2.8.1. Soluble urokinase plasminogen activator (suPAR)
suPAR has been reported as a promising prognostic marker. Poor outcome and disease progression in cancer, HIV, tuberculosis, malaria, SIRS, diabetes, renal disease, ischemic stroke and coronary artery disease correlated with elevated suPAR levels [51]. The urokinase plg activator receptor, a well-described versatile protein [49], is found on many cell surfaces and soluble suPAR can be detected in blood, serum, plasma, urine and cerebrospinal fluid. However, biological function of suPAR is not clear [50,388]. Elevated suPAR levels in S. pneumoniae bacteraemia on admission were prognostic for in-hospital mortality [389]. Elevated suPAR levels during the first 1-4 days in S. pneumonia, β- haemolytic streptococci and Escherichia coli bacteraemia predicted increased 30-day in- hospital mortality [390]. In addition, low levels of suPAR may be a positive predictor for overall survival in patients with sepsis of mixed aetiology [391].
Two meta-analyses have evaluated the potential use of suPAR in critically ill intensive care patients, as a prognostic marker for in-hospital mortality and as a diagnostic marker for infection [53,54]. In the study of Backes et al., suPAR had a low diagnostic value in differential diagnosis of infection in patients with SIRS [53]. On the other hand, the prognostic value of suPAR was significant and complementary to other biomarkers and clinical classifications in the study of Donadello et al. [54]. In conclusion, these studies emphasised that elevated suPAR predicts mortality in sepsis, but is not diagnostic for infection in SIRS patients.
2.8.2. Soluble apoptosis biomarkers
Apoptosis, or active gene-directed cell death, is both a physiological and pathologic phenomenon [392]. When it is triggered by death-receptor pathway markers, measurable
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concentrations of soluble Fas protein (human membrane protein, member of necrosis factor proteins) and Fas protein ligand (both studied as apoptosis biomarkers) are produced. Increased levels of soluble Fas protein were detected in patients with sepsis and multiple organ dysfunction syndrome [393]. Soluble Fas protein may be a therapeutic target in preventing post traumatic hyperinflammation [394]. In patients with bacteraemia, including 24% patients with SAB, apoptosis biomarkers were found not to be prognostic, but they correlated with high SOFA score in patients with bacteraemia [395].
2.8.3. Pentraxin 3
Pentraxin 3 (PTX3) is an acute phase protein. The of PTX3 as a diagnostic marker for infection and as a prognostic marker for mortality in critically ill patients was recently reviewed by Liu et al. [396]. Based on the evaluation of seven studies on critically ill patients with SIRS, PTX3 levels in patients with bacteraemia were found significantly higher than those in blood-culture negative patients. However, PTX3 levels were not significantly different in patients with gram-negative bacteraemia compared to those with gram- positive bacteraemia. As a prognostic marker for mortality, PTX3 levels measured on days 1-4 were significantly higher in patients with fatal outcome (both in 28-30 days and in 90 days) compared to survivors. PTX3 is complementary, not superior, to the other commonly used biological markers CRP and PCT [396]. In one study including SAB patients, PTX3 was found to be an independent prognostic marker in sepsis and showed better prognostic value than CRP [397]. Another recent study evaluated PTX3 values upon admission and it revealed good prognostic value of fatal outcome in patients with confirmed bacteraemia. However, the proportion of SAB in patients in this study was not mentioned [398].
2.8.4. Procalcitonin
PCT, a glycoprotein and a precursor of calcitonin, [399] is a useful marker in distinguishing serious infection from non-infectious diseases [400,401]. Originally, very high concentrations of PCT were measured in paediatric patients who had severe bacterial infections. Low levels were seen in patients who had viral infections, local bacterial colonization or infections without sepsis. In this same study, PCT levels were higher in severely burned children with infectious complications than those without an infection [400]. Later studies on adult SIRS patients also demonstrated that PCT levels have a significant predictive value for sepsis [402] and bacteraemia [403]. PCT appears to be valuable in discriminating blood contamination and clinical infection when coagulase- negative staphylococci were cultured from blood [404]. In addition, there seems to be some predilection of PCT for gram negative bacteraemia, since higher PCT levels were
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detected in bacteraemia due to gram-negative bacteria than gram-positive bacteraemia [405].
In guiding antibiotic treatment, PCT may be effective. However, as reviewed recently, cost- effectiveness, variable kinetics, and concerns related to the diagnostics of different infection foci and pathogens were found to limit the utility of PCT [406]. In a general emergency department (ED) patient population, evidence-based support for PCT in guiding antibiotic therapy was inadequate [407]. However, another study found that PCT had prognostic value of moderate accuracy in ED patients in identifying septic patients with fatal outcome [408]. A recent ICU study found that a combination of CRP, PCT and sepsis related SOFA-score together was better than those used separately in diagnosing sepsis as early as possible [409]. Finally, a meta-analysis of 21 studies on pneumonia and use of PCT concluded that elevated PCT was a risk factor for death in both health care-associated and community-associated pneumonia [410].
2.8.5. Cell-free DNA
The presence of cell-free DNA (cf-DNA) in human blood was first detected in 1984 [411]. Circulating cf-DNA levels are related to necrosis, apoptosis and cell lysis [412,413]. cf-DNA levels are elevated in septic patients [414]. In patients with septic shock, cf-DNA levels are significantly compared to patients with severe sepsis [415]. The diagnostic accuracy of cf-DNA is equal with PCT but better than CRP in identifying infection in febrile patients. Normal cf-DNA levels excluded infection with 97% specificity in febrile patients, and high concentrations of cf-DNA are prognostic of fatal outcome [416]. In one study on bacteraemic patients, which also included SAB patients, cf-DNA was demonstrated to be an independent prognostic marker for increased mortality [417]. In another study in sepsis patients, cf-DNA demonstrated independent prognostic value of mortality in patients with severe sepsis [418].