Evaluation and validation of discovered biomarkers for early prognostic stratification of septic patients

Sepsis is a life-threatening condition due to a dysregulated response to infection which can lead to shock, multiple organ failure, and death. Early diagnostic and prognostic stratification of patients with sepsis is a difficult clinical challenge and despite of recent progress, the mortality rate has remained high. Sepsis is one of the most important health issues growing in the emergency department (ED) and there is lack of validated prognostic biomarkers to aid the hospitalization decisions in patients presenting to ED with a suspected infection. In this study, we evaluated novel molecules as possible biomarkers of sepsis. In particular, we focused on the long pentraxin PTX3, a soluble acute phase protein produced in response to proinflammatory cytokines, and on soluble IL-1R2, a negative regulator of the IL-1 pathway known to be correlated with severity of infection in critically ill patients. Methods: Plasma samples were collected from patients diagnosed with Sepsis-3 criteria at admission to ED of Humanitas Hospital and after 5 days of hospitalization. Levels of PTX3 and sIL-1R2 were measured by home-made or commercial ELISA and correlated with clinical parameters received from the hospital. Moreover, a cytokine panel has been measured in plasma of patients. Results: Circulating levels of PTX3 and sIL-1R2 increased significantly in sepsis patients on admission, with the highest levels measured in shock patients, and decreased after 5 days of hospitalization. Receiver operating characteristic (ROC) analysis showed that PTX3 and sIL-1R2 can discriminate sepsis and septic shock patients from healthy controls and also from non-sepsis patients. PTX3 and sIL-1R2 levels were correlated with severity score of disease (SOFA) and 28-day mortality outcome. In a univariate and multivariate Cox regression analysis, PTX3 and sIL-1R2 independently predicted 28-day mortality. The combination index including PTX3, sIL-1R2, C-reactive protein, creatinine and age showed better prognosis of 28-day mortality compared to the use of single biomarkers. In addition, PTX3 and sIL-1R2 strongly correlated with both proand anti-inflammatory cytokines in sepsis and septic shock patients. Conclusion: These data suggest that PTX3 can play a role as a promising prognostic biomarker of 28-day mortality in an ED setting for sepsis patients.