Search

Neonatal sepsis still remains a major cause of morbidity and mortality in neonatal intensive care unit (NICU). Recently, soluble CD14 subtype (sDC14-ST) also named presepsin, was proposed as an effective biomarker for diagnosing, monitoring, and assessing the risk of neonatal sepsis and septic shock. The aim of this study was to investigate the diagnostic accuracy of sCD14-ST presepsin in diagnosing neonatal bacterial sepsis and in discriminating non-bacterial systemic inflammatory response syndrome (SIRS) from bacterial sepsis. This study involved 65 critically ill full-term and preterm newborns admitted to the neonatal intensive care unit (NICU), divided into three groups: 25 newborns with bacterial neonatal sepsis (group A); 15 newborns with a diagnosis of non-bacterial SIRS and with no localizing source of bacterial infection (group B); and 25 babies with no clinical or bacteriological signs of systemic or local infection receiving routine NICU care, most of them treated with phototherapy for neonatal jaundice (group C). A total of 102 whole blood samples were collected, 40 in group A, 30 in group B and 32 in group C. In 10 babies included in group A, sCD14-ST presepsin was also measured in an additional second blood sample collected 3 days after the start of antibiotic treatment. sCD14-ST presepsin was measured by a commercially available chemiluminescent enzyme immunoassay (CLEIA) optimized on an automated immunoassay analyzer. Statistical analysis was performed by means of MedCalc® statistical package; receiver operating characteristic (ROC) analysis was computed, and the area under the ROC curve (AUC) was used to evaluate the ability of sCD14-ST to discriminate neonatal bacterial sepsis from non-bacterial SIRS. Blood sCD14-ST presepsin levels were found significantly higher in bacterial sepsis when compared with controls (p<0.0001); similarly, they were higher in non-bacterial SIRS when compared with controls (p<0.0001). However, no statistically significant difference was found between bacterial sepsis and non-bacterial SIRS (p=0.730). In our population, CRP and sCD14-ST did not correlate with each other. ROC analysis revealed that sCD14-ST presepsin has an area under the curve (AUC) of 0.995 (95% C.I.: 0.941-1.00) greater than that of CRP (0.827; 95% C.I.: 0.72-0.906). Similarly, in the group of babies with non-infectious SIRS, sCD14-ST AUC was greater than CRP AUC (0.979; 95% C.I.: 0.906-0.999 versus 0.771; 95% C.I.: 0.647-0.868). In controls, preliminary reference intervals for sCD14-ST ranged 223.4-599.7 ng/L, being significantly different from those previously published elsewhere. In conclusion, sCD14-ST presepsin could be introduced in clinical practice as a diagnostic tool for improving the management of neonatal sepsis and non-bacterial SIRS., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Metabolomics, the latest of omics disciplines, has been successfully used in various fields of basic research such as pharmacology and toxicology. Recently, this new science has gained an important role in the translational research of diagnostics. In this regard, the challenge for neonatologists and medical laboratories is to diagnose neonatal sepsis, a disease with high mortality and morbidity due to the difficulty in diagnosing it. Metabolomics, through its ability to identify perturbations caused by this condition, aims at recognizing metabolites that characterize neonatal sepsis with high specificity and sensitivity. The purpose of this review is to highlight the ability of metabolomics to find early biomarkers for this condition, as well as to predict the toxic effects caused by antibiotics.

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are antagonistic ligands that bind to the extracellular domain of the Tie-2 receptor, which is almost exclusively expressed by endothelial cells. Angiopoietins can directly stimulate both endothelial cells and neutrophils for an overall proinflammatory and proangiogenic response. An increasing number of experimental and clinical studies gave evidence that in the course of sepsis the serum levels of Ang-1 and Ang-2 as well as their ratio significantly differ from those in healthy subjects, in non-septic hospitalized patients, and in patients with non-infectious systemic inflammatory response syndrome (SIRS) or critical illness. Further evidences have demonstrated that the magnitude of Ang-2 dysregulation correlates with the severity of sepsis and the mortality rate. Since the onset of neonatal sepsis is often subtle and the diagnosis occurs later, Ang-1 and Ang-2 appear to be very promising biomarkers for improving the diagnosis and the management of septic newborns.

The first aim of this study was to assess the diagnostic performance of presepsin (sCD14-ST) in postmortem serum from femoral blood compared to procalcitonin (PCT) to detect sepsis-related fatalities. The second aim was to compare sCD14-ST levels found in postmortem serum to the values in pericardial fluid to investigate the usefulness of the latter as an alternative biological fluid. Two study groups were formed, a sepsis-related fatalities group and a control group. Radiology (unenhanced CT scans and postmortem angiographies), autopsies, histology, neuropathology, and toxicology as well as other postmortem biochemistry investigations were performed in all cases. Microbiological investigations on right cardiac blood were carried out exclusively in septic cases. The results of this study indicated that postmortem serum PCT and sCD14-ST levels, individually considered, allowed septic cases to be identified. Even though increases in both PCT and sCD14-ST concentrations were observed in the control cases, coherent PCT and sCD14-ST results in cases with suspected sepsis allowed the diagnosis to be confirmed. Conversely, no relevant correlation was identified between postmortem serum and pericardial fluid sCD14-ST levels in either the septic or control groups.

Despite a 35% decline in the mortality rate for infants aged <5 years over the past two decades, every year nearly 40% of all deaths in this age group occur in the neonatal period, defined as the first 28 days of life. New knowledge on molecular and biochemical pathways in neonatal diseases will lead to the discovery of new candidate biomarkers potentially useful in clinical practice. In the era of personalized medicine, biomarkers may play a strategic role in accelerating the decline in neonatal mortality by assessing the risk of developing neonatal diseases, by implementing tailored therapeutic treatment, and by predicting the clinical outcome. However, there is an urgent need to reduce the gap in translating newly acquired knowledge from bench to bedside. Traditional and candidate biomarkers for neonatal sepsis and necrotizing enterocolitis will be discussed in this review, such as C-reactive protein (CRP), procalcitonin (PCT), serum amyloid A (SAA), soluble form of CD14 subtype presepsin (sCD14-ST), lipolysaccharide binding protein (LBP), angiopoietins (Ang)-1 and -2, soluble form of triggering receptor expressed on myeloid cells (sTREM-1), soluble form of urokinase-type plasminogen activator receptor (suPAR), platelet-activating factor (PAF) and calprotectin. New frontiers in managing critically ill newborns may be opened by metabolomics, a diagnostic tool based on the recognition of metabolites contained in biological fluids. Metabolomics represents the passage from a descriptive science to a predictive science, having the potential to translate benchtop research to real clinical benefits., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The high incidence of neonatal sepsis worldwide and the considerably high mortality rate of severe sepsis and septic shock call for an earlier diagnosis and more accurate monitoring of the disease. Conventional laboratory tests, such as white blood cell count (WBC) and differential count, micro-erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have a number of limitations associated with their limited sensitivity in the early phase of the disease and their non-specific increase in the course of various severe neonatal clinical conditions like asphyxia, meconium aspiration and prolonged rupture of membranes. Next-generation biomarkers encompass new molecular tests, accurate measurement of the proteins and enzymes mainly involved in the innate immunity biochemical pathways, application of proteomics and metabolomics for risk stratification and prognosis, and the clinical use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the identification of various bacteria and yeasts. The availability of sophisticated biochemical and molecular tests and of innovative technologies can significantly improve baby outcomes in terms of earlier and more accurate diagnosis, tailored therapeutic treatment, shorter hospitalization and thus minimized complications, and ultimately can prevent and monitor nosocomial and healthcare-associated infections. As a consequence, costs can be significantly reduced over a full cycle of care by investing in high quality laboratory medicine.

Several biochemical markers have been proposed over the past years to manage critically ill newborns with acute inflammation and sepsis. The state of the art in diagnosing and monitoring neonatal sepsis, severe sepsis and septic shock consists of the measurement of plasma C-reactive protein (CRP) and procalcitonin (PCT) at the onset and in the course of the disease. CRP and PCT in combination are clinically significant in diagnosing and monitoring septic newborns; however, CRP and PCT have a very limited value for risk stratification and in predicting outcome. The availability of commercial methods for the automated measurement of the soluble CD14 subtype presepsin (sCD14-ST) and lipopolysaccharide binding protein (LBP) represent a challenge for the evaluation in clinical practice of reliable markers of neonatal sepsis, specifically for the very early diagnosis, the classification into class of severity, and the prediction of complications and death.

Neutrophil gelatinase-associated lipocalin (NGAL) and Netrin-1 have been proposed over the past years as emergent biomarkers for the early and accurate diagnosis and monitoring of acute kidney injury (AKI). During the early phases of AKI, a rapid and massive up-regulation of NGAL mRNA takes place in the thick ascending limb of Henle's loop and in the collecting ducts, and therefore, changes in urinary NGAL (uNGAL) excretion seem to be more specific than plasma NGAL in assessing early kidney injury. The availability of a new automated immunoassay for measuring uNGAL facilitates its introduction in the clinical routine, especially in an emergency setting. However, in critically ill newborns AKI often develops during sepsis, which in turn induces an up-regulation of NGAL mRNA in neutrophils. To improve the effectiveness of therapeutic treatment in septic newborns with AKI, there is the need to accurately distinguish NGAL molecular forms originating within the distal nephron from those originating from neutrophils. This concise review summarizes properties and perspectives of uNGAL and Netrin-1 for their appropriate clinical utilization.

Procalcitonin (PCT) has been proposed as an interesting marker in the diagnosis, prognosis, and response to treatment of patient with neonatal sepsis. Fifty-nine neonates (34 males and 25 females) with a mean gestational age of approximately 31 weeks and a mean weight of about 1750 g admitted in the Neonatal Intensive Care Unit of Cagliari (Italy) were evaluated in controls and in infected neonates, before and after 48 h of life. From our experience it emerges that PCT is a marker of early and late neonatal sepsis which is reliable in preterm neonates. A cut-off of 0.5 ng/ml starting from the third day of life appears to be capable of ensuring good test sensitivity and specificity.

Procalcitonin (PCT) is the precursor of calcitonin, normally synthesized in the C-cells of the thyroid gland. Systemic inflammation and sepsis induce PCT production by various cell types, including hepatocytes, nephrons, monocytes. PCT begins to rise four hours after exposure to bacterial endotoxins, peaking at six to eight hours, and remaining raised for at least 24 hours with a half-life of 25-30 hours. Serum PCT levels significantly increase in systemic bacterial infection, necrotizing enterocolitis, and during both early and late onset neonatal sepsis. By using a cut-off limit of 0,5 microg/L, the PCT positive likelihoud ratio was found of 12.5. PCT has a theoretical advantage as a marker of systemic induction in sepsis and its half-life suitable for daily monitoring of disease progress. PCT may be useful in assessing the severity of infection, following the progress of treatment, and predicting outcomes.

Early diagnosis and treatment of neonatal sepsis are essential to prevent severe and life threatening complications. Consequently, rapid diagnostic tests capable to differentiate infected from non-infected newborns have the potential to make a significant impact on neonatal care. A new real-time polymerase chain reaction (PCR; LightCycler SeptiFast test M GRADE) has been proposed in the routine assessment of neonatal sepsis for the detection and identification of bacterial and fungal DNA from microorganisms which cause approximately 90% of all blood stream infections. The LightCycler SeptiFast test can detect and identify simultaneously the 25 most important bacterial and fungal species causing bloodstream infections within few hours by using a small volume of a single whole blood sample. Real-time PCR can be easily incorporated into the hospital setting for term or near-term infants admitted to the neonatal intensive care unit for sepsis evaluation.

In this study, we examine C-reactive protein (CRP) and serum amyloid protein A (SAA). Although the former is the best known and most commonly used indicator of inflammation, certain considerations underline the inadequacy of CRP determination alone for the early diagnosis of infection. In fact symptoms often precede the CRP elevation. SAA protein comprises a family of polymorphic apolipoproteins produced mainly by the liver. and several studies have stressed its importance in the diagnosis and monitoring of various diseases. Pathological SAA values are often detected in association with normal CRP concentrations. SAA rises earlier and more sharply than CRP. Finally, contrary to CRP, SAA presents the same trend in viral as well as bacterial infections. Although the data available on SAA in neonates are currently very limited, it is possible to postulate a role of primary importance for SAA in the management of neonatal infections. [ABSTRACT FROM AUTHOR]