體位不明患者的嚴重細菌感染-流行病學、臨床預測及疫苗效力探討

Severe Bacterial Infection in Heterotaxy: epidemiology, clinical prediction, and vaccination

邵蓓嵐(Pei-Lan Shao)

指導教授 ： 黃立民 ； 陳美如

國立臺灣大學/醫學院/臨床醫學研究所/博士(2018年)

https://doi.org/10.6342/NTU201800916

摘要

背景 體位不明症候群是一種先天發育異常。在胚胎發育時，胸部及腹部的器官並非對稱發育，在胸腔內的肺臟、氣管支氣管及心臟，以及腹腔內的肝臟、脾臟及腸胃道，正常是左右不對稱的。體位不明症候群病人會失去正常的左右不對稱性，而有著鏡像對稱的器官。體位不明症候群依照心耳的型態，大分為右心房同位症和左心房同位症。右心房同位症病患常有複雜先天性心臟病，且脾臟沒有發育或發育不良，也因此有人將這種疾病稱作”無脾症”。左心房同位症病人也有心臟問題，且有多個脾臟，有些人將這種疾病稱作”多脾症”。在亞洲族群中，右心房同位症發生率特別高，過去我們累積了相當多體位不明症候群族群，許多右心房同位症病人開刀成果、死亡風險、心律不整情形，以及預期及非預期死亡研究都來自台灣。
脾臟是重要的免疫器官，過去在脾臟切除患者常發現有感染問題，包括致命的脾臟切除後嚴重感染。我們過去的研究，右心房同位症病人中，感染占了非預期死亡的23%，因此這些體位不明症候群患者很有可能類似脾臟切除病人般有很高的感染風險。然而，這些病人常合併複雜性先天性心臟病，反覆開刀住院本就容易產生感染問題，因此這些病人的感染風險究竟是因為脾臟免疫功能低下或是單純與反覆住院有關，過去並沒有相對應的研究。因為缺乏感染相關的流行病學研究，也難以針對體位不明患者制定良好的預防和照護準則。脾臟免疫功能的評估相當困難，傳統上是以Howell-Jolly小體的數量作為脾臟功能低下的指標，然而其敏感度及客觀性都不佳。M型免疫球蛋白記憶性B細胞(IgM memory B cell)在脾臟的邊緣區生成，與脾臟免疫功能高度相關，然而其臨床應用仍未知。
肺炎鏈球菌等具莢膜的細菌感染已知是脾臟免疫功能低下患者的嚴重威脅。肺炎鏈球菌疫苗自從開發之後，已經大幅改變了肺炎鏈球菌疾病的生態，也大幅降低了侵襲性肺炎鏈球菌疾病，不只在正常兒童，在高風險族群也同樣觀察到這種現象。然而在體位不明症候群等脾臟免疫功能不佳的患者，其保護效力仍未明。
研究主題 首先，我們研究體位不明症候群病人嚴重細菌感染的的流行病學及風險因子，並以複雜性先天性心臟病人做對照組，以排除干擾因子。
其次，我們將評估M型免疫球蛋白記憶性B細胞用來預測嚴重細菌感染的效度，並了解是否能優於現行的脾臟影像學檢查。
最後，我們將測試在這些體位不明症候群伴有脾臟功能低下患者，肺炎鏈球菌疫苗的效力，並了解現行接種情形。
方法與結果 從西元2001至2011年，95位體位不明症候群病人，及142位複雜性先天性心臟病病人納入流行病學研究，嚴重細菌感染定義為培養陽性的敗血症或無菌部位膿瘍。在1026人年追蹤後，在體位不明症候群及複雜性先天性心臟病的五年存活率分別為52%及65.7%，兩者並無顯著差別(p=0.239)。社區嚴重細菌感染只發生在體位不明症候群患者，總共10位病童有13次嚴重細菌感染事件，2年及5年嚴重細菌感染率分別為9.6%及14.5%，社區嚴重細菌感染死亡率為31%。肺炎鏈球菌及弗氏檸檬酸桿菌(Citrobacter freundii)為最常見的致病菌。影像學上有無脾臟病人的社區嚴重細菌感染率相當(10.3% vs. 10.6%)。院內感染發生率為33%，在體位不明症候群及複雜性先天性心臟病病人，每住院100人天的院內感染率為0.59及0.52次，致病菌在兩組並無明顯差別。這個結果顯示體位不明症候群，不論影像學有無看到脾臟，都是社區嚴重細菌感染的高危險群，且有高死亡率。此風險只與體位不明症候群相關，並非肇因於心臟病手術及反覆住院過程。
其次，我們研究在2010年至2012年，規則在台大醫院追蹤且年齡大於1歲的體位不明症候群患者。我們檢測M型免疫球蛋白記憶性B細胞在CD22+B型淋巴球的百分比，同時納入複雜性先天性心臟病與簡單型先天性心臟病病人作為對照組。我們發現M型免疫球蛋白記憶性B細胞的百分比在體位不明症候群病人最低，比起複雜性先天性心臟病與簡單型先天性心臟病病人有顯著差異(1.8±2.1% 比3.9±3.2% 比5.1±4.7%，P<.001)。在體位不明症候群病人，有41.3%病人M型免疫球蛋白記憶性B細胞百分比為低的(佔B型淋巴球<1%)。在體位不明症候群病人中，有7位曾有社區細菌感染，其中85.7%有低的M型免疫球蛋白記憶性B細胞百分比，以回歸分析顯示社區感染唯一的危險因子為低的M型免疫球蛋白記憶性B細胞百分比，這也表示其作為體位不明症候群感染風險預測指標可行性。
最後，我們分析從2010至2015年，在臺大醫院追蹤的體位不明症候群與複雜性先天性心臟病病人，我們記錄這些病人注射肺炎鏈球菌疫苗情形，檢測他們的肺炎鏈球菌血清型6B，14，19F及23F的抗體效價。我們發現這四種血清型的抗體幾何平均濃度，在體位不明症候群與複雜性先天性心臟病病人相比並無差異。且抗體幾何平均濃度與脾臟功能低下(以M型免疫球蛋白記憶性B細胞百分比做為指標)及有無脾臟(以影像學檢測)無關。大部分病人在注射完肺炎鏈球菌多醣體疫苗或肺炎鏈球菌接合型疫苗之後4-5年，抗體幾何平均濃度都大於世界衛生組織建議的最低保護濃度0.35 μg/mL之上。此外有些病人在接種肺炎鏈球菌疫苗之後抗體效價會逐漸下降，這也顯示追加疫苗的重要。調查也發現在42位體位不明症候群病人，21.4%完全沒有接種過肺炎鏈球菌疫苗，而且沒有任何病人完全依照現行的肺炎鏈球菌疫苗注射準則施打。
結論
從流行病學研究，我們發現社區嚴重細菌感染在體位不明症候群病人遠比複雜性先天性心臟病為多，同時仍有相當高死亡率。從脾臟免疫功能指標研究，我們發現M型免疫球蛋白記憶性B細胞百分比是社區細菌感染最好的預測指標。而在體位不明症候群肺炎鏈球菌疫苗的研究，我們發現肺炎鏈球菌疫苗的效果，在體位不明症候群即使是脾臟功能低下的病人，仍是有相當效力，然而在台灣，肺炎鏈球菌疫苗的注射率，依照現行準則仍然不盡理想。

關鍵字

體位不明症候群 ； 複雜性先天性心臟病 ； 嚴重細菌感染 ； 社區細菌感染 ； 院內感染 ； M型免疫球蛋白記憶性B細胞 ； 流式細胞儀 ； 肺炎鏈球菌疫苗 ； 肺炎鏈球菌多醣體疫苗 ； 肺炎鏈球菌接合型疫苗

並列摘要

Background Heterotaxy syndrome is a kind of developmental defect. During fetal stage, normally, the thoracic and visceral organs including the lungs, tracheobronchi, heart, and visceral organs developed asymmetrically. However, in heteotaxy syndrome patients, internal organs developed in pairs as mirror images, instead of having the unique right and left asymmetry characteristics. It can be further divided into right atrial isomerism (RAI) and left atrial isomerism (LAI). In RAI, complex congenital heart disease (CHD) is very common, and spleen is always non-developed or mal-developed. They are also called asplenism. By contrary, the patients of LAI are also called polysplenism. The prevalence of RAI is significantly higher in Asian population, and it is a featured disease in Taiwan.
Patients with heterotaxy syndrome often associated with abnormal splenic function. Spleen is an important immune organ, and patients receiving splenectomy are susceptible to infection, including lethal overwhelming postsplenectomy infection. Therefore, the suspectibility to severe infection in these heterotaxy syndrome patients may be similar to postsplenectomy patients. Because of the frequent association with concomitant complex CHD, whether the increasing risk of infection is related to hyposplenism or repeated admission is unknown.
Immunological function of spleen is still difficult to evaluate nowadays. Traditionally, Howell-Jolly body count was suggested as a marker of hyposplenism. Neither is the sensitivity optimal nor is the count objective, which limits its clinical use. IgM memory B cell represents the potential counterpart of B lymphocyte in the marginal zone of the spleen, and has good correlation with splenic function. However, its clinical use is still uncertain.Patients with impaired splenic function is susceptible to encapsulated bacteria, such as pneumococcus. Pneumococcal vaccine, since its introduction, has changed the disease pattern and incidence of invasive pneumococcal disease, not only in general population but also in high risk patients. However, its protective function in heterotaxy patients is still unknown.
Thesis First, through the largest cohort in the world, we define the epidemiology data and risks of severe bacterial infection (SBI) in these heterotaxy patients.
Second, we delineate the clinical implication of I IgM memory B cell in predicting the high risk group of SBI in heterotaxy syndrome.
Third, we exam the efficacy of pneumococcal vaccine in these heterotaxy patients. We also investigate the pneumococcal vaccination status in these patients.
Methods and Results In epidemiology study, we enroll consecutive 95 patients with heterotaxy syndrome and 142 patients with other complex CHDs born between 2001 and 2011 in our hospital. SBI was defined as sepsis with positive culture results or infection with abscess formation at sterile sites. With 1026 person-years follow-up, the 5-year survival rate was 52% and 65.7% in heterotaxy and complex CHD groups, respectively (p=0.239). Community acquired SBI (CASBI) occurred only in heterotaxy syndrome (13 episodes in 10 patients) with 2 and 5 years cumulative SBI rate of 9.6% and 14.5%, respectively. The overall mortality rate of those with community acquired SBI was 31%. Pneumococcus and Citrobacter freundii were the most common pathogens. Nosocomial SBI occurred in 33.3% of all patients. The rates and the pathogens of nosocomial SBI were similar between heterotaxy and complex CHD groups. The results implied that heterotaxy syndrome patients are at high risk for community acquired SBI and also have high mortality rate.
Second, we enrolled 46 heterotaxy syndrome patients, aged > 1 year, and followed during the period 2010-2012 in our hospital. We analyzed IgM+IgD+memory B cell percentages. Patients with simple CHD and complex CHD served as controls. The mean IgM memory B cell were the lowest in the heterotaxy syndrome group, compared with those in complex CHD and simple CHD groups. In the heterotaxy syndrome group, 41.3% had low IgM memory B cell percentages (<1% of B cells). Seven had a history of community-acquired bacterial infection and 85.7% of these had low IgM memory B cell percentages, which was the only significant factor related to community-acquired bacterial infection. (p=0.028).
Third, we analyzed the pneumococcal vaccination status for all patients with heterotaxy and complex CHD in our institution between 2010 and 2015. The geometric mean concentrations (GMCs) of serotypes 6B, 14, 19F, and 23F did not differ significantly between patients with heterotaxy and those with complex CHD. The GMCs were also not affected by impaired splenic function. Most patients had GMCs higher than 0.35 μg/mL (protection level) 4-5 years after either PPV or PCV injection. In some patients, the durability of PPV and PCV decreased with time, highlighting the importance of booster doses. In addition, 21.4% of 42 patients with heterotaxy did not receive any dose of pneumococcal vaccine, and none of 42 patients completely adhered to the vaccine guidelines.
Conclusion From epidemiology study, we found the CASBI was significantly higher in heterotaxy syndrome than other complex CHD patients, with high mortality rate. We also found IgM memory B cell percentage by flow cytometery analysis was the best predictive marker of community-acquired BI. The pneumococcal vaccine efficacy was acceptable in the heterotaxy syndrome, even in patients with impaired splenic function. However, the adherence to the vaccination guideline is still unsatisfactory.

並列關鍵字

heterotaxy ； complex congenital heart disease ； severe bacterial infection ； community acquired ； nosocomial ； IgM memory B cell ； flow cytometry ； pneumococcal conjugate vaccine ； pneumococcal polysaccharide vaccine

參考文獻

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