New Biomarkers of Sepsis with Clinical Relevance

*Débora Maria da Gomes Cunha, Guilherme Galdino da Silva and Mike Yoshio Hamasaki*

### **Abstract**

A 2016 task force convened by multiple societies proposed a new definition of sepsis, termed Sepsis 3. The new clinical diagnosis of sepsis is based on variation points in the Sequential (Sepsis-related) Organ Assessment Score (SOFA) and excluded Systemic Inflammatory Response Syndrome (SIRS) as a criterion for defining the diagnosis. Although the new definitions have provided improvements in understanding the disease, the main concern generated by Sepsis 3 is the reduced sensitivity to detect cases that might have an unfavorable course, mainly in early conditions. By limiting the diagnosis to organic dysfunction, the new concept tends to select a more severely ill population. In this way, biomarkers to diagnose sepsis may allow early intervention, which can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate's effectiveness and may be used as a tool for staging the disease, prognosis, and response to intervention. The objective of this chapter is to present possible new biomarkers that are clinically relevant.

**Keywords:** biomarkers, cytokines, haptoglobin, lactate, sRAGE, sepsis

#### **1. Introduction**

The first definition of sepsis was described in a consensus conference in 1991. Known as Sepsis 1, it advocated the hypothesis that infection was directly proportional to the systemic inflammatory response syndrome (SIRS). Ten years later, in a new conference (Sepsis 2), the SIRS diagnostic method was already questioned by the scientific community about its low specificity. However, in the current situation, Sepsis 2 did not offer many alternatives because of the lack of evidence to substantiate the above arguments [1, 2].

Although SIRS criteria have been described for more than three decades as a host's clinical expression to systemic infection and have contributed greatly to the understanding of sepsis in various pathophysiological areas, the need for a new conference in 2016 was recognized, where the sepsis' concepts were reviewed again [2, 3].

Sepsis 3 was proposed by the Society of Critical Care Medicine (SCCM) together with the European Society of Intensive Care Medicine (ESICM), which established that the disease is linked to life-threatening organic dysfunction that is secondary to the body's unregulated responses to the infection. This new definition extinguished the term of severe sepsis and completely abandoned the use of SIRS in the diagnosis of sepsis [4].

In order to promote a new and more sensitive diagnostic method than the previous one, the score of sequential organ failure assessment (SOFA) was instituted. Due to the complexity of the SOFA's rapid completion and the concern of the impossibility of a fast and early disease identification, "quick SOFA" (qSOFA) was also established in Sepsis 3 [3].

Despite the improvements obtained through Sepsis 3, in the same year of the new guidelines, Williams et al. [4] demonstrated in 2016 that the new diagnostic model is not very sensitive in the early stages of disease. These observations are of great clinical relevance because the treatment of sepsis is more effective in early stages.

One of the alternatives used for the early diagnosis of patients in several diseases is the Point-of-Care Testing (POCT), a laboratory test carried out in the places where the intensive treatment is done. POCT has become popular among physicians because its agility in the patients' diagnosis has been shown to be effective, including requiring fewer samples collected from the patient [5].

Unlike traditional laboratory tests, POCT does not require a permanent dedicated space, since it has kits and instruments that can be transported to where the patient is, thus immediately allowing the dosage of several substances, not only in hospital or professional environments, and can be operated by patients in their home [6].

Currently, POCT is used to test a range of pathological conditions, including diabetes, hypertension, hyperlipidemia, and asthma, as well as monitoring of bone density, body composition, and anticoagulation, and these tests are expanding rapidly (from 12 to 15% annually) [6].

Despite the great validity of the POCT test, this method presents operational and environmental instability and is difficult to standardize in intensive care settings [7, 8]. In addition, the clinical status of patients with sepsis is very unstable and the disease severity usually changes abruptly [1]. Thus, it is necessary to recognize new specific and sensitive biological markers for the sepsis diagnosis.

Biomarkers were defined by the National Institute of Health as a characteristic that should be measured and served as an indicator of a normal, pathological state or a response to a pharmacological agent. They shall be characterized by accuracy and reproducibility and may be used as important tools for diagnosis, as well as promoting early diagnosis, indicating the stage of the disease, prognosis, and mechanisms of intervention.

More than 100 biomarkers have already been described and proposed for sepsis; combinations between them have also been demonstrated. However, due to the different stages of severity observed in sepsis in the most diverse populations, it has been complicated to define which marker can be used as a parameter to improve therapeutic strategies. Therefore, for sepsis, a good biomarker has to be able to identify early alterations in order to prevent multiple organ dysfunction and consequently reduce the mortality of patients with this pathology.

New biomarkers could promote better monitoring of the patient's condition and, possibly, a more accurate definition of the disease prognosis. This chapter aims to describe the biological markers already established for sepsis, as well as to cite those that in our opinion show promising results.
