Nora Hofer

An Update on the Use of C-Reactive Protein in Early-Onset Neonatal Sepsis: Current Insights and New Tasks

C-reactive protein (CRP) is one of the most studied and most used laboratory tests for neonatal sepsis. As part of the acute-phase reaction to infection, it plays a central role in the humoral response to bacterial invasion. The delayed synthesis during the inflammatory response accounts for its low sensitivity during the early phases of the disease. Diagnostic accuracy clearly improves by the performance of serial determinations and by the combination with earlier markers such as interleukins or procalcitonin. CRP is as well particularly useful for monitoring the response to treatment and guiding antibiotic therapy, though nothing replaces the clinical impression and the gold standard (i.e. culture results). In spite of the large amount of research done on CRP in neonates, some topics are still not fully understood, such as the influence of noninfectious factors on CRP levels in healthy as well as in symptomatic neonates and the role of gestational age and birthweight on CRP kinetics. In this review, we aim to give an update on the current evidence on the use of CRP in neonates.

Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life

Abstract Background: Our aim was to analyze C-reactive protein (CRP) values in term and preterm infants and correlate non-infection-associated increases with various neonatal disorders. Methods: Retrospective cohort study that included all newborns hospitalized at a tertiary care center between 2004 and 2007 with documented CRP values in the first 3 days of life. Analysis of differences in CRP values between term and preterm newborns and cases with CRP increases in sepsis negative newborns. Results: For diagnosis of blood culture proven sepsis (19 and 14 cases, respectively) in 353 preterm and 179 term newborns, CRP at a cut-off of 8 mg/L had sensitivities of 53% and 86% and specificities of 91% and 88%, respectively. The area under the receiver operating characteristics curves were 0.799 and 0.890, respectively. Preterm newborns had lower median values compared to term newborns in sepsis positive (9 vs. 18.5 mg/L, p<0.001) and negative newborns (0.5 vs. 2 mg/L, p<0.001). Increases in individuals without infection were correlated significantly with meconium aspiration syndrome and surfactant application in term newborns (p=0.009 and 0.025, respectively) and with surfactant application and higher birth weight in preterm newborns (p<0.001 and 0.031, respectively). Conclusions: CRP values were significantly lower in preterm compared to term newborns, and its application in the diagnosis of sepsis in preterm newborns was not as reliable as in term newborns. Meconium aspiration syndrome, surfactant application, and high birth weight were associated significantly with increased CRP values.

Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant

BACKGROUND Septic episodes in preterm infants recently have been reported to be associated with periventricular leukomalacia (PVL). The role of hypocarbia as an independent risk factor for PVL in clinical studies raises many questions without conclusive answers. AIMS To evaluate risk factors for cystic PVL focussing on the influence of hypocarbia. STUDY DESIGN Retrospective single centre case-control study. SUBJECTS Preterm infants 24 to 35 weeks of gestational age and matched (1:2 for gender, birth year, gestational age and birth weight) controls. OUTCOME MEASURES Multivariate analysis of perinatal factors being associated with cystic PVL diagnosed by serial ultrasound examinations. RESULTS Univariate analysis of risk factors revealed lower 5 and 10 min Apgar scores, and higher rates of neonatal seizures, early-onset sepsis, neonatal steroids, respiratory distress syndrome with surfactant replacement therapy, and episodes of hypocarbia significantly being associated with PVL. Multivariate analysis using a logistic regression model revealed early-onset sepsis and hypocarbia being significantly associated with PVL (p=.022 and .024, respectively). Lowest PaCO(2) values did not differ as did not the duration of hypocarbia, but the onset of hypocarbia was significantly later in PVL cases compared to controls (mean 26 vs. 15 h, p=.033). Neurodevelopmental follow-up at a median time of 46 months was poor showing 88% of the cases having an adverse neurological outcome. CONCLUSION We found early-onset sepsis and episodes of hypocarbia within the first days of life being independently associated with PVL.

Performance of the definitions of the systemic inflammatory response syndrome and sepsis in neonates.

Abstract Aims: The aim of this study was to examine the applicability of the definitions of the systemic inflammatory response syndrome (SIRS) and sepsis to neonates during the first 3 days of life. Methods: This is a retrospective study of all term neonates hospitalized within the first 24 h of life from 2004 to 2010 at our neonatal intensive care unit. Results: Of 476 neonates, 30 (6%) had a diagnosis of culture-proven early-onset sepsis (EOS) and 81 (17%) had culture-negative clinical EOS or suspected EOS. SIRS and sepsis criteria were applied to 116 (24%) and 61 (13%) neonates, respectively. Of 30 neonates with culture proven, EOS 14 (53%) fulfilled SIRS and sepsis criteria. The single diagnostic criterion of SIRS applied to 20% (hypothermia or fever), 43% (white blood cell count/immature-to-total neutrophil ratio), 87% (respiratory symptoms), and 33% (cardiocirculatory symptoms) of all neonates with culture-proven EOS. Conclusions: The definitions of SIRS and sepsis did not apply to about half of all cases of culture-proven EOS. An evidence-based approach to find the appropriate criteria for defining EOS in the neonate is needed.

Neonates presenting with temperature symptoms: role in the diagnosis of early onset sepsis.

Background:  In this study, we aimed to evaluate the role of fever, hypothermia, and temperature instability in term and preterm newborns during the first 3 days of life and to identify risk factors for early onset sepsis (EOS) among newborns presenting with these temperature symptoms.

Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B

OBJECTIVES Although amphotericin B (AmB) and its lipid formulations are used for the treatment of fungal infections of the CNS, the kinetics of AmB in the CSF after intravenous administration of liposomal amphotericin B (LAmB) are not well characterized. PATIENTS AND METHODS From 14 paediatric haemato-oncological patients (aged 0.4-19.5 years, median 7.6 years), we obtained 30 CSF samples by means of routine punctures (performed for intrathecal treatment of the underlying diseases) at different timepoints after the prophylactic intravenous infusion of LAmB (AmBisome, 3 mg/kg/day). Concurrent serum samples were obtained to calculate the transfer rates. An HPLC method was used for AmB detection. RESULTS CSF levels of AmB 1-100 h after the intravenous infusion of LAmB were between 10 and 120 ng/mL, except in one case with a level of 529 ng/mL. Concurrent serum levels were about 1000-fold higher, ranging between 3 and 75 μg/mL. CSF levels did not show a clear time-dependent concentration profile, but remained at a steady-state for longer than 48 h after infusion. The transfer rate ranged from 0.02% to 0.92% (median 0.13%) and correlated significantly (r=0.801, P<0.001) with increasing time after infusion. CONCLUSIONS After the intravenous administration of LAmB, AmB CSF levels were low, confirming published animal data. CSF levels remained at a steady-state level for longer than 48 h. As indicated by published post mortem data, higher levels in brain tissue, which would be necessary for the successful treatment of CNS infections, might be possible.

Cord blood procalcitonin and Interleukin-6 are highly sensitive and specific in the prediction of early-onset sepsis in preterm infants

Abstract We studied the predictive value of cord blood procalcitonin (PCT) and interleukin-6 (IL-6) in the diagnosis of early-onset sepsis (EOS) in the preterm infant. Retrospectively, PCT and IL-6 were correlated with clinical and/or blood culture positive EOS and negative infectious status between February 2008 and March 2011. Receiver operating curves (ROC) were generated and the area under the curve (AUC) was calculated by use of Youdens Index to detect the best cut-off values for sensitivity and specificity. Thirty of 218 preterm infants (13.8%) were diagnosed as having EOS. The optimal cut-off value for PCT was 0.235 μg/L (sensitivity 78.6%, specificity 86.3%), and for IL-6 15.85 ng/L (sensitivity 73.7%, specificity 84.2%), the combination of PCT and IL-6 revealed sensitivity 77.1% and specificity 91.7%. The combined determination of PCT and IL-6 from cord blood was highly sensitive and specific in the prediction of EOS.

Meconium aspiration syndrome--a 21-years' experience from a tertiary care center and analysis of risk factors for predicting disease severity.

Aim of this study was to describe the course of perinatal factors in neonates with meconium aspiration syndrome (MAS) from 1990 to 2010 and to determine risk factors for a severe course of the disease.All neonates with MAS hospitalized in our level III neonatal intensive care unit from 1990 to 2010.Retrospective analysis of trends of perinatal factors in neonates with MAS over time and of the association of these factors with severe MAS (need for invasive mechanical ventilation for ≥7 days, or need for high frequency oscillation or need for extracorporeal membrane oxygenation).We included 205 neonates with MAS, 55 had severe MAS (27%). MAS incidence and absolute number of MAS cases per year decreased during the observation period (p=0.003 and 0.005, respectively) as well as rates of outborn deliveries (p=0.004), duration of invasive mechanical ventilation (p=0.004), and hospital stay (p=0.036). Incidence and absolute number of severe MAS cases per year decreased (p=0.008 and 0.006, respectively), though the percentage of severe MAS among all neonates with MAS did not change. Risk factors for severe MAS were acute tocolysis (odds ratio 18.2 (95% confidence interval 2.1-155.3), p<0.001) fetal distress (3.4 (1.8-6.4), p<0.001), and severe and moderate birth asphyxia (4.4 (2.0-9.7), p=0.001 and 2.9 (1.5-5.6), p=0.009).The incidence and absolute numbers of MAS and severe MAS cases changed during the study period as well as neonatal management. Acute tocolysis, fetal distress, and asphyxia were associated with severe MAS.

Early-Onset Neonatal Sepsis: Still Room for Improvement in Procalcitonin Diagnostic Accuracy Studies

Abstract To perform a systematic review assessing accuracy and completeness of diagnostic studies of procalcitonin (PCT) for early-onset neonatal sepsis (EONS) using the Standards for Reporting of Diagnostic Accuracy (STARD) initiative. EONS, diagnosed during the first 3 days of life, remains a common and serious problem. Increased PCT is a potentially useful diagnostic marker of EONS, but reports in the literature are contradictory. There are several possible explanations for the divergent results including the quality of studies reporting the clinical usefulness of PCT in ruling in or ruling out EONS. We systematically reviewed PubMed, Scopus, and the Cochrane Library databases up to October 1, 2014. Studies were eligible for inclusion in our review if they provided measures of PCT accuracy for diagnosing EONS. A data extraction form based on the STARD checklist and adapted for neonates with EONS was used to appraise the quality of the reporting of included studies. We found 18 articles (1998–2014) fulfilling our eligibility criteria which were included in the final analysis. Overall, the results of our analysis showed that the quality of studies reporting diagnostic accuracy of PCT for EONS was suboptimal leaving ample room for improvement. Information on key elements of design, analysis, and interpretation of test accuracy were frequently missing. Authors should be aware of the STARD criteria before starting a study in this field. We welcome stricter adherence to this guideline. Well-reported studies with appropriate designs will provide more reliable information to guide decisions on the use and interpretations of PCT test results in the management of neonates with EONS.

The Role of C-Reactive Protein in the Diagnosis of Neonatal Sepsis

During the last decades advances in neonatal intensive care have led to an impressive decrease of neonatal mortality and morbidity. However, infectious episodes in the early postnatal period still remain serious and potentially life-threatening events with a mortality rate of up to 50% in very premature infants. [1, 2] The signs and symptoms of neonatal sepsis can be clinically indistinguishable from various noninfectious conditions such as respiratory distress syndrome or maladaptation. Therefore rapid diagnosis is crucial for preventing the child from an adverse outcome. The current practice of starting empirical antibiotic therapy in all neonates showing infection-like symptoms results in their exposure to adverse drug effects, nosocomial complications, and in the emergence of resistant strains. [3]