脓毒症真菌感染流行病学特征和防御素遗传变异
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摘要
第一部分重症脓毒症侵袭性真菌感染的流行病学调查
研究目的：
真菌是重症脓毒症中重要的病原微生物。在罹患重症脓毒症的危重病患者中,侵袭性真菌感染可能导致死亡率的进一步增高和相应医疗资源消耗的增加。本研究旨在通过流行病学研究,报道国内大学附属医院重症监护室(ICU)内重症脓毒症患者真菌感染的流行病学特征,并通过配对研究阐明侵袭性真菌感染对脓毒症预后的影响。
研究方法：
调阅国内十家大学附属医院外科ICU2004年12月至2005年11月期间所有患者的病历记录,筛选出住ICU期间发生重症脓毒症者,登记相应的人口学信息、ICU日常监测指标和检验结果、真菌感染情况、住院时间、住ICU时间和预后。根据是否发生侵袭性真菌感染(由真菌培养或病理组织学检查证实),将重症脓毒症患者分为真菌感染组和对照组。根据所在ICU、性别、年龄以及APACHEⅡ评分等参数,在两组中选择相应病人按1：1配对,进行统计分析。
研究结果：
在所研究的时间段内,十家参与单位的外科ICU共收入318名重症脓毒症患者,其中有90人(28.3%)发生了侵袭性真菌感染。在这些患者的血液、体液或组织标本中共分离到真菌100株,其中最主要的菌种为白色念珠菌(C. albicans,占58%)。Logistic回归分析表明,机械通气(大于3天)、APACHEⅡ评分、同时合并革兰阳性和革兰阴性细菌感染以及留置导尿(大于3天)是重症脓毒症患者ICU内发生侵袭性真菌感染的独立危险因素。配对研究发现,相比未发生真菌感染的重症脓毒症患者,发生侵袭性感染者具有更高的死亡率(p<0.001)和住院费用(p=0.038),以及更长的住ICU时间(p<0.001)和住院时间(p=0.020)。
研究结论：
侵袭性真菌感染是重症脓毒症患者中的一种常见感染,且与死亡风险增高、住ICU和住院时间延长、医疗资源消耗增加相关。
第二部分β-防御素1基因多态性与重症脓毒症真菌易感性的相关性研究
研究目的：
通过病例—对照关联研究,探讨β-防御素1(DEFB1)基因多态性与重症脓毒症患者真菌感染易感性的相关性。
研究方法：
依据1992年和2002年美国胸科医师协会／美国危重病学会(ACCM/SCCM)联席会议制订的重症脓毒症定义,将重症监护病房(ICU)中符合重症脓毒症诊断标准的211例患者纳入研究,并根据住ICU期间是否发生真菌感染将其进一步分为真菌感染组和对照组。通过DNA直接测序、聚合酶联反应双引物等位基因特异性扩增法(PCR-ASA)或Taqman方法检测DEFB1基因-1816A／G、-390A／T、-52A／G、-44C／G、-20A／G等五个位点在两组患者中的等位基因和基因型,用遗传分析法计算其单倍型的分布频率,采用x~2检验或Fisher精确概率法分析这些遗传变异与重症脓毒症患者真菌感染易感性的相关性,并以相对风险度(odds ratio, OR)反映该遗传因素与其关联的程度。
研究结果：
真菌感染组共纳入80例患者,对照组为131例。真菌感染组中男性43例(53.8%),平均年龄60.81±18.30岁；对照组男性80例(61.1%),平均年龄60.42±17.03岁。两组间性别组成、平均年龄无显著性差异(p>0.05)。DEFB1基因-1816A／G、-390A／T、-52A／G、-44C／G和-20A／G位点在两组人群中都遵守Hardy-Weinberg平衡,其基因型分布和等位基因频率在真菌感染组和对照组之间无显著性差异(所有p>0.05)。上述5个位点的常见单倍型AAACG, ATGCA, GTGGG和ATACG在真菌感染组和对照组之间的分布频率无统计学差异(所有p>0.05)
研究结论：
DEFB1基因-1816A／G、-390A／T、-52A／G、-44C／G和-20A／G位点与重症脓毒症患者真菌感染的发生不相关,提示DEFB1基因遗传变异可能不是重症脓毒症患者真菌易感性的一个重要遗传学靶标。
Part 1 Epidemiology of invasive fungal infection in severe sepsis
Objective:
Invasive fungal infection (IFI) is increasingly common in critical illness with severe sepsis and may be associated with extra mortality and resourse consumption. The aim of this study was to determine the rate and characteristics of IFI in severe sepsis within Chinese intensive care units (ICUs), as well as to investigate the impact of IFI on the outcomes of critically ill surgical patients with severe sepsis by means of matched cohort analysis.
Methods:
Records for all admissions to 10 university hospital surgical intensive care units (ICUs) from December 2004 to November 2005 were reviewed. Patients who met criteria for severe sepsis were included. IFI was identified using established criteria based on microbiologic or histological evidence. A matched cohort study was conducted to analyze the relationship between IFI and outcomes of severe sepsis.
Results:
A total of 318 patients with severe sepsis were enrolled during the study period, of whom 90 (28.3%) were identified as having IFI. A total of 100 strains of fungi (58% Candida albicans) were isolated from these patients. Independent risk factors for IFI in patients with severe sepsis included mechanical ventilation (>3 days), Acute Physiology and Chronic Health Evaluation score, coexisting infection with both Gram-positive and Gram-negative bacteria, and urethral catheterization (>3 days). Compared with the control cohort, IFI was associated with increased hospital mortality (P＜0.001), high hospital costs (P=0.038), and prolonged stay in the ICU (P<0.001) and hospital (P =0.020).
Conclusion:
IFI is frequent in patients with severe sepsis in surgical ICUs and is associated with excess risk for hospital mortality, longer ICU and hospital stays, and greater consumption of medical resources.
Part 2 Association study betweenβ-defensin 1 gene polymorphisms and fungal infection in severe sepsis
Objective:
To investigate whether single nucleotide polymorphisms (SNPs) and haplotypes within the promoter ofβ-defensin 1 (DEFB1) gene are associated with the incidence of fungal infection in patients suffering from severe sepsis by case-control association analysis.
Method:
In the present case-control study,211 patients with severe sepsis were enrolled. Sepsis was diagnosed according to the American College of Chest Physician/Society of Critical Care Medicine Consensus Conference Communittee criteria and severity of sepsis was assessed using the Sepsis-related Organ Failure Assessment Score. Based on the detection of fungal infection during the ICU stay, the 211 patients were divided into the fungal infection group (groupⅠ) or the control group (group C). Genotypes of-1816A/G,-390A/T,-52A/G,-44C/G and-20A/G within DEFB1 gene were assayed in all 211 patients by means of direct sequencing, Allele-specific PCR amplifications or high-throughput site-specific TaqMan assay. Haplotype was estimated using StatSNPs program. The association between the genomic variations (allele, genotype and haplotype) and fungal infection were analyzed using x2-test or Fisher's exact test. Odds ratios in the case-control study were calculated to evaluate allele's risk for the predisposition to fungal infection in severe sepsis.
Results:
GroupⅠenrolled 80 patients,43 of which were male, with a mean age of 60.81±18.30. GroupⅠenrolled 131 patients,80 of which were male, with a mean age of 60.42±17.03. The two groups had similar gender composition and mean age (all, p>0.05) Assayed SNPs of both groups were in Hardy-Weinberg equilibrium. The distributions of allelic frequencies and genotype frequencies between groupⅠand group C showed no significant difference (all, p>0.05). Four common haplotypes AAACG, ATGCA, GTGGG and ATACG were estimated in the studied cohort. The distributions of haplotype frequencies in the defined groups showed no significant difference (all, p>0.05).
Conclusion:
The genomic variations within DEFB1 gene were not associated with fungal infections in severe sepsis. These findings suggest that DEFB1 gene polymorphism may not serve as an important genetic marker for predisposition to fungal infection in severe sepsis.
研究目的：
真菌是重症脓毒症中重要的病原微生物。在罹患重症脓毒症的危重病患者中,侵袭性真菌感染可能导致死亡率的进一步增高和相应医疗资源消耗的增加。本研究旨在通过流行病学研究,报道国内大学附属医院重症监护室(ICU)内重症脓毒症患者真菌感染的流行病学特征,并通过配对研究阐明侵袭性真菌感染对脓毒症预后的影响。
研究方法：
调阅国内十家大学附属医院外科ICU2004年12月至2005年11月期间所有患者的病历记录,筛选出住ICU期间发生重症脓毒症者,登记相应的人口学信息、ICU日常监测指标和检验结果、真菌感染情况、住院时间、住ICU时间和预后。根据是否发生侵袭性真菌感染(由真菌培养或病理组织学检查证实),将重症脓毒症患者分为真菌感染组和对照组。根据所在ICU、性别、年龄以及APACHEⅡ评分等参数,在两组中选择相应病人按1：1配对,进行统计分析。
研究结果：
在所研究的时间段内,十家参与单位的外科ICU共收入318名重症脓毒症患者,其中有90人(28.3%)发生了侵袭性真菌感染。在这些患者的血液、体液或组织标本中共分离到真菌100株,其中最主要的菌种为白色念珠菌(C. albicans,占58%)。Logistic回归分析表明,机械通气(大于3天)、APACHEⅡ评分、同时合并革兰阳性和革兰阴性细菌感染以及留置导尿(大于3天)是重症脓毒症患者ICU内发生侵袭性真菌感染的独立危险因素。配对研究发现,相比未发生真菌感染的重症脓毒症患者,发生侵袭性感染者具有更高的死亡率(p<0.001)和住院费用(p=0.038),以及更长的住ICU时间(p<0.001)和住院时间(p=0.020)。
研究结论：
侵袭性真菌感染是重症脓毒症患者中的一种常见感染,且与死亡风险增高、住ICU和住院时间延长、医疗资源消耗增加相关。
第二部分β-防御素1基因多态性与重症脓毒症真菌易感性的相关性研究
研究目的：
通过病例—对照关联研究,探讨β-防御素1(DEFB1)基因多态性与重症脓毒症患者真菌感染易感性的相关性。
研究方法：
依据1992年和2002年美国胸科医师协会／美国危重病学会(ACCM/SCCM)联席会议制订的重症脓毒症定义,将重症监护病房(ICU)中符合重症脓毒症诊断标准的211例患者纳入研究,并根据住ICU期间是否发生真菌感染将其进一步分为真菌感染组和对照组。通过DNA直接测序、聚合酶联反应双引物等位基因特异性扩增法(PCR-ASA)或Taqman方法检测DEFB1基因-1816A／G、-390A／T、-52A／G、-44C／G、-20A／G等五个位点在两组患者中的等位基因和基因型,用遗传分析法计算其单倍型的分布频率,采用x~2检验或Fisher精确概率法分析这些遗传变异与重症脓毒症患者真菌感染易感性的相关性,并以相对风险度(odds ratio, OR)反映该遗传因素与其关联的程度。
研究结果：
真菌感染组共纳入80例患者,对照组为131例。真菌感染组中男性43例(53.8%),平均年龄60.81±18.30岁；对照组男性80例(61.1%),平均年龄60.42±17.03岁。两组间性别组成、平均年龄无显著性差异(p>0.05)。DEFB1基因-1816A／G、-390A／T、-52A／G、-44C／G和-20A／G位点在两组人群中都遵守Hardy-Weinberg平衡,其基因型分布和等位基因频率在真菌感染组和对照组之间无显著性差异(所有p>0.05)。上述5个位点的常见单倍型AAACG, ATGCA, GTGGG和ATACG在真菌感染组和对照组之间的分布频率无统计学差异(所有p>0.05)
研究结论：
DEFB1基因-1816A／G、-390A／T、-52A／G、-44C／G和-20A／G位点与重症脓毒症患者真菌感染的发生不相关,提示DEFB1基因遗传变异可能不是重症脓毒症患者真菌易感性的一个重要遗传学靶标。
Part 1 Epidemiology of invasive fungal infection in severe sepsis
Objective:
Invasive fungal infection (IFI) is increasingly common in critical illness with severe sepsis and may be associated with extra mortality and resourse consumption. The aim of this study was to determine the rate and characteristics of IFI in severe sepsis within Chinese intensive care units (ICUs), as well as to investigate the impact of IFI on the outcomes of critically ill surgical patients with severe sepsis by means of matched cohort analysis.
Methods:
Records for all admissions to 10 university hospital surgical intensive care units (ICUs) from December 2004 to November 2005 were reviewed. Patients who met criteria for severe sepsis were included. IFI was identified using established criteria based on microbiologic or histological evidence. A matched cohort study was conducted to analyze the relationship between IFI and outcomes of severe sepsis.
Results:
A total of 318 patients with severe sepsis were enrolled during the study period, of whom 90 (28.3%) were identified as having IFI. A total of 100 strains of fungi (58% Candida albicans) were isolated from these patients. Independent risk factors for IFI in patients with severe sepsis included mechanical ventilation (>3 days), Acute Physiology and Chronic Health Evaluation score, coexisting infection with both Gram-positive and Gram-negative bacteria, and urethral catheterization (>3 days). Compared with the control cohort, IFI was associated with increased hospital mortality (P＜0.001), high hospital costs (P=0.038), and prolonged stay in the ICU (P<0.001) and hospital (P =0.020).
Conclusion:
IFI is frequent in patients with severe sepsis in surgical ICUs and is associated with excess risk for hospital mortality, longer ICU and hospital stays, and greater consumption of medical resources.
Part 2 Association study betweenβ-defensin 1 gene polymorphisms and fungal infection in severe sepsis
Objective:
To investigate whether single nucleotide polymorphisms (SNPs) and haplotypes within the promoter ofβ-defensin 1 (DEFB1) gene are associated with the incidence of fungal infection in patients suffering from severe sepsis by case-control association analysis.
Method:
In the present case-control study,211 patients with severe sepsis were enrolled. Sepsis was diagnosed according to the American College of Chest Physician/Society of Critical Care Medicine Consensus Conference Communittee criteria and severity of sepsis was assessed using the Sepsis-related Organ Failure Assessment Score. Based on the detection of fungal infection during the ICU stay, the 211 patients were divided into the fungal infection group (groupⅠ) or the control group (group C). Genotypes of-1816A/G,-390A/T,-52A/G,-44C/G and-20A/G within DEFB1 gene were assayed in all 211 patients by means of direct sequencing, Allele-specific PCR amplifications or high-throughput site-specific TaqMan assay. Haplotype was estimated using StatSNPs program. The association between the genomic variations (allele, genotype and haplotype) and fungal infection were analyzed using x2-test or Fisher's exact test. Odds ratios in the case-control study were calculated to evaluate allele's risk for the predisposition to fungal infection in severe sepsis.
Results:
GroupⅠenrolled 80 patients,43 of which were male, with a mean age of 60.81±18.30. GroupⅠenrolled 131 patients,80 of which were male, with a mean age of 60.42±17.03. The two groups had similar gender composition and mean age (all, p>0.05) Assayed SNPs of both groups were in Hardy-Weinberg equilibrium. The distributions of allelic frequencies and genotype frequencies between groupⅠand group C showed no significant difference (all, p>0.05). Four common haplotypes AAACG, ATGCA, GTGGG and ATACG were estimated in the studied cohort. The distributions of haplotype frequencies in the defined groups showed no significant difference (all, p>0.05).
Conclusion:
The genomic variations within DEFB1 gene were not associated with fungal infections in severe sepsis. These findings suggest that DEFB1 gene polymorphism may not serve as an important genetic marker for predisposition to fungal infection in severe sepsis.
引文
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