Prevalencia de sepsis neonatal confirmada microbiológicamente en una maternidad de la Ciudad Autó noma de Buenos Aires / Prevalence of microbiologically confirmed neonatal sepsis at a maternity center in the City of Buenos Aires

Introducción. En neonatos internados es frecuente sospechar sepsis neonatal, pero solo en el 25 % al 30 % se confirma con cultivos positivos. La selección del esquema antibiótico basándose en la epidemiología local favorece el uso racional y minimiza sus efectos colaterales. Objetivo primario. Describir la prevalencia de sepsis precoz y tardía con rescate microbiológico y sus características clínicas. Población y método. Estudio transversal retrospectivo, realizado del 1 de enero de 2013 al 31 de diciembre de 2017, en una maternidad pública de Argentina, que incluyó todos los recién nacidos internados en la unidad con diagnóstico de sepsis precoz y tardía con rescate microbiológico, y aquellos reingresados dentro del mes de vida. Resultados. Ingresaron 3322 recién nacidos, 1296 evaluados por sospecha de sepsis precoz, cultivos positivos en 25 (1,9 %; tasa: 0,86 ‰). El 52 % eran menores de 33 semanas de edad gestacional. Microorganismos: Escherichia coli 5, Listeria monocytogenes 4, Streptococcus agalactiae (SGB) 3, Streptococcus pneumoniae 3. Sepsis tardía (tasa 8,73 ‰), el 68 % ocurridas en menores de 33 semanas. Microorganismos intrahospitalarios: Staphylococcus coagulasa negativos 115, Staphylococcus aureus 47, Escherichia coli 30, Cándida spp. 16, Enterococcus faecalis 13, Klebsiella pneumoniae 11 y Streptococcus agalactiae 10. En los reingresos: E. coli 11, S. aureus 12, SGB 3 y Haemophilus influenzae 3. Conclusiones. Se observa en el período estudiado una frecuencia de sepsis precoz similar a los reportes internacionales, con predominio de E. coli y L. monocytogenes. La tasa de sepsis tardía presentó una tendencia descendente en los años analizados, con predominio de los cocos grampositivos

Introduction. Neonatal sepsis is often suspected in hospitalized newborn infants, but only in 25­30% of cases it is confirmed via a positive culture. Selecting the antibiotics based on local epidemiology favors their rational use and minimizes their side effects. Primary objective. To describe the prevalence of early- and late-onset sepsis with microorganism isolation and their clinical characteristics. Population and method. Retrospective, cross-sectional study conducted between 01-01-2013 and 12-31-2017 in a public maternity center of Argentina in all hospitalized newborn infants with a diagnosis of early- and late-onset sepsis with microorganism isolation, and those re-admitted in their first month of life. Results. A total of 3322 newborn infants were admitted; 1296 were assessed for suspected early- onset sepsis; 25 had a positive culture (1.9%; rate: 0.86‰). Of these, 52% were born before 33 weeks of gestation. Microorganisms: Escherichia coli 5, Listeria monocytogenes 4, Streptococcus agalactiae (SGB) 3, Streptococcus pneumoniae 3. Also, 68% of late-onset sepsis cases (rate: 8.73‰) occurred in infants born before 33 weeks of gestation. Hospital-acquired microorganisms: coagulase-negative Staphylococcus 115, Staphylococcus aureus 47, Escherichia coli 30, Candida spp. 16, Enterococcus faecalis 13, Klebsiella pneumoniae 11, and Streptococcus agalactiae 10. In re-admissions: E. coli 11, S. aureus 12, SGB 3, and Haemophilus influenzae 3. Conclusions. During the study period, the frequency of early-onset sepsis was similar to international reports, with a predominance of E. coli and L. monocytogenes. The rate of late-onset sepsis showed a downward trend in the analyzed years, with a predominance of Gram-positive cocci.

Device-associated infections in neonatal care units in a middle-income country, 2016-2018.

OBJECTIVE: Describe the device-associated infections in the NICUs in Cali - Colombia, a middle-income country, between August 2016 to December 2018. METHODS: Observational cross-sectional study evaluating reports of device-associated infections in 10 NICUs in Cali, Colombia, between August 2016 and December 2018. Socio-demographic and microbiological data were obtained from the National Public Health surveillance system, through a specialized notification sheet. The relationship of device-associated infections with several outcomes including birth weight, microorganisms, and mortality was evaluated using OR CI95%, using the logistic regression model. Data processing was performed using the statistical program STATA 16. RESULTS: 226 device-associated infections were reported. The rate of infection with central line-associated bloodstream infections was 2.62 per 1000 days of device use and 2.32 per 1000 days for ventilator-associated pneumonia. This was higher in neonates under 1000 g; 4.59 and 4.10, respectively. 43.4% of the infections were due to gram-negative bacteria and 42.3% were due to gram-positive bacteria. Time from hospitalization to diagnosis of all device-associated infections had a median of 14 days. When compared by weight, infants with a weight lower than 1000 g had a greater chance of death (OR 3.61; 95% CI 1.53-8.49, p = 0.03). Infection by gram-negative bacteria was associated with a greater chance of dying (OR 3.06 CI 95 1.33-7.06, p = 0.008). CONCLUSIONS: These results highlight the need to maintain epidemiological surveillance processes in neonatal intensive care units, especially when medical devices are used.

Prevalence of microbiologically confirmed neonatal sepsis at a maternity center in the City of Buenos Aires. / Prevalencia de sepsis neonatal confirmada microbiológicamente en una maternidad de la Ciudad Autónoma de Buenos Aires.

Introduction. Neonatal sepsis is often suspected in hospitalized newborn infants, but only in 25-30% of cases it is confirmed via a positive culture. Selecting the antibiotics based on local epidemiology favors their rational use and minimizes their side effects. Primary objective. To describe the prevalence of early- and late-onset sepsis with microorganism isolation and their clinical characteristics. Population and method. Retrospective, cross-sectional study conducted between 01-01-2013 and 12-31-2017 in a public maternity center of Argentina in all hospitalized newborn infants with a diagnosis of early- and late-onset sepsis with microorganism isolation, and those re-admitted in their first month of life. Results. A total of 3322 newborn infants were admitted; 1296 were assessed for suspected early- onset sepsis; 25 had a positive culture (1.9%; rate: 0.86‰). Of these, 52% were born before 33 weeks of gestation. Microorganisms: Escherichia coli 5, Listeria monocytogenes 4, Streptococcus agalactiae (SGB) 3, Streptococcus pneumoniae 3. Also, 68% of late-onset sepsis cases (rate: 8.73‰) occurred in infants born before 33 weeks of gestation. Hospital-acquired microorganisms: coagulase-negative Staphylococcus 115, Staphylococcus aureus 47, Escherichia coli 30, Candida spp. 16, Enterococcus faecalis 13, Klebsiella pneumoniae 11, and Streptococcus agalactiae 10. In re-admissions: E. coli 11, S. aureus 12, SGB 3, and Haemophilus influenzae 3. Conclusions. During the study period, the frequency of early-onset sepsis was similar to international reports, with a predominance of E. coli and L. monocytogenes. The rate of late-onset sepsis showed a downward trend in the analyzed years, with a predominance of Gram-positive cocci.

Introducción. En neonatos internados es frecuente sospechar sepsis neonatal, pero solo en el 25 % al 30 % se confirma con cultivos positivos. La selección del esquema antibiótico basándose en la epidemiología local favorece el uso racional y minimiza sus efectos colaterales. Objetivo primario. Describir la prevalencia de sepsis precoz y tardía con rescate microbiológico y sus características clínicas. Población y método. Estudio transversal retrospectivo, realizado del 1 de enero de 2013 al 31 de diciembre de 2017, en una maternidad pública de Argentina, que incluyó todos los recién nacidos internados en la unidad con diagnóstico de sepsis precoz y tardía con rescate microbiológico, y aquellos reingresados dentro del mes de vida. Resultados. Ingresaron 3322 recién nacidos, 1296 evaluados por sospecha de sepsis precoz, cultivos positivos en 25 (1,9 %; tasa: 0,86 ‰). El 52 % eran menores de 33 semanas de edad gestacional. Microorganismos: Escherichia coli 5, Listeria monocytogenes 4, Streptococcus agalactiae (SGB) 3, Streptococcus pneumoniae 3. Sepsis tardía (tasa 8,73 ‰), el 68 % ocurridas en menores de 33 semanas. Microorganismos intrahospitalarios: Staphylococcus coagulasa negativos 115, Staphylococcus aureus 47, Escherichia coli 30, Cándida spp. 16, Enterococcus faecalis 13, Klebsiella pneumoniae 11 y Streptococcus agalactiae 10. En los reingresos: E. coli 11, S. aureus 12, SGB 3 y Haemophilus influenzae 3. Conclusiones. Se observa en el período estudiado una frecuencia de sepsis precoz similar a los reportes internacionales, con predominio de E. coli y L. monocytogenes. La tasa de sepsis tardía presentó una tendencia descendente en los años analizados, con predominio de los cocos grampositivos.

Device-associated infections in neonatal care units in a middle-income country, 2016-2018

Abstract Objective: Describe the device-associated infections in the NICUs in Cali - Colombia, a middle-income country, between August 2016 to December 2018. Methods: Observational cross-sectional study evaluating reports of device-associated infections in 10 NICUs in Cali, Colombia, between August 2016 and December 2018. Socio-demographic and microbiological data were obtained from the National Public Health surveillance system, through a specialized notification sheet. The relationship of device-associated infections with several outcomes including birth weight, microorganisms, and mortality was evaluated using OR Cl95%, using the logistic regression model. Data processing was performed using the statistical program STATA 16. Results: 226 device-associated infections were reported. The rate of infection with central line-associated bloodstream infections was 2.62 per 1000 days of device use and 2.32 per 1000 days for ventilator-associated pneumonia. This was higher in neonates under 1000 g; 4.59 and 4.10, respectively. 43.4% of the infections were due to gram-negative bacteria and 42.3% were due to gram-positive bacteria. Time from hospitalization to diagnosis of all device-associated infections had a median of 14 days. When compared by weight, infants with a weight lower than 1000 g had a greater chance of death (OR 3.61; 95% CI 1.53-8.49, p = 0.03). Infection by gram-negative bacteria was associated with a greater chance of dying (OR 3.06 CI 95 1.33-7.06, p = 0.008). Conclusions: These results highlight the need to maintain epidemiological surveillance processes in neonatal intensive care units, especially when medical devices are used.

Plasma D-dimer level in early and late-onset neonatal sepsis.

BACKGROUND: Neonatal sepsis is a life-threatening disease. Early diagnosis is essential, but no single marker of infection has been identified. Sepsis activates a coagulation cascade with simultaneous production of the D-dimers due to lysis of fibrin. D-dimer test reflects the activation of the coagulation system. AIM: To assess the D-dimer plasma level, elaborating its clinicopathological value in neonates with early-onset and late-onset neonatal sepsis. METHODS: The study was a prospective cross-sectional study that included ninety neonates; divided into three groups: Group I: Early-onset sepsis (EOS); Group II: Late-onset sepsis (LOS); and Group III: Control group. We diagnosed neonatal sepsis according to our protocol. C-reactive protein (CRP) and D-dimer assays were compared between EOS and LOS and correlated to the causative microbiological agents. RESULTS: D-dimer was significantly higher in septic groups with a considerably higher number of cases with positive D-dimer. Neonates with LOS had substantially higher levels of D-dimer than EOS, with no significant differences in CRP. Neonates with LOS had a significantly longer hospitalization duration and higher gram-negative bacteriemia and mortality rates than EOS (P < 0.01). Gram-negative bacteria have the highest D-dimer levels (Acinetobacter, Klebsiella, and Pseudomonas) and CRP (Serratia, Klebsiella, and Pseudomonas); while gram-positive sepsis was associated with relatively lower levels. D-dimer had a significant negative correlation with hemoglobin level and platelet count; and a significant positive correlation with CRP, hospitalization duration, and mortality rates. The best-suggested cut-off point for D-dimer in neonatal sepsis was 0.75 mg/L, giving a sensitivity of 72.7% and specificity of 86.7%. The D-dimer assay has specificity and sensitivity comparable to CRP in the current study. CONCLUSION: The current study revealed a significant diagnostic value for D-dimer in neonatal sepsis. D-dimer can be used as an adjunct to other sepsis markers to increase the sensitivity and specificity of diagnosing neonatal sepsis.

Monocyte-to-HDL ratio and non-HDL cholesterol were predictors of septic shock in newborns.

BACKGROUND: The association between lipoprotein levels and late-onset neonatal sepsis has shown controversial results. The aims are to assess lipid profile, cytokines, and Monocyte-to-HDL (M/H) ratio as diagnostic and prognostic markers for late-onset neonatal sepsis. METHODS: This prospective study included 49 septic neonates and 17 controls. Cholesterol (CT), Triglyceride (TG), Very-Low-Density (VLDLc), Low-Density (LDLc), and High-Density Lipoproteins (HDLc) were measured at admission (D0) and on days 3, 7 and 10 to evaluate septic shock outcomes. Cytokines and monocytes were evaluated by flow cytometry. RESULTS: Septic newborns showed higher IL-6 and IL-8 at D0 and CT levels on D7 and on D10, which also presented higher TG, VLDLc and non-HDL cholesterol concentrations than controls. The septic shock group (n = 22) revealed a higher number of male subjects, CRP, IL-6, IL-8 and IL-10 levels, while lower TG, HDLc, monocyte numbers and M/H ratio at admission compared to the non-shock group (n = 27). M/H ratio and non-HDL cholesterol on D0 were risk factors for septic shock (OR = 0.70, 0.49‒0.99; OR = 0.96, 0.92‒0.99, respectively). Decreasing levels from D0 to D3 of CT (OR = 0.96, 0.93‒0.99), VLDLc (OR = 0.91, 0.85‒0.98), and non-HDL cholesterol (OR = 0.92, 0.87‒0.98) were also predictors of septic shock. CONCLUSIONS: Lower M/H ratios and non-HDL cholesterol at admission and decreasing levels of cholesterol, VLDLc and non-HDL cholesterol during a hospital stay are associated with the development of septic shock in newborns with late-onset neonatal sepsis.

The role of nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in diagnosis of late onset neonatal sepsis.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality among neonates. Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a core element for innate immune protection. The study aims to estimate the expression of NLRP3 inflammasome in full term newborn infants who suffer from late onset sepsis, in order to assess its diagnostic value. METHOD: This case-control study was conducted in NICU. 40 newborns with late onset sepsis, and 40 control neonates were included. The analysis of NLRP3 inflammasome was done by ELISA. RESULTS: There was a significant elevation of NLRP3 inflammasome in the serum of neonates with late onset sepsis group than the control group, P values were < 0.001, and the best cut off value of NLRP3 to detect late onset septic was > 3 ng/ml with sensitivity of 92.5% and specificity of 97.5%. Receiver operating characteristic curve showed that the best cut off point of NLRP3 to predict mortality in cases group was > 7.29 with sensitivity of 75.0%, specificity of 91.67%, PPV of 50.0%, NPV of 97.1% and total accuracy of 0.84%. n-SOFA scoring system increased significantly among LOS group and there was positive correlation with NLRP 3 inflammasome, P < 0.012. CONCLUSION: NLRP3 inflammasome can be used for the diagnosis of late onset neonatal sepsis. The increase of its values was not affected by gender, birth weight, gestational age and postnatal age. It was the novel sepsis markers that were not fully studied in neonatal population. The prognostic values may need further studies.

The NICU Antibiotics and Outcomes (NANO) trial: a randomized multicenter clinical trial assessing empiric antibiotics and clinical outcomes in newborn preterm infants.

BACKGROUND: Early-onset sepsis is an important cause of neonatal morbidity and mortality in the preterm population. Infants perceived to be at increased risk for early-onset sepsis are often treated empirically with broad-spectrum antibiotics while awaiting confirmatory blood cultures, despite an overall incidence of early-onset sepsis of 2-3% among extremely-low-birthweight (ELBW) infants. Recent observational studies associate perinatal antibiotic use with an increased incidence of necrotizing enterocolitis, late-onset sepsis, and mortality among ELBW infants. Given currently available data and variability in clinical practice, we designed a prospective multi-institutional randomized controlled trial to determine the safety of early antibiotic use in ELBW infants. METHODS: The NICU Antibiotics and Outcomes (NANO) trial is a multicenter, double-blinded, randomized controlled trial. A sample of 802 ELBW preterm infants will undergo web-based stratified block randomization to receive empiric antibiotics (EA; ampicillin and gentamicin) or placebo during routine evaluation for early-onset sepsis. Participating sites will use preexisting institutional protocols for antibiotic dosage and duration. Infants born at participating sites with a gestational age of 29 weeks or less are eligible for enrollment. Exclusion criteria include maternal intrauterine infection, hemodynamic or respiratory instability, delivery by caesarean section for maternal indications without labor or prolonged rupture of membranes, and prior administration of antibiotics. The primary outcome is the composite incidence of necrotizing enterocolitis, late-onset sepsis, or death during participants' index hospitalization. Maternal and infant samples will be collected longitudinally and assessed for differences in microbiome composition and diversity. DISCUSSION: The NANO trial is designed to compare the rate of adverse outcomes of EA use at birth versus placebo in ELBW preterm infants. If EA at birth worsens clinical outcomes, then the results of the trial may help providers decrease antibiotic utilization in the NICU and subsequently decrease the incidence of complications associated with early antibiotic use in ELBW infants. If we instead find that EA improve outcomes, then the trial will validate a longstanding clinical practice that has not previously been supported by high-quality data. Future studies will assess long-term clinical and microbial outcomes in infants who received empiric antibiotics following delivery. TRIAL REGISTRATION: Trial registration data: June 25, 2019  NCT03997266 .

cfDNA and DNases: New Biomarkers of Sepsis in Preterm Neonates-A Pilot Study.

INTRODUCTION: An early and accurate diagnosis of early onset neonatal sepsis (EONS) and late onset neonatal sepsis (LONS) is essential to improve the outcome of this devastating conditions. Especially, preterm infants are at risk. Reliable biomarkers are rare, clinical decision-making depends on clinical appearance and multiple laboratory findings. Markers of NET formation and NET turnover might improve diagnostic precision. Aim of this study was to evaluate the diagnostic value of NETs in sepsis diagnosis in neonatal preterm infants. METHODS: Plasma samples of neonatal preterm infants with suspected sepsis were collected. Blood samples were assayed for markers of NET formation and NET turnover: cfDNA, DNase1, nucleosome, NE, and H3Cit. All clinical findings, values of laboratory markers, and epidemiological characteristics were collected retrospectively. Two subpopulations were created to divide EONS from LONS. EMA sepsis criteria for neonatal sepsis were used to generate a sepsis group (EMA positive) and a control group (EMA negative). RESULTS: A total of 31 preterm neonates with suspected sepsis were included. Out of these, nine patients met the criteria for sepsis according to EMA. Regarding early onset neonatal sepsis (3 EONS vs. 10 controls), cfDNA, DNase I, nucleosome, and CRP were elevated significantly. H3Cit and NE did not show any significant elevations. In the late onset sepsis collective (6 LONS vs. 12 controls), cfDNA, DNase I, and CRP differed significantly compared to control group.

MicroRNA Expression in Neonates with Late-onset Sepsis - A Cross-sectional Comparative Study.

BACKGROUND: Neonatal sepsis is a major health concern among neonates with higher morbidity and mortality rate. Studies have recently speculated the importance of differential expression of circulating mature micro-RNAs (miRNAs) which could serve as diagnostic as well as prognostic markers for risk of mortality in neonatal sepsis. This study aimed to analyze the expression pattern and to assess the diagnostic/prognostic value of miRNAs miR-21, miR-29a miR-31, miR-146a, and miR-155 in late-onset neonatal sepsis. METHODS: A cross-sectional comparative study was conducted including 42 healthy controls and 42 neonates with late-onset neonatal sepsis. SYBR green-based miScript RT-PCR assay was used for the expression analysis and the comparative Ct method 2-delta (Ct) method was used for relative quantification of the candidate miRNAs in plasma. Significantly higher expression of miR-21 and miR-155 and lower expression of miR-29a and miR-146a was observed in cases compared to control except miR-31. In subgroups analysis, miR-21(p = .03) showed a significant difference between pre-term and term neonates and miR-31 (p = .01) and miR-155 (p = .03) showed a significant difference between low-birth-weight and normal-birth-weight neonates. miR-146a showed significantly lower expression in the non-survivor group compared to the survivor group (p = .005). A receiver operating characteristic curve (ROC) analysis of miR-21 and miR-29a (0.829 and 0.787 AUC of ROC curves) showed good discrimination for the identification of sepsis from non-sepsis neonates. CONCLUSION: The current study shows evidence of differential expression of miRNAs in neonatal sepsis and this altered expression of candidate miRNAs could be involved in immune dysregulation, thus leading to sepsis-related severity in newborns.

Monocyte-to-HDL ratio and non-HDL cholesterol were predictors of septic shock in newborns

Abstract Background The association between lipoprotein levels and late-onset neonatal sepsis has shown controversial results. The aims are to assess lipid profile, cytokines, and Monocyte-to-HDL (M/H) ratio as diagnostic and prognostic markers for late-onset neonatal sepsis. Methods This prospective study included 49 septic neonates and 17 controls. Cholesterol (CT), Triglyceride (TG), Very-Low-Density (VLDLc), Low-Density (LDLc), and High-Density Lipoproteins (HDLc) were measured at admission (D0) and on days 3, 7 and 10 to evaluate septic shock outcomes. Cytokines and monocytes were evaluated by flow cytometry. Results Septic newborns showed higher IL-6 and IL-8 at D0 and CT levels on D7 and on D10, which also presented higher TG, VLDLc and non-HDL cholesterol concentrations than controls. The septic shock group (n = 22) revealed a higher number of male subjects, CRP, IL-6, IL-8 and IL-10 levels, while lower TG, HDLc, monocyte numbers and M/H ratio at admission compared to the non-shock group (n = 27). M/H ratio and non-HDL cholesterol on D0 were risk factors for septic shock (OR = 0.70, 0.49‒0.99; OR = 0.96, 0.92‒0.99, respectively). Decreasing levels from D0 to D3 of CT (OR = 0.96, 0.93‒0.99), VLDLc (OR = 0.91, 0.85‒0.98), and non-HDL cholesterol (OR = 0.92, 0.87‒0.98) were also predictors of septic shock. Conclusions Lower M/H ratios and non-HDL cholesterol at admission and decreasing levels of cholesterol, VLDLc and non-HDL cholesterol during a hospital stay are associated with the development of septic shock in newborns with late-onset neonatal sepsis.

Evaluation of serum and salivary C-reactive protein for diagnosis of late-onset neonatal sepsis: A single center cross-sectional study

Abstract Objective: To evaluate the diagnostic utility of salivary C-reactive protein (CRP) and its potential correlation with serum CRP levels in full-term neonates with late-onset sepsis (LOS). Methods: This cross-sectional study included 90 neonates assigned to three equal groups: culture proven LOS, clinical LOS and a control group. Clinical findings and routine laboratory data including complete blood pictures and blood culture results were documented. Highly sensitive serum CRP was measured according to hospital protocol, while salivary CRP levels were measured using enzyme-linked immunosorbent assay. Results: The median serum CRP was significantly higher in septic neonates compared to controls (p < 0.001). For serum CRP, the optimum cut-off value for LOS diagnosis was found to be 7.2 mg/L with sensitivity, specificity, positive and negative predictive values of 91, 100, 100, and 85.7%, respectively. No significant difference was observed in levels of salivary CRP among the 3 study groups (p = 0.39). No correlation was found between the levels of salivary and serum CRP (r = 0.074, p = 0.49). Conclusion: Serum CRP, at a cut-off value of 7.2 mg/L, exhibited a high specificity and positive predictive value in LOS diagnosis, whereas salivary CRP levels weren't significantly different between the 3 study groups nor did they predict abnormal serum CRP thresholds in newborns with sepsis.

C-Reactive Protein, Interleukin-6, and Procalcitonin in Diagnosis of Late-Onset Bloodstream Infection in Very Preterm Infants.

BACKGROUND: Late-onset bloodstream infection (LOBSI) is common in very preterm infants. Early and accurate diagnosis is crucial for prognosis and outcome. We aimed to analyze the accuracy of routinely used inflammatory biomarkers in the diagnosis of LOBSI as compared to uninfected controls. METHODS: In this single-center, retrospective case-control study, interleukin-6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) were routinely measured, when infection was clinically suspected. The definition of LOBSI was based on positive blood culture, clinical signs of infection, and onset more than 72 hours after birth. RESULTS: Among 285 enrolled infants, 66 developed LOBSI. IL-6 was superior to other markers, and levels greater than 100 ng/L had a sensitivity of 94% and a specificity of 99% for the presence of LOBSI. Receiver operating characteristic curve of IL-6 had area under the curve of 0.988 (95% CI = 0.975-1.00, P < .001). The negative predictive value of IL-6, CRP, and PCT for optimal cutoff values was 99%, 95%, and 93%, respectively. The logistic regression model of IL-6 > 100 ng/L or CRP > 10 mg/L were successfully predicted LOBSI in 97.9% of cases. CONCLUSIONS: The combination of IL-6 and CRP seems to have great potential in routine rapid diagnosis of LOBSI development. High negative predictive value of all tested markers could encourage the early discontinuation of antibiotic treatment.

Cell-Surface Biomarkers, C-Reactive Protein and Haematological Parameters for Diagnosing Late Onset Sepsis in Pre-term Neonates.

OBJECTIVE: To compare the diagnostic accuracy of white blood cell-surface biomarkers (CD64, CD11b and HLA-DR), C-reactive protein (CRP) and hematological parameters to diagnose definite sepsis among pre-term neonates presenting with suspected late-onset neonatal sepsis (LONS). DESIGN: This was a prospective, single-gate, diagnostic study in a Level III neonatal unit. Fifty-three neonates (gestation, <34 weeks) with LONS (onset, >72 age), were enrolled. Cell-surface biomarkers, CRP and haematological parameters were assayed at 0 and 48 h after onset. The reference standard was definite sepsis, defined as a positive blood culture with a non-contaminant organism. The index tests (cell-surface biomarkers, CRP and haematological parameters) were compared between subjects with or without 'definite sepsis'. The area under the receiver operator characteristics curves (AUC) generated for each index test at 0 and 48 h was compared. SETTING: Level III neonatal unit in a tertiary care institute. RESULTS: Of 53 enrolled pre-term infants, 24 had definite sepsis. Among all the index tests evaluated, CRP at 48 h had the highest AUC [0.82 (95% confidence interval, 0.69, 0.92)]. The expression of CD11b and HLA-DR was significantly reduced among the septic neonates. Among the cell-surface biomarkers, the maximum AUC was recorded for HLA-DR at 48 [0.68 (95% CI, 0.54, 0.81)]. Comparisons between index tests were not statistically significant. CONCLUSION: C-reactive protein is superior to other sepsis screen biomarkers and white blood cell-surface biomarkers in diagnosing culture-positive LONS among pre-term infants. CD64, CD11b and HLA DR as diagnostic tests in this group have limited discriminatory value. LAY SUMMARY: The diagnosis of neonatal blood stream infections is a challenge. In response to bacterial blood stream infections, white blood cells are known to produce an excess of certain types of specialized proteins on their surface, including CD64, CD11b and HLA-DR. In this study we evaluated the concentration of these cell-surface proteins for diagnosing blood stream infections in pre-mature newborn babies, whose onset of infection was beyond 72 h of life. We compared these tests against standard tests that are currently in clinical use, such as C-reactive protein and blood white cell counts. All tests were performed at the time of initially suspecting the infection and 48 h later. The gold standard against which all these tests were evaluated was blood culture, in which the offending bacteria are grown in specialized laboratory media. Of 53 pre-mature babies with suspected infection, 24 had blood culture-proven infection. Among all tests, C-reactive protein at 48 h had the best ability to distinguish definite infection from no infection. The expression of CD11b and HLA-DR was significantly reduced among infected neonates. We conclude that C-reactive protein is superior to white blood cell-surface proteins and white cell count in diagnosing definite late-onset infections among pre-term infants.

Evaluation of serum and salivary C-reactive protein for diagnosis of late-onset neonatal sepsis: A single center cross-sectional study.

OBJECTIVE: To evaluate the diagnostic utility of salivary C-reactive protein (CRP) and its potential correlation with serum CRP levels in full-term neonates with late-onset sepsis (LOS). METHODS: This cross-sectional study included 90 neonates assigned to three equal groups: culture proven LOS, clinical LOS and a control group. Clinical findings and routine laboratory data including complete blood pictures and blood culture results were documented. Highly sensitive serum CRP was measured according to hospital protocol, while salivary CRP levels were measured using enzyme-linked immunosorbent assay. RESULTS: The median serum CRP was significantly higher in septic neonates compared to controls (p < 0.001). For serum CRP, the optimum cut-off value for LOS diagnosis was found to be 7.2 mg/L with sensitivity, specificity, positive and negative predictive values of 91, 100, 100, and 85.7%, respectively. No significant difference was observed in levels of salivary CRP among the 3 study groups (p = 0.39). No correlation was found between the levels of salivary and serum CRP (r = 0.074, p = 0.49). CONCLUSION: Serum CRP, at a cut-off value of 7.2 mg/L, exhibited a high specificity and positive predictive value in LOS diagnosis, whereas salivary CRP levels weren't significantly different between the 3 study groups nor did they predict abnormal serum CRP thresholds in newborns with sepsis.

Association of inflammatory biomarkers with subsequent clinical course in suspected late onset sepsis in preterm neonates.

BACKGROUND: Sepsis is a major health issue in preterm infants. Biomarkers are used to diagnose and monitor patients with sepsis, but C-reactive protein (CRP) is proven not predictive at onset of late onset neonatal sepsis (LONS) diagnosis. The aim of this study was to evaluate the association of interleukin-6(IL-6), procalcitonin (PCT) and CRP with subsequent sepsis severity and mortality in preterm infants suspected of late onset neonatal sepsis. METHODS: The study was conducted at the Erasmus University Medical Center-Sophia Children's Hospital Rotterdam. Patient data from January 2018 until October 2019 were reviewed for all preterm neonates born with a gestational age below 32 weeks with signs and symptoms suggestive of systemic infection, in whom blood was taken for blood culture and for inflammatory biomarkers determinations. Plasma IL-6 and PCT were assessed next to CRP at the moment of suspicion. We assessed the association with 7-day mortality and sepsis severity (neonatal sequential organ failure assessment (nSOFA) score, need for inotropic support, invasive ventilation and thrombocytopenia). RESULTS: A total of 480 suspected late onset neonatal sepsis episodes in 208 preterm neonates (gestational age < 32 weeks) were retrospectively analyzed, of which 143 episodes were classified as sepsis (29.8%), with 56 (11.7%) cases of culture negative, 63 (13.1%) cases of gram-positive and 24(5.0%) cases of gram-negative sepsis. A total of 24 (5.0%) sepsis episodes resulted in death within 7 days after suspicion of LONS. Both IL-6 (adjusted hazard ratio (aHR): 2.28; 95% CI 1.64-3.16; p < 0.001) and PCT (aHR: 2.91; 95% CI 1.70-5.00; p < 0.001) levels were associated with 7-day mortality; however, CRP levels were not significantly correlated with 7-day mortality (aHR: 1.16; 95% CI (0.68-2.00; p = 0.56). Log IL-6, log PCT and log CRP levels were all significantly correlated with the need for inotropic support. CONCLUSIONS: Our findings show that serum IL-6 and PCT levels at moment of suspected late onset neonatal sepsis offer valuable information about sepsis severity and mortality risk in infants born below 32 weeks of gestation. The discriminative value was superior to that of CRP. Determining these biomarkers in suspected sepsis may help identify patients with imminent severe sepsis, who may require more intensive monitoring and therapy.

Patient monitoring as a predictor of blood culture results in a tertiary neonatal intensive care unit.

We present a mesoergonomic approach to the early detection of neonatal sepsis, analyzing clinical data for 4999 patients from a neo-natal intensive care unit to predict positive culture results. The Apgar score at birth predicted positive results. For neonates with poor and intermediate Apgar scores, culture results for monitored infants were more likely to be positive than those for unmonitored infants. Thus, the medical staff tended to monitor infants who eventually had a greater chance for positive test results. A cost-effectiveness analysis indicated that for infants with high Apgar scores, the physician should decide whether to obtain a blood culture, based on the patient's characteristics. For infants with lower Apgar scores, it may be advisable to obtain a blood culture whenever one decides to monitor a neonate. The study demonstrates that staff decisions regarding a patient can serve as input for further clinical decision-making.

TLR2 and TLR4 expressions in late-onset neonatal sepsis: Is it a potential novel biomarker?

BACKGROUND: Late-onset neonatal sepsis (LONS) detection is problematic as no single examinations (blood culture, c-reactive protein (CRP), procalcitonin (PCT)) are reliable. Toll-like receptors (TLRs), which detect the presence of pathogen-associated molecular patterns is a promising novel biomarker, but less studied in LONS. This study aimed to determine neutrophils and monocytes TLR2 and TLR4 expression in LONS and their diagnostic value. METHODS: A cross-sectional study conducted in May and June 2017 involving 52 neonates with clinical late-onset (>72 hours of age) sepsis. We examine complete blood count, I/T ratio, CRP, PCT, as well as TLR2 and TLR4 expression to compared with blood culture as the gold standard. We classified cases into proven or unproven sepsis. RESULT: The incidence of LONS was 32.6% in the subjects. The expression of TLR2 was low in LONS, while TLR4 was high. TLR4 neutrophil expression has 88.2% sensitivity, 20% specificity, 34.9% positive predictive value (PPV), 77.8% negative predictive value (NPV), and an AUC of 0.541. TLR4 monocyte expression has 92.1% sensitivity, 11.4% specificity, 34% PPV, 80% NPV, and an AUC of 0.528. The AUC of CRP is increased from 0.608 to 0.843 after combination with TLR4, comparable with CRP + PCT (AUC 0.829). CONCLUSION: The increase in TLR4 expression has good sensitivity but low specificity. TLR4 expression, in combination with CRP, could become a reliable biomarker for the diagnosis of LONS.

Clinical characteristics and etiological analysis of early-onset and late-onset neonatal sepsis / 中华临床感染病杂志

Objective:To analyze the clinical characteristics, etiology and outcome of early-onset neonatal sepsis (EONS) and late-onset neonatal sepsis (LONS).Methods:The clinical data of 265 neonates with NS admitted in the neonatal ward of the the Affiliated Hospital of Qingdao University from January 2014 to September 2020 were enrolled, including 76 cases of EONS and 189 cases of LONS. The general information, clinical manifestation, laboratory findings, pathogen distribution, treatment and outcome of the two groups were analyzed with SPSS25.0 statistical software.Results:The rates of meconium-stained amniotic fluid, prenatal maternal fever, abnormal white blood cell (WBC) count and neutrophil count in EONS group were significantly higher than those in LONS group ( P<0.05 or <0.01). However, the rates of indwelling central venous catheters, mechanical ventilation, fever, abdominal distension, abnormal platelet count and serum prealbumin level in LONS group were significantly higher than those in EONS group ( P<0.05 or <0.01). Staphylococcus epidermidis(135/265)and Staphylococcus aureus (22/265) were the most common gram-positive bacteria and Escherichia coli (13/265) was the most common gram-negative bacteria in NS. The proportion of gram-positive bacteria was the highest in both EONS group (85.5%) and LONS group (84.7%), which was mainly Staphylococcus epidermidis of coagulase negative staphylococci. The proportion of Listeria monocytogenes and Streptococcus infections in EONS group was significantly higher than that in LONS group ( P<0.05 or <0.01). The proportion of Staphylococcus aureus infection in LONS group was significantly higher than that in EONS group ( P<0.01). There was no significant difference in case fatality rate between EONS group and LONS group (6.6% vs 2.6%, P>0.05). Conclusions:Perinatal amniotic fluid pollution and prenatal maternal fever are risk factors for the occurrence of EONS, while indwelling central venous catheter and mechanical ventilation are risk factors for the occurrence of LONS. Abnormal platelet count and abnormal serum prealbumin are more common in the LONS group. The bacteria detected in EONS and LONS are mainly Staphylococcus epidermidis. Clinical diagnosis and treatment of EONS and LONS should be managed differently.

A Predictive Model Based on Machine Learning for the Early Detection of Late-Onset Neonatal Sepsis: Development and Observational Study.

BACKGROUND: Neonatal sepsis is associated with most cases of mortalities and morbidities in the neonatal intensive care unit (NICU). Many studies have developed prediction models for the early diagnosis of bloodstream infections in newborns, but there are limitations to data collection and management because these models are based on high-resolution waveform data. OBJECTIVE: The aim of this study was to examine the feasibility of a prediction model by using noninvasive vital sign data and machine learning technology. METHODS: We used electronic medical record data in intensive care units published in the Medical Information Mart for Intensive Care III clinical database. The late-onset neonatal sepsis (LONS) prediction algorithm using our proposed forward feature selection technique was based on NICU inpatient data and was designed to detect clinical sepsis 48 hours before occurrence. The performance of this prediction model was evaluated using various feature selection algorithms and machine learning models. RESULTS: The performance of the LONS prediction model was found to be comparable to that of the prediction models that use invasive data such as high-resolution vital sign data, blood gas estimations, blood cell counts, and pH levels. The area under the receiver operating characteristic curve of the 48-hour prediction model was 0.861 and that of the onset detection model was 0.868. The main features that could be vital candidate markers for clinical neonatal sepsis were blood pressure, oxygen saturation, and body temperature. Feature generation using kurtosis and skewness of the features showed the highest performance. CONCLUSIONS: The findings of our study confirmed that the LONS prediction model based on machine learning can be developed using vital sign data that are regularly measured in clinical settings. Future studies should conduct external validation by using different types of data sets and actual clinical verification of the developed model.