**2. Established biological markers**

#### **2.1 Lactate**

Lactate (or lactic acid) is the anaerobic glycolysis end product, and its blood levels increase significantly in the hypoperfusion or hypoxia cases. Due to an

**13**

*New Biomarkers of Sepsis with Clinical Relevance DOI: http://dx.doi.org/10.5772/intechopen.82156*

prognosis in patients diagnosed with septic shock.

from the disease.

sepsis [14].

**2.2 C-reactive protein**

phagocytosis [17].

control groups.

patients with sepsis.

imbalance between lactate production and lactate clearance in patients with sepsis,

The first study that connected the production of lactate with sepsis was performed by Bakker et al. [11] in 1991. In this study, they demonstrated that the tissues of patients with sepsis or septic shock did not adequately use the O2 molecule and that survivors of the disease had lower blood lactate levels than those who died

Five years after this finding, Bernardin et al. [12] demonstrated that the changes in the blood lactate level occur within the first 24 hours of treatment, and in addition to blood pressure fluctuation, may be strong indicators of short-term survival

In a paper published in 2013, a Brazilian clinical care research group has demonstrated that hyperlactatemia can be caused by mitochondrial dysfunction and the use of adrenergic drugs in the condition of septic shock [13]. Léguillier et al. [14] demonstrated in 2018 that the lactate dosage, associated with POCT, bring a possible new strategy for the early treatment of patients with suspicion of

As predicted in Sepsis 3, the most common use of lactate dosage is in the differentiation between sepsis and septic shock in intensive care units (ICUs), and this

dosage of arterial lactate is not satisfactory in recognizing the sepsis prognosis. Therefore, they suggest that such dosages need to be supported by results from other biological markers, such as C-reactive protein (CRP), B-type natriuretic

However, Guo et al. [15] demonstrated in their study that an isolated and simple

C-reactive protein (CRP) is an acute inflammatory phase protein produced in the liver, currently believed to be a reliable indicator of inflammation and tissue damage, as it is elevated in cases of infection, inflammatory response, damage, and necrosis of the tissue [16]. Among its actions are platelet activation, chemotaxis acceleration, and enhancement of cell-mediated immunity by promoting

One of the first studies to correlate CRP with sepsis was conducted in 1987 by Mustard et al. In this study, it was observed that postoperative CRP levels can

This protein is also used to differentiate the sepsis of a noninfectious systemic inflammatory response syndrome in trauma patients, in which the high level of this protein in the first 4 days after injury is a reliable indication of infection [19].

In 2013, a study conducted at the Department of Pediatrics at Yonsei University of Medicine showed that high levels of CRP in the mother may indicate a risk of infection of the newborn and that these values would be related to the severity of

Also, in 2013, Oliveira et al. [20] compared CRP with another established biomarker, procalcitonin (PCT). In this study, it was observed that the protein is as effective as PCT to guide antibiotic therapy in patients with sepsis, showing that the group guided by CRP levels required less treatment time when compared to the

In a study published in 2017, Wang et al. [21] once again correlated CRP with sepsis when comparing the CRP's serum level with those of other proinflammatory cytokines, suggesting that this would be a potential target for the treatment of

predict septic complications even before its clinical manifestation [18].

information is very important and useful for medical professionals.

peptide (BNP), and N-terminal proBNP (NT-proBNP).

the disease presented by these babies [16].

hyperlactatemia is a common condition in these patients [9, 10].

#### *New Biomarkers of Sepsis with Clinical Relevance DOI: http://dx.doi.org/10.5772/intechopen.82156*

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

also established in Sepsis 3 [3].

rapidly (from 12 to 15% annually) [6].

mechanisms of intervention.

home [6].

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

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, includ-

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

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

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

More than 100 biomarkers have already been described and proposed for sepsis;

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

Lactate (or lactic acid) is the anaerobic glycolysis end product, and its blood levels increase significantly in the hypoperfusion or hypoxia cases. Due to an

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 conse-

quently reduce the mortality of patients with this pathology.

that in our opinion show promising results.

**2. Established biological markers**

ing requiring fewer samples collected from the patient [5].

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

**12**

**2.1 Lactate**

imbalance between lactate production and lactate clearance in patients with sepsis, hyperlactatemia is a common condition in these patients [9, 10].

The first study that connected the production of lactate with sepsis was performed by Bakker et al. [11] in 1991. In this study, they demonstrated that the tissues of patients with sepsis or septic shock did not adequately use the O2 molecule and that survivors of the disease had lower blood lactate levels than those who died from the disease.

Five years after this finding, Bernardin et al. [12] demonstrated that the changes in the blood lactate level occur within the first 24 hours of treatment, and in addition to blood pressure fluctuation, may be strong indicators of short-term survival prognosis in patients diagnosed with septic shock.

In a paper published in 2013, a Brazilian clinical care research group has demonstrated that hyperlactatemia can be caused by mitochondrial dysfunction and the use of adrenergic drugs in the condition of septic shock [13]. Léguillier et al. [14] demonstrated in 2018 that the lactate dosage, associated with POCT, bring a possible new strategy for the early treatment of patients with suspicion of sepsis [14].

As predicted in Sepsis 3, the most common use of lactate dosage is in the differentiation between sepsis and septic shock in intensive care units (ICUs), and this information is very important and useful for medical professionals.

However, Guo et al. [15] demonstrated in their study that an isolated and simple dosage of arterial lactate is not satisfactory in recognizing the sepsis prognosis. Therefore, they suggest that such dosages need to be supported by results from other biological markers, such as C-reactive protein (CRP), B-type natriuretic peptide (BNP), and N-terminal proBNP (NT-proBNP).

### **2.2 C-reactive protein**

C-reactive protein (CRP) is an acute inflammatory phase protein produced in the liver, currently believed to be a reliable indicator of inflammation and tissue damage, as it is elevated in cases of infection, inflammatory response, damage, and necrosis of the tissue [16]. Among its actions are platelet activation, chemotaxis acceleration, and enhancement of cell-mediated immunity by promoting phagocytosis [17].

One of the first studies to correlate CRP with sepsis was conducted in 1987 by Mustard et al. In this study, it was observed that postoperative CRP levels can predict septic complications even before its clinical manifestation [18].

This protein is also used to differentiate the sepsis of a noninfectious systemic inflammatory response syndrome in trauma patients, in which the high level of this protein in the first 4 days after injury is a reliable indication of infection [19].

In 2013, a study conducted at the Department of Pediatrics at Yonsei University of Medicine showed that high levels of CRP in the mother may indicate a risk of infection of the newborn and that these values would be related to the severity of the disease presented by these babies [16].

Also, in 2013, Oliveira et al. [20] compared CRP with another established biomarker, procalcitonin (PCT). In this study, it was observed that the protein is as effective as PCT to guide antibiotic therapy in patients with sepsis, showing that the group guided by CRP levels required less treatment time when compared to the control groups.

In a study published in 2017, Wang et al. [21] once again correlated CRP with sepsis when comparing the CRP's serum level with those of other proinflammatory cytokines, suggesting that this would be a potential target for the treatment of patients with sepsis.

However, although there is considerable sensitivity in the CRP oscillation to describe the disease intensity in already diagnosed patients, this biomarker has low specificity in determining sepsis, which prevents CRP from being alone an indicator for the diagnosis of the pathology [15].

#### **2.3 B-type natriuretic peptide**

B-type natriuretic peptide (BNP) is a cardiac hormone with natriuretic, diuretic, and vasodilatory properties. It is produced by the ventricular myocardium in response to the stretching of the cardiac muscle, having as its main role the cardiac pressure regulation and homeostasis of the intravascular volume [22]. In this sense, septic shock is recognized as a condition that causes severe changes in blood pressure.

BNP or its inactive N-terminal proBNP cleavage product (NT-proBNP) is mainly used as a biomarker for congestive heart failure [23]. However, Papanikolaou et al. [24] demonstrated in 2014 that the severity of sepsis is the major determinant of BNP increase in the disease-induced myocardial depression in patients with a septic shock. In addition, the same study suggests that the increase in BNP serum levels on the second day of the condition is a strong indication of a poor prognosis.

However, due to the inconsistency of results and the specificity limitations, harsh criticism of this biomarker use has recently arisen, demonstrating the need for further studies to validate the use of this as a biomarker in the sepsis condition [25].

It is currently believed that BNP and NT-proBNP have moderate potential to assess the diseased patients' prognosis. As Bai demonstrated in his meta-analysis published in 2018, the peptide can be used as a tool for defining how the condition will evolve, but further studies are needed to assess the real importance of BNP in the clinic [26].

#### **2.4 Procalcitonin**

Procalcitonin (PCT) is a prohormone precursor of calcitonin produced by thyroid C cells. Under normal conditions, PCT is not detected in the circulation; however, in situations of great stress, such as sepsis, it is possible to observe a high extrathyroidal production of PCT. PCT is currently used as a tool to differentiate bactericidal infection from other inflammatory and infectious processes [27].

PCT is correlated with sepsis since 1993 when Assicot et al. [28] demonstrated that this protein was detectable in the plasma of diseased patients and with other types of infection. Since then, studies have demonstrated the efficacy of this tool in the prognosis of patients with sepsis, as demonstrated in the review published in 2001 by Meisner [29], in which it was observed that the PCT's concentration during the sepsis and SIRS stages is high and is directly proportional to the severity of the condition.

This method provides additional information to the diagnosis by other parameters of an inflammatory response; such additional information is not provided by conventional parameters of systemic inflammation. Mustafić et al. [30] also demonstrated in 2018 that it is possible to use PCT to reveal the disease severity and prevent a fatal outcome for the patient with sepsis.

In the same year, Bilgili et al. [31] demonstrated that PCT can differentiate even gram-negative bacteremia from a Gram-positive one, noting that protein values are higher in patients infected with Gram-negative bacteria. However, in these cases, PCT should be used only as a support tool for predictive purposes in diagnostic tests.

**15**

*New Biomarkers of Sepsis with Clinical Relevance DOI: http://dx.doi.org/10.5772/intechopen.82156*

the development of multiresistant bacteria [20].

*Biomarkers and their predictive parameters in sepsis.*

**3.1 Receptor for advanced glycation end products**

**3. Promising biomarkers**

propagating inflammation.

mortality of patients with septic shock [35].

involved in endothelial injury and coagulopathy.

inflammation.

**Table 1.**

Several studies have shown that PCT's serum levels may be a guide in antibiotic therapy and can also be used to safely reduce the excessive exposure of these patients to drugs, thus reducing the adverse effects of sepsis treatment and avoiding

**Biomarker Sensitivity (%) Specificity (%) AUC NPV PPV References** Lactate 58.3 88.1 0.66 78.7 73.7 [33] CRP 66 80 0.81 88 51 [34] Pro-BNP 70.8 47.6 0.66 74.1 43.6 [33] PCT 88 80 0.87 95 57 [33, 34] sRAGE 75 85 — — — [35, 36]

Considering several studies cited in this chapter, the sepsis survival campaign published in 2017 suggested that the PCT monitoring should be used to verify the dosage and duration of antimicrobial treatment in patients with sepsis [32].

In **Table 1**, we summarize some parameters that reveal the predictive potential of the biomarkers mentioned above. Among them, we emphasize the sensitivity and specificity of each biomarker demonstrated by the ROC curve. The area under the ROC curve (AUC) represents the performance of the biomarker. We also speci-

The receptor for advanced glycation end products (RAGE) recipient is a standard recognition receptor that participates in a wide variety of physiological and pathological processes, such as diabetic complications, cancer, atherosclerosis, and

The studies that relate soluble RAGE (sRAGE), the extracellular domain of RAGE, to the sepsis are very recent since even the discovery of this receptor's soluble form occurred in 2009 [37]. It has been reported that an increase in the level of sRAGE would be a protective mechanism since its presence in plasma contributes to the removal or neutralization of ligands for RAGE, thus acting as a "false" receptor [38]. However, Wang et al. [39] reported a deletion effect of sRAGE in the inflammatory process, since it would bind to CD11b receptors of leukocytes, thus

Based on these contradictory results in scientific literature, in 2014, our group published a study demonstrating a positive correlation between serum levels of sRAGE with IFN-γ in patients with sepsis. We also observed significant correlations between levels of IL-1α, IL-6, IL-8, IL-10, and IP-10 and sRAGE in patients with septic shock. We concluded that sRAGE blood levels may be associated with the

Further studies support this assertion, such as the study by Matsumoto et al. [40] demonstrated that the sRAGE serum level of patients with sepsis increases directly proportional to the severity of the disease, suggesting that sRAGE reflects on the RAGE's signaling pathway inducing an excessive inflammatory response

fied in the table the positive and negative predictive values for each marker.



**Table 1.**

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

for the diagnosis of the pathology [15].

**2.3 B-type natriuretic peptide**

pressure.

condition [25].

the clinic [26].

condition.

**2.4 Procalcitonin**

However, although there is considerable sensitivity in the CRP oscillation to describe the disease intensity in already diagnosed patients, this biomarker has low specificity in determining sepsis, which prevents CRP from being alone an indicator

B-type natriuretic peptide (BNP) is a cardiac hormone with natriuretic, diuretic,

BNP or its inactive N-terminal proBNP cleavage product (NT-proBNP) is mainly used as a biomarker for congestive heart failure [23]. However, Papanikolaou et al. [24] demonstrated in 2014 that the severity of sepsis is the major determinant of BNP increase in the disease-induced myocardial depression in patients with a septic shock. In addition, the same study suggests that the increase in BNP serum levels on

and vasodilatory properties. It is produced by the ventricular myocardium in response to the stretching of the cardiac muscle, having as its main role the cardiac pressure regulation and homeostasis of the intravascular volume [22]. In this sense, septic shock is recognized as a condition that causes severe changes in blood

the second day of the condition is a strong indication of a poor prognosis.

However, due to the inconsistency of results and the specificity limitations, harsh criticism of this biomarker use has recently arisen, demonstrating the need for further studies to validate the use of this as a biomarker in the sepsis

It is currently believed that BNP and NT-proBNP have moderate potential to assess the diseased patients' prognosis. As Bai demonstrated in his meta-analysis published in 2018, the peptide can be used as a tool for defining how the condition will evolve, but further studies are needed to assess the real importance of BNP in

Procalcitonin (PCT) is a prohormone precursor of calcitonin produced by thyroid C cells. Under normal conditions, PCT is not detected in the circulation; however, in situations of great stress, such as sepsis, it is possible to observe a high extrathyroidal production of PCT. PCT is currently used as a tool to differentiate bactericidal infection from other inflammatory and infectious processes [27].

PCT is correlated with sepsis since 1993 when Assicot et al. [28] demonstrated that this protein was detectable in the plasma of diseased patients and with other types of infection. Since then, studies have demonstrated the efficacy of this tool in the prognosis of patients with sepsis, as demonstrated in the review published in 2001 by Meisner [29], in which it was observed that the PCT's concentration during the sepsis and SIRS stages is high and is directly proportional to the severity of the

This method provides additional information to the diagnosis by other parameters of an inflammatory response; such additional information is not provided by conventional parameters of systemic inflammation. Mustafić et al. [30] also demonstrated in 2018 that it is possible to use PCT to reveal the disease severity and

In the same year, Bilgili et al. [31] demonstrated that PCT can differentiate even gram-negative bacteremia from a Gram-positive one, noting that protein values are higher in patients infected with Gram-negative bacteria. However, in these cases, PCT should be used only as a support tool for predictive purposes

prevent a fatal outcome for the patient with sepsis.

**14**

in diagnostic tests.

*Biomarkers and their predictive parameters in sepsis.*

Several studies have shown that PCT's serum levels may be a guide in antibiotic therapy and can also be used to safely reduce the excessive exposure of these patients to drugs, thus reducing the adverse effects of sepsis treatment and avoiding the development of multiresistant bacteria [20].

Considering several studies cited in this chapter, the sepsis survival campaign published in 2017 suggested that the PCT monitoring should be used to verify the dosage and duration of antimicrobial treatment in patients with sepsis [32].

In **Table 1**, we summarize some parameters that reveal the predictive potential of the biomarkers mentioned above. Among them, we emphasize the sensitivity and specificity of each biomarker demonstrated by the ROC curve. The area under the ROC curve (AUC) represents the performance of the biomarker. We also specified in the table the positive and negative predictive values for each marker.
