Table 2. Presepsin as a prognostic marker in sepsis.

APACHE II: Acute physiology and chronic health evaluation II, ARDS: Acute respiratory distress syndrome, CAP: Community acquired pneumonia, CR: Clearance ratio, CRP: C-reactive protein, DIC: Disseminated intravascular coagulation, ED: Emergency department, EMBASE: Excerpta medica database, hsCRP: high sensitivity C-reactive protein, ICU: Intensive care unit, IL: Interleukin, MEDLINE: Medical Literature Analysis and Retrieval System Online, MEDS: Mortality in emergency department sepsis, MR-proADM: mid-regional pro-adrenomedullin, PCT: Procalcitonin, SCD14-ST: soluble Cluster of Differentiation 14 subtype, SIRS: Systemic inflammatory response syndrome, SOFA: Sequential Organ Failure Assessment, WBC: White blood cell.

1st Author and year of publication	Study design	Type of patients/database	Major findings
Shimoyama [31], 2021	Prospective cohort study	Single center ICU, 83 patients	Presepsin elevation upon ICU admission and on day 2 was a prognostic factor for acute renal failure, presepsin on days 1-3 as well as a composite factor comprising of presepsin elevation and the Glasgow prognostic score predicted the development of ARDS, whereas presepsin elevation on the first 2 days of ICU admission predicted the development of DIC.
Aliu-Bejta [42], 2020	Prospective cohort study	100 patients admitted with sepsis in 2 tertiary care centers	Presepsin levels at baseline were significantly elevated in patients with septic shock compared to patients with simple sepsis according to the sepsis-3 definition. Presepsin correlated strongly with the SOFA score. CRP and procalcitonin elevation did not differentiate between sepsis and septic shock.
Zhao [21], 2020	Prospective cohort study	Multicenter study of 225 patients with ARDS	Presepsin elevation enabled the discrimination of ARDS due to sepsis from ARDS due to other causes, and quantitative presepsin levels were strongly correlated with SOFA score and the risk of mortality in ARDS due to sepsis.
Wen [43], 2019	Prospective cohort study	Cohort of 128 patients hospitalized due to sepsis	Presepsin correlated strongly with the SOFA score and was an independent predictor of in-hospital mortality. The combination of presepsin elevation with the SOFA score was a stronger predictor of mortality than either marker used separately.
Kondo [29], 2019	Meta-analysis	Critically ill adults from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials	A meta-analysis based on data from three electronic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials) included 19 studies with 3012 critically ill adult patients aimed to evaluate the diagnostic value of procalcitonin and presepsin in the diagnosis of sepsis. It was showed that the diagnostic accuracy of both biomarkers in detecting infection was similar, also both are useful for early diagnosis of sepsis and reduction of mortality in critically ill adults.
Ugajin [51], 2019	Retrospective cohort study	172 hospitalized patients with pneumonia	The study investigated the effects of presepsin on clinical outcomes in patients with pneumonia based on the review of electronic medical records. The results showed that the patients who died had higher presepsin levels on admission. The authors concluded that in hospitalized patients with pneumonia, the plasma presepsin levels on admission could be a useful predictor of 30-day mortality.
Fujii [32], 2019	Retrospective cohort study	18 ICU patients	This retrospective study published aimed to determine the correlation between presepsin value trend and prognosis, based on ICU sepsis patients. The results showed that the 90-day mortality rate in the group of patients with decreased presepsin levels significantly improved, even when presepsin values were high on admission. The authors concluded that fifty percent decrease in presepsin levels could be served as a useful prognostic predictor of sepsis.
Hassan [35], 2019	Prospective cohort study	68 ICU patients	An observational study was conducted on 68 ICU patients with sepsis aiming to determine early predictors of sepsis-related in-hospital mortality, also to monitor the levels of presepsin and hsCRP during admission in relation to the applied treatment and the development of complications. Levels of presepsin were significantly higher at days 0 and 3 in non-survivors vs. survivors. When compared to hsCRP, presepsin was an early predictor of sepsis-related in-hospital mortality in ICU patients. The authors concluded that changes in presepsin concentrations over time may be useful for sepsis monitoring and for stratifying high-risk patients on ICU admission that benefit from intensive treatment.
Titova [50], 2018	Prospective cohort study	75 patients with sepsis due to pneumonia	This study was intended to evaluate presepsin as a marker of diagnosing severe pneumonia and sepsis. 75 patients with pneumonia, sepsis, and other inflammatory diseases were assessed and have been investigated for the level of the presepsin. All enrolled patients had obtained an antibacterial therapy in other health care centers before entering the hospital. Results showed that presepsin in patients with pneumogenic sepsis was higher compared to presepsin of patients with severe pneumonia and non-severe pneumonia. The high level of presepsin is an indication of an active infectious disease and reflects the severity of the pneumonia and development of sepsis.
Bamba [53], 2018	Prospective cohort study	11 patients hospitalized for fungal infection	This prospective study investigated the plasma levels of presepsin in fungal bloodstream infections in relation to the disease severity and in comparison to bacterial infections. The investigators assessed the associations of CRP, procalcitonin, and presepsin concentrations with the severity of fungemia. Plasma presepsin levels were found elevated in patients with fungal bloodstream infection, with a positive relation to the disease severity. They concluded that presepsin could be a useful biomarker of sepsis due to fungal infections.
Yang [30], 2018	Systematic review and meta-analysis	10 studies and 1617 patients	This systematic review was conducted to evaluate the mortality prediction value of presepsin in sepsis, a total of 10 studies and 1617 patients were included. The levels of presepsin in the first (within 24 hours) sampling were significantly lower among survivors comparing to non-survivors. The results demonstrated some mortality prediction value in presepsin in patients with sepsis.
Brodska [44], 2018	Prospective cohort study	60 patients with sepsis and SIRS	Procalcitonin, C-reactive protein, presepsin and lactate were analyzed in 60 consecutive patients with sepsis and SIRS in the study. The SOFA score was determined also daily in patients’ assessment. The results of the study showed that presepsin did not outperform the traditional biomarkers in diagnosing sepsis from SIRS and in mortality prognosis in critically ill patients. The authors concluded that presepsin may have a limited adjunct value for diagnosis and early risk stratification, performing independently of clinical illness severity.
Matera [38], 2017	Prospective cohort study	58 ICU patients	58 ICU patients with suspected sepsis were enrolled in an observational, prospective study which aimed to evaluate the role of presepsin in predicting the outcome in parallel with procalcitonin and CRP. Presepsin levels were significantly higher in non-survivors vs survivors at the same time point. Presepsin concentrations were also significantly increased in patients with positive blood cultures. The authors concluded that presepsin has an optimal prognostic and diagnostic value in patients with severe sepsis.
Kim [33], 2017	Retrospective case-series study	Case series of 157 sepsis patients	157 septic patients were enrolled in this retrospective study. Biomarkers such as procalcitonin, presepsin, galectin-3, and soluble suppression of tumorigenicity 2 were evaluated and their concentrations were analyzed in relation to the 30-day all-cause mortality. Results showed a possible prognostic utility of all four biomarkers in sepsis. This multi-biomarker approach could be a beneficial approach for an optimized management of sepsis patients.
Song [52], 2016	Prospective cohort study	61 patients with enterocutaneous fistula (ECF) and abdominal sepsis	71 patients with enterocutaneous fistula were enrolled in a study when these were diagnosed with abdominal sepsis. The aim was to evaluate the prognostic value of presepsin in ECF. Patients with higher presepsin levels had more severe intra-abdominal infection, also high risks of complications and failure of fistula closure compared with those having lower presepsin levels. The authors concluded that presepsin seems to have prognostic values for source control of abdominal sepsis and clinical courses of enterocutaneous fistula.
Klouche [36], 2016	Prospective cohort study	144 patients in 2 ICUs in France	An observational prospective study based on data from 2 ICUs in France aimed to assess the diagnostic and prognostic value of presepsin in ICU patients with severe sepsis, septic shock and severe community-acquired pneumonia. 144 patients were enrolled in the study. Presepsin and procalcitonin levels were significantly higher in septic than in non-septic patients and in patients with septic shock. The sepsis diagnostic accuracy of presepsin was not superior to that of PCT. In the patients admitted for respiratory failure, the capability of presepsin to diagnose severe community acquired pneumonia (CAP) was significantly better than PCT. Serum levels of presepsin were predictive of ICU mortality in sepsis and in CAP patients.
Enguix-Armada [34], 2016	Prospective cohort study	388 ICU patients over 12 months period	A cohort study with 388 patients admitted in the ICU over a 12-month period, assessed whether the combination of CRP, PCT, presepsin or SCD14-ST and mid-regional pro-adrenomedullin (MR-proADM) measured in the first 24 h from ICU admission could offer a better diagnostic and prognostic management of septic patients. Among the above biomarkers, PCT, MR-proADM and presepsin were found to be complementary markers in the management of septic patients when they were measured in the first 24 h after ICU admission.
Carpio [47], 2015	Prospective case-control study	123 patients with suspected infection in the ED and 123 healthy controls	The validity of presepsin in the Emergency Department setting was assessed in this study of 123 patients with suspected infection and 123 healthy individuals. Presepsin was determined on admission, after 8, 24 and 72 h. Results showed that presepsin had a similar outcome prediction on admission to the clinical scores MEDS and APACHE II. Combination of presepsin with MEDS score improved the power for outcome prediction.
Popa [46], 2015	Retrospective cohort study	95 patients with suspected infection in the ED	A retrospective study of patients with suspected infection who presented in the Emergency Department aimed to evaluate among other parameters the relationship between values of presepsin and clinical outcome. The authors concluded that presepsin had a diagnostic and early prognostic value and is an early marker of mortality in patients with sepsis.
Masson [40], 2015	Multicenter Albumin Italian Outcome Sepsis (ALBIOS) trial	997 patients with severe sepsis and septic shock	Plasma presepsin values were measured 1, 2, and 7 days in 997 patients with severe sepsis or septic shock who were enrolled in the multicenter Albumin Italian Outcome Sepsis (ALBIOS) trial. The association of single measurements of presepsin or changes over time with clinical events, organ dysfunctions, appropriateness of antibiotic therapy, and ICU or 90-day mortality were then tested. Results of the study showed that baseline presepsin was independently associated with the risk of ICU and 90-day mortality. Increasing concentrations of presepsin from day 1 to day 2 were related to higher ICU and 90-day mortality. Changes in concentrations over time seem to reflect the appropriateness of antibiotic therapy. It was concluded that presepsin seems to be an early predictor of host response and mortality in septic patients.
Sargentini [37], 2015	Prospective cohort study	21 ICU patients	Presepsin was evaluated as a potential biomarker for bacterial infection relapse in critical care patients. 21 adult patients were studied during hospitalization in an Italian Critical Care Unit. The results showed that in patients with a clinical recurrence of sepsis, while procalcitonin levels were normalized during the transient remission phase, presepsin levels remained high. The existence of maximal presepsin levels could alert clinicians not to suspend antibiotic treatments in sepsis patients.
Behnes [39], 2014	Prospective cohort study	116 ICU patients with suspected severe sepsis or septic shock	A mono-centric prospective study with 116 patients with suspected severe sepsis or septic shock aimed to evaluate the diagnostic and prognostic accuracy of presepsin in these patients during the first week of ICU treatment. The enrolled patients were followed up for six months and measurement of several biomarkers was performed. Presepsin revealed a valuable diagnostic capacity to differentiate sepsis severity compared to other used biomarkers for sepsis such as PCT, IL-6, CRP, WBC. Presepsin and IL-6 also showed prognostic value regarding 30 days and 6 months all-cause mortality throughout the first week of ICU treatment.
Endo [48], 2014	Multicenter prospective cohort study	103 patients with sepsis admitted to the ED or ICU. Also sepsis severity scores were calculated	A multicenter prospective study compared the clinical utility of presepsin with other sepsis biomarkers including procalcitonin, interleukin-6, and CRP for evaluating the severity of sepsis during follow-up. 103 patients with sepsis admitted to the ED or ICU were enrolled and classified into 3 groups: sepsis, severe sepsis and septic shock. The patients were further divided into the favorable and unfavorable prognosis groups on the basis of sepsis severity scores (i.e., SOFA and APACHE II). The patients in the favorable prognosis group had significant decreases in all biomarker levels on days 3 and 7 after admission. In the unfavorable prognosis group, only presepsin levels did not decrease significantly during follow-up. This group had significantly higher 28-day mortality than the favorable prognosis group. Presepsin levels correlated with sepsis severity during follow-up in comparison with other conventional sepsis biomarkers.
Ishikura [49], 2014	Prospective cohort study	82 patients with ≥1 SIRS criteria who were admitted in the ED. 11 biomarkers were evaluated	A study enrolled 82 patients with ≥1 SIRS criteria who were admitted in the ED, aimed to define a biomarker panel to predict sepsis-induced disseminated intravascular coagulation (DIC). 11 biomarkers were evaluated on ED admission. Among the 11 biomarkers, the optimal 2-marker panel comprised presepsin and protein C with the best accuracy of predicting sepsis. It was concluded that this biomarker panel of presepsin and protein C is predictive of the severity of sepsis-induced DIC in suspected ED patients.
Masson [41], 2014	Prospective cohort (ALBION study)	Patients with sepsis in Italian ICUs	A retrospective, case-control study of a multicenter, randomized clinical trial enrolling patients with severe sepsis or septic shock in ICUs in Italy evaluated the prognostic value of presepsin and compared it to PCT. 50 survivors and 50 non-survivors at ICU discharge, matched for age, sex and time from sepsis diagnosis were enrolled. Plasma samples were collected for 1, 2 and 7 days. Results showed that presepsin was the only variable independently associated with ICU and 28-day mortality. It also showed better prognostic accuracy than PCT in the range of SOFA score.