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

Date Published: February 13, 2017

Publisher: Public Library of Science

Author(s): Maria Eugenia Niño, Sergio Eduardo Serrano, Daniela Camila Niño, Diana Margarita McCosham, Maria Eugenia Cardenas, Vivian Poleth Villareal, Marcos Lopez, Antonio Pazin-Filho, Fabian Alberto Jaimes, Fernando Cunha, Richard Schulz, Diego Torres-Dueñas, Aamir Ahmad.


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.

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.

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.

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.

Partial Text

Sepsis is a complex, multisystemic, and variable clinical process, produced by pathogenic microorganisms causing a deleterious systemic response in the host [1]. In the United States, the incidence of severe sepsis is estimated to be 300 cases per 100 000 persons [2]. Many resources and research projects have focused on the study of biomarkers for sepsis that would allow early diagnosis of this syndrome, improve its course, and decrease morbidity and mortality. In this regard, there have been multiple biomarkers used in the diagnosis and stratification of sepsis, including interleukins, cytokines, C-reactive protein, procalcitonin, lipopolysaccharide binding protein, coagulation factors, atrial natriuretic peptide and brain natriuretic peptide (ANP and BNP respectively), among many others [3,4].

Graphic tests of the normality of the variables were performed and it was found that the variables followed an approximately normal distribution; therefore, means with their respective confidence intervals were used.

Currently mortality remains very high in sepsis and even more so in septic shock. In addition, diagnosis and course definition are complex due to the multiple factors involved [19]. Current studies suggest that people with a pre-existing chronic disease, people of older age, male gender and/or black race with an acute infection deteriorate faster and therefore are more susceptible to develop severe sepsis. Furthermore, the epidemiology of severe sepsis in developing countries may differ significantly from developed countries, which should be defined and taken into account in future research [20]. Hence, it represents a challenge to find biomarkers that improve diagnostic accuracy, define the course, timing and type of therapeutic intervention [4, 21].

Taking everything into account, our study presents a multivariate model with five variables, four significant variables which include TIMP1, and MMP9 as a confounding variable with potential use in clinical practice. Therefore, and considering the size of the patient population and the multivariate prediction model of mortality used here, 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 ratio. Further studies are required to better define the pathophysiological role of TIMP1 and how it could be a therapeutic target.




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