TIMP1 and MMP9 are predictors of mortality in septic patients in the emergency department and intensive care unit unlike MMP9/TIMP1 ratio: Multivariate model

Introduction
Matrix metalloproteinases and tissue inhibitors of metalloproteinases could be promising biomarkers for establishing prognosis during the development of sepsis. It is necessary to clarify the relationship between matrix metalloproteinases and their tissue inhibitors. We conducted a cohort study with 563 septic patients, in order to elucidate the biological role and significance of these inflammatory biomarkers and their relationship to the severity and mortality of patients with sepsis.
Materials and methods
A multicentric prospective cohort was performed. The sample was composed of patients who had sepsis as defined by the International Conference 2001. Serum procalcitonin, creatinine, urea nitrogen, C-Reactive protein, TIMP1, TIMP2, MMP2 and MMP9 were quantified; each patient was followed until death or up to 30 days. A descriptive analysis was performed by calculating the mean and the 95% confidence interval for continuous variables and proportions for categorical variables. A multivariate logistic regression model was constructed by the method of intentional selection of covariates with mortality at 30 days as dependent variable and all the other variables as predictors.
Results
Of the 563 patients, 68 patients (12.1%) died within the first 30 days of hospitalization in the ICU. The mean values for TIMP1, TIMP2 and MMP2 were lower in survivors, MMP9 was higher in survivors. Multivariate logistic regression showed that age, SOFA and Charlson scores, along with TIMP1 concentration, were statistically associated with mortality at 30 days of septic patients; serum MMP9 was not statistically associated with mortality of patients, but was a confounder of the TIMP1 variable.
Conclusion
It could be argued that plasma levels of TIMP1 should be considered as a promising prognostic biomarker in the setting of sepsis. Additionally, this study, like other studies with large numbers of septic patients does not support the predictive value of TIMP1 / MMP9.

引言
基质金属蛋白酶（matrix metalloproteinases, MMPs）与金属蛋白酶组织抑制剂（tissue inhibitors of metalloproteinases, TIMPs）有望成为脓毒症病程中预后评估的潜在生物标志物。明确二者之间的关联具有重要临床意义。本研究纳入563例脓毒症患者开展队列研究，旨在阐明这类炎症性生物标志物的生物学作用与临床价值，以及其与脓毒症患者病情严重程度和病死率的关联。

材料与方法
本研究为多中心前瞻性队列研究。研究对象为符合2001年国际脓毒症会议诊断标准的脓毒症患者。对患者血清中的降钙素原、肌酐、尿素氮、C反应蛋白、基质金属蛋白酶组织抑制剂1（TIMP1）、基质金属蛋白酶组织抑制剂2（TIMP2）、基质金属蛋白酶2（MMP2）及基质金属蛋白酶9（MMP9）进行定量检测；对所有患者进行随访，直至患者死亡或随访满30天。针对连续变量计算均值及95%置信区间，针对分类变量计算构成比，以此完成描述性分析。以患者30天病死率为因变量，其余所有指标为预测变量，采用协变量定向选择法构建多因素logistic回归模型。

结果
563例研究对象中，68例（12.1%）在ICU住院前30天内死亡。存活患者的血清TIMP1、TIMP2及MMP2水平均低于非存活患者，而MMP9水平则高于非存活患者。多因素logistic回归分析结果显示，年龄、序贯器官衰竭评分（Sequential Organ Failure Assessment, SOFA）、查尔森评分（Charlson scores）以及血清TIMP1浓度与脓毒症患者30天病死率存在统计学关联；血清MMP9水平与患者病死率无统计学关联，但为TIMP1的混杂因素。

结论
综上可见，血浆TIMP1水平可作为脓毒症预后评估的潜在生物标志物。此外，本研究与其他纳入大量脓毒症患者的研究一致，均不支持TIMP1/MMP9的预测价值。