化膿性肝膿瘍致病菌、危險因子及其臨床特性之研究

Pathogens, Risk Factors and Clinical Characteristics of Pyogenic Liver Abscesses

陳宣志(Shiuan-Chih Chen)

指導教授 ： 林肇堂 ； 李孟智

中山醫學大學/醫學院/醫學研究所/博士(2006年)

摘要

研究背景和目的： 化膿性肝膿瘍一直是危及生命的疾病，且隨著時代的進展，其主要病因和致病菌亦有所不同。其中仍存在許多問題尚待釐清。本論文包含四部分的研究。研究一：主要是描述膽因(biliary origin)和致病因不明(cryptogenic origin)所致的化膿性肝膿瘍之臨床表徴，並比較這兩組致病因的病患臨床結果(outcome)之差異。研究二：主要是探討Escherichia coli所致的化膿性肝膿瘍之臨床表徴，及影響死亡之預後因子(prognostic factors related to mortality)。研究三：E. coli和Klebsiella pneumoniae為化膿性肝膿瘍最常見的致病菌；此研究主要是比較這兩種致病菌所致化膿性肝膿瘍的病患臨床結果(outcome)之差異。研究四：主要是探究化膿性肝膿瘍發展成肝外轉移性感染之危險因子。
研究方法：研究一：研究對象為1996年1月至2003年12月間，年齡大於等於19歲，因化膿性肝膿瘍而在中山醫學大學附設醫院住院的病人共86名。收集並記錄這些病患的人口學和住院臨床資料。依據其致病因的不同，此86名病患分成兩組，分別為膽因組34名，致病因不明組52名。研究二：研究對象為1996年7月至2002年6月間，年齡大於等於18歲，因E. coli所致化膿性肝膿瘍而於臺灣中部兩所醫學中心住院的病人共72名。收集並記錄這些病患的人口學和住院臨床資料來進一步分析。研究三：研究對象為2000年7月至2005年6月間，因E. coli或K. pneumoniae所致的化膿性肝膿瘍而在臺灣中部一所醫學中心住院的病人共202名(128名男性，74名女性；年齡為19至89歲)。回溯性地收集並記錄這些病患的人口學和病歷資料。依據其致病菌的不同，此202名病患分成兩組，分別為E. coli組55名，K. pneumoniae組147名。運用多變量分析其預測因子和危險因子。研究四：研究對象為1995年1月至2000年6月間，年齡為19至93歲，因化膿性肝膿瘍而在臺灣中部一所醫學中心住院的病人共225名。回溯性地收集並記錄這些病患的人口學和住院臨床資料。依據其發展成肝外轉移性感染之有無，將此225名病患分成兩組，分別為有轉移性感染組24名，非轉移性感染組201名。
研究結果：研究一：膽因組的病患有較高的比例患有癌症病史和Murphy’s sign。關於致病菌方面，E. coli較常出現在膽因組，K. pneumoniae則有較高的比例出現在致病因不明組，而厭氧菌則較少在致病因不明組培養出來。控制年齡、性別和入院前症狀出現的天數等變項，兩組在死亡率上並無差異(膽因組vs.致病因不明組：15% vs. 8%; 調整後勝算比[adjusted odds ratio, adjusted OR], 1.43; 95%信賴區間[confidence interval, CI], 0.24-8.3; p = 0.899)。同樣地控制這些變項，膽因組在入院後發燒超過一週(time to defervesce > 1 week) (膽因組vs.致病因不明組：68% vs. 40%; adjusted OR, 3.1; 95% CI, 1.1-9.0, p = 0.030)和住院超過三週(hospital stay > 3 weeks) (膽因組vs.致病因不明組：47% vs. 15%; adjusted OR, 4.3; 95% CI, 1.5-14; p = 0.007)上，有明顯較高的比例。研究二：E. coli所致化膿性肝膿瘍的死亡率(overall mortality rate)為26%。E. coli所致化膿性肝膿瘍大部分為單一膿瘍、侵犯肝右葉、及合併有多重細菌感染(polymicrobial infections)。這些肝膿瘍的致病因源自膽道系統疾病有48名(67%)。同時罹患的疾病中，最常見為糖尿病(31%)和癌症(31%)。有4名病患被發現有轉移性感染(metastatic infection)。經由多變量分析顯示，罹患癌症病史(underlying malignancy)(p = 0.034)、顯著的低白蛋白血症(profound hypoalbuminemia; serum albumin level < 2.5 g/dL)(p = 0.008) 、及多發性肝膿瘍(multiple liver abscesses)(p = 0.004)為影響死亡的預後因子。研究三：經由控制年齡、性別和入院前症狀出現的天數等變項，E. coli組有較高的比例患有膽石症、癌症、膽因所致肝膿瘍、多重細菌感染、厭氧菌感染、多重抗藥菌種、及不適當的起始抗生素治療；此外，這組病患在入院之後有較長的發燒天數。而在K. pneumoniae組有較高的比例患有糖尿病、肝膿瘍直徑> 5公分、及致病因不明的肝膿瘍。經調整之後，E. coli組有較高的死亡率(E. coli組vs. K. pneumoniae組, 26% vs. 4%; adjusted OR, 5.9; 95%CI, 2.0-17; p = 0.001)。兩組在住院天數並無差異。將兩組病患合併，經由多變量分析顯示，罹患癌症(p = 0.005)、多重抗藥菌種(p = 0.001)、右葉肝膿瘍(p = 0.01)、及肋膜積水(p = 0.03)，顯著地與其致死有關。研究四：經由控制年齡、性別和入院前症狀出現的天數等變項，糖尿病(adjusted OR, 12; 95% CI, 3.3-67)、酒精中毒(adjusted OR, 5.2; 95% CI, 1.4-20)、症狀開始至適當抗生素給予時間> 7天(adjusted OR, 3.9; 95% CI, 1.2-13)、菌血症(adjusted OR, 5.4; 95% CI, 1.4-30)、及K. pneumoniae感染(adjusted OR, 5.0; 95% CI, 1.1-47)等變項，與肝外轉移性感染有關。另一方面，發燒(adjusted OR, 0.28; 95% CI, 0.089-0.92)和右上腹部壓痛(adjusted OR, 0.091; 95% CI, 0.0020-0.50)較少出現在有肝外轉移性感染的患者。經由多變量分析顯示，罹患糖尿病(multivariate OR, 7.7; 95% CI, 2.1-29)和酒精中毒(multivariate OR, 8.9; 95% CI, 2.6-30)為發展肝外轉移性感染之危險因子；然右上腹部壓痛(multivariate OR, 0.11; 95% CI, 0.014-0.87)則為無轉移性感染之預測因子。
研究結論： 研究一結果發現致病因不明組的病患有較少的比例需要住院超過三週和入院後發燒超過一週，顯示這組的病患比膽因組有較佳臨床反應(clinical response)。研究二結果顯示E. coli所致化膿性肝膿瘍最主要的致病因，為膽道系統疾病(biliary diseases)；同時此研究亦發現E. coli所致化膿性肝膿瘍之致死，與罹患癌症、顯著的低白蛋白血症及多發性肝膿瘍有關。研究三結果發現E. coli所致化膿性肝膿瘍明顯比K. pneumoniae所致之死亡率還高，其導因於E. coli所致化膿性肝膿瘍患者有較高比例罹患癌症、有肋膜積水、及具有多重抗藥菌種。研究四顯示糖尿病和酒精中毒為化膿性肝膿瘍發展成肝外轉移性感染之危險因子；此研究結果似乎顯示病患的罹病狀態影響著肝外轉移性感染之形成。

關鍵字

化膿性肝膿瘍 ； 大腸桿菌 ； 克雷伯氏肺炎桿菌 ； 危險因子 ； 轉移性感染 ； 臨床特性

並列摘要

Background and Objectives: Pyogenic liver abscess is a potentially life-threatening disorder affecting a wide variety of patients. The main pathogenesis and the leading causative pathogen of pyogenic liver abscesses have changed over time. This thesis includes four studies. The aim of the studies is (1) to delineate the clinical features of pyogenic liver abscesses of biliary and cryptogenic origin, and to compare the differences in outcome of patients between the two groups; (2) to investigate the clinical characteristics, outcome, and prognostic factors related to mortality in patients with Escherichia coli liver abscess; (3) to compare patient outcome between those with E. coli and those with Klebsiella pneumoniae liver abscesses; (4) to identify the risk factors for developing extra-hepatic metastases from pyogenic liver abscesses.
Methods: (1) Study 1: I studied 86 patients, aged 19 years or older, with pyogenic liver abscess admitted to Chung Shan Medical University Hospital, Taichung, Taiwan, between January 1996 and December 2003. The demographic data and medical information of the patients were reviewed and recorded. Of the 86 patients, 34 were classified into the biliary group and 52 were classified into the cryptogenic group. (2) Study 2: I retrospectively analyzed 72 patients aged 18 years and older who were diagnosed as having E. coli liver abscesses from July 1996 to June 2002 at two medical centers in Taiwan. (3) Study 3: I conducted a retrospective study of 202 patients (128 men and 74 women; age, 19-89 years) with a discharge diagnosis of pyogenic liver abscess with either E. coli or K. pneumoniae from a medical centre in Taiwan, from July 2000 to June 2005. Clinical data were collected from medical records. Of the 202 patients, 55 were classified into the E. coli group and 147 were classified into the K. pneumoniae group. Clinical predictors and risk factors were analyzed by multivariate analysis. (4) Study 4: I conducted a retrospective study and reviewed 225 patients (age, 19-93 years) with a discharge diagnosis of pyogenic liver abscess from a large medical centre in Taiwan, between January 1995 and June 2000. Clinical data were collected from medical records. Of the 225 patients with a pyogenic liver abscess, 24 had extra-hepatic metastases and were classified into the metastatic infection group; the remaining 201 were classified into the non-metastatic infection group and served as the control group. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by exact logistic regression.
Results: (1) Study 1: Patients with pyogenic liver abscesses of biliary origin had a higher frequency of underlying malignancy and Murphy’s sign compared to those with pyogenic liver abscesses of cryptogenic origin. With respect to specific pathogens, E. coli were more prevalent in the biliary group while K. pneumoniae were more prevalent in the cryptogenic group. Anaerobic isolates were less frequently cultured in the cryptogenic group than in the biliary group. After adjustment for age, sex, and the duration of symptoms before admission, there was no difference in mortality between both groups (biliary vs. cryptogenic: 15% vs. 8%; adjusted OR, 1.4; 95% CI, 0.24-8.3; p = 0.899). After adjustment for confounders, patients in the biliary group had higher frequencies of time to defervesce >1 week after admission (68% vs. 40%; adjusted OR, 3.1; 95% CI, 1.1-9.0, p = 0.030) and hospital stay > 3 weeks (47% vs. 15%; adjusted OR, 4.3; 95% CI, 1.5-14; p = 0.007) than those in the cryptogenic group. (2) Study 2: The overall mortality rate was 26%. The majority of E. coli liver abscesses was solitary, involved the right lobe of the liver, and comprised polymicrobial infections. The cause of the liver abscess involved the biliary system in 48 patients (67%). The most common concomitant diseases were diabetes mellitus (31%) and underlying malignancy (31%). Metastatic infection was found in 4 patients (6%). Mmultivariate analysis revealed that underlying malignancy (p= 0.034), profound hypoalbuminemia (< 2.5 g/dL) (p= 0.008), and multiple abscesses (p= 0.004) were the most significantly prognostic factors for mortality. (3) Study 3: After adjusting for sex, age, and the duration of prodromal symptoms before admission, patients in the E. coli group had a higher frequency of biliary stone disorder, underlying malignancy, abscess of biliary origin, mixed bacterial infection, anaerobes, multi-drug resistant isolates, and inappropriate initial antibiotic treatment; furthermore, these patients required a longer duration of time to defervesce after admission. Patients in the K. pneumoniae group had a higher proportion of diabetes mellitus, abscess size > 5 cm in diameter, and abscess of cryptogenic origin. After covariate adjustment, patients in the E. coli group had a higher mortality rate than those in the K. pneumoniae group (26% vs. 4%; adjusted OR, 5.9; 95% CI, 2.0 to 17; p = 0.001). There were no differences in recurrence of abscess or duration of hospital stay between the two groups. To identify the risk factors for mortality among all patients, I performed bivariate and multivariate analysis and found that malignancy (p = 0.005), multi-drug resistant isolates (p = 0.001), right-lobe abscess (p = 0.01), and presence of pleural effusion (p = 0.03) were significantly associated with mortality. (4) Study 4: After adjustment for age, sex, and the duration of symptoms before admission, diabetes mellitus (adjusted OR, 12; 95% CI, 3.3-67), alcoholism (adjusted OR, 5.2; 95% CI, 1.4-20), the time interval > 7 days from the onset of symptoms to the time appropriate antibiotics were administered (adjusted OR, 3.9; 95% CI, 1.2-13), bacteremia (adjusted OR, 5.4; 95% CI, 1.4-30), and Klebsiella pneumoniae infection (adjusted OR, 5.0; 95% CI, 1.1-47) were associated with the development of extra-hepatic metastases from pyogenic liver abscesses. On the other hand, fever (adjusted OR, 0.28; 95% CI, 0.089-0.92) and right upper quadrant pain/tenderness (adjusted OR, 0.091; 95% CI, 0.0020-0.50) were associated with the non-metastatic abscesses. I performed a multivariate analysis and found that diabetes mellitus (multivariate OR, 7.7; 95% CI, 2.1-29) and alcoholism (multivariate OR, 8.9; 95% CI, 2.6-30) were the independent risk factors for developing metastatic infections; yet right upper quadrant pain/tenderness (multivariate OR, 0.11; 95% CI, 0.014-0.87) was the predictor of no metastatic abscesses.
Conclusions: Study 1: This report highlights that pyogenic liver abscesses of cryptogenic origin had a benign clinical response, which was associated with shorter duration of hospitalization and time to defervesce after admission, compared to those of biliary origin. Study 2: The predominant cause of E. coli liver abscess is biliary diseases. Underlying malignancy, profound hypoalbuminemia and multiple abscesses are the prognostic factors for mortality among patients with E. coli liver abscesses. Study 3: Our data suggest that patients with E. coli liver abscesses have a high mortality rate due to high frequency of underlying malignancy, the presence of pleural effusion, and multi-drug resistant isolates. Study 4: Our results suggest that diabetes mellitus and alcoholism are significant risk factors for developing metastatic infections from pyogenic liver abscesses. The findings seem to imply that underlying conditions of the host influence the development of extra-hepatic metastases from pyogenic liver abscesses.

並列關鍵字

pyogenic liver abscess ； Escherichia coli ； Klebsiella pneumoniae ； risk factor ； metastatic infection ； clinical characteristics

參考文獻

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