To the best of our knowledge, this is the largest prospective observational study on both the diagnostic and prognostic value of presepsin in non-infectious organ failure, sepsis, and septic shock, in accordance with the latest Sepsis-3 definitions. Presepsin had excellent accuracy in discriminating sepsis from non-infectious organ failure and had fair accuracy in discriminating septic shock from sepsis. The discriminating power of presepsin was comparable to that of PCT among patients with non-infectious organ failure, sepsis, and septic shock. The prognostic value of presepsin was superior to that of PCT and CRP in patients with sepsis and septic shock.
Our results showed that the optimal cut-off value to discriminate sepsis (including shock) from non-infectious organ failure was 582 pg/mL (AUC = 0.877, sensitivity = 70.1%, specificity = 89.4%). Several studies have reported different performance efficiencies of presepsin as an indicator of different types of infection. Optimal cut-off values (sensitivity, specificity, respectively) to discriminate sepsis from non-sepsis were 907 (70%, 83%)18, 686 (47%, 91%)19, 670 (70%, 81%)20, 729 (81%, 63%)21, 600 (86%, 72%)22, 600 (79%, 62%)23, 542 (77%, 76%)24, 430 (88%, 82%)25, and 466 (90%, 55%) pg/mL26. The difference in cut-off values reported by these studies may be caused by the heterogeneity of the studies in terms of clinical setting (ED vs. ICU), study design (prospective vs. retrospective), sepsis severity, comorbidities, and type of sample (plasma vs. whole blood vs. serum). However, these studies were performed according to the previous Sepsis-2 definitions.
A recent study using Sepsis-3 reported that presepsin and PCT were superior to CRP and lactate in discriminating sepsis, including shock from non-sepsis with SIRS and a SOFA score ≥ 2 16. The AUC values used to discriminate sepsis from non-sepsis were 0.88 for presepsin, 0.81 for PCT, and 0.65 for CRP 0.65, respectively. The AUC value of presepsin in the study was similar to that in our study (AUC = 0.877), and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of presepsin for diagnosing sepsis (including shock) using a cut-off value of 508 pg/mL were 87%, 86%, 93%, 76%, and 87%, respectively. The cut-off value found in the previous study (508 pg/mL) was lower than that in our study (582 pg/mL). Our study is similar to the previous study in that it was performed in the ED according to the latest Sepsis-3 definitions. However, we included a much larger population and used qSOFA as a screening tool instead of SIRS because it is no longer recommended as a diagnostic criterion for sepsis in the new definitions1. These differences might have caused the difference in the cut-off values between the two studies. Another study using Sepsis-3 in a Spanish population also reported that presepsin can effectively discriminate sepsis from non-infectious SIRS16. However, these two studies using Sepsis-3 did not evaluate the prognostic value of presepsin.
A previous study reported that presepsin was superior to PCT and CRP in discriminating sepsis from SIRS in acute abdominal conditions27. In contrast, another study showed that the diagnostic capacity of presepsin was not superior to that of PCT19, suggesting that its introduction and routine use in clinical practice were not justified. Another study also reported that presepsin did not outperform traditional biomarkers in distinguishing sepsis from SIRS and predicting mortality28. In fact, results reported about the diagnostic value of presepsin are controversial, probably due to different study designs and settings. Therefore, specific decision levels are required to determine the clinical roles of presepsin in different settings of non-infectious and infectious diseases29.
A multicenter prospective study reported that mean presepsin levels were significantly higher in non-survivors of sepsis than in survivors23. However, in that study, no significant correlation was observed between PCT levels and survival outcomes23. Similar to the previous study, our results showed that presepsin levels were significantly higher in non-survivors than in survivors. No significant differences in PCT levels were observed between the non-survivors and survivors. In our study, Kaplan–Meier survival curve analysis according to the optimal cut-off value of presepsin showed that 30-day mortality was significantly higher in patients with higher presepsin levels. In accordance with our study, a systematic review and meta-analysis revealed that presepsin levels on the first day had prognostic value in predicting in-hospital or 30-day mortality in adult patients with sepsis30. The combination of presepsin with PCT, Galectin-3, and soluble suppression of tumorigenicity-2 showed better performance in predicting mortality than the single use of presepsin in sepsis patients10. The study demonstrated that the combination of presepsin with other biomarkers could help clinicians predict mortality. Further studies with larger cohorts are required to determine the optimal cut-off value of presepsin for predicting mortality associated with sepsis.
The present study had some limitations. First, although the present study included a large sample size compared to that of previous studies, it was a single-center ED-based study. Thus, our results may not be applicable to other EDs or ICUs. Second, only plasma presepsin levels in the ED were measured, and follow-up changes in markers were not determined. Although a previous study reported that dynamic monitoring of presepsin could effectively predict prognosis31,32, other trials demonstrated that single measurements of presepsin in the ED also had valuable prognostic value in patients with sepsis12,23. Third, although a previous study reported that presepsin levels were markedly elevated in patients with chronic kidney disease receiving hemodialysis33, our study did not consider kidney function. Further studies are needed to investigate the influence of kidney dysfunction on presepsin levels using repeated marker measurements. Fourth, because the present study included patients with organ dysfunction enrolled in the ED, this might have resulted in selection bias. Nevertheless, we postulate that our study, based on an organ failure cohort, could reflect the clinical characteristics of patients in a real ED setting.
To summarize, the present study, according to the Sepsis-3 definitions, demonstrated the diagnostic and prognostic value of presepsin levels among patients with non-infectious organ failure, sepsis, and septic shock. Its ability to discriminate sepsis, including shock, from non-infectious organ failure was excellent, and its prognostic ability could help clinicians to prognosticate patients with sepsis and septic shock. Further multicenter prospective studies with larger populations are needed to determine the optimal cut-off value of presepsin for the diagnosis and prognosis of sepsis.