Presepsin as a Diagnostic and Prognostic Biomarker in Sepsis

Sepsis is a condition characterized by high morbidity and mortality which is commonly encountered in an emergency and critical care setting. Despite a substantial body of research, the ideal biomarker for the diagnosis and prognostic stratification of septic patients remains unknown. This review aimed to summarize the publications referring to the validity of the biomarker presepsin when used for the detection, monitoring and prognosis in patients suffering with sepsis. This work is a narrative review based on a PubMed/Medline search conducted in order to identify all relevant publications referring to the use of presepsin in sepsis. Search was not limited by year of publication so all articles archived in the database would be retrieved. No article from before 2010 was identified. A total of 57 publications of the last decade were included, all of which support the use of presepsin as a biomarker for the assessment of septic patients. It has been used alone or in combination with commonly used biomarkers in the evaluation of patients with sepsis in settings such as the emergency department and the intensive care unit. It is useful in the initial workup of patients with suspected sepsis in the emergency setting and may be a predictive factor of mortality and the most severe complication of sepsis. Presepsin seems to be a valuable tool for the laboratory workup of sepsis, especially when used in conjunction with other biomarkers and clinical rating scores with an established role in this population. Further research is needed to evaluate the clinical implications of utilizing presepsin measurements in the workup of sepsis.


Introduction And Background
Sepsis is among the most common causes of death for hospitalized patients and despite recent progress mortality rates remain unacceptably high, especially if septic shock is present. The financial burden of the syndrome is significant as it commonly requires prolonged treatment in the intensive care unit [1]. The pathogenesis of the syndrome involves a complex interplay between the pathogen (typically gram-negative bacteria) and the host immune response. Several biomarkers have been used in clinical practice for better monitoring, management and risk stratification of the sepsis syndrome. Presepsin is an immunologic biomarker which has been identified during the past decade as a new, emerging, early indicator for the detection of infections [2]. of patients who are suspected to be septic. Compared to other biomarkers used for this purpose (procalcitonin, C-reactive protein) it is hypothesized to be more specific for sepsis, as it is directly implicated in the pathogenesis of the syndrome. Several studies have investigated the validity of presepsin when used in clinical practice [4]. It should be noted that presepsin measurement is not ubiquitously available yet unlike other biomarkers of sepsis. Its role as a diagnostic and prognostic biomarker for the risk stratification of sepsis is further evaluated in clinical settings including the Emergency Department and the Intensive Care Unit. The promising role of presepsin was reported in the review by Pizzolato in 2014, as it was noted that presepsin had a high sensitivity and good specificity for sepsis, is readily available in the emergency department and correlated to in-hospital mortality in patients with sepsis and septic shock. It was noted that presepsin levels may have similar specificity and sensitivity to clinical rating systems such as the MEDS and SOFA scores, the diagnostic and accuracy of which may be substantially improved if they are combined with presepsin and other biomarkers [4]. The promising role of presepsin as a new biomarker for early diagnosis of sepsis was identified in another review published the same year [5]. The authors noted that presepsin may have better prognostic validity than procalcitonin, C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR), while being more specific for infection compared to both lactate and the ESR [4]. Herein we present a review of all identified bibliography which is related to the use of presepsin in sepsis.

Review Methods
A PubMed search was conducted on December 2020 using the terms 'presepsin in sepsis' as "Title/Abstract" or as "MeSH Terms". The structure of the search in the "Search details" window of the PubMed website was presepsin [All Fields] AND ("sepsis"[MeSH Terms] OR "sepsis"[All Fields]). The literature search was limited to articles referring only to adult patients and the extracted bibliography was further searched for more related publications, by hand search of the references of retrieved articles. Studies focusing exclusively on postoperative patients were excluded as the value of presepsin measurement in this population would best be evaluated separately, with studies grouped based on the type of surgical procedure. Only manuscripts written in the English language were included in this review. Though this work is a narrative review, a PRISMA flowchart is provided (Figure 1).

Presepsin as a Diagnostic Marker of Infection
Several studies have evaluated the use of presepsin measurements to diagnose infection during the initial presentation of the patient. It is hypothesized that it may be the ideal biomarker for diagnosing bacterial infection as it is directly implicated in the innate immune response and its concentration rises within hours of infection. This has been evaluated in a few systematic reviews and meta-analyses apart from original studies. A meta-analysis published in 2015 evaluated presepsin for the diagnosis of sepsis based on publications retrieved from medical databases until November 7, 2014. Eleven studies were finally included in this meta-analysis. This systematic review showed that presepsin was an effective adjunct biomarker for sepsis diagnosis, but insufficient to detect or rule out sepsis when used alone [6]. Another meta-analysis published also in 2015, based on PubMed, Embase, Web of Science and Cochrane databases included eight studies with a total of 1,815 patients. It was reported that presepsin exhibits a very good diagnostic accuracy (Area under the curve, AUC=0.89) for the diagnosis of sepsis [7]. The same year another meta-analysis by Wu et al. was published based on database search up to 15 December 2014. Nine studies with 10 trials and 2159 cases were included. It was demonstrated that presepsin had some superiority in the management of patients, and could be a helpful biomarker in sepsis early diagnosis. However, presepsin showed a moderate diagnostic accuracy in differentiating sepsis from non-sepsis cases [8]. In 2015 another systematic review was published, a bivariate meta-analysis based on data from PubMed and EMBASE which included 11 publications with 3,106 subjects. Presepsin found to have a valuable role in the diagnosis of sepsis, but the results should be interpreted carefully in clinical practice and in comparison to the traditional markers [9].
One of the first clinical applications of presepsin measurement that was investigated was its use for the initial diagnosis of infection upon patient presentation to the emergency department. For this purpose presepsin could be used alone or in conjunction with other biomarkers commonly employed for this purpose, such as procalcitonin (PCT) and C-reactive protein (CRP). Based upon the available evidence presepsin is comparable in sensitivity to the aforementioned biomarkers and more specific compared to complete blood count abnormalities such as increased white blood cell count [10], though it may not offer any significant advantages over PCT, which is more widely available [11]. The sensitivity of presepsin (approximately 95% with a cutoff value of 729 pg/mL for a positive test [12]) may be sufficient to rule out infection, but it must be used in conjunction with other biomarkers and clinical scoring systems to definitively rule in infection. Presepsin values have a strong positive correlation with the CRP, PCT and the SOFA and MEDS scores [13]. Higher values of presepsin are associated with septic shock compared to severe sepsis without shock, a trend similar to that observed with PCT [1]. In probable infections with an identifiable focus, presepsin may be of value in differentiating whether an exacerbation of chronic obstructive pulmonary disease is due to pneumonia or non-infectious in etiology [14], and may also be useful in patients presenting with nephrolithiasis and systemic inflammatory response syndrome (SIRS) symptoms to rule out pyelonephritis as a cause [15], and may aid in differentiating between the causes of acute abdomen [16]. In patients with definite pyelonephritis, a higher presepsin cutoff may be used to test for the presence of bacteremia [17]. A similar effect was found in a study of burn patients, who are at increased risk for severe disseminated infection [18].
In hospitalized patients or individuals already being treated in an ICU setting presepsin may retain its utility for the diagnosis of emerging infections. In an ICU setting it may be comparable to other emerging biomarkers, including pro-adrenomedullin [19] and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) [20], and a combination of these biomarkers may be superior for the diagnosis of sepsis compared to either used alone. In this it could also be useful for the differential diagnosis of acute respiratory distress syndrome (ARDS), as it appears to be elevated only in ARDS due to sepsis and not in non-infectious causes of the syndrome [21]. Outside of the ICU, presepsin may be useful to differentiate sepsis from non-infectious SIRS with accuracy comparable to procalcitonin [22][23][24]. It should be noted that although its biological function is mostly associated with the response to gram negative bacteremia, an early study found presepsin measurements did not differentiate gram negative and gram positive bloodstream infection [25]. Presepsin was found to be an accurate biomarker for sepsis in geriatric individuals over 75 years of age in combination with PCT and the early warning score [26]. It was also useful for the diagnosis of bacteremia in hematological patients undergoing stem cell transplant with a cutoff value of 218 pg/ml [27] and in another study of hematological patients undergoing chemotherapy was found useful for the differentiation between bacterial and fungal infection [28]. This study confirmed the relative specificity of presepsin for bacterial infection and the authors that elevated CRP in conjunction with presepsin within the normal reference range was in favor of fungal infection in this group of immunocompromized individuals. A summary of the studies on the diagnostic role of presepsin can be found in Table 1 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. 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.

Presepsin as a Prognostic Indicator in Sepsis
Similarly to other biomarkers of infection, serial presepsin measurements may be useful for the prognostic stratification of septic patients. Higher measurements may be associated with greater mortality and increased risk of the severe complications of sepsis that are typically encountered in an ICU setting, specifically acute renal failure, septic shock, acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC). Two meta-analyses which evaluated the prognostic role of presepsin in septic patients have been published, one in a critical care setting [29] and the other upon admission to the hospital [30]. By comparing the population of survivors with non-survivors both found consistently elevated presepsin levels in non-survivors, suggesting that presepsin elevation reflects mortality risk and may be useful as an independent predictor of mortality, thus aiding in the identification of patients most likely to deteriorate.
Serial presepsin measurements may be used to evaluate changes in a patient's condition in the intensive care setting. The first few days after ICU admission are crucial, as that is when the most severe complications of sepsis typically develop. A recent study indicated that 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 two days of ICU admission predicted the development of DIC [31], findings which may be of great interests to intensivists should presepsin measurements become more widely available. Presepsin elevation also predicts mortality in sepsis-induced ARDS [21]. In the same vein, a marked reduction in presepsin levels may foreshadow clinical improvement, indicating response to treatment [32]. It is clear from these results that if serial presepsin measurements are obtained a downtrend is a good prognostic indicator while an uptrend is indicative of a worse prognosis and a more complicated clinical course [21,32].
Several studies in an ICU compared the prognostic utility of presepsin to other commonly used biomarkers and clinical rating scales, including PCT, lactate, CRP, proadrenomedullin, gelactin-3 [33], and the APACHE, MELD and SOFA scores. Presepsin consistently outperformed CRP [34,35] but was not characterized by any significant advantage in comparison to PCT or the clinical rating scores that were examined, though its value may lie in the utility of its combination with other biomarkers [33,36,37]. Presepsin levels correlate significantly with both PCT and the SOFA score and are an independent predictor of mortality in patients treated in the ICU for sepsis [38][39][40][41], and similar findings were also observed in cohorts of hospitalized patients not in intensive care [42,43]. Only in one cohort were there no promising results [44] at all in the comparison between presepsin, PCT, CRP and lactate. One particularly interesting article reported on the prognostic value of the clearance ratio of presepsin as ascertained by serial measurements which was superior to the clearance ratio of PCT as a predictor of mortality in inpatients with severe sepsis, which warrants further investigation [45]. One study found a sustained elevation of presepsin with simultaneous normalization of PCT predicted relapse of sepsis, though further research is required to evaluate whether these findings are reproducible [37].
Presepsin may also retain a significant predictive value in the emergency department setting, where initial elevation may be a significant predictor of early mortality due to sepsis [46,47]. One study which evaluated it along CRP, interleukin-6 and PCT reported that presepsin was the only biomarker that remained elevated after treatment initiation in the group with the most severe initial presentation and retained an association with an elevated risk of mortality throughout the follow-up period [48]. Another study found presepsin and CRP elevation in the emergency room to be predictive factors of DIC, with the combination of both having a stronger association with an increased risk of DIC than either alone [49]. These findings suggest it may be of superior prognostic value compared to other commonly used biomarkers in the emergency setting, though further research is required to evaluate these associations.
The prognostic utility of presepsin has also been evaluated in hospitalized patients with a known cause of infection. Two studies on patients with confirmed pneumonia noted an association between presepsin elevation and mortality, with presepsin elevation being more pronounced in septic patients compared to those with the relatively milder presentation of severe pneumonia [50,51]. Similar findings were also reported in a cohort of patients with another definite focus of infection, an enterocutaneous fistula [52]. The authors concluded that presepsin seems to have prognostic values for source control of abdominal sepsis . A single prospective study evaluated whether presepsin elevation could be predictive of mortality in disseminated fungal infection with fungemia as it is in bacterial sepsis. The authors noted pronounced presepsin elevation with normal procalcitonin, challenging the notion that presepsin is in fact specific for bacterial infection [53]. The degree of presepsin elevation appeared to correlate with clinical severity and mortality in patients with disseminated fungemia. A summary of studies on presepsin as a prognostic indicator in sepsis can be found in Table 2 definition. Presepsin correlated strongly with the SOFA score. CRP and procalcitonin elevation did not differentiate between sepsis and septic shock.

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.

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 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. 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.

Presepsin and Renal Failure
Due to its relatively low molecular weight, presepsin is filtered by the glomeruli in the kidneys, where it is subsequently reabsorbed and proteolyzed in the proximal tubule. In healthy individuals, the small amounts of presepsin produced in the absence of infection are removed from circulation primarily by the glomerular filtration in the kidney. Thus it would be expected that patients suffering from renal failure (characterized by a reduction of the glomerular filtration rate) would have higher baseline presepsin concentrations. This may be particularly pronounced in dialysis-dependent individuals with end stage renal disease, as presepsin is not filtered during dialysis. In critically ill septic patients, rapidly rising presepsin levels may be indicative of acute renal failure, which is a grim but unfortunately common complication of sepsis.
A range of presepsin levels in the absence of acute pathology was established for individuals with normal renal function compared with patients with chronic renal failure. Individuals with grade 3, 4 and 5 renal failure had baseline presepsin values significantly above the other group, with values of 208.1 ± 70.2 pg/mL, 320.2 ± 170.1 pg/mL, 712.8 ± 336.3 pg/mL, respectively [54]. Three studies on patients presenting with acute kidney injury and sepsis indicated that in the validity of presepsin measurement in this population was reduced [55,56] and procalcitonin was superior as a diagnostic and prognostic marker of sepsis in this group [57]. The authors however noted that presepsin could also be used, with the caveat that a different reference range for values be utilized and its use be limited to less severe presentations of acute renal failure ( Table 3).

Discussion
Early diagnosis and timely treatment are the corner stones of survival improvement in sepsis syndrome. There is still a need for identifying the 'ideal' biomarker as none of the common applied in clinical practice such as the white blood cell count (WBC), procalcitonin (PCT), C-reactive protein (CRP) and interleukin-6 (IL-6), has a 100% sensitivity and specificity. Apart from these commonly used biomarkers, many attempts of using molecules which are participating in the sepsis cascades failed to identify the most appropriate one in clinical practice.
CD14, a glycoprotein expressed on monocytes and macrophages, is part of the innate immune system serving as a receptor for lipopolysaccharides (LPS) of bacteria and activating the pro-inflammatory signaling cascade. CD14 molecule is a pattern recognition receptor existing in two forms: a membrane-bound type (mCD14) and a soluble form (sCD14). Both forms play a role in recognition of bacteria LPS and in cell activation. During the progression of the sepsis cascades where the soluble CD14 fragments are cleaved, the soluble CD14 subtype (sCD14-ST) also called as presepsin elevates significantly and is readily measured using a chemiluminescent enzyme immunoassay. It is a small 13 kDa protein that arises due to cleavage of the N-terminal fragment of CD14 by elastase [2]. Presepsin is filtered through the glomeruli, then reabsorbed, and catabolized within the proximal tubular cells. Presepsin should be interpreted attentively in patients with kidney disease, as elevated presepsin levels were found in patients with decreased renal function, also inverse correlation has been described between presepsin and GFR as well [58,59].
This molecule is now recognized as a new sepsis biomarker and can also be used in the differentiation between bacterial infections and non-infectious SIRS [25]. Presepsin is normally present in very low concentrations in the serum of healthy individuals. In response to bacterial infections, its concentration increases within 2 hours, according to the severity of the disease and the cut-off levels for sepsis have been reported between 400-600 pg/ml. The early increase in levels of presepsin during the sepsis cascade and other bacterial infections have made it an attractive indicator for laboratory testing.
The findings of this review indicate that presepsin is a molecule that has been used in clinical practice the latest years in an attempt to evaluate patients suffering from sepsis. Among the extracted bibliography, there are some studies which do not indicate a superiority of presepsin in regards to the already used biomarkers [12,29,37]. However, there are studies which propose presepsin as a highly sensitive and specific marker of sepsis, as its concentration significantly correlates with the severity of sepsis syndrome and inhospital mortality [1,2,39,41]. Furthermore, some studies provide preliminary evidence that in certain settings presepsin may be a superior diagnostic and prognostic biomarker of sepsis compared to the more common biomarkers CRP and PCT [8,22,60,61]. Other studies also emphasize the role of presepsin in the assessment of sepsis in combination with commonly used biomarkers and clinical rating scales, as part of a multi-biomarker approach of sepsis in view of the absence of the 'ideal' biomarker [6,13,28,33]. Presepsin is a promising biomarker for the evaluation of sepsis both in the emergency department to aid in the initial assessment of the patient and in the intensive care setting where patients are most likely to be in a state of multiple organ failure [34,39,40,62].
Although a strong body of literature favors the validity of presepsin as a biomarker for the diagnosis, prognosis and risk stratification of sepsis, presepsin measurement is not yet ubiquitously available as a routine laboratory test. The studies in favor of the use of presepsin are heterogenous, examining different patient groups at risk of sepsis in a variety of different settings, with the small sample size being a common limitation. Presepsin does not appear to be clearly superior to the biomarkers commonly used in the assessment of sepsis, but may be valuable when used in conjunction with other established tests to better identify patients at risk of clinical deterioration. Further studies are indicated to establish whether it is useful for predicting the most severe complications of sepsis in the intensive care setting, and the evidence regarding its use in the postoperative setting also warrants a careful appraisal.

Conclusions
Presepsin has some value in the evaluation of the severity and prognosis of sepsis and as the results of the test are available within 2 hours, widespread clinical use is feasible, though it is unclear at this time whether it would significantly affect clinical practice. As sepsis syndrome remains an entity with high mortality rates and increased socioeconomic implications and the 'ideal' biomarker has not yet been identified, further research is warranted to evaluate the role of presepsin alone or in combination with other biomarkers in the assessment of sepsis.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.