated pneumococcal vaccine in these hyposplenism patients. The role ofprophylactic antibiotics in these RAI patients will be defined also.