**Abstract**

Sepsis is defined as a life-threatening condition with organ failure, caused by an inadequate response of the host to the infection. It is a public health and economic problem worldwide. Early and accurate diagnosis of sepsis and timely inclusion of appropriate therapy are important for the outcome of the treatment of patients with sepsis. Sepsis biomarkers may provide information to achieve an early diagnosis, and predict prognosis and therapeutic response. Today, the literature lists more than 250 different biomarkers related to sepsis. However, stronger clinical evidence of clinical usefulness has emerged only for a few biomarkers from many published studies and meta-analyses. Among them, presepsin (sCD14-ST) appears to be one of the most promising biomarkers of sepsis in daily clinical practice. This chapter highlights the utility of presepsin as a diagnostic and prognostic biomarker of sepsis both in adult and pediatric patients.

**Keywords:** biomarker, diagnosis, infections, presepsin, prognosis, sepsis

## **1. Introduction**

Sepsis is recognized as a global health problem worldwide and an important public health issue with considerable economic consequences. Sepsis can be the clinical manifestation of infections acquired both in the community setting and in health care facilities. Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) from 2016 defines sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection." This definition emphasizes the central pathogenetic role of the non-homeostatic host response to microorganisms rather than the infection *per se* [1]**.** Organ dysfunction was described using scoring systems such as the Sequential (Sepsis-related) Organ Failure Assessment score (SOFA score). A SOFA score ≥ 2 points were set as a criterion for more rapid identifying patients with sepsis in intensive care units (ICU). Patients with a SOFA score of 2 or more had an overall mortality risk of approximately 10% in a general hospital population with suspected infection. Sepsis-3 has also introduced a new simpler score, called the quick Sequential Organ Failure Assessment (qSOFA) for use in non-ICU settings, to identify septic patients in out-of-hospital, emergency department, or general hospital ward setting. The qSOFA consists of three variables: respiratory rate ≥ 22 breaths per min, systolic blood pressure ≤ 100 mmHg, and altered mentation. A qSOFA score ≥ 2 was found to be significantly predictive of increased all-cause mortality in patients outside of the

ICU. According to Sepsis-3 definition, septic shock was defined as a subset of sepsis in which underlying circulatory and metabolic abnormalities are profound enough to substantially increase mortality. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/l (>18 mg/dl) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40% [1].

Neonatal sepsis is a systemic condition of bacterial, viral, or fungal (yeast) origin that is associated with hemodynamic changes and other clinical manifestations and results in substantial morbidity and mortality. The symptoms are variable and nonspecific. Based on the onset neonatal sepsis could be classified into two types: (a) earlyonset sepsis (EOS), which manifests as respiratory distress within 72 h of birth, and is mainly due to bacteria acquired before and/or during delivery (maternal-fetal infection); (b) late-onset sepsis (LOS), which manifests as septicemia after 72 h of birth and is due to bacteria acquired after delivery like nosocomial ones (community or hospitalacquired), and affects preterm and very-low-birth-weight neonates in particular [2].

The global burden of sepsis is difficult to ascertain. A meta-analysis of studies on adults admitted to hospitals from seven high-income countries suggested global estimates of 31.5 million sepsis (19.4 million severe sepsis cases), and 5.3 million sepsis-related deaths annually [3]. The recent article published by Rudd et al. [4] is the first comprehensive global report on the epidemiology of sepsis. It assessed the burden of sepsis across 195 countries and territories within the framework of all 282 underlying causes of death, both sexes, and 23 age groups for the years 1990 to 2017 in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 study. It is estimated that in 2017, there were 48.9 million cases and 11 million sepsis-related deaths worldwide, i.e., almost 20% of all global deaths. Approximately 85% of sepsis cases and sepsis-related deaths worldwide occurred in countries with low to middle sociodemographic indices that had much higher rates than those with higher indices. Nearly half of all sepsis-related deaths occur secondary to sepsis complicating an underlying injury or non-communicable disease. In 2017, almost half of all global sepsis cases occurred among children, with an estimated 20 million cases and 2.9 million global deaths in children under five years of age. The hospital mortality rate of sepsis was estimated to be 27% and mortality in ICU-treated sepsis was 42%. Among adult sepsis survivors, one in three died within a year, and one in six experienced significant, long-term morbidity [5]. Patients who survive sepsis often have long-term physical, psychological, and cognitive disabilities with significant health care and social implications.

Fleischmann-Struzek et al. [6] published an extensive systemic review analyzing the global burden of pediatric and neonatal sepsis. The review was based on 1270 studies published from 1979 to 2016. They performed the largest meta-analysis of population-based sepsis incidence in neonates and children, including 15 studies from 12 middle- and high-income countries on four continents. They estimated that 48 children per 100,000 population develop sepsis, 22 children per 100,000 population develop severe sepsis. Mortality ranged from 1.3% to 5.4% for sepsis, and 9–20% for severe sepsis. The population-level estimated for neonatal sepsis was 2202 per 100,000 live births, with mortality between 11% and 19%. This would translate to an incidence of 3 million cases of neonatal sepsis and 1.2 million cases of pediatric sepsis annually. These estimates are exploratory because of the considerable heterogeneity between data and the lack of population-based data from low-income and middleincome settings. Analyzing these alarming data, it is clear why the WHO, in 2017, listed sepsis as a key healthcare priority for the coming decade.

#### *Presepsin as a Diagnostic and Prognostic Biomarker in Sepsis DOI: http://dx.doi.org/10.5772/intechopen.107955*

Sepsis is treatable, but early diagnosis is highly needed, due to significant clinical heterogeneity and the non-specificity of clinical symptoms. If it is not identified early and timely managed, sepsis may lead to severe and life-threatening complications such as septic shock, multiple organ failure, and death [7]. Early diagnosis is also important from an economic view since the earlier diagnosis of sepsis lowers the costs [8]. Sepsis-3 Task Force reiterates the concept that sepsis shall be identified using clinical criteria for life-threatening organ dysfunction and blood culture. Although blood culture has been considered the gold standard reference method for detecting and isolating pathogenic organisms from sterile body fluid specimens, its accuracy remains limited because of overall low diagnostic sensitivity, with high false negative rates in patients after initiation of antibiotic therapy, and in patients with severe localized infections or in the noninfectious cause of sepsis and preanalytical variables (inaccurate skin antisepsis, failure to use sterile gloves collection through central venous caterers, use of open blood collection systems, inadequate filling of blood culture bottles, long-term storage under inappropriate conditions, etc.). The drawbacks of blood culture are long turnaround time (its results are rarely available in a useful timeframe for decision-making), large sample volume, and frequent need for repeated testing [9, 10].

We have witnessed over the last years that an extensive variety of technologies for the identification of pathogens have been examined [11, 12]. Although some molecular diagnostic techniques, such as DNA/RNA rapid amplification followed by mass spectrometry or nuclear magnetic resonance are available and enable molecular identification of the causative organism in a few hours, limitations in their diagnostic performance still exist and must be overcome. Additional well-known drawbacks include: the need of dedicated often expensive equipment, high sensitivity of technique used for lysis and nucleic acids extraction, vulnerability to environmental contaminations, possible generation of false positive results due to deep-seated infections, doubts about the optimal sample matrix, interference from host nucleic acid and additional substances, amplification bias, off-target interactions, as well as to current limitedness and insufficient standardization of test panels [9]*.*

Delays in the initiation of antimicrobial treatment are associated with a worse prognosis [13]*.* The current treatment guidelines for treating sepsis promulgate initiation of effective antibiotics within 1–3 h [14]*.* A large number of patients with sepsis still remain microbiologically undiagnosed in that period, thus, amplifying the risk of indiscriminate use of empiric antibiotics as broad-spectrum treatment. It contributes to the spread of antibiotic resistance genes, further exacerbating the emergence of multidrug-resistant microbial pathogens and secondary fungal infections [15]*.* Sometimes, empiric antibiotics are often administered to patients before arriving in the hospital and before exhibiting progressive signs of sepsis, thereby precluding an accurate microbial diagnosis by standard culture.

Due to explained limitations, there has been intense interest in identifying biomarkers of sepsis. Numerous serum/plasma sepsis biomarkers have been commercialized over the past decades. We are the witnesses that a growing body of literature over the last years revealed more than 250 sepsis biomarkers that offer utility for diagnosis, prognosis, early disease recognition, risk stratification, and appropriate treatment for patients with sepsis or suspected sepsis [16]*.* It is very well known that the ideal sepsis biomarker should be present at symptoms onset (or even earlier) and allow for an early diagnosis, should offer both high specificity and sensitivity for infections, be capable to identify the causative microorganism, be informative on the clinical course, provide valuable information on the prognosis, and guide therapeutic decisions. Additionally, the ideal biomarker should be non/invasive, easily measured by a single, widely available test, reproducible, accurate, with defined optimal cut-off(s), known release kinetics, and cost-effective [17]*.* Despite a large number of biomarkers studied, no single biomarker emerged as a consistently reliable indicator for diagnosis and prognosis of sepsis. Given that none of these biomarkers fulfill all features of ideal sepsis biomarker, it is not surprising that the Sepsis-3 definition consensus states the role of biomarkers in sepsis diagnosis remains undefined [1], Surviving Sepsis Campaign guidelines for the management of sepsis mention that sepsis biomarkers can complement clinical evaluation [18].

Recent evidence suggests that an increased concentration of some sepsis biomarkers more reliably reflects the systemic host response to infection. Only a few biomarkers were reported to have a role specifically related to sepsis pathophysiology, rather than to a more general inflammatory reaction. However, only a handful of these has reached the point of clinical availability, i.e., validation in clinical practice. The measurement of some sepsis biomarkers in addition to blood culture or molecular biology further improves the diagnostic management of patients with possible sepsis. It appears that some sepsis biomarkers are favorable markers for the evaluation of sepsis severity, for garnering valuable prognostic information, and guiding therapeutic decision-making i.e., antibiotic stewardship.

Among the emerging biomarkers of sepsis, the soluble CD14 subtype (sCD14-ST) also known as presepsin received increasing attention as one of the most promising. This chapter will summarize our current knowledge of presepsin with emphasis on its clinical usefulness as a diagnostic and prognostic biomarker in sepsis.
