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Introduction: Deficiencies in innate immune responses may contribute to the increased susceptibility to infection in preterm infants. In vivo cytokine profiles in response to sepsis in very preterm infants are not fully understood., Aims: To characterise plasma pro- and anti-inflammatory cytokine concentrations and pre-defined ratios in very preterm infants with late-onset sepsis (LOS)., Methods: In this observational study, peripheral blood samples were collected at the time of evaluation for suspected LOS from 31 preterm infants (<30 weeks gestational age). Plasma cytokine concentrations were determined by 12-plex immunoassay., Results: IL-10, IFN-γ, IL-12p70, IP-10, IL-6 and CCL2 were elevated in the majority infants with LOS (n = 12) compared to those without LOS (n = 19). There was no difference in TNF-α, IL-1β, IL-17AF, IL-8 and IL-15 concentrations between groups. IL-10/TNF-α ratios were increased, while CCL2/IL-10 and IL-12p70/IL-10 ratios were decreased in infants with LOS compared to those without., Conclusion: Very preterm infants have a marked innate inflammatory response at the time of LOS. The increase in IL-10/TNF-α ratio may indicate early immune hypo-responsiveness. Longitudinal studies with a larger number of participants are required to understand immune responses and clinical outcomes following LOS in preterm infants., Competing Interests: The authors have declared that no competing interests exist.

Aims: Infection-induced inflammation is associated with adverse long-term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants., Method: An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12 h for two days (60 mg kg -1 per 12 h), and in infants with confirmed diagnosis of LOS or NEC, for 6 h for another 4 days (30 mg kg -1 per 6 h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling., Results: The preterm infants (n = 26) had a median (range) gestation of 24.8 weeks (23.3-30.4) and birthweight of 689 g (370-1285). PTX was well tolerated and without treatment-limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six-fold difference in exposure between 24 and 35 weeks postmenstrual age., Conclusions: The developed model can be used to explore dosing strategies based on size and maturation for preterm infants., (© 2018 The British Pharmacological Society.)

Background: The circulating neutrophil count was commonly believed to be influenced by altitude. At present, neutrophil reference ranges (RRs) for very low birth weight (VLBW) neonates are only available from the sea level and from high altitude. This study aimed to construct RRs for neutrophils in VLBW infants in an intermediate-altitude area and assess its usefulness in evaluation for sepsis., Methods: This was a multicenter retrospective study of 2173 VLBW infants admitted to 20 hospitals in Chongqing in southwest of China with altitude from 1000 to 2600 feet. The RRs for absolute total neutrophils (ATN), absolute total immature neutrophils (ATI), and immature: total neutrophil proportion were constructed based on "normal" neonates (unlikely infection). Values of neutrophil from septic and uninfected neonates were respectively assessed using the revised RRs and the previous Mouzinho's and Schmutz's RRs. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were compared using the McNemar's test or χ2 test., Results: The upper limits for ATN and ATI using the revised RRs were much higher than those using Mouzinho's RRs, but lower than those using Schmutz's RRs. The revised RRs and Mouzinho's RRs had higher sensitivities than Schmutz's RRs at 73-672 h. The revised RRs had a higher specificity than Mouzinho's RRs at both 0-72 h and 73-672 h. The NPV for any abnormality in neutrophil values was high at both 0-72 h and 73-672 h irrespective of the RRs used., Conclusion: Altitude-appropriate RRs for neutrophils is more suitable to guide the diagnosis and management of neonatal sepsis in VLBW infants., Competing Interests: The authors have declared that no competing interests exist.

Background: The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants., Objective: The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs)., Methods: This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml., Results: Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia., Conclusions: Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Introduction: In the German Neonatal Network (GNN) 10% of very-low-birth weight infants (VLBWI) suffer from blood-culture confirmed sepsis, while 30% of VLBWI develop clinical sepsis. Diagnosis of sepsis is a difficult task leading to potential over-treatment with antibiotics. This study aims to investigate whether the results of blood multiplex-PCR (SeptiFast®) for common sepsis pathogens are relevant for clinical decision making when sepsis is suspected in VLBWI., Methods: We performed a prospective, multi-centre study within the GNN including 133 VLBWI with 214 episodes of suspected late onset sepsis (LOS). In patients with suspected sepsis a multiplex-PCR (LightCycler SeptiFast MGRADE-test®) was performed from 100 μl EDTA blood in addition to center-specific laboratory biomarkers. The attending neonatologist documented whether the PCR-result, which was available after 24 to 48 hrs, had an impact on the choice of antibiotic drugs and duration of therapy., Results: PCR was positive in 110/214 episodes (51%) and blood culture (BC) was positive in 55 episodes (26%). Both methods yielded predominantly coagulase-negative staphylococci (CoNS) followed by Escherichia coli and Staphylococcus aureus. In 214 BC-PCR paired samples concordant results were documented in 126 episodes (59%; n = 32 were concordant pathogen positive results, n = 94 were negative in both methods). In 65 episodes (30%) we found positive PCR results but negative BCs, with CoNS being identified in 43 (66%) of these samples. Multiplex-PCR results influenced clinical decision making in 30% of episodes, specifically in 18% for the choice of antimicrobial therapy and in 22% for the duration of antimicrobial therapy., Conclusions: Multiplex-PCR results had a moderate impact on clinical management in about one third of LOS-episodes. The main advantage of multiplex-PCR was the rapid detection of pathogens from micro-volume blood samples. In VLBWI limitations include risk of contamination, lack of resistance testing and high costs. The high rate of positive PCR results in episodes of negative BC might lead to overtreatment of infants which is associated with risk of mortality, antibiotic resistance, fungal sepsis and NEC.

Objective: To compare the use of a generic molecular assay to 'standard' investigations used to assist the diagnosis of late onset bacterial sepsis in very low birth weight infants (VLBW, <1500 g)., Methods: VLBW infants, greater than 48 hours of age, who were clinically suspected to have sepsis were investigated using standard tests (full blood count, C-reactive protein (at presentation) and blood culture), in addition, blood was taken for a universal molecular assay (16S rRNA reverse transcriptase PCR) for comparison. Clinical data were recorded during the suspected infection episode. A validated sepsis score (NEO-KISS) was used to retrospectively determine the presence of sepsis (independent of blood culture). The performance of each of the tests were compared by sensitivity, specificity, positive/negative likihood ratios (+/-LR) and postive/negative predictive values (PPV/NPV)., Results: Sixty-five babies with suspected clinical sepsis were prospectively included. The performance indicators are presented with 95% confidence limits. For the detection of bacteria, blood culture had sensitivity of 0.57 (0.34-0.78), specificity of 0.45 (0.30-0.61); +LR of 1.05 (0.66-1.66) and-LR of 0.94 (0.52-1.7); PPV of 33.3 (18.56-50.97) and NPV of 68.97 (49.17-87.72). Serum CRP had sensitivity of 0.92 (0.64-1) and specificity of 0.36 (0.17-0.59); +LR of 1.45 (1-2.1) and-LR of 0.21 (0.03-1.5); PPV of 44.46 (26.6-66.6) and NPV of 88.9 (51.8-99.7). The universal molecular assay had sensitivity of 0.76 (0.53-0.92), specificity of 0.95 (0.85-0.99); +LR of 16.8 (4.2-66.3) and-LR of 0.25 (0.1-0.5); PPV of 88.9 (65.3-98.6) and NPV of 89.4 (76.9-96.5)., Conclusions: In VLBW infants this universal molecular assay performed better in the diagnosis of late onset sepsis (LOS) than blood culture and CRP. Further development is required to explore and improve the performance of the assay in real-time diagnosis.

Introduction: The role of CD64 in late onset sepsis (LOS) in preterm infants has been described in several studies. Aim of this study was to investigate whether CD64 expression is increased in the days before clinical manifestation of LOS., Methods: Patients with birth weight below 1,500 g were eligible for study participation. During routine blood sampling CD64 index was determined between day of life 4 and 28. Patients were allocated to one of four groups: (1) blood-culture positive sepsis, (2) clinical sepsis, (3) symptoms of infection without biochemical evidence of infection, or (4) patients without suspected infection. Kinetics of CD64 expression were compared during a period before and after the day of infection in the respective groups., Results: 50 infants were prospectively enrolled and allocated to each group as follows: group (1) n = 7; group (2) n = 10; group (3) n = 8; and group (4) n = 25. CD64 index was elevated in 57% of patients in group (1) at least two days before infection. In contrast only 20% in the clinical sepsis group and 0% in group (3) had an elevated CD64 index in the days before infection. 10 of the 25 patients in the control group (4) presented increased CD64 index values during the study period., Conclusions: The CD64 index might be a promising marker to detect LOS before infants demonstrate signs or symptoms of infection. However, larger prospective studies are needed to define optimal cut-off values and to investigate the role of non-infectious inflammation in this patient group.

Introduction: Advances in modern medicine have given very low birth weight (VLBW) infants a better chance of survival; however, these infants remain at high risk for developing nosocomial infections associated with increased morbidity and mortality. The ability of antistaphylococcal immunoglobulins, Altastaph and INH A-2, to augment the neonatal immune system to prevent infections has been studied and evaluated in a 2009 Cochrane review., Areas Covered: Our objective is to evaluate the safety and efficacy of a third antistaphylococcal immunoglobulin, pagibaximab, in the prevention of staphylococcal infection in preterm infants. Three studies of pagibaximab, Phases I, II and III, were examined in terms of study design, pharmacokinetics, development of sepsis and adverse effects., Expert Opinion: These studies demonstrated safety and tolerability of pagibaximab with no observed reduction in sepsis. Reported adverse events in both treatment and placebo groups were similar and consistent with events commonly observed in VLBW infants. Antistaphylococcal immunoglobulins alone have been unsuccessful in preventing nosocomial infections. Further investigations need to evaluate any potential immunomodulating products in preterm animal models prior to human studies. Future studies are required to determine how to best augment the immature immune system, likely through the use of multiple immunomodulating agents to successfully prevent infections in preterm infants.

Objective: To assess the accuracy of lipopolysaccharide binding protein (LBP) for diagnosing late-onset neonatal sepsis (LONS) in very low birth weight (VLBW) infants., Study Design: Observational, prospective study. We assessed the diagnostic performance of LBP in 26 suspected LONS episodes among 54 patients. Proven and probable LONS episodes were recorded according to established criteria. Receiver operating characteristic curve analysis was performed to evaluate LBP's ability to predict LONS., Results: LONS was diagnosed in 17 of 26 episodes. LBP levels were significantly higher in confirmed LONS episodes (P<0.001). The area under the curve of LBP was 0.89. A cut-off of 17.5 μg/mL had a sensitivity of 94.1%, a specificity of 77.8%, a positive predictive value of 88.9% and a negative predictive value of 87.5%., Conclusions: Serum LBP measurement may be useful as an additional tool in the evaluation of suspected LONS in VLBW infants.

In order to prevent fatty acid deficiency and to supply enough energy, intravenous fat emulsion is necessary for parenteral nutrition in preterm neonates. However, parenteral administration of intravenous fat emulsion can induce lipid intolerance. The purpose of this study was to analyze risk factors for lipid intolerance in very low birth weight infants. This retrospective study included 80 preterm neonates whose birth weight was less than 1,500 g. Subjects were divided into 2 categories: those with a serum triglyceride level of ≥ 200 mg/dl (n = 33, 41%) and those with a serum triglyceride level of < 200 mg/dl (n = 47, 59%). We conducted logistic regression analysis using variables which were significant in univariate analysis. All statistical analyses were processed in SPSS version 19.0. Four risk factors for lipid intolerance were obtained through analysis of the electronic medical record. Lipid intolerance occurred more frequently in neonates with sepsis; those with a birth weight less than 1,000 g; those who was administered intravenous fat emulsion more than 2.6 g/kg/day; and those whose gestational age was less than 28 weeks. It is suggested that serum triglyceride levels should be closely monitored to prevent lipid intolerance in preterm neonates with the aforementioned characteristics.

Sepsis is an important cause of death in very-low-birth-weight (VLBW) neonates. Although conventional diagnostic indicator of sepsis has been done by blood cultures, this took much longer time. The measurement of platelet-associated parameters such as mean platelet volume (MPV) and platelet distribution width (PDW) become more reliable and accurate parameters as a non-specific marker for sepsis. Our objective is to examine the usefulness of those platelet hematological parameters as a supplementary diagnostic tool for sepsis in VLBW infants. This study is a retrospective cohort study of neonates subject to the diagnosis of sepsis from October 2006 to July 2010. This study was conducted at Korea University medical center. We studied total 2,336 infants for 32 days from birth (Day 0) to Day 31. We compared three groups of infants to examine differences of platelet parameters according to their age from birth to Day 31: (i) full-terms versus VLBW without sepsis, (ii) VLBW without sepsis versus VLBW with sepsis and (iii) thrombocytopenic VLBW without sepsis versus those with sepsis. The platelet-associated parameters were significantly distinguishable between septic and non-septic groups at their early age (∼ 1 week), especially platelet counts (PLT) (p = 0.0091), MPV (p = 0.007) and PDW (p = 0.0372) in thrombocytopenic VLBW infants. The decreased PLT, elevated MPV and PDW were major characteristics of septic group. We suggested maximum cutoff values of the platelet factors by performing receiver operating characteristic curve analysis between septic and non-septic thrombocytopenic VLBW infants, among which MPV was the most promising index (AUCMPV = 0.7044 > AUCPLT = 0.6921 > AUCPDW = 0.6593). Platelet-associated hematological parameters are useful for the early diagnosis of sepsis as a more efficient and supplementary diagnostic method in thrombocytopenic VLBW infants.

Background: The added clinical value of multisite near-infrared spectroscopy (NIRS) monitoring to detect low organ tissue perfusion in preterm infants at risk of circulatory failure remains unclear., Objectives: To evaluate the associations between multisite NIRS measurements and clinical signs of circulatory failure in relation to short-term outcome in preterm infants with clinical sepsis., Methods: Prospective cohort study of preterm infants (gestational age <32 weeks) with clinical sepsis. We monitored cerebral, renal, and intestinal oxygen saturation using NIRS for 72 h following sepsis workup and calculated fractional tissue oxygen extraction (FTOE). We recorded clinical signs of circulatory failure every 8 h. We analyzed the associations between FTOE values, clinical signs of circulatory failure, and short-term outcome., Results: In 28 preterm infants with clinical sepsis, intraindividual and interindividual associations between NIRS values and clinical signs of circulatory failure were weak. At several points of time during the study period, cerebral and renal FTOE were higher in infants who developed intestinal complications compared with infants who did not, while clinical signs of circulatory failure never differed between groups. After correcting for multiple testing, significant differences disappeared., Conclusions: The associations between multisite FTOE values and clinical signs of circulatory failure were weak in preterm infants with clinical sepsis. Nevertheless, in contrast to clinical signs of circulatory failure, cerebral and renal FTOE values were associated with adverse short-term intestinal outcome in the uncorrected analyses. Multisite NIRS monitoring might help to detect critically low tissue oxygen delivery leading to adverse intestinal outcome not detected by routine hemodynamic measurements., (© 2015 S. Karger AG, Basel.)

Objective: To assess the diagnostic and prognostic utility of CD64 expression as a marker of early-onset sepsis (EOS) in very low birth weight (VLBW) neonates., Methods: Neutrophil CD64 expression (CD64 index) was assessed in 129 VLBW neonates within 72 h after birth. The accuracy of the CD64 index in predicting EOS was determined by receiver operating characteristic curve analysis. The relationship between the expression of the CD64 index and neonatal outcomes was evaluated by multivariate analysis., Results: The highest performance of the CD64 index was achieved at 24 h after birth; accuracy, sensitivity, and negative predictive values were 0.85, 0.89, and 0.99, respectively, with a cut-off value of 2.4. The increased expression of CD64 index was significantly associated with subsequent infections (relative risk 1.54; 95% confidence interval 1.02-2.33)., Conclusions: The CD64 index could be used as a reliable marker of EOS in VLBW neonates and it is an independent risk factor for late-onset infections.

Objective: To determine frequency of thrombocytopenia and thrombocytosis, the MPV (mean platelet volume) and PDW (platelet distribution width) in patients with probable and culture proven neonatal sepsis and determine any association between platelet counts and mortality rate., Study Design: Descriptive analytical study., Place and Duration of Study: NICU, Fazle Omar Hospital, from January 2011 to December 2012., Methodology: Cases of culture proven and probable neonatal sepsis, admitted in Fazle Omar Hospital, Rabwah, were included in the study. Platelet counts, MPV and PDW of the cases were recorded. Mortality was documented. Frequencies of thrombocytopenia (< 150000/mm3) and thrombocytosis (> 450000/mm3) were ascertained. Mortality rates in different groups according to platelet counts were calculated and compared by chi-square test to check association., Results: Four hundred and sixty nine patients were included; 68 (14.5%) of them died. One hundred and thirty six (29%) had culture proven sepsis, and 333 (71%) were categorized as probable sepsis. Thrombocytopenia was present in 116 (24.7%), and thrombocytosis was present in 36 (7.7%) cases. Median platelet count was 213.0/mm3. Twenty eight (27.7%) patients with thrombocytopenia, and 40 (12.1%) cases with normal or raised platelet counts died (p < 0.001). Median MPV was 9.30, and median PDW was 12.30. MPV and PDW of the patients who died and who were discharged were not significantly different from each other., Conclusion: Thrombocytopenia is a common complication of neonatal sepsis. Those with thrombocytopenia have higher mortality rate. No significant difference was present between PDW and MPV of the cases who survived and died.

Background: Late-onset sepsis (LOS) in very low birth weight (VLBW) infants is associated with significant morbidity and mortality. The ability to predict mortality in infants with LOS based on clinical and laboratory factors at presentation of illness remains limited., Objectives: To identify predictors of sepsis-associated mortality from a composite risk profile that includes demographic data, category of infecting organism, clinical and laboratory data at onset of illness., Study Design: Data were collected from VLBW infants with at least 1 episode of LOS admitted to Yale Neonatal Intensive Care Unit from 1989 through 2007. Episodes were categorized as Gram-positive, Gram-negative or fungal. Multivariate logistic regression analysis was used to compare and contrast different types of infections and to assess independent risk factors for death., Results: Four hundred twenty-four cases of LOS were identified in 424 VLBW infants. Of these, 262 (62%) were categorized as Gram-positive, 126 (30%) as Gram-negative and 36 (8%) as fungal. Multivariate analyses revealed that infants with Gram-positive infections had significantly lower odds of death compared to those with Gram-negative (adjusted odds ratio: 0.17; 95% confidence interval: 0.08-0.36) or fungal LOS (adjusted odds ratio: 0.22; 95% confidence interval: 0.07-0.64). Need for intubation, initiation of pressors, hypoglycemia and thrombocytopenia as presenting laboratory signs of infection and necrotizing enterocolitis were independent risk factors for sepsis-related death., Conclusions: We identified presenting clinical and laboratory factors, including category of infecting organism, which predict the increased risk of LOS-related death. This information can be useful in estimating prognosis shortly after the onset of disease.

Objective: To analyze the implementation of a protocol proposed by the Brazilian National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária - ANVISA) to improve sepsis diagnosis in very low birth weight newborns., Methods: This was a prospective study that evaluated the implementation of a protocol involving clinical and laboratory criteria (hematologic scoring system of Rodwell and C-reactive protein serial measurements), recommended by ANVISA, to improve the diagnosis of neonatal sepsis in very low birth weight newborns. The study included all patients who were born and remained in the neonatal intensive care unit until discharge or death, and excluded those with congenital diseases. The main outcomes measured in newborns before (2006-2007) and after implementation of the protocol (2008) were the rates of early and late-onset sepsis, use of antibiotics, and mortality. Means were compared by Student's t-test and categorical variables were compared by the chi-squared test; the significance level for all tests was set at 95%., Results: The study included 136 newborns with very low birth weight. There was no difference between groups regarding general clinical characteristics in the studied periods. There was, however, a decrease in the number of diagnoses of probable early-onset sepsis (p<0.001), use of antimicrobial regimens (p<0.001), and overall mortality and infection-related mortality (p=0.009 and p=0.049, respectively)., Conclusion: The implementation of the protocol allowed improvement of sepsis diagnosis by reducing the diagnosis of probable early-onset sepsis, thus promoting efficient antimicrobial use in this population., (Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: Conventional blood culture is still the gold standard for sepsis diagnosis but results are not immediately available and pathogens are only detected in approximately 25% of cases. New molecular assays for the detection of blood stream pathogens are promising diagnostic tools., Objectives: The aim of the study was to adapt and evaluate a multiplex PCR system using 100 µl blood. -, Methods: 46 blood specimens of very low birth weight infants (818 ± 242 g) with suspected sepsis were analyzed using the Roche SeptiFast MGRADE PCR with a modified DNA extraction protocol and software handling tool for decreased blood volume requirements., Results: In the non-infected group, 5/21 infants had a positive PCR result with coagulase-negative staphylococci. All pathogens detected in the blood culture positive group (n = 15) were also detected by PCR. In addition, 4/6 patients had a positive PCR result in the clinical sepsis group (clinical and laboratory signs of sepsis but negative blood culture). Overall, the PCR was demonstrated to have a higher sensitivity (90.5%; 95%CI 68.2-98.3%) in comparison to blood culture (71.4%; 95%CI 47.7-87.8%) including clinical sepsis cases, even though it had a lower specificity (80.0%; 95%CI 58.7-92.4% versus 100.0%; 95%CI 83.4-100.0%)., Conclusions: These first data demonstrate the usability and potential benefit of this multiplex PCR using a modified DNA extraction for the rapid detection of nosocomial sepsis in preterm infants in addition to blood culture., (Copyright © 2013 S. Karger AG, Basel.)

Unlabelled: Procalcitonin (PCT), a prohormone of calcitonin has been described as a specific biomarker of sepsis., Objectives: To compare the predictive value of PCT, C reactive protein (CRP) and white blood cell count (WBC) for the diagnosis of late onset sepsis (LOS) in very low birth weight (VLBW) neonates., Methods: We prospectively determined the serum concentration of PCT, CRP and WBC in 53 VLBW newborns with clinical suspicion of LOS. 25 had confirmed sepsis with positive blood culture; 28 had clinical sepsis (negative blood cultures), Results: PCT levels were significantly higher in the infected group (3.0 ng/ml) compared to the non infected group (0.4 ng/ml) (p < 0.05). PCT had the highest area under the ROC curve 0.83 (95% CI 0.70-0.92) p = 0.001 compared to CRP 0.51 (95%CI 0.37-0.65) and WBC 0.53 (95%CI 0.38-0.66) for the diagnosis of LOS .The best PCT cut off value was 0.9 ng/ml. The sensitivity, specificity and negative predictive value were 88%, 72% and 87%, respectively., Conclusions: The determination of PCT could be more useful than CRP and WBC in the diagnosis of LOS in VLBW newborns.

Introduction: We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009-2010., Methods: Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp., Results: In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters., Discussion: Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care.

Background: Pagibaximab, a human chimeric monoclonal antibody developed against lipoteichoic acid, was effective against staphylococci preclinically and seemed safe and well tolerated in phase 1 studies., Objective: To evaluate the clinical activity, pharmacokinetics, safety, and tolerability of weekly pagibaximab versus placebo infusions in very low birth weight neonates., Patients and Methods: A phase 2, randomized, double-blind, placebo-controlled study was conducted at 10 NICUs. Patients with a birth weight of 700 to 1300 g and 2 to 5 days old were randomly assigned to receive 3 once-a-week pagibaximab (90 or 60 mg/kg) or placebo infusions. Blood was collected for pharmacokinetics, bacterial killing, and safety analyses. Adverse event and clinical outcome data were collected., Results: Eighty-eight patients received pagibaximab at 90 (n = 22) or 60 (n = 20) mg/kg or placebo (n = 46). Groups were not different in demography, mortality, or morbidity. Pagibaximab demonstrated linear pharmacokinetics, a 14.5-day half-life, and nonimmunogenicity. Definite staphylococcal sepsis occurred in 0%, 20%, and 13% (P < .11) and nonstaphylococcal sepsis occurred in 0%, 10%, and 15% (P < .15) of patients in the 90 mg/kg, 60 mg/kg, and placebo groups, respectively. In all patients with staphylococcal sepsis, estimated or observed pagibaximab levels were <500 μg/mL (target level) at infection., Conclusions: Three once-a-week 90 or 60 mg/kg pagibaximab infusions, in high-risk neonates, seemed safe and well tolerated. No staphylococcal sepsis occurred in infants who received 90 mg/kg. Target levels were only consistently achieved after 2 to 3 doses. Dose optimization should enhance protection.

To determine the diagnostic utility of serum calprotectin, a mediator of innate immune response against infections, we performed a multicenter study involving newborns with a birth weight < 1500 g and a postnatal age >72 hours of life. The diagnostic accuracy of serum calprotectin was compared with that of the most commonly used markers of neonatal sepsis (white blood cell count, immature-to-total-neutrophil ratio, platelet count, and C-reactive protein). We found that the serum calprotectin concentration was significantly higher (P < .001) in 62 newborns with confirmed sepsis (3.1 ± 1.0  μg/mL) than in either 29 noninfected subjects (1.1 ± 0.3 μg/ml) or 110 healthy controls (0.91 ± 0.58 μg/ml). The diagnostic accuracy of serum calprotectin was greater (sensitivity 89%, specificity 96%) than that of the traditional markers of sepsis. In conclusion, serum calprotectin is an accurate marker of sepsis in very low birth weight newborns.

Introduction: The mortality rate from sepsis is high and the risk of sepsis increases in prematurity in proportion to the decrease in birth weight., Material and Method: The authors report the assessment of serum interleukin-6 levels in 12 term, at-risk newborn infants after birth and 60 VLBW neonates after detection of non-specific signs of infection or sepsis, treated in NICU at the Semmelweis University, 1st Department of Obstetrics and Gynecology in 2005-2006. The serum IL-6 level with a rapid test (Milenia Quickline IL-6 and PicoScan system) was investigated. The simultaneous assessment of C-reactive protein levels was analysed as well., Results: The assessment of serum interleukin-6 and CRP levels for the early diagnosis of sepsis can be established or ruled out. The sensitivity of serum IL-6 level assessment was 100%. There were no false negative cases. The positive predictive value was 93%. There was a significant difference between the sepsis and infection group of VLBW infants in the serum Il-6 levels ( p = 0.048), and between the infection and non-infection groups in the interleukin-6 levels ( p < 0.005)., Conclusions: In comparing the diagnostic value of IL-6 measurement in VLBW infants with signs of infection to the diagnostic methods currently in use, results showed that a combination of early assessment of IL-6 and CRP seems to increase diagnostic accuracy in attempting to differentiate between septic and nonseptic patients. Such increased accuracy will decrease neonatal morbidity as well as the financial cost of treatment.

Objective: Thrombocytopenia is commonly observed in very low birth weight (VLBW) neonates with sepsis. Specific platelet responses to different infectious agents have not been extensively characterized. The objectives of this study were to examine platelet counts and platelet indices in preterm neonates with culture-proven sepsis to determine if there are organism-specific platelet responses., Study Design: We analyzed a cohort of all VLBW neonates (birthweight <1500 g) born over a 4-year period and admitted to a single level III neonatal intensive care unit (N = 943). Thrombocytopenia was defined as a platelet count <100,000/mm(3). Platelet count, nadir, duration of thrombocytopenia, and mean platelet volume (MPV) were examined during episodes of culture-proven sepsis. Analysis of variance, Kruskal-Wallis, Mann-Whitney U, and chi(2) tests were used to compare groups, and data are expressed as mean +/- standard deviation., Results: Sepsis was diagnosed in 154 (16%) of 943 patients in the study population. Of the sepsis episodes, 54% were associated with thrombocytopenia and 61% with an elevation in MPV. Infections were grouped by organism type: Gram-positive bacteria (117/154, 76%), Gram-negative bacteria (24/154, 16%), and fungi (13/154, 8%). When compared with patients with Gram-positive sepsis, those with Gram-negative or fungal sepsis had a significantly lower initial platelet count, a lower platelet nadir, a higher incidence of thrombocytopenia, and a greater duration of thrombocytopenia. The decrease in platelet count from baseline was also significantly less in the Gram-positive infections than in the fungal infections. Although there was an overall increase in MPV from baseline, there were no differences between groups., Conclusions: In our population of VLBW infants, sepsis is frequently associated with thrombocytopenia and an elevation in MPV. However, fungal and Gram-negative pathogens are associated with a lower platelet count and more prolonged thrombocytopenia compared with Gram-positive pathogens. We conclude that common pathogens causing sepsis have different effects on platelet kinetics.

The risk of sepsis associated with neutropenia in infants born to mothers with preeclampsia remains controversial. The objective of this study is to investigate the incidence of culture-proven sepsis along with changes in the complete blood count in very-low-birth-weight infants born to mothers with preeclampsia. We conducted a retrospective cohort study of infants cared for at a single tertiary care neonatal intensive care unit during a 4-year period. Infants born to mothers with preeclampsia (n = 88) were compared to infants born to mothers without preeclampsia (n = 416) by univariate and multivariate analysis. Although infants born to mothers with preeclampsia had lower absolute neutrophil and platelet counts throughout the first week of life, they were no more likely to have a platelet count <100,000 /mm3, and only more likely to be neutropenic at 24 and 72 hr of life compared to infants born to mothers without preeclampsia. After controlling for potential confounding variables, there was no increase in the odds of culture proven sepsis in infants born to mothers with preeclampsia (odds ratio 1.6, 95% confidence intervals 0.7-3.6, p = 0.3) compared to those infants born to mothers without preeclampsia. We conclude that very-low-birth-weight infants born to mothers with preeclampsia are not at increased risk of culture proven sepsis despite a reduction in absolute neutrophils.

Aims: To evaluate the commonly used markers--namely IL-6, TNF alpha, IL-1 beta, C-reactive protein and E-selection for identification of late onset neonatal sepsis; to define the optimal cutoff value for each marker in preterm neonates; to assess whether these markers could assist in early discontinuation of antibiotics in non-infected cases; and to delineate the profile of these markers during systemic infection and in relation to successful treatment., Methods: Very low birthweight infants in whom clinical sepsis was suspected when they were > 72 hours of age were eligible for study. A full sepsis screen was performed in each episode. Cytokines, C-reactive protein, and E-selectin were serially measured on days 0 (at the time of sepsis evaluation), 1, 2, 4 and 7. The optimal cutoff value for each marker was calculated after minimising the number of misclassified episodes over all possible cutoff values for days 0 and 1. The sensitivity, specificity, positive and negative predictive values for each test and combination of tests for predicting systemic infection were also determined., Results: One hundred and one episodes of suspected clinical sepsis were investigated in 68 infants. Forty five episodes were proved to be infections. The optimal cutoff values were IL-6 31 pg/ml, TNF alpha 17 pg/ml, IL-1 beta 1 pg/ml, C reactive protein 12 mg/l and E-selectin 174 ng/ml. IL-6 had the highest sensitivity (89%) and negative predictive value (91%) for detecting late onset infection on day 0. However, between 24 and 48 hours of onset, C-reactive protein was the best single marker, with an overall sensitivity and specificity of 84% and 96%, respectively. The use of serial and multiple markers in the first 48 hours further enhanced the sensitivity and specificity of these tests. Performing IL-6 and C-reactive protein on day 0, together with either TNF alpha on day 1 or C-reactive protein on day 2, showed the best overall sensitivity (98%) and specificity (91%) for the diagnosis of late onset infection., Conclusions: Optimal cutoff values for these markers in detecting late onset systemic infection in very low birthweight infants have been defined. Withholding antibiotic treatment at the onset of infection could be fatal and is not recommended, but the concomitant use of IL-6 and C-reactive protein or TNF alpha should allow antimicrobial treatment to be discontinued at 48 hours without waiting for microbiological results, provided that the infants are in good clinical condition.

Objective: To study the effect of sepsis on circulating neutrophils in very low birth weight neonates and to assess the usefulness of recently revised reference ranges for circulating neutrophils in the diagnosis of sepsis in this population by comparison with previously reported reference ranges., Methods: Neutrophil parameters (absolute total neutrophils, absolute total immature neutrophils, and the immature:total neutrophil proportion) were analyzed retrospectively in 202 sepsis episodes in 192 neonates (birth weight = 1055 +/- 246 g, X +/- SD; estimated gestational age = 29 +/- 2 weeks) between birth and 30 days of age. The percentage of values lying outside the reference ranges reported recently by Mouzinho et al and previously by Manroe et al were compared. To more accurately assess possible differences in specificity between the two reference ranges, neonates with early-onset group B streptococcal infection (n = 19) were compared with a matched control group (n = 51) using conditional logistic regression., Results: Greater sensitivity was observed using the previous reference ranges of Manroe et al over the entire study period (0 to 720 hours) both for the initial and the second complete blood count (CBC). The previous reference ranges also were more sensitive than the revised ranges for the initial CBC at 0 to 72 and at 73 to 720 hours and for infections attributable to coagulase-negative staphylococci. However, specificity in neonates without group B streptococcal infection was significantly greater with the revised reference ranges compared with those of Manroe et al (initial CBC, 73% vs 45%; serial CBCs, 59% vs 10%)., Conclusion: The observed differences in sensitivities may be of limited clinical significance because very low birth weight infants often are begun on antibiotic therapy regardless of laboratory values. However, the striking differences in specificity using the revised reference ranges suggest that these ranges may be clinically useful in determining length of antimicrobial therapy in infants in whom cultures remain sterile.