miR-155 Predicts Long-Term Mortality in Critically Ill Patients Younger than 65 Years

Abstract

Introduction: Alterations in miR-155 serum levels have been described in inflammatory and infectious diseases. Moreover, a role for miR-155 in aging and age-related diseases was recently suggested. We therefore analyzed a potential age-dependent prognostic value of circulating miR-155 as a serum-based marker in critical illness.

Methods: Concentrations of circulating miR-155 were determined in 218 critically ill patients and 76 healthy controls.

Results: By using qPCR, we demonstrate that miR-155 serum levels are elevated in patients with critical illness when compared to controls. Notably, levels of circulating miR-155 were independent on the severity of disease, the disease etiology, or the presence of sepsis. In the total cohort, miR-155 was not an indicator for patient survival. Intriguingly, when patients were subdivided according to their age upon admission to the ICU into those younger than 65 years, lower levels of miR-155 turned out as a strong marker, indicating patient mortality with a similar accuracy than other markers frequently used to evaluate critically ill patients on a medical ICU.

Conclusion: In summary, the data provided within this study suggest an age-specific role of miR-155 as a prognostic biomarker in patients younger than 65 years. Our study is the first to describe an age-dependent miRNA-based prognostic biomarker in human diseases.

Figure 1

Serum miR-155 levels of critically ill patients at ICU admission. (a) qPCR was used to determine the concentrations of circulating miR-155 at admission to the ICU. In this analysis, critically ill patients (n = 218) displayed significantly higher serum levels of miR-155 compared to healthy controls (n = 76). (b) Serum miR-155 concentrations were independent on disease severity. (c) Serum concentrations of miR-155 were measured in patients with/without diabetes mellitus type 2. (d) Serum concentrations of miR-155 independent on the presence of obesity. (e) Serum concentrations of miR-155 did not vary with respect to patients' sex. ^∗∗∗ p < 0.001.

Figure 2

Serum levels of miR-155 are not predictive for patients' overall prognosis. (a) Serum levels of miR-155 were analyzed by qPCR in critically ill patients that survived in the long-term follow-up or succumbed to death. No difference between these groups became apparent. (b) Patients with miR-155 levels below or higher than the median of all patients displayed a similar long-term survival.

Figure 3

Serum concentrations of ICU predict long-term survival specifically in young ICU patients. (a) miR-155 serum levels in patients younger or older than 65 years. (b, c) Kaplan-Meier curve analysis demonstrating that patients < 65 years (but not older patients) with miR-155 concentrations below the median of all patients had an increased overall mortality. (d) The Youden index was used to calculate the optimal threshold for distinguishing between long-term survivors and patients that did not survive in the group of patients < 65 years old. Kaplan-Meier survival curve analyses revealed that patients with miR-155 concentrations below this threshold had an increased overall mortality. (e) Kaplan-Meier curve analysis was performed in patients > 65 years old, revealing that the mortality of these patients was independent of their miR-155 serum concentration. (f) ROC curve analysis revealing that miR-155 serum levels display a superior prognostic value in critically ill patients younger than 65 years. ^∗ p < 0.05.