Table 1. Presepsin as a diagnostic marker of infection.

APACHE II: Acute physiology and chronic health evaluation II, ARDS: Acute respiratory distress syndrome, CAP: Community acquired pneumonia, CD64: Cluster of differentiation 64, COPD: Chronic obstructive pulmonary disease, CR: Clearance ratio, CRP: C-reactive protein, DIC: Disseminated intravascular coagulation, DNA: Deoxyribonucleic acid, ED: Emergency department, EMBASE: Excerpta medica database, hsCRP: high sensitivity C-reactive protein, HSCT: Hematopoietic stem cell transplantation, 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, pro-ADM: Proadrenomedullin, ROC: Receiver operating characteristic, sTREM-1: soluble triggering receptor expressed on myeloid cells-1, 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
Halıcı [14], 2020	Prospective cohort study	126 patients admitted for COPD exacerbation in a single tertiary center	Presepsin at admission was accurate for diagnosing pneumonia as a cause of acute COPD exacerbation, but a positive associated between elevated presepsin and mortality did not reach statistical significance.
Chen [20], 2020	Prospective case-control	60 patients admitted to a single ICU with sepsis and 60 matched controls	Presepsin and the biomarker sTREM-1 were more sensitive for the diagnosis of sepsis in the ICU compared to procalcitonin and CRP, with the most accurate indicator being a composite biomarker of presepsin and sTREM-1. In patients diagnosed with sepsis, higher values of both biomarkers were associated with mortality. A cutoff value of 1025 pg/ml presepsin had 83% specificity and 85% sensitivity for the diagnosis of sepsis.
Ruangsomboon [26], 2020	Prospective cohort	Single center study of 250 patients > 75 years of age admitted on suspicion of sepsis	Presepsin had a similar diagnostic and prognostic accuracy as procalcitonin and the early warning score. The combination of the three biomarkers was superior to the use of either alone, and may be useful for the timely diagnosis of sepsis in the geriatric population.
Stoma [28], 2019	Prospective	Hematological patients with sepsis	This prospective study enrolled 64 hematological hospitalized patients to receive chemotherapy. These had proven or probable invasive fungal infection or microbiologically proven bacterial bloodstream infection. In total, 53 patients with bacterial bloodstream infections and 11 with invasive fungal infections participated in the study. Results showed that a combination of CRP >120 with PCT <1.25 or presepsin <170 could be a possible combined biomarker for invasive fungal infections in immunocompromised patients.
Lu [10], 2018	Prospective cohort study	Patients with sepsis and SIRS in the ED	The values of presepsin, PCT, CRP and WBC were evaluated in patients with sepsis and SIRS when assessed in the Emergency Department in the study by Lu. 72 patients with sepsis and 23 patients with non-infectious SIRS were enrolled. The levels of the above biomarkers were apparently higher in sepsis patients than in the non-bacterial SIRS group (P < 0.05). Also, the levels of presepsin and the APACHE II score demonstrated a significant difference among sepsis, severe sepsis and septic shock group of patients (P < 0.05). The authors concluded that presepsin was a promising biomarker for initially diagnosis and risk stratification of sepsis, also a potential marker to distinguish gram-positive and gram-negative bacterial infection.
Sargentini [19], 2017	Prospective case-control study	64 ICU patients	64 ICU patients were enrolled in this case-control study, where values of inflammatory biomarkers PCT, presepsin and pro-ADM were evaluated. These biomarkers were significantly lower in controls than in sepsis or septic shock groups. Preliminary data showed that, despite presepsin and pro-ADM being able to differentiate between septic and non-septic patients with accuracy, PCT remains the most reliable marker available.
Claessens [17], 2017	Prospective cohort study	312 patients with acute pyelonephritis and bacteremia	Values of presepsin were assessed in patients with acute pyelonephritis and controls, and their capacity to predict bacteraemia on admission was evaluated. In 312 patients with acute pyelonephritis, presepsin concentrations were higher than in controls, and increased in patients with bacteraemia and in those requiring admission. Performance of presepsin to predict bacteraemia was similar to CRP and less accurate than PCT. Although presepsin seems to be a valuable biomarker to detect patients with acute pyelonephritis did not offer advantage when comparing to CRP and PCT due to mild prediction of bacteraemia and need for admission.
de Guadiana Romualdo [11], 2017	Prospective cohort study	223 patients with suspected sepsis in the ED	The diagnostic accuracy of presepsin for infection and sepsis, compared with PCT and CRP was evaluated in the emergency department (ED) setting. 223 patients with suspected infection were enrolled in the study. Results showed that median CRP, PCT and presepsin levels were significantly higher in patients with infection and sepsis. PCT had the highest performance for infection and for sepsis, PCT and presepsin performed a similar one. The diagnostic accuracy of presepsin in this study does not improve that of PCT.
Stoma [27], 2017	Observational, prospective study	52 neutropenic patients after hematopoietic stem cell transplantation (HSCT)	A prospective observational study based on data from 52 neutropenic patients after hematopoietic stem cell transplantation (HSCT) was conducted in order to assess the diagnostic values of presepsin, PCT, and CRP in these patients in a condition of high prevalence of gram-negative pathogens. Results showed the best diagnostic value for presepsin and this biomarker may be recommended in adult patients with suspected gram-negative blood stream infection after HSCT as a possible additional supplementary test with a cut-off value of 218 pg/mL
Ali [22], 2016	Prospective cohort study	51 patients with SIRS and suspected sepsis, 25 healthy controls	Plasma presepsin, PCT and CRP levels in patients with SIRS and suspected sepsis were serially measured in order to evaluate the diagnostic and prognostic performance of presepsin in comparison to PCT and CRP. Results of the study showed that presepsin and PCT yielded similar diagnostic accuracy, whereas presepsin performed significantly better than CRP. Presepsin and PCT had comparable accuracy in differentiating between septic and non-septic patients. Finally, early changes in presepsin concentrations might reflect the appropriateness of the therapeutic modality.
Leli [23], 2016	Prospective cohort study	92 patients with suspected sepsis	The diagnostic accuracy of presepsin in predicting bacteraemia and bacterial DNAaemia in patients with suspected sepsis, and its comparison with that of PCT and CRP was assessed in this study. The presepsin median values were significantly higher in bacteraemic vs non-bacteraemic patients and in patients with bacterial DNAaemia vs patients without. This study concluded that when sepsis is suspected, presepsin and PCT had a good diagnostic accuracy in predicting both bacteraemia and bacterial DNAaemia, superior to CRP.
Zhang [6], 2015	Meta-analysis	11 studies	Presepsin is an effective adjunct biomarker for sepsis diagnosis, but insufficient to detect or rule out sepsis when used alone.
Zhang [7], 2015	Meta-analysis	8 studies with a total of 1,815 patients	Presepsin exhibits a very good diagnostic accuracy for diagnosing sepsis.
Wu [8], 2015	Meta-analysis	9 studies with 10 trials and 2159 cases	Presepsin had some superiority and may be a helpful biomarker in sepsis early diagnosis.
Tong [9], 2015	Bivariate meta-analysis	11 publications with 3,106 subjects	Valuable role in the diagnosis of sepsis, but should be interpreted carefully in clinical practice and in comparison to traditional markers.
Hou [15], 2015	Prospective cohort study	39 patients with nephrolithiasis presenting with SIRS	A prospective study aimed to evaluate the diagnostic ability of presepsin in the differential diagnosis between SIRS, infection, or sepsis and to compare its diagnostic value with other used biomarkers (CRP, PCT, and WBC) in patients of nephrolithiasis presenting with SIRS. 39 patients were enrolled in the study and the plasma presepsin was detected by the Pathfast presepsin assay system. ROC analysis showed that presepsin had a high diagnostic value compared with both PCT and CRP. In the early stage of SIRS, presepsin remained a highly sensitive and specific diagnostic marker compared with either PCT, CRP, or WBC.
Kweon [24], 2014	Prospective cohort study	118 patients presenting to the ED with suspected sepsis	Higher diagnostic accuracy of presepsin compared to other conventional biomarkers
De Guardiana-Romualdo [12], 2014	Prospective cohort study	226 patients with SIRS in the ED	226 patients with SIRS who were admitted in the Emergency Department assessed in an attempt to compare the validity of presepsin with the commonly used available sepsis biomarkers. The results showed that presepsin values were significantly higher in the SIRS group with bacteremia compared to the non-bacteremic SIRS group. The best cut-off value was 729 pg/mL and this was associated with a negative predictive value of 94.4%. It was concluded that presepsin may contribute to rule out the diagnosis of bacteremia in SIRS patients in the ED setting.
Cakır Madenci [18], 2014	Prospective cohort study	37 sepsis patients in a burn center	The validity of presepsin was evaluated in the diagnosis and follow up of sepsis in burn patients. A prospective study in a burn center included 37 patients. Presepsin, PCT, CRP and WBC levels were measured. Patients were classified as sepsis or non-sepsis according to the American Burn Association Consensus Criteria (ABA) 2007. The authors concluded that presepsin plasma levels had comparable performance in burn sepsis.
Liu [13], 2013	Prospective cohort study	859 patients with at least 2 diagnostic criteria for SIRS in the ED	A prospective study conducted in the ED enrolled 859 patients with at least 2 diagnostic criteria for SIRS. The aim was to evaluate the early diagnostic and prognostic value of presepsin compared with PCT, mortality in Emergency Department Sepsis (MEDS) score and APACHE II score in septic patients in the ED setting. Plasma presepsin levels in septic patients were significantly higher in non-survivors at 28 days' follow-up. Presepsin and both MEDS and APACHE II scores were independent predictors of severe sepsis, septic shock and 28-day mortality in septic patients. Levels of plasma presepsin were positively correlated with PCT, MEDS score and APACHE II score in every septic group, thus was considered a valuable marker for early diagnosis of sepsis and risk stratification.
Ulla [1], 2013	Case-control study	106 patients in the ED with suspected sepsis/septic shock, and 83 patients with SIRS but without clinical evidence of infection	In 2013 a two-center study was published based on 106 patients who presented in the ED with suspected sepsis or septic shock, and another 83 patients affected by SIRS but without clinical evidence of infection. The blood samples of the patients were analyzed using the PATHFAST presepsin assay for sCD14. In septic patients it was observed elevated presepsin concentrations on admission compared to controls. The same trend was observed for mean values of PCT. Mean presepsin values were significantly higher in non-survivor septic patients than in survivors. On the contrary, no significant correlation was noted between PCT and survival. Presepsin had a significant prognostic value in the population assessed in the ED.
Vodnik [16], 2013	Prospective cohort study	70 patients with bacterial and non-bacterial infection in acute abdominal conditions	The clinical usefulness of presepsin in the differentiation between bacterial and non-bacterial infection in acute abdominal conditions was reported in this study. The presepsin values were significantly higher in patients with sepsis than the SIRS patients. It was concluded that presepsin was a significantly sensitive indicator of sepsis and a useful biomarker for the rapid diagnosis of sepsis.
Endo [25], 2012	Multi-center prospective cohort study	207 patients with bacterial and non-bacterial infections	207 patients were enrolled in a multi-center prospective study which aimed to assess the clinical usefulness of presepsin in bacterial and non-bacterial infections. Levels of presepsin, PCT, and IL-6 were significantly higher in patients with bacterial infectious disease. Presepsin levels did not differ significantly between patients with gram+ and gram- bacterial infections. The usefulness of presepsin for diagnosing sepsis was concluded, also presepsin possible superiority to conventional biomarkers and blood culture.