Department of Anesthesiology and Intensive Therapy, Semmelweis University, Kútvölgyi út 4, Budapest, Hungary.
Crit Care. 2010;14(2):R79. doi: 10.1186/cc8992. Epub 2010 Apr 29.
Activation of inflammation and coagulation are closely related and mutually interdependent in sepsis. The acute-phase protein, plasminogen activator inhibitor-1 (PAI-1) is a key element in the inhibition of fibrinolysis. Elevated levels of PAI-1 have been related to worse outcome in pneumonia. We aimed to evaluate the effect of functionally relevant 4G/5G polymorphism of PAI-1 gene in pneumonia induced sepsis.
We enrolled 208 Caucasian patients with severe sepsis due to pneumonia admitted to an intensive care unit (ICU). Patients were followed up until ICU discharge or death. Clinical data were collected prospectively and the PAI-1 4G/5G polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism technique. Patients were stratified according to the occurrence of multiple organ dysfunction syndrome, septic shock or death.
We found that carriers of the PAI-1 4G/4G and 4G/5G genotypes have a 2.74-fold higher risk for multiple organ dysfunction syndrome (odds ratio [OR] 95% confidence interval [CI] = 1.335 - 5.604; p = 0.006) and a 2.57-fold higher risk for septic shock (OR 95%CI = 1.180 - 5.615; p = 0.018) than 5G/5G carriers. The multivariate logistic regression analysis adjusted for independent predictors, such as age, nosocomial pneumonia and positive microbiological culture also supported that carriers of the 4G allele have a higher prevalence of multiple organ dysfunction syndrome (adjusted odds ratio [aOR] = 2.957; 95%CI = 1.306 -6.698; p = 0.009) and septic shock (aOR = 2.603; 95%CI = 1.137 - 5.959; p = 0.024). However, genotype and allele analyses have not shown any significant difference regarding mortality in models non-adjusted or adjusted for acute physiology and chronic health evaluation (APACHE) II. Patients bearing the 4G allele had higher disseminated intravascular coagulation (DIC) score at admission (p = 0.007) than 5G/5G carriers. Moreover, in 4G allele carriers the length of ICU stay of non-survivors was longer (p = 0.091), fewer ventilation-free days (p = 0.008) and days without septic shock (p = 0.095) were observed during the first 28 days.
In Caucasian patients with severe sepsis due to pneumonia carriers of the 4G allele of PAI-1 polymorphism have higher risk for multiple organ dysfunction syndrome and septic shock and in agreement they showed more fulminant disease progression based on continuous clinical variables.
在脓毒症中，炎症和凝血的激活密切相关且相互依存。纤溶酶原激活物抑制剂-1（PAI-1）是急性期蛋白，是抑制纤维蛋白溶解的关键因素。PAI-1 水平升高与肺炎的预后较差有关。我们旨在评估肺炎引起的脓毒症中 PAI-1 基因功能相关 4G/5G 多态性的作用。
我们纳入了 208 名因肺炎导致严重脓毒症并入住重症监护病房（ICU）的高加索患者。患者被随访至 ICU 出院或死亡。前瞻性收集临床数据，并通过聚合酶链反应-限制性片段长度多态性技术对 PAI-1 4G/5G 多态性进行基因分型。根据是否发生多器官功能障碍综合征、感染性休克或死亡对患者进行分层。
我们发现，PAI-1 4G/4G 和 4G/5G 基因型携带者发生多器官功能障碍综合征的风险增加 2.74 倍（优势比[OR]95%置信区间[CI] = 1.335-5.604；p = 0.006），发生感染性休克的风险增加 2.57 倍（OR 95%CI = 1.180-5.615；p = 0.018），而 5G/5G 携带者。多变量逻辑回归分析调整了年龄、医院获得性肺炎和阳性微生物培养等独立预测因素后，也支持携带 4G 等位基因的患者多器官功能障碍综合征（调整优势比[aOR] = 2.957；95%CI = 1.306-6.698；p = 0.009）和感染性休克（aOR = 2.603；95%CI = 1.137-5.959；p = 0.024）的发生率更高。然而，在非调整或调整急性生理学和慢性健康评估（APACHE）II 的模型中，基因型和等位基因分析均未显示死亡率存在任何显著差异。携带 4G 等位基因的患者在入院时弥散性血管内凝血（DIC）评分更高（p = 0.007），而 5G/5G 携带者则更低。此外，在 4G 等位基因携带者中，非幸存者的 ICU 住院时间更长（p = 0.091），无通气天数（p = 0.008）和无感染性休克天数（p = 0.095）在第 28 天前减少。
在因肺炎导致严重脓毒症的高加索患者中，PAI-1 多态性 4G 等位基因携带者发生多器官功能障碍综合征和感染性休克的风险更高，并且根据持续的临床变量，他们表现出更严重的疾病进展。
