**6.2. White blood cell count (WBC)**

• provide information regarding the prognosis including the patient in subpopulations

• provide, in the clinical course, useful information on how the patient responds to therapy

• be easily determinable and reproducible and difficult to influence by disturbing factors; • have low costs and be easily used to quantify intervention actions, costs and benefits;

• in the case of sepsis, allow differential diagnosis between infectious and non-infectious

The use of biomarkers must always be integrated with the information deriving from a careful medical history collection, from a complete clinical objective examination, from the results of laboratory analyzes and diagnostic methods required in different cases. In fact, only the set of all these elements make it possible to reduce the number of evaluation errors deriving from a hasty decision, often dictated by superficiality or by incorrect knowledge. At present, there is no biomarker that ensures 100% correlation with a single pathology. In fact, we speak of "highly significant values" for a given pathological condition. Other potential uses of biomarkers include their prognostic role and, consequently, the ability to drive antibiotic therapy and to evaluate the response to the therapy itself, identifying those patients who most likely will

In the literature, there are many biomarkers already evaluated, such biomarkers for chemo-

The available markers for the diagnosis of sepsis are numerous. There are leukocyte count, C-reactive protein (CRP), procalcitonin (PCT), endotoxin, cytokine, IL-1 receptor, complement factors, endothelin-1, ICAM-1 and VCAM-1, fosofolipase A2, PGE2, lactoferrin, neopterin, elastase, different interleukins (ILS), adrenomedullin (ADM) and proADM, atrial natriuretic peptide (ANP) and proANP, pro-vasopressin (copeptin), interferon-γ (IFN-γ), triggering receptor expressed on myeloid cells 1 (TREM-1) and resistin [41–44]. In several recently published studies, the most relevant biomarkers used, as they have a high diagnostic and prognostic capacity are CRP [45], PCT [46], ADM [47], copeptin [48], natriuretic peptide

Unfortunately, in the sepsis, an ideal marker has not yet been identified and those normally used (fever, leukocytosis, CRP, PCT, etc.) often have little sensitivity and specificity, consequently they have limited use in patient management. Their dosage should be used and evaluated in the context of the clinical situation in which the patient is located and therefore it is essential to determine the appropriateness of the individual markers' request in collaboration with the clinician to exploit their potential to the full diagnostics, therapeutic monitoring and

This section will discuss about white blood cell count (WBC), serum lactate, C-reactive protein (CRP), procalcitonin (PCT), presepsin and bioadrenomedullin as biomarker of sepsis.

whose outcome is better/worse than the population in question;

and eventually help in modulating the therapeutic strategy;

• high specificity and sensitivity;

etiology.

prognosis.

• have a clinically useful half-life time;

66 Biomarker - Indicator of Abnormal Physiological Process

face complications and organ dysfunction [32].

kine, cellular, receptor, hemostasis and vascular and others [42].

(MR-proANP) [49], presepsin (or CD 14 ligand) [50] and suPAR [51].

White blood cell is a part of innate immune response by localizing infection. Otherwise in systemic sepsis process, there is profound leucocyte activation. Systemic sepsis also leading to organ damage and organ dysfunction attenuated by inhibition of leukocyte-endothelial interactions, systemic leukocyte activation and disseminated leukocyte adhesion [52].

The WBC results were considered abnormal if both the total number of neutrophils and the immature/total neutrophil ratio were abnormal simultaneously [53]. The sensitivity and specificity WBC for sepsis diagnosis in the literature vary widely, since there are significant differences in definitions used to count total neutrophils and sub-fractions; with sensitivity varying from 17 to 100% and specificity from 31 to 100%. A study by Caldas et al., reported that combination of WBC and CRP had sensitivity better than WBC alone [54].

In 2001, Zahorec introduced the use of neutrophil and lymphocyte count ratio (NLCR) as one of infection marker [55]. There is also correlation between NLCR and disease severity, also predictor for bacteremia [56].

The sepsis criteria recently changed from Sepsis-2 to Sepsis-3 highlighting on life-threatening organ damage caused by dysregulated host response to infection. This also affecting the use of biomarker in the diagnosis of sepsis, based on Ljungstrom et al., the AUC of NLCR to predict positive culture was 0.71, similar to previous study by Loonen showed AUC of 0.73 and 0.77 [56–58].

#### **6.3. Serum lactate**

Lactate is an important source of energy, particularly during starvation. Lactate also contributes to acidic environment by converting to lactic acid. Lactate value of 1400–1500 mmol/L per day resulted from anaerobic glycolysis activity as the reduction of pyruvate, moreover in tissue hypoxia [59]. Excretion of lactate mostly occurs in liver (60%) followed by kidney (30%) and other organs [60]. Shock status, such as cardiogenic or septic shock, is an important source of lactate production. The mortality rate was 46.1% for patients with both hypotension and lactate ≥4 mmol/L, 36.7% for septic patients with hypotension alone and 30% for patients with lactate ≥4 mmol/L alone [61, 62].

According to the new definition, septic shock can be diagnosed under two circumstances. The first one is persistent hypotension and the second one is increase of lactate serum level for more than 2 mmol/L, with additional note that lactate cut off were changed from 4 to 2 mmol/L. Therefore, increase of lactate serum level for more than 2 mmol/L can be recognized as a sign of septic shock. This condition greatly affects by hypotension and the use of vasopressor which caused further tissue hypoxia [62].

Ljungstrom et al. showed lactate correlate well with Sepsis-2 criteria in diagnosis of sepsis and septic shock, with specificity, accuracy and DOR were 97, 92 and 56.3%, respectively, by using cutoff 3.5 mmol/L. The downside of lactate is that even lactate level alone is widely used for diagnosis in early sepsis, the elevated level is not considered specific for sepsis diagnosis, hence it is proven to be more valuable in predicting mortality. The suggestion is to use combination of several biomarkers including lactate in diagnosing septic and septic shock [56].

#### **6.4. C-reactive protein (CRP)**

C-reactive protein (CRP) is synthesized by the liver after the action of various inflammation mediators such as IL-1, IL-6 and IL-8. This biomarker is produced 4–6 h after the phlogistic stimulus, and doubles its concentration in the circulation within 8 h and reaches its peak in 36–50 h [2, 63, 64].

injection; between 6 and 8 h after the concentration of PCT increases rapidly up to a plateau about 12 h after injection. Over the next 2–3 days, the PCT values decrease until they reach

Biomarkers Utility for Sepsis Patients Management http://dx.doi.org/10.5772/intechopen.76107 69

PCT concentrations above 0.5 ng/mL always indicate an acute infection or inflammation, with particularly high values in patients with severe bacterial infections in the acute phase and with septic inflammation. Plasma PCT concentration in the presence of serious infections and sepsis; however, can vary from 1 to 1000 ng/mL and PCT, in these cases, is probably not produced by C cells of the thyroid, but is inclined to believe that origin from neuroendocrine cells

The release of PCT is determined only by the systemic reaction of the organism toward the infection, therefore local bacterial colonizations, encapsulated abscesses and localized and limited infections do not cause PCT release. In addition to bacterial infections, plasma PCT concentration has been shown to increase in acute forms of malaria and fungal infections. PCT, on the other hand, does not appear or appear to be not very significant, in the presence of viral infections, autoimmune diseases, neoplasia or traumatic surgery [69]. It could thus become one of the first-choice tests to be performed in patients with fever of unknown origin

Bacterial endotoxins play the most important role in the mechanism of PCT release. At the end of the acute inflammatory reaction, the PCT concentration decreases according to the plasma half-life time. From these considerations it is clear that PCT, besides being a diagnostic marker of systemic bacterial infections, also has an important prognostic value. The medical literature, in fact, has shown the correlation between the severity of the clinical picture, the risk of development of multi-organ failure (MOF), long-term outcomes and one-year mortality, with

• decreased PCT levels indicate favorable prognosis, improvement of inflammation or ad-

PCT thus becomes essential for the identification of patients at greatest risk, for guiding their

The areas in which the PCT could be used are numerous. In addition to patients who come to the emergency room with fever or suspected sepsis, PCT has been evaluated as both diagnostic [72, 73] and prognostic [74, 75] markers in pneumonia of bacterial origin. Even in this case, if associated with the clinical picture, the radiographic imaging and the values of the inflammatory indexes (CRP and white blood cells in particular), the PCT has shown to have a high predictive value as a biomarker. For the same reasons listed above, PCT should be measured in patients with significant dyspnea affected by COPD. The bacterial origin of exacerbations is often responsible for hospitalizations and mortality, and early intervention could reduce both

in the emergency room, to unmask an underlying bacterial infection [46, 70].

• high values of PCT protracted over time indicate an inflammation in progress; • constantly increasing PCT levels are an unequivocal sign of poor prognosis;

plasma PCT values; in particular it was established that:

equate therapeutic treatment of infection.

of these two harmful consequences [76, 77].

therapy and for monitoring them over time [69, 71].

their normal value [67, 68].

of the lung or intestine [67].

CRP has both pro-inflammatory and anti-inflammatory characteristics, its half-life is 19 h and its levels in the blood stream remain elevated for a few days after the infection has disappeared [63]. Elevated plasma CRP levels indicate the presence of an infection and/or organ damage while protein synthesis will be significantly reduced in the case of hepatic failure [65]. The normal value of plasma CRP is <1 mg/dL, while it may increase up to 50 mg/dL in case of acute severe infection. The increase in CRP does not appear to be related to the severity of inflammation and also increases in cases of non-infectious diseases such as autoimmune diseases, acute coronary syndromes, rheumatic disorders, malignant tumors and after traumas or surgical interventions [66].

In conclusion, the values of CRP do not allow to distinguish between sepsis and SIRS of a non-infectious nature. This marker appears to be more sensitive than parameters such as the leukocyte count and the temperature but less specific than others such as PCT. However, CRP is a commonly used low cost and widely available marker.

#### **6.5. Procalcitonin (PCT)**

"Procalcitonin" (PCT) is a protein consisting of 116 amino acids, with a molecular weight of approximately 13 kDalton. The amino acid sequence of PCT is identical to that of calcitonin prohormone; it comprises the sequence of calcitonin from position 60 to 91 (32 amino acids). Through specific proteolysis, PCT (116 amino acids) and, in healthy intracellular individuals, calcitonin (32 amino acids) are released from this protein. Currently, four genes corresponding to calcitonin with homologies in the nucleotide sequence are known. These genes are all called "genetic family of calcitonin", although not all of them produce the calcitonin peptide hormone. The "CALC-I" gene, a candidate responsible for the production of procalcitonin induced by the inflammatory state, is one of the first examples of a process called "alternative splicing". The primary transcript can give rise to different mRNAs for inclusion or exclusion of the different exons present. Calcitonin encoding mRNA is the main product of CALC-I transcription in thyroid C cells, whereas CGRP-I mRNA (CGRP = calcitonin gene-related peptide) is produced in the nervous tissue of the central and peripheral nervous system (115). The plasma concentrations of procalcitonin in healthy individuals are very low, on the order of picograms, and in any case below the limits of determination of the test used for the immunoluminometric assay (<0.1 ng/mL, LUMItest PCT, BRAHMS Diagnostica, Berlin). PCT is a very stable protein in vivo and in vitro. In plasma it does not degrade to active calcitonin hormone; its in vivo half-life time is approximately 25–30 h [67] [115]. PCT production was stimulated in healthy volunteers through the intravenous injection of small amounts of bacterial endotoxin (lipopolysaccharide). PCT can be observed in the plasma 2 h after endotoxin injection; between 6 and 8 h after the concentration of PCT increases rapidly up to a plateau about 12 h after injection. Over the next 2–3 days, the PCT values decrease until they reach their normal value [67, 68].

**6.4. C-reactive protein (CRP)**

68 Biomarker - Indicator of Abnormal Physiological Process

or surgical interventions [66].

**6.5. Procalcitonin (PCT)**

is a commonly used low cost and widely available marker.

36–50 h [2, 63, 64].

C-reactive protein (CRP) is synthesized by the liver after the action of various inflammation mediators such as IL-1, IL-6 and IL-8. This biomarker is produced 4–6 h after the phlogistic stimulus, and doubles its concentration in the circulation within 8 h and reaches its peak in

CRP has both pro-inflammatory and anti-inflammatory characteristics, its half-life is 19 h and its levels in the blood stream remain elevated for a few days after the infection has disappeared [63]. Elevated plasma CRP levels indicate the presence of an infection and/or organ damage while protein synthesis will be significantly reduced in the case of hepatic failure [65]. The normal value of plasma CRP is <1 mg/dL, while it may increase up to 50 mg/dL in case of acute severe infection. The increase in CRP does not appear to be related to the severity of inflammation and also increases in cases of non-infectious diseases such as autoimmune diseases, acute coronary syndromes, rheumatic disorders, malignant tumors and after traumas

In conclusion, the values of CRP do not allow to distinguish between sepsis and SIRS of a non-infectious nature. This marker appears to be more sensitive than parameters such as the leukocyte count and the temperature but less specific than others such as PCT. However, CRP

"Procalcitonin" (PCT) is a protein consisting of 116 amino acids, with a molecular weight of approximately 13 kDalton. The amino acid sequence of PCT is identical to that of calcitonin prohormone; it comprises the sequence of calcitonin from position 60 to 91 (32 amino acids). Through specific proteolysis, PCT (116 amino acids) and, in healthy intracellular individuals, calcitonin (32 amino acids) are released from this protein. Currently, four genes corresponding to calcitonin with homologies in the nucleotide sequence are known. These genes are all called "genetic family of calcitonin", although not all of them produce the calcitonin peptide hormone. The "CALC-I" gene, a candidate responsible for the production of procalcitonin induced by the inflammatory state, is one of the first examples of a process called "alternative splicing". The primary transcript can give rise to different mRNAs for inclusion or exclusion of the different exons present. Calcitonin encoding mRNA is the main product of CALC-I transcription in thyroid C cells, whereas CGRP-I mRNA (CGRP = calcitonin gene-related peptide) is produced in the nervous tissue of the central and peripheral nervous system (115). The plasma concentrations of procalcitonin in healthy individuals are very low, on the order of picograms, and in any case below the limits of determination of the test used for the immunoluminometric assay (<0.1 ng/mL, LUMItest PCT, BRAHMS Diagnostica, Berlin). PCT is a very stable protein in vivo and in vitro. In plasma it does not degrade to active calcitonin hormone; its in vivo half-life time is approximately 25–30 h [67] [115]. PCT production was stimulated in healthy volunteers through the intravenous injection of small amounts of bacterial endotoxin (lipopolysaccharide). PCT can be observed in the plasma 2 h after endotoxin PCT concentrations above 0.5 ng/mL always indicate an acute infection or inflammation, with particularly high values in patients with severe bacterial infections in the acute phase and with septic inflammation. Plasma PCT concentration in the presence of serious infections and sepsis; however, can vary from 1 to 1000 ng/mL and PCT, in these cases, is probably not produced by C cells of the thyroid, but is inclined to believe that origin from neuroendocrine cells of the lung or intestine [67].

The release of PCT is determined only by the systemic reaction of the organism toward the infection, therefore local bacterial colonizations, encapsulated abscesses and localized and limited infections do not cause PCT release. In addition to bacterial infections, plasma PCT concentration has been shown to increase in acute forms of malaria and fungal infections. PCT, on the other hand, does not appear or appear to be not very significant, in the presence of viral infections, autoimmune diseases, neoplasia or traumatic surgery [69]. It could thus become one of the first-choice tests to be performed in patients with fever of unknown origin in the emergency room, to unmask an underlying bacterial infection [46, 70].

Bacterial endotoxins play the most important role in the mechanism of PCT release. At the end of the acute inflammatory reaction, the PCT concentration decreases according to the plasma half-life time. From these considerations it is clear that PCT, besides being a diagnostic marker of systemic bacterial infections, also has an important prognostic value. The medical literature, in fact, has shown the correlation between the severity of the clinical picture, the risk of development of multi-organ failure (MOF), long-term outcomes and one-year mortality, with plasma PCT values; in particular it was established that:


PCT thus becomes essential for the identification of patients at greatest risk, for guiding their therapy and for monitoring them over time [69, 71].

The areas in which the PCT could be used are numerous. In addition to patients who come to the emergency room with fever or suspected sepsis, PCT has been evaluated as both diagnostic [72, 73] and prognostic [74, 75] markers in pneumonia of bacterial origin. Even in this case, if associated with the clinical picture, the radiographic imaging and the values of the inflammatory indexes (CRP and white blood cells in particular), the PCT has shown to have a high predictive value as a biomarker. For the same reasons listed above, PCT should be measured in patients with significant dyspnea affected by COPD. The bacterial origin of exacerbations is often responsible for hospitalizations and mortality, and early intervention could reduce both of these two harmful consequences [76, 77].

Finally, an increase in PCT has also been shown in bacterial endocarditis [78] and in acute coronary syndromes [79, 80], while its prognostic use as a marker of infection has been exploited in the monitoring of patients undergoing major surgery [81].

**6.7. Bioadrenomedullin**

inflammation [90].

Adrenomedullin (ADM) is a peptide with 52 amino acids initially isolated from the adrenal gland. It is produced in many organs and tissues including the vasculature. ADM has numerous actions, including vasodilation, natriuresis, antiapoptosis and stimulation of NO production. ADM is released from the vascular wall and acts as an autocrine or a paracrine hormone to regulate vascular tone and blood pressure. It may also be involved in the different stages of the cardiovascular continuum as well as in the hemodynamic changes in septic shock [90, 91].

Biomarkers Utility for Sepsis Patients Management http://dx.doi.org/10.5772/intechopen.76107 71

A study by Crain et al. showed that in critically ill patients on admission, there was a stepwise increase in MR-proADM levels from patients without infection (e.g. SIRS) to patients with sepsis, severe sepsis and septic shock. Median proADM levels was 1.1 nmol/L (0.3–3.7 nmol/L) in patients with SIRS, 1.8 nmol/L (0.4–5.8 nmol/L) in patients with sepsis, 2.3 nmol/L (1.0– 17.6 nmol/L) in patients with severe sepsis and in patients with septic shock it was 4.5 nmol/L (0.9–21 nmol/L). There are two primary mechanisms that might be responsible for the marked increase in circulating MR-proADM and mature ADM levels in sepsis. The first mechanism, as a member of the CALC gene family, ADM is widely expressed and extensively synthesized during sepsis, just like other calcitonin peptides including PCT, that upregulated by bacterial endotoxins and pro-inflammatory cytokines [92]. The second potential mechanism is the decreased clearance of MR-proADM by the kidneys in sepsis that may be responsible for its increased level. This hypothesis is also supported by a significant correlation between MR-proADM and creatinine levels (r = 0.76; *P* < 0.001). The study showed increase of plasma ADM five times higher that normal individuals, that did not changed after hemodialysis. An ideal sepsis marker should permit early diagnosis, should inform about the course of disease, and should help one to differentiate bacterial from non-infectious and viral causes of systemic

Recently, the combined use of two biomarkers, procalcitonin (PCT) and mid-regional proadrenomedullin (MR-proADM) has been reported in sepsis diagnosis and prognosis. In the last years, many articles have been published on the role of PCT and MR-proADM in the diagnosis and prognosis of bacterial infections in different settings. Angeletti et al. showed that MR-proADM differentiates sepsis from non-infectious systemic inflammatory response syndrome with high specificity and that the simultaneous measurement of MR-proADM and PCT in septic patients increases the post-test diagnostic probability compared to the independent determination of individual markers. A score derived from the combination of PCT and MR-proADM has been recently proposed as a useful clinical tool to provide rapid diagnosis as well as to suggest prognosis of bacterial infections. The combined score, calculated on the basis of defined score assigned for each PCT and MR-proADM value, can predict bacterial infections and differentiate localized infections from systemic infections, as suggested by receiver operating characteristic curve analysis. On the basis of the score values, localized infections could be differentiated from systemic infections and the severity of the infectious disease can be predicted. The importance of the use of this multi-marker approach in the diagnosis and prognosis of sepsis is more evident since the publication of the new definition of sepsis that has been updated assigned an important role to the organ dysfunction [93].

Despite the wide space that scientific research has devoted to PCT, its exact mechanism of action still remains partially unknown. The rapid induction of PCT after administration of bacterial endotoxins and its relationship to cytokines, such as TNF-α, suggest the existence of a close correlation between PCT and pro-inflammatory cytokines, which earned him the name "ormokina" [82]. In the clinic, it was observed that there is a correlation between the timing of PCT, IL-6 and TNF-α. In acute inflammation, PCT values increase a few hours after the increase of IL-6 and TNF-α; at the end of the inflammation, the PCT begins to decrease after the decrease of the IL-6 and in any case before the CRP values start to decrease. This would demonstrate a pathophysiological function of PCT in the immune response. It would be responsible for increasing nitric oxide synthesis and monocyte migration to the site of infection [83].

#### **6.6. Presepsin**

Presepsin is another name for the sCD14 subtype (sCD14-ST), is a new biomarker associated with sepsis. Soluble CD14 subtype is one fragment of CD14 soluble that is a molecular fragment produced by plasma protease activity during the inflammatory process [84]. Presepsin is present in the cell membranes of macrophages, monocytes and granulocyte cells and said to play a role for the intracellular transduction of endotoxin signals [85]. Presepsin has close relation with infection and is found to increase significantly in sepsis.

Behnes et al. showed that presepsin was moderately significant to determine between sepsis and non sepsis patient, with slightly overlapping value of 817.9 ± 572.7 and 294.2 ± 121.4 pg/ mL for sepsis and non sepsis patient, respectively [50]. The level of presepsin in serum usually raised within 2 h after infection and reach maximum level within 3 h, therefore it is useful in diagnosis of sepsis patient during early stages [86, 87].

Wu et al. reported a meta-analysis about diagnostic value of presepsin of some studies. The result showed that the sensitivity of presepsin ranged from 0.67 to 1.0, while the specificity of presepsin ranged from 0.33 to 0.98. The pooled sensitivity and specificity obtained by the HSROC method were 0.84 (95% CI 0.80–0.87) and 0.76 (95% CI 0.67–0.84), respectively. While ROC for presepsin showed the AUC was 0.88 (95% CI 0.85–0.90 [88].

When compared to PCT, presepsin showed similar diagnostic accuracy for sepsis with sensitivity 0.78 [95% CI: 0.76–0.80] and 0.77 [95% CI: 0.72–0.81], specificity 0.83 [95% CI: 0.80–0.85] and 0.79 [95% CI: 0.74–0.84], AUCs 0.89 [95% CI: 0.84–0.94] and 0.85 [95% CI: 0.81–0.88], for presepsin and procalcitonin, respectively, to diagnose patient with sepsis and SIRS without infection [89].

However, there are some superiority of presepsin over PCT. Presepsin raised earlier in the event of infection therefore can be used in earlier and faster in sepsis. The PATHFAST analysis system also allow presepsin assay on takes 17 min to be done, therefore can be used accordingly with the guidelines of diagnosis and treatment of sepsis.

#### **6.7. Bioadrenomedullin**

Finally, an increase in PCT has also been shown in bacterial endocarditis [78] and in acute coronary syndromes [79, 80], while its prognostic use as a marker of infection has been exploited

Despite the wide space that scientific research has devoted to PCT, its exact mechanism of action still remains partially unknown. The rapid induction of PCT after administration of bacterial endotoxins and its relationship to cytokines, such as TNF-α, suggest the existence of a close correlation between PCT and pro-inflammatory cytokines, which earned him the name "ormokina" [82]. In the clinic, it was observed that there is a correlation between the timing of PCT, IL-6 and TNF-α. In acute inflammation, PCT values increase a few hours after the increase of IL-6 and TNF-α; at the end of the inflammation, the PCT begins to decrease after the decrease of the IL-6 and in any case before the CRP values start to decrease. This would demonstrate a pathophysiological function of PCT in the immune response. It would be responsible for

increasing nitric oxide synthesis and monocyte migration to the site of infection [83].

Presepsin is another name for the sCD14 subtype (sCD14-ST), is a new biomarker associated with sepsis. Soluble CD14 subtype is one fragment of CD14 soluble that is a molecular fragment produced by plasma protease activity during the inflammatory process [84]. Presepsin is present in the cell membranes of macrophages, monocytes and granulocyte cells and said to play a role for the intracellular transduction of endotoxin signals [85]. Presepsin has close relation

Behnes et al. showed that presepsin was moderately significant to determine between sepsis and non sepsis patient, with slightly overlapping value of 817.9 ± 572.7 and 294.2 ± 121.4 pg/ mL for sepsis and non sepsis patient, respectively [50]. The level of presepsin in serum usually raised within 2 h after infection and reach maximum level within 3 h, therefore it is useful in

Wu et al. reported a meta-analysis about diagnostic value of presepsin of some studies. The result showed that the sensitivity of presepsin ranged from 0.67 to 1.0, while the specificity of presepsin ranged from 0.33 to 0.98. The pooled sensitivity and specificity obtained by the HSROC method were 0.84 (95% CI 0.80–0.87) and 0.76 (95% CI 0.67–0.84), respectively. While

When compared to PCT, presepsin showed similar diagnostic accuracy for sepsis with sensitivity 0.78 [95% CI: 0.76–0.80] and 0.77 [95% CI: 0.72–0.81], specificity 0.83 [95% CI: 0.80–0.85] and 0.79 [95% CI: 0.74–0.84], AUCs 0.89 [95% CI: 0.84–0.94] and 0.85 [95% CI: 0.81–0.88], for presepsin and procalcitonin, respectively, to diagnose patient with sepsis and SIRS without

However, there are some superiority of presepsin over PCT. Presepsin raised earlier in the event of infection therefore can be used in earlier and faster in sepsis. The PATHFAST analysis system also allow presepsin assay on takes 17 min to be done, therefore can be used accord-

in the monitoring of patients undergoing major surgery [81].

70 Biomarker - Indicator of Abnormal Physiological Process

with infection and is found to increase significantly in sepsis.

diagnosis of sepsis patient during early stages [86, 87].

ROC for presepsin showed the AUC was 0.88 (95% CI 0.85–0.90 [88].

ingly with the guidelines of diagnosis and treatment of sepsis.

**6.6. Presepsin**

infection [89].

Adrenomedullin (ADM) is a peptide with 52 amino acids initially isolated from the adrenal gland. It is produced in many organs and tissues including the vasculature. ADM has numerous actions, including vasodilation, natriuresis, antiapoptosis and stimulation of NO production. ADM is released from the vascular wall and acts as an autocrine or a paracrine hormone to regulate vascular tone and blood pressure. It may also be involved in the different stages of the cardiovascular continuum as well as in the hemodynamic changes in septic shock [90, 91].

A study by Crain et al. showed that in critically ill patients on admission, there was a stepwise increase in MR-proADM levels from patients without infection (e.g. SIRS) to patients with sepsis, severe sepsis and septic shock. Median proADM levels was 1.1 nmol/L (0.3–3.7 nmol/L) in patients with SIRS, 1.8 nmol/L (0.4–5.8 nmol/L) in patients with sepsis, 2.3 nmol/L (1.0– 17.6 nmol/L) in patients with severe sepsis and in patients with septic shock it was 4.5 nmol/L (0.9–21 nmol/L). There are two primary mechanisms that might be responsible for the marked increase in circulating MR-proADM and mature ADM levels in sepsis. The first mechanism, as a member of the CALC gene family, ADM is widely expressed and extensively synthesized during sepsis, just like other calcitonin peptides including PCT, that upregulated by bacterial endotoxins and pro-inflammatory cytokines [92]. The second potential mechanism is the decreased clearance of MR-proADM by the kidneys in sepsis that may be responsible for its increased level. This hypothesis is also supported by a significant correlation between MR-proADM and creatinine levels (r = 0.76; *P* < 0.001). The study showed increase of plasma ADM five times higher that normal individuals, that did not changed after hemodialysis. An ideal sepsis marker should permit early diagnosis, should inform about the course of disease, and should help one to differentiate bacterial from non-infectious and viral causes of systemic inflammation [90].

Recently, the combined use of two biomarkers, procalcitonin (PCT) and mid-regional proadrenomedullin (MR-proADM) has been reported in sepsis diagnosis and prognosis. In the last years, many articles have been published on the role of PCT and MR-proADM in the diagnosis and prognosis of bacterial infections in different settings. Angeletti et al. showed that MR-proADM differentiates sepsis from non-infectious systemic inflammatory response syndrome with high specificity and that the simultaneous measurement of MR-proADM and PCT in septic patients increases the post-test diagnostic probability compared to the independent determination of individual markers. A score derived from the combination of PCT and MR-proADM has been recently proposed as a useful clinical tool to provide rapid diagnosis as well as to suggest prognosis of bacterial infections. The combined score, calculated on the basis of defined score assigned for each PCT and MR-proADM value, can predict bacterial infections and differentiate localized infections from systemic infections, as suggested by receiver operating characteristic curve analysis. On the basis of the score values, localized infections could be differentiated from systemic infections and the severity of the infectious disease can be predicted. The importance of the use of this multi-marker approach in the diagnosis and prognosis of sepsis is more evident since the publication of the new definition of sepsis that has been updated assigned an important role to the organ dysfunction [93].

#### **6.8. Comparison between biomarker of sepsis**

Lactate should be evaluated at least within 24 h after emergency admission, the decrease of lactate after 24 h related to poor prognosis of the patients [94]. CRP can increase within 24–48 h duration to 1000 folds during the acute phase and decrease to low normal value after the acute phase [95]. Procalcitonin start to rise 3–6 h after infection occur and reach its peak on 6–8 h, then remained in the blood until 12–48 h [96]. Meanwhile presepsin increase faster within 2–3 h after sepsis developed and rapidly decreased after symptoms resolved [97] so it can be used to determine whether the treatment is successful in patient with sepsis.

Availability and cost of these examination will be favored more on white blood cell count because it is part of routine practice everywhere, while for lactate, the difference between patient examined for lactate around \$39.53/patient whereas the usual care cost \$33.20/patient but the effectiveness in term of patient outcome and survival are better in those with lactate examination [119]. On the other hand, the use of CRP in England shows the use of CRP can also increase quality of treatment and decrease cost for patient which leads to fewer antibiotic prescriptions [120]. One study about procalcitonin use as part of management of patient with pneumonia find that procalcitonin although promising not significantly reduce cost of care, due to lack of data, since non adherence of the physician. This condition might be due to lack of experience of using procalcitonin and need for more guided protocol of procalcitonin use

, Muhammad Anshory<sup>2</sup>

1 Clinical Pathology Department, Faculty of Medicine, Universitas Brawijaya, Malang,

2 Internal Medicine Department, Faculty of Medicine, Universitas Brawijaya, Malang,

3 Department of Medical-Surgery Sciences and Translational Medicine, Sapienza University

[1] Russell JA. Management of sepsis. New England Journal of Medicine. 2006;**355**(16):

[2] Ventetuolo CE, Levy MM. Biomarkers: Diagnosis and risk assessment in sepsis. Clinics

[3] Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ ESICM/ACCP/ATS/SIS international sepsis definitions conference. Critical Care

[4] Angus DC, Van der Poll T. Severe sepsis and septic shock. The New England Journal of

[5] Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune

[6] Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: From cellular dysfunctions to immunotherapy. Nature Reviews. Immunology. 2013;**13**(12):862

and Salvatore Di Somma3

Biomarkers Utility for Sepsis Patients Management http://dx.doi.org/10.5772/intechopen.76107 73

\*

in patient [121].

**Author details**

Agustin Iskandar<sup>1</sup>

Indonesia

Indonesia

of Rome, Italy

**References**

1699-1713

, Hani Susianti1

in Chest Medicine. 2008;**29**(4):591-603

responses to sepsis. Virulence. 2014;**5**(1):36-44

Medicine. 2003;**31**(4):1250-1256

Medicine. 2013;**369**(9):840-851

\*Address all correspondence to: salvatore.disomma@uniroma1.it

Several conditions can increase lactate in any person, such condition as inadequate oxygen delivery oxygen demands mismatch and inadequate oxygen utilization [94]. CRP increase in bacterial infection as part of innate immune response [95, 98]. It can also increase in condition of inflammation even can predict the cardiovascular event such as the sign of atherogenesis and pathogenesis of myocardial injury and used as predictor in healthy individuals [99, 100]. It also can be a predictor of mortality in hemodialysis patient [101, 102]. Procalcitonin will rise in the event of sepsis, systemic infection and severe inflammation. Procalcitonin will not rise in the event of viral infection, autoimmune and neoplasma, but it can rise in some people with some neuroendocrine tumor such as medullare carcinoma of thyroid, small cell lung carcinoma and renal failure [96, 103]. Procalcitonin is also known to rise in person with trauma [97]. Some inflammation can trigger the rise of procalcitonin are pancreatitis [104], appendicitis [105], burns [106], heat stroke [107], multitrauma [108] and extensive surgery [109]. Presepsin do not increase in patient with trauma without associated infection, thus make it specific in patient with sepsis [97]. Presepsin also reliable in patient with sepsis and both acute kidney injury and those who do not, but it has caveats in patient with advanced kidney injury and end stage renal disease [110].

Head to head study by cochrane comparing procalcitonin, presepsin and CRP is still ongoing [111]. Several data about sensitivity and specificity of these parameters are already covered by some journal. The study about diagnostic value of lactate in cancer patient with sepsis showed for the cutoff value of lactate more than 1 mmol/L could predict sepsis with sensitivity of 86.36% and specificity of 28.12%, with additional data that the value were not different in patient with and without cancer [112]. Another study showed 34.0% sensitivity and 82.0% specificity at the cutoff point of 2.0 mmol/L that emphasized the low sensitivity but high specificity in diagnosing sepsis [113]. While other study measures prognostic value of lactate showed that lactate value over 4.0 mmol/L have increased mortality with sensitivity and specificity of 36 and 92%, respectively [114]. CRP found to be useful as part of screening in sepsis patient with sensitivity and specificity 98.5 and 75%, respectively, for cutoff value 5 mg/dL or more [115]. Another study use CRP as parameter for successful treatment in ICU patient showed that decreasing level of CRP by 25% or more are good indicator with sensitivity of 97% and specificity of 95% [116]. A study showed that sensitivity and specificity of procalcitonin were 75 and 79%, respectively [117]. While another study in patient with renal impairment proposed different cutoff to determine if patient is in septic condition, due to the caveats of procalcitonin in renal failure patient [118]. Another study comparing CRP, procalcitonin and presepsin showed advantage of presepsin, with AUC of presepsin was 0.845, compared to PCT (0.652), and CRP (0.815). With sensitivity and specificity of presepsin with cutoff value 600 pg./mL was 87.8 and 81.4%, respectively [84].

Availability and cost of these examination will be favored more on white blood cell count because it is part of routine practice everywhere, while for lactate, the difference between patient examined for lactate around \$39.53/patient whereas the usual care cost \$33.20/patient but the effectiveness in term of patient outcome and survival are better in those with lactate examination [119]. On the other hand, the use of CRP in England shows the use of CRP can also increase quality of treatment and decrease cost for patient which leads to fewer antibiotic prescriptions [120]. One study about procalcitonin use as part of management of patient with pneumonia find that procalcitonin although promising not significantly reduce cost of care, due to lack of data, since non adherence of the physician. This condition might be due to lack of experience of using procalcitonin and need for more guided protocol of procalcitonin use in patient [121].
