Severe sepsis is a syndrome accompanied by lethal organ dysfunction due to dysregulated host responses to infection, and is associated with a mortality rate higher than 50% [14]. Sepsis initiates the activation of both pro- and anti-inflammatory responses [15], both of which are amplified by non-immunologic pathways including cardiovascular, neuronal, autonomic, hormonal, bioenergetic, metabolic, and coagulation pathways [16–18]. PCT is a diagnostic marker used for bacterial sepsis with the highest specificity and widely used in clinical settings, but can give false-positive results as its values can increase even during non-septic conditions (e.g., severe trauma, invasive surgical procedure, critical burn injuries) [5–7]. These false-positive results may be obstructive toward obtaining information on whether or not to initiate aggressive and supportive therapy in sepsis patients or other critically ill patients within the first few hours after ICU admission. Presepsin, a subtype of CD14-ST, is secreted from granulocytes by infectious stimuli in an animal sepsis model [19] and can thus be used as a highly specific biomarker for diagnosing bacterial sepsis. Presepsin values are useful for diagnosing early stage sepsis in emergent patients and are independently associated with the degree of organ dysfunction, coagulation disorders, and ICU mortality [20, 21].
The present study demonstrated that presepsin is a better predictor of mortality in septic patients. AUC values of presepsin for predicting 28-day mortality were all higher than each of the presepsin AUC values for 60-, 90-, and 180-day mortality. Moreover, multivariate analysis revealed that only the presepsin value on Day 1 predicted mortality rates. Collectively, these findings suggest that the AUC of presepsin on Day 1 might be effective in predicting early mortality (Tables S1, S4).
We also investigated the ability of presepsin values on Day 1 to predict early mortality (i.e., death within 7 days of ICU admission). The AUC of presepsin on Day 1 to predict death within 7 days of ICU admission was 0.84 (Tables S5). Multivariate logistic regression analysis for mortality found the presepsin value on Day 1 to be a significant independent predictor of death within 7 days of ICU admission (OR, 1.0007; 95%CI, 1.0001–1.0013; p = 0.032; Table S7). Ulla et al. reported that a higher level of presepsin at presentation in the emergency department was correlated to 60-day mortality [22]. Masson et al. found that presepsin levels measured at the time of presentation among patients with severe sepsis or septic shock were higher in non-survivors than in survivors [23], and our findings were consistent with these results.
In the present study, presepsin cut-off values for predicting each designation of mortality were higher than previously reported cut-offs for diagnosing either sepsis (300 to 500 pg/ml) or severe sepsis (500 to 1000 pg/ml) [24, 25]. Klouche reported that a cut-off presepsin value for mortality in sepsis patients was 1926 pg/ml [26]. These results suggest the need to adopt a higher presepsin cut-off value for predicting mortality associated with sepsis.
The presepsin values for ΔDay 3-Day 1 in 28- or 180-day mortality showed higher specificity for predicting 28- or 180-day mortality compared with presepsin values on Days 1, 2, 3, and 5 alone for all mortality (Table S1). These findings suggest that Δpresepsin Day 3-Day 1 may be useful as a “rule in” test for predicting mortality. Log-rank test also revealed Δpresepsin Day 3-Day 1 and Δpresepsin Day 2-Day 1 to be independent predictors of mortality in septic patients (Table S2). Presepsin values on Days 3 and 5 had higher AUCs for predicting 28-day mortality than the presepsin values on Days 1 and 2 (Table S1). These results suggest the importance not only of measuring presepsin values at the time of ICU admission but also monitoring its changes on Day 2 and thereafter following ICU admission, in order to predict mortality in sepsis patients.
The AUC, sensitivity, and specificity of PNI for predicting 28-day mortality were 0.73, 70%, and 80%, respectively (Table S1). Log-rank test revealed PNI as an independent predictor of all mortality in sepsis patients (Table S2). Previously, we found that NLR is superior to other inflammation-based prognostic scores in predicting mortality among patients with gastrointestinal perforation and pneumonia [27, 28]. With regard to 28-day mortality, however, the present study found PNI to be a predictor of mortality in sepsis patients. Pinato et al. [29] reported that PNI is a predictor of poor overall survival in patients with hepatocellular carcinoma. In the Albumin Italian Outcome Sepsis trial, albumin replacement did not improve survival at 28 and 90 days among patients with severe sepsis or septic shock [30]. However, our findings suggest that, of the many variables that can be investigated for assessing inflammation, hypoalbuminemia and lymphocytopenia (albumin and lymphocyte counts used to calculate PNI) are important variables for predicting mortality in sepsis patients. In the context of predicting 28-day mortality, PNI shows a lower AUC than that of presepsin, but in clinical environments where presepsin values cannot be measured, PNI at presentation may be useful for determining 28-day mortality.
No previous study has assessed the association between presepsin values, PNI, and mortality in patients with sepsis according to the Sepsis-3 definition. Our findings are novel in this respect. Further studies will be needed to clarify how presepsin values and PNI can predict mortality in sepsis patients.