Sepsis is a life-threatening clinical syndrome caused by a dysregulated host inflammatory response to infection, often associated with multiple organ dysfunction syndrome and death [1]. It is recognized as a leading cause of death worldwide, as highlighted by the Global Burden of Disease, which estimated 48.9 million incident cases in 2017, accounting for 19.7% of all global deaths [2]. The economic and health burden of sepsis worldwide is alarming; mortality in sepsis patients has been estimated to be ≥10%, rising above 40% when evolving to septic shock [1]; in 2011 the total sepsis-related costs for US hospitals accounted for more than US $20 billion [1].

The definition of sepsis has undergone several revisions over the years because of the highly variable clinical spectrum: the 2001 American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference Committee criteria for the host systemic inflammatory response syndrome (SIRS) are currently outdated because of their demonstrated poor ability to discriminate between different degrees of clinical severity [3]. Reassessment of these criteria in a clinical setting has shown that they are often found in many inpatients, including those who are noninfectious and who do not proceed to adverse outcomes [3]. The latest definition of sepsis, named “Sepsis-3”, was proposed in 2016 by the SCCM and the European Society of Intensive Care Medicine (ESICM) [1]. According to the SCCM/ESICM, sepsis is defined as a life-threatening organ dysfunction (ascertained as acute change in Sepsis-related Organ Failure Assessment (SOFA score) total score ≥2) “due to a dysregulated host response to infection” [1]. Septic shock is defined as a “subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities substantially increase mortality” [1].

Rapid detection of sepsis is mandatory since the patient’s overall clinical impairment and degree of organ damage are triggered by an extremely complex chain of events involving the recognition of pathogen-associated molecular patterns (PAMPs) of microorganisms by the host immune system [4]. As happens in other acute pathologic conditions such as acute encephalitis [5], but also in several diseases not directly provoked by an infection such as ischemic stroke [6,7,8], atrial fibrillation [9], and many others [10], the characteristics of the interaction between host and pathogen fundamentally affect the degree and severity of the systemic involvement of the patient. The damage-associated molecular patterns (DAMPs) released by the spillover from the injured cells [11] can result in an escalating state of inflammation that can abruptly lead to multiple organ failure (MOF) and can result in death. The prompt initiation of a broad spectrum empirical antibiotic therapy and patient-driven supportive strategies such as fluid resuscitation optimize outcomes. The so-called early goal-directed therapy in the first hour of documented hypotension leads to a 79.9% survival rate, each hour of delay being associated with an average decrease in survival of 7.6% [12]. Despite the development of bedside screening tools to facilitate the early detection of septic patients, a tool to which a definitive diagnostic value can be attributed is still missing, thus the diagnosis is today still challenging, and it continues to depend on the clinical judgment based on nonspecific clinical and laboratory variables. In addition, rapid discrimination between infectious and noninfectious causes presents a daunting challenge. The diagnosis of systemic infection is mainly based on direct microbiological tests such as cultures or polymerase chain reaction-based methods or indirectly using specific immunoglobulin dosage. Unfortunately, microbiology results often take several days to became positive and are not diagnostic in patients with ongoing infection in up to one-third of cases, especially if cultures were collected when antibiotic treatment had already been started [13].

Since the combined sensitivity and specificity of actual biomarkers (e.g., C-reactive protein (CPR), Procalcitonin (PCT) and Interleukin-6 (IL-6)) do not allow for the rapid ascertainment of the diagnosis [14,15] and sepsis-related adverse outcomes rise with every hour of delay of proper intervention, new early biomarkers are urgently needed.

There is a growing amount of data about non-codingRNA, a group of transcripts that do not code proteins at first deemed as redundant RNAs but lately described as highly conserved transcripts involved in gene expression regulation through the modulation of chromatin rearrangement, histone modification, alternative splicing regulation and many other biological processes [16]. Recent findings speculate that circularRNAs (circRNAs), a particular type of long non-codingRNAs (lncRNAs) distinguished by a covalently closed-loop structure with neither 5′ to 3′ polarity nor polyadenosine tail, participates in gene regulation in a different way, regulating the microRNA (miRNAs) concentration in body fluids by competing with several miRNAs and regulating the downstream of messenger RNAs (mRNAs) [17].

Further demonstrating the increasing biological value that non-coding RNAs are proving to have, they seem to play a role in the pathogenesis of different diseases [18], and, given the complex interweaving between circRNAs, miRNAs, lncRNAs and mRNAs, various studies have addressed the issue of their role as novel diagnostic markers and therapeutic targets in many pathologic conditions including sepsis [19,20,21,22,23,24,25].

2. Role of Biomarkers in Sepsis

2.1. C-Reactive Protein (CRP)

2.2. Procalcitonin (PCT)

2.3. Presepsin