Search

Background: An accurate diagnosis of early-onset sepsis (EOS) is challenging because of subtle symptoms and the lack of a good diagnostic tool, resulting in considerable antibiotic overtreatment. A biomarker, discriminating between infected and non-infected newborns at an early stage of the disease, could improve EOS prediction. Numerous biomarkers have been tested, but have never been compared directly., Objectives: We aimed to provide a comprehensive overview of early biomarkers and their diagnostic value in maternal samples, umbilical cord blood, and neonatal serum., Data Sources: PubMed-Medline, EMBASE, The Cochrane Library, and Web of Science were searched up to 1 March 2023, without restrictions on publication date, population, or language., Study Eligibility Criteria: Articles describing the diagnostic value of at least one biomarker in the detection of EOS in neonates, independent of gestational age, were included., Assessment of Risk of Bias: The QUADAS-2 tool was used to assess study quality., Methods of Data Synthesis: Three independent researchers assessed the articles using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was performed with all manuscripts describing diagnostic accuracy using a random-effects model., Results: Of 2296 identified articles, 171 reports were included in the systematic review and 69 in the meta-analysis. Literature showed mixed and inconsistent evidence for most biomarkers and sample types, because of a lack of a uniform EOS case definition, small sample sizes, and large heterogeneity between studies. Interesting markers were procalcitonin (pooled sensitivity 79%, 95% CI 71-84%; specificity 91%, 95% CI 83-96%, n = 11) and interleukin (IL)-6 (pooled sensitivity 83%, 95% CI 71-90%; specificity 87%, 95% CI 78-93%, n = 8) in umbilical cord blood and presepsin (pooled sensitivity 82%, 95% CI 62-93%; specificity 86%, 95% CI 73-93%, n = 3) and serum amyloid A (pooled sensitivity 92%, 95% CI 75-98%; specificity 96%, 95% CI 78-99%, n = 4) in neonatal serum. Studies on the combination of biomarkers were scarce., Conclusions: A biomarker stand-alone test is currently not reliable for direct antibiotic stewardship in newborns, although several biomarkers show promising initial results. Further research into biomarker combinations could lead to an improved EOS diagnosis, reduce antibiotic overtreatment, and prevent associated health-related problems., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Aim: The diagnosis of early-onset neonatal sepsis (EOS) remains difficult. The main aim was to study the effect of a new algorithm for EOS, which includes the level of procalcitonin in umbilical cord blood, on the exposure to antibiotic therapy of premature newborn infants., Methods: This was a monocentric, observational and retrospective study with before-and-after design. The duration and dose of antibiotic therapy provided as well as the morbidity and mortality were compared in two groups, one included 01 May 2015-30 November 2015 when procalcitonin was not used, and one after the change 01 November 2016-30 May 2017 when procalcitonin was used in a hospital setting in Nice, France., Results: Sixty newborn infants were included in the before group and 54 in the after group. Antibiotic therapy was stopped after 24 h for 18 newborn infants in the after group and four in the before group, and after 48 h for 26 newborn infants in the after group and 10 in the before group., Conclusion: The implementation of a new decision-making algorithm including early procalcitonin assay of premature newborn infants significantly reduced exposure to antibiotics without modifying mortality or morbidity., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim: This retrospective cohort study aimed to assess the utility of maternal C-reactive protein (CRP) and leukocyte levels in predicting neonatal sepsis after preterm premature rupture of membranes (pPROM)., Methods: We conducted a retrospective cohort study (2009-2021), encompassing preterm infants born ≤29 + 6 weeks of gestation following pPROM. The primary outcome was early-onset neonatal sepsis within the initial 72 h of life., Results: We analysed data from 706 patients with a median gestational age at pPROM of 25.1 weeks and a median gestational age at birth of 26.4 weeks. Overall survival rate was 86.1%, with 65.7% survival without severe morbidities. These rates were significantly worse in preterm infants with sepsis. Maternal CRP and leukocyte levels correlated significantly with neonatal infection markers and sepsis. However, their predictive values, correlation coefficients, and area under the curve values were generally low. Using maternal CRP ≥2 mg/dL to predict neonatal sepsis yielded a positive predictive value of 18.5%, negative predictive value of 91.5%, AUC of 0.589, 45.5% sensitivity, and 74.5% specificity., Conclusion: Maternal CRP and leukocyte levels were ineffective as a tool for predicting early-onset neonatal sepsis following early pPROM. Consequently, these biomarkers lack the reliability required for clinical decision-making in this context., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Introduction: We aimed to evaluate the use of "Neonatal Sequential Organ Failure Assessment" (nSOFA) scoring in predicting mortality, to compare the accuracy of nSOFA scores at different time points in very preterm infants with late-onset sepsis (LOS), and to investigate other possible parameters that would improve the prediction., Methods: This single-center, retrospective study included preterm infants born atS<32 weeks' gestation with culture-proven LOS. The nSOFA scores of non-fatal and fatal episodes were compared at nine time points., Results: Of 120 culture-proven LOS episodes in 106 infants, 90 (75%) episodes were non-fatal and 30 (25%) episodes were fatal. The mean birth weight (BW) of the infants who died was lower than that of survivors (p=0.038). In the fatal LOS episodes, median nSOFA scores were higher at all time points measured before sepsis evaluation, at the time of evaluation, and at all time points measured after the evaluation (p<0.001). nSOFA scores before death and at 48 hours were higher in the fatal episodes (p<0.001). At the time of sepsis assessment, nSOFA score>4 was associated with a 7- to 16-fold increased risk of mortality. Adjustment for BW, lymphocyte and monocyte counts increased the risk to 9- to 18-fold., Conclusion: This study demonstrated that the use of nSOFA to predict mortality and morbidity in extremely preterm infants seems feasible. The scoring system could be improved by evaluating the other parameters., Competing Interests: The authors declare that they have no competing interests, (Thieme. All rights reserved.)

Background: Neonatal sepsis is responsible for significant morbidity and mortality worldwide. Its accurate and timely diagnosis is hindered by vague symptoms and the urgent necessity for early antibiotic intervention. The gold standard for diagnosing the condition is the identification of a pathogenic organism from normally sterile sites via laboratory testing. However, this method is resource-intensive and cannot be conducted continuously., Objective: This study aimed to predict the onset of late-onset sepsis (LOS) with good diagnostic value as early as possible using non-invasive biosignal measurements from neonatal intensive care unit (NICU) monitors., Methods: In this prospective multicenter study, we developed a multimodal machine learning algorithm based on a convolutional neural network (CNN) structure that uses the power spectral density (PSD) of recorded biosignals to predict the onset of LOS. This approach aimed to discern LOS-related pathogenic spectral signatures without labor-intensive manual artifact removal., Results: The model achieved an area under the receiver operating characteristic score of 0.810 (95 % CI 0.698-0.922) on the validation dataset. With an optimal operating point, LOS detection had 83 % sensitivity and 73 % specificity. The median early detection was 44 h before clinical suspicion. The results highlighted the additive importance of electrocardiogram and respiratory impedance (RESP) signals in improving predictive accuracy. According to a more detailed analysis, the predictive power arose from the morphology of the electrocardiogram's R-wave and sudden changes in the RESP signal., Conclusion: Raw biosignals from NICU monitors, in conjunction with PSD transformation, as input to the CNN, can provide state-of-the-art prediction performance for LOS without the need for artifact removal. To the knowledge of the authors, this is the first study to highlight the independent and additive predictive potential of electrocardiogram R-wave morphology and concurrent, sudden changes in the RESP waveform in predicting the onset of LOS using non-invasive biosignals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antti Kallonen has patents pending on the methodology (EP21801580, US2023-0290511 and FI20205993). Other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Predicting and finding the viral agents responsible for neonatal late-sepsis has always been challenging., Method: In this cross-sectional study, which has been done from September 2020 to December 2022, 145 hospitalized neonates suspected to late-onset sepsis alongside routine sepsis workup, were also evaluated for severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2) infection, by nasopharyngeal real-time polymerase chain reaction (RT-PCR) or serological tests., Result: 145 neonates including 81 girls and 64 boys with a mean age of 12.3 ± 5.9 days and an average hospitalization stay of 23.1 ± 15.4 days were enrolled in the study. While 76.6% of them had negative bacterial culture, 63 patients (43.4%) showed evidence of SARS-COV-2 infection in RT-PCR or serology tests. None of the underlying factors including gender, age, and laboratory investigation had a significant relationship with SARS-COV-2 infection. Similarly, the outcomes of death and length of hospitalization were not different between the two groups with positive and negative SARS-COV-2 RT-PCR (P < 0.05). There was only a significant relationship between radiological changes including reticulonodular pattern, consolidation, pleural effusion, and different types of infiltrations and SARS-COV2 infection., Conclusion: Considering the widespread of coronavirus disease 2019 (COVID-19) in newborns, it seems logical to investigate the SARS-COV-2 infection in late-sepsis., (© 2024. The Author(s).)

Plasma gelsolin (pGSN) correlates with clinical improvement in septic patients. We aimed to investigate pGSN levels as a diagnostic and prognostic marker of neonatal late-onset-sepsis (LOS). A case-control study was done on 184 neonates (92 with LOS and 92 controls). All participants were subjected to detailed history taking, full clinical evaluation, sepsis workup, and pGSN enzyme-linked immunosorbent-assay measurement. We detected significantly lower pGSN level among cases compared to controls (90.63 ± 20.64 vs 451.83 ± 209.59). It was significantly related to the severity of sepsis and mortality, with significantly lower values among cases with septic shock and multiorgan failure and non-survivors. Follow-up pGSN significantly increased after sepsis improvement in survivors compared to admission values. pGSN might be a reliable diagnostic and prognostic marker for LOS., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Neonatal clinical sepsis is recognized as a significant health problem, This study sought to identify a predictive model of risk factors for clinical neonatal sepsis. A retrospective study was conducted from 1 October 2018 to 31 March 2023 in a large tertiary hospital in China. Neonates were divided into patients and controls based on the occurrence of neonatal sepsis. A multivariable model was used to determine risk factors and construct models.The utilization and assessment of model presentation were conducted using Norman charts and web calculators, with a focus on model differentiation, calibration, and clinical applicability (DCA). Furthermore, the hospital's data from 1 April 2023 to 1 January 2024 was utilized for internal validation. In the modelling dataset, a total of 339 pairs of mothers and their newborns were included in the study and divided into two groups: patients (n = 84, 24.78%) and controls (n = 255, 75.22%). Logistic regression analysis was performed to examine the relationship between various factors and outcome. The results showed that maternal age < 26 years (odds ratio [OR] = 2.16, 95% confidence interval [CI] 1.06-4.42, p = 0.034), maternal gestational diabetes (OR = 2.17, 95% CI 1.11-4.27, p = 0.024), forceps assisted delivery (OR = 3.76, 95% CI 1.72-5.21, p = 0.032), umbilical cord winding (OR = 1.75, 95% CI 1.32-2.67, p = 0.041) and male neonatal sex (OR = 1.59, 95% CI 1.00-2.62, p = 0.050) were identified as independent factors influencing the outcome of neonatal clinical sepsis. A main effects model was developed incorporating these five significant factors, resulting in an area under the curve (AUC) value of 0.713 (95% CI 0.635-0.773) for predicting the occurrence of neonatal clinical sepsis. In the internal validation cohort, the AUC value of the model was 0.711, with a 95% CI of 0.592-0.808. A main effects model incorporating the five significant factors was constructed to help healthcare professionals make informed decisions and improve clinical outcomes., (© 2024. The Author(s).)

Objective: To assess the applicability of albumin (ALB) and C-reactive protein (CRP) concentrations in the diagnosis of sepsis in neonates on the day of admission, and to help with early identification and intervention in the development of sepsis., Methods: This retrospective study included all neonates who were admitted to the neonatal intensive care unit from January 2020 to June 2023. We studied 160 full-term neonates, including 80 with sepsis and 80 healthy controls. A multivariate analysis was conducted to evaluate the associations between ALB, CRP, and sepsis., Results: CRP concentrations were significantly higher in neonates with sepsis than in controls (26.5 ± 8.6  vs. 3.6 ± 1.2 ng/L). At a cut-off point of 10.8 ng/L, CRP showed a sensitivity of 74.3% and a specificity of 80%. Moreover, ALB concentrations were significantly lower in neonates with sepsis than in controls (25.4 ± 2.5 g/L vs. 29.2 ± 2.6 g/L). At a cut-off point of 26.8, ALB showed a sensitivity of 75.6% and a specificity of 84.2%., Conclusions: Our findings suggest that ALB and CRP concentrations on the first day of admission are different between neonates who do and those who do not develop sepsis. Higher CRP concentrations and lower ALB concentrations may indicate an increased risk of sepsis., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Context and Objectives: Neonatal sepsis accounts for 15% of all neonatal deaths. Early detection enables prompt administration of antibiotic treatment, reducing morbidity and mortality. This study aims to review the sensitivity and specificity of procalcitonin in diagnosing microbiologically-proven sepsis in neonates to determine the optimal procalcitonin cut-off value for use in clinical practice., Data Sources, Study Selection, and Data Extraction: Medline, EMBASE and PubMed were searched on 3 May 2023 for original studies in symptomatic neonates in whom both blood culture and procalcitonin levels were taken, and a procalcitonin cut-off with either sensitivity or specificity reported. Studies that included asymptomatic or culture-negative neonates in the proven sepsis group were excluded. Risk of bias was assessed using the Qualitative Assessment of Diagnostic Accuracy Studies 2 tool., Results: Nineteen original studies enrolling a total of 1920 symptomatic neonates (721 with proven sepsis) were included. Six studies used a procalcitonin cut-off of 0.5 ng/mL and found a sensitivity of 87% to 100% and specificity of 17% to 89%. Nine studies evaluated higher procalcitonin cut-off values between 0.99 ng/mL and 2 ng/mL, which were 67% to 98% sensitive and 41% to 89% specific. All other procalcitonin thresholds were neither sensitive nor specific. Meta-analysis was not performed because of high risk of bias within the identified studies., Conclusions: This review found that procalcitonin was highly sensitive (87% to 100%) at a cut-off value of 0.5 ng/mL, although specificity varied greatly across all cut-off values reviewed. The variation in diagnostic accuracy between studies suggests that procalcitonin may be useful to guide antibiotic cessation but should not be used alone as a diagnostic marker for neonatal sepsis., (Copyright © 2024 by the American Academy of Pediatrics.)

Early-onset sepsis (EOS) is a global health issue, considered one of the primary causes of neonatal mortality. Diagnosis of EOS is challenging because its clinical signs are nonspecific, and blood culture, which is the current gold-standard diagnostic tool, has low sensitivity. Commonly used biomarkers for sepsis diagnosis, including C-reactive protein, procalcitonin, and interleukin-6, lack specificity for infection. Due to the disadvantages of blood culture and other common biomarkers, ongoing efforts are directed towards identifying innovative molecular approaches to diagnose neonates at risk of sepsis. This review aims to gather knowledge and recent research on these emerging molecular methods. PCR-based techniques and unrestricted techniques based on 16S rRNA sequencing and 16S-23S rRNA gene interspace region sequencing offer several advantages. Despite their potential, these approaches are not able to replace blood cultures due to several limitations; however, they may prove valuable as complementary tests in neonatal sepsis diagnosis. Several microRNAs have been evaluated and have been proposed as diagnostic biomarkers in EOS. T2 magnetic resonance and bioinformatic analysis have proposed potential biomarkers of neonatal sepsis, though further studies are essential to validate these findings.

Given the long-life expectancy of the newborn, research aimed at improving sepsis diagnosis and management in this population has been recognized as cost-effective, which at early stages continues to be a tremendous challenge. Despite there is not an ideal-specific biomarker, the simultaneous detection of biomarkers with different behavior during an infection such as procalcitonin (PCT) as high specificity biomarker with one of the earliest biomarkers in sepsis as interleukin-6 (IL-6) increases diagnostic performance. This is not only due to their high positive predictive value but also, since it can also help the clinician to rule out infection and thus avoid the use of antibiotics, due to their high negative predictive value. To this end, we explore a cutting-edge micromotor (MM)-based OFF-ON dual aptassay for simultaneous determination of both biomarkers in 15 min using just 2 μL of sample from low-birth-weight neonates with gestational age less than 32 weeks and birthweight below 1000 g with clinical suspicion of late-onset sepsis. The approach reached the high sensitivities demanded in the clinical scenario (LOD PCT  = 0.003 ng/mL, LOD IL6  = 0.15 pg/mL) with excellent correlation performance (r > 0.9990, p < 0.05) of the MM-based approach with the Hospital method for both biomarkers during the analysis of diagnosed samples and reliability (Er < 6% for PCT, and Er < 4% for IL-6). The proposed approach also encompasses distinctive technical attributes in a clinical scenario since its minimal sample volume requirements and expeditious results compatible with few easy-to-obtain drops of heel stick blood samples from newborns admitted to the neonatal intensive care unit. This would enable the monitoring of both sepsis biomarkers within the initial hours after the manifestation of symptoms in high-risk neonates as a valuable tool in facilitating prompt and well-informed decisions about the initiation of antibiotic therapy.These results revealed the asset behind micromotor technology for multiplexing analysis in diagnosing neonatal sepsis, opening new avenues in low sample volume-based diagnostics., (© 2024. The Author(s).)

Background: Late-onset neonatal sepsis (LOS) is common in preterm neonates, with increasing incidence in recent years. In the present study, we examined the epidemiology, clinical presentation, and complications of LOS in Cyprus and quantified possible risk factors for the development of this condition., Methods: The study subjects were preterm neonates admitted in the Neonatal Intensive Care Unit (NICU) of Archbishop Makarios III Hospital, the only neonatal tertiary centre in Cyprus. A prospective, case-control study was designed, and carried out between April 2017-October 2018. Depending on blood culture results, preterm neonates were classified as "Confirmed LOS": positive blood culture - microorganism isolated and LOS symptoms, "Unconfirmed LOS": negative blood culture and LOS symptoms, and "Controls" group: negative blood culture and absence of LOS symptoms. Comparisons between the 3 groups were performed and the associations between demographic, clinical and treatment characteristics with the likelihood of LOS were assessed using univariate and multivariate logistic regression., Results: A total of 350 preterm neonates were included in the study and the incidence of LOS was 41.1%. 79 (22.6%) and 65 (18.6%) neonates were classified as "Confirmed LOS", and "unconfirmed LOS" cases respectively while 206 (58.9%) served as controls. The rate of confirmed LOS ranged from 12.2% in moderate to late preterm neonates to 78.6% in extremely preterm neonates. In the multivariate model, we demonstrated an independent association between LOS and duration of hospitalization (OR: 1.06, 95%CI: 1.01-1.10), duration of ventilation (OR: 1.23, 95%CI: 1.07-1.43) and necrotising enterocolitis (OR: 3.41, 95%CI: 1.13-10.25)., Conclusions: The present study highlights the epidemiology of LOS in preterm neonates in Cyprus and its association with the duration of ventilation and hospitalization as well as with necrotizing enterocolitis. Establishment of protocols for the prevention of nosocomial infections during hospitalization in the NICUs and mechanical ventilation of preterm neonates is recommended., (© 2024. The Author(s).)

Introduction: Compared with multivariate risk assessment, traditional category-based risk assessment (CRA) approaches for neonatal early-onset sepsis (EOS) screening are usually straightforward to use, do not require electronic devices, but are associated with higher rates of antibiotic use. This study aims to evaluate the performance of a novel enhanced CRA (eCRA) framework on EOS admissions and antibiotic use and to investigate whether a modified version with adjustments in risk factor weighting can allow its performance to match the EOS calculator while remaining easy to implement., Method: This is a prospective, single-center, two-phase observational study. Infants of all gestations delivered in a tertiary hospital in Hong Kong with risk factors or clinical features of EOS were recruited., Phase I: A novel eCRA framework (period 2) was compared with the CDC 2010-based protocol (period 1)., Phase Ii: A modified eCRA framework was compared theoretically with the EOS calculator. EOS-specific admissions and antibiotic use were measured., Results: Phase I: 1,025 at-risk infants were recruited during period 2 and compared with 757 infants of period 1. Admissions and antibiotic use decreased from 45.8% to 29.4% and 41.1% to 28.2%, respectively. Antibiotics among those at-risk but well-appearing infants decreased from 25.3% to 16.3% (p &lt; 0.001 for all)., Phase Ii: antibiotic use was similar (7.3 vs. 6.4%, p = 0.42) between the modified eCRA framework and the EOS calculator., Conclusions: An eCRA framework can effectively and safely provide individualized guidance for EOS screening without the need for tools such as the EOS calculator., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objective: To evaluate the efficiency of the sepsis risk calculator and the serial clinical observation in the management of late preterm and term newborns with infectious risk factors., Method: Single-center, observational, two-phase cohort study comparing the rates of neonates born ≥35 weeks' gestation, ≥2000 g birthweight, and without major congenital anomalies, who were screened and/or received antibiotics for early-onset neonatal sepsis risk at our center during two periods, before (January/2018-June/2019) and after (July/2019-December/2020) the implementation of the sepsis risk calculator., Results: A total of 1796 (Period 1) and 1867 (Period 2) patients with infectious risk factors were included. During the second period, tests to rule out sepsis were reduced by 34.0 % (RR, 95 %CI): 0.66 (0.61, 0.71), blood cultures by 13.1 %: 0.87 (0.77, 0.98), hospital admissions by 13.5 %: 0.86 (0.76, 0.98) and antibiotic administration by 45.9 %: 0.54 (0.47, 0.63). Three cases of early-onset neonatal sepsis occurred in the first period and two in the second. Clinical serial evaluation would have detected all true cases., Conclusions: The implementation of a sepsis risk calculator in the management of newborns ≥35 weeks GA, ≥2000 g birthweight, without major congenital anomalies, with infectious risk factors is safe and adequate to reduce laboratory tests, blood cultures, hospital admissions, and antibiotics administration. Serial clinical observation, in addition, could be instrumental to achieve or even improve this goal., Competing Interests: Conflicts of interest No financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article., (Copyright © 2023 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: The diagnosis of neonatal early-onset sepsis (EOS) is challenging, and inflammatory markers are widely used to guide decision-making and therapies., Objectives: This narrative review presents the current state of knowledge regarding the diagnostic value and potential pitfalls in the interpretation of inflammatory markers for EOS., Sources: PubMed until October 2022 and searched references in identified articles using the search terms: neonatal EOS, biomarker or inflammatory marker, and antibiotic therapy or antibiotic stewardship., Content: In situations with a high or low probability of sepsis, the measurements of inflammatory markers have no impact on the decision to start or stop antibiotics and are just gimmick, whereas they may be a game changer for neonates with intermediate risk and therefore an unclear situation. There is no single or combination of inflammatory markers that can predict EOS with high probability, allowing us to make decisions regarding the start of antibiotics based only on inflammatory markers. The main reason for the limited accuracy is most probably the numerous noninfectious conditions that influence the levels of inflammatory markers. However, there is evidence that C-reactive protein and procalcitonin have good negative predictive accuracy to rule out sepsis within 24 to 48 hours. Nevertheless, several publications have reported more investigations and prolonged antibiotic treatments with the use of inflammatory markers. Given the limitations of current strategies, using an algorithm with only moderate diagnostic accuracy may have a positive impact, as reported for the EOS calculator and the NeoPInS algorithm., Implications: As the decision regarding the start of antibiotic therapy is different from the process of stopping antibiotics, the accuracy of inflammatory markers needs to be evaluated separately. Novel machine learning-based algorithms are required to improve accuracy in the diagnosis of EOS. In the future, inflammatory markers included in algorithms may be a game changer reducing bias and noise in the decision-making process., Competing Interests: Transparency declaration The authors declare that they have no conflicts of interest., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Neonatal sepsis is traditionally classified as early-onset sepsis (EOS) and late-onset sepsis (LOS) disease categories. This paradigm was based on observed epidemiological data from high income settings. However, increasing availability of microbiology results from diverse settings challenges these assumptions, necessitating re-examination of neonatal sepsis classifications., Objectives: To review the literature describing the aetiology of EOS and LOS in hospitalized neonates with stratification of pathogen spectrum by low- (LIC), middle- (MIC) and high-income (HIC) country settings, to critically re-examine the continued appropriateness of the 'EOS vs. LOS' sepsis paradigm in all settings., Sources: PubMed was searched for peer-reviewed English full-text articles published from inception up until 8 August 2022., Content: Studies often report on either EOS or LOS, rather than both. We identified only 49 original articles reporting on pathogen distribution of both EOS and LOS in the same hospital setting. Clear differences in sepsis aetiology were shown between LIC, MIC and HIC settings, with increasing importance of Klebsiella pneumoniae and decreasing importance of Group B Streptococcus in the first 72 hours of life in LIC and MIC., Implications: The concept of 'EOS vs. LOS' may be less useful for predicting the pathogen spectrum of neonatal sepsis in LIC and MIC, but the paradigm has shaped reporting of neonatal sepsis, and our understanding. Future neonatal sepsis reporting should utilize strengthening the reporting of observational studies in epidemiology for newborn infection (STROBE-NI) reporting guidelines and clearly describe timing of infection by day, and variation in pathogen spectrum across the neonatal period. Data identified in this review challenge the generalizability of the prevailing EOS/LOS paradigm in LIC and MIC., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Neonatal sepsis is an invasive infection of the bloodstream in neonates and a leading cause of morbidity and mortality among them., Aim: To investigate the role of procalcitonin (PCT) and C-reactive protein (CRP) in the management of neonatal sepsis., Materials and Methods: This was a prospective case-control study over one-year period using convenience sampling. Blood samples for PCT and CRP were taken from all neonates, while blood culture and white blood cell count samples were additionally taken from babies with neonatal sepsis. PCT and CRP were repeated at 24 and 48 hours. The continuous variables were found to have a nonparametric distribution. They were presented as median and interquartile range, and compared using Wilcoxon signed rank and Friedman test as appropriate., Results: The blood culture analysis yielded a prevalence of 12.7% with Staphylococcus aureus being the commonest organism. Baseline concentrations of PCT (1.28 ng/ml) and CRP (17.31 mg/L) in neonates with sepsis were higher than that of controls (PCT-0.63 ng/ml, CRP-5.40 mg/L). PCT concentrations decreased after two days of antibiotic treatment, while CRP concentrations decreased after a day. The concentration of both decreased to normal levels after two days of treatment., Conclusion: This study showed that CRP was more reliable in monitoring antibiotic therapy, unlike other studies which suggested PCT. In cases where the management of neonatal sepsis may be limited by a low blood culture yield, therapeutic monitoring may be aided by CRP and/or PCT., (Copyright © 2023 Copyright: © 2023 Nigerian Journal of Clinical Practice.)

Introduction: The neutrophil to lymphocyte ratio (NLR), an inflammatory biomarker, measures innate-adaptive immune system balance. In this systematic review and meta-analysis, we aim to analyze the current literature to evaluate the diagnostic role of NLR in neonatal sepsis., Methods: PubMed, Web of Science, and Scopus were used to conduct a systematic search for relevant publications published before May 14, 2022., Results: Thirty studies, including 2328 neonates with sepsis and 1800 neonates in the control group, were included in our meta-analysis. The results indicated that NLR is higher in neonates with sepsis compared to healthy controls (SMD = 1.81, 95% CI = 1.14-2.48, P-value < 0.001) in either prospective (SMD = 2.38, 95% CI = 1.40-3.35, P-value < 0.001) or retrospective studies (SMD = 0.87, 95% CI = 0.63-1.12, P-value < 0.001) with a pooled sensitivity of 79% (95% CI = 62-90%), and a pooled specificity of 91% (95% CI = 73-97%). Also, we found that NLR is higher in neonates with sepsis compared to those who were suspected of sepsis but eventually had negative blood cultures (SMD =1.99, 95% CI = 0.76-3.22, P-value = 0.002) with a pooled sensitivity of 0.79% (95% CI = 0.69-0.86%), and a pooled specificity of 73% (95% CI = 54-85%). In addition, neonates with sepsis had elevated levels of NLR compared to other ICU admitted neonates (SMD = 0.73, 95% CI = 0.63-0.84, P < 0.001). The pooled sensitivity was 0.65 (95% CI, 0.55-0.80), and the pooled specificity was 0.80 (95% CI, 0.68-0.88)., Conclusion: Our findings support NLR as a promising biomarker that can be readily integrated into clinical settings to aid in diagnosing neonatal sepsis. As evidenced by our results, restoring balance to the innate and adaptive immune system may serve as attractive therapeutic targets. Theoretically, a reduction in NLR values could be used to measure therapeutic efficacy, reflecting the restoration of balance within these systems., (© 2023. The Author(s).)

Background: Despite significant advances in neonatal care, neonatal sepsis remains a major contributor to mortality, morbidity, and protracted hospitalization. The development of early possible diagnostic indicators for newborn sepsis is critical. Since calprotectin participates in major biological processes, it could be a diagnostic marker for infection/inflammation. This study aimed to estimate serum calprotectin in neonates with clinical sepsis. In addition, we compared serum calprotectin with standard sepsis markers and serum procalcitonin to evaluate its diagnostic accuracy., Methods: A hospital-based cross-sectional diagnostic study of neonates identified with clinical sepsis using standard criteria was carried out. We compared estimated serum calprotectin levels to serum procalcitonin levels and conventional sepsis markers (leucocyte count, blood culture, immature to total neutrophil ratio, and C- reactive protein). We used SPSS version 25 to analyze the data. To examine diagnostic accuracy and determine a cut-off value for serum calprotectin, we used the receiver operating characteristics (ROC) curve., Results: Of the 83 subjects included, 36.5% (30/83) had blood culture positive status, the median value of serum calprotectin being 0.93 ng/ml (0.67 to 1.3). Respiratory, cardiovascular, and gastrointestinal instabilities were present in 67.5% (56/83), 59% (49/83), and 50.1% (42/83) cases, respectively. The median values of serum calprotectin, procalcitonin, TLC, and I/T ratio between neonates withpositive blood culturesand negative culturesdid not differ significantly.. On ROC, calprotectin was not predictive for blood culture positivity (sensitivity: 50%; specificity: 44% at 0.83 ng/ml of serum calprotectin) and C-reactive protein (CRP) levels (sensitivity: 57%; specificity: 67% at serum calprotectin levels of 0.89 ng/ml). However, compared with serum procalcitonin, serum calprotectin at 1.2 ng/ml had sensitivity and specificity of 60% and 73%, respectively., Conclusions: Serum calprotectin did not show a distinct advantage over the existing sepsis markers. Serum calprotectin level at 1.2 ng/ml had a sensitivity and specificity of 60% and 73%, respectively, compared to serum procalcitonin in detecting neonatal sepsis., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Ramineni P et al.)

Objectives: To compare blood pressures (BP) between neonates with culture-proven sepsis and clinical sepsis in the first 120 h of sepsis onset and to examine association between BP and in-hospital mortality., Methods: In this cohort study, consecutively enrolled neonates with 'culture-proven' sepsis [growth in blood/ cerebrospinal fluid (CSF) within 48 h] and clinical sepsis (sepsis workup negative, cultures sterile) were analyzed. Their BP was recorded every 3-hourly for initial 120 h and averaged in 20 time-epochs of 6 h each (0-6 h to 115-120 h). BP Z-scores were compared between neonates with culture-proven vs. clinical sepsis and survivors vs. non-survivors., Results: Two hundred twenty eight neonates (102-culture-proven and 126-clinical sepsis) were enrolled. Both groups had comparable BP Z-scores except significantly lower diastolic BP (DBP) and mean BP (MBP) in 0-6 and 13-18 time-epochs in culture-proven sepsis group. Fifty-four neonates (24%) died during their hospital stay. BP Z-scores in the initial 54 h of sepsis were independently associated with mortality [systolic BP (SBP) Z-scores in first 54 h, DBP Z-scores in first 24 h, and MBP Z-scores in first 24 h] after adjusting for gestational age, birth weight, cesarean delivery, and 5-min Apgar score. On receiver operating characteristic curves, SBP Z-scores showed better discriminative ability than DBP and MBP to identify non-survivors., Conclusions: Neonates with culture-proven and clinical sepsis had comparable BP Z-scores except low DBP and MBP in the initial few hours in culture-proven sepsis. BP in initial 54 h of sepsis was significantly associated with in-hospital mortality. SBP discriminated non-survivors better than DBP and MBP., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Objectives: In low and middle income countries, there is a need for affordable and accurate biomarkers to identify neonates at risk of early onset neonatal sepsis (EOS). Cord blood hematological parameters if reliable and accurate for the detection of EOS are cost effective and can reduce the need for repeated venipuncture in the neonate., Methods: In this prospective cohort study, the umbilical cord parameters of newborns with gestational age >34 weeks were collected. These neonates were followed up for 72 h and septic screen was employed in those babies who had risk factors or developed clinical features of sepsis. The cord blood parameters of the normal newborn and those who had sepsis were analyzed., Results: A total of 513 neonates were enrolled for the study, 32 required septic screening of whom 13 neonates were found to meet the criteria for sepsis: either blood culture positive or sepsis screen positive with clinical features. Cord blood parameters were analyzed using independent t test. Red cell distribution width (RDW) and band cells were statistically significant (p 0.007 and 0.009 respectively) between the septic and normal neonates. Increased RDW had a sensitivity of 61.54 %, specificity of 54.60 %. Increased band cells with a cut off of >15 cells had a sensitivity of 7.7 % with specificity of 100 % with higher numbers in septic neonates. Increased RDW and band cells in combination had sensitivity of 61.54 % and specificity of 54.6 %., Conclusions: RDW and band cell can be potential markers of EOS in cord blood but require further study in a larger population., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background: The epidemiology of neonatal early-onset sepsis (EOS) has changed with time and with changes in prevention strategy. Population-representative contemporary data provide insights on how to further improve EOS prevention and triage strategies., Methods: Neonates born in public hospitals in Hong Kong from January 1, 2006, to December 31, 2017 were included. The epidemiological characteristics of EOS and the use of intrapartum antibiotic prophylaxis (IAP) were compared between the 2 epochs before (January 1, 2006 to December 31, 2011) and after (January 1, 2012 to December 31, 2017) the territory-wide implementation of universal maternal group B Streptococcus (GBS) screening., Results: EOS developed in 1.07‰ of live births (522/490,034). After the implementation of universal GBS screening, the EOS rate decreased in neonates born ≥34 weeks (1.17‰-0.56‰, P < 0.001) and remained similar in those born <34 weeks (7.8‰-10.9‰, P = 0.15), whereas the proportions of IAP coverage increased in both groups [7.6%-23.3% ( P < 0.001) and 28.5%-52.0% ( P < 0.001), respectively]. The major pathogen for EOS shifted from GBS to Escherichia coli , and for early-onset meningitis from GBS to Streptococcus bovis . IAP was associated with subsequent isolation of pathogens resistant to ampicillin [adjusted odds ratio (aOR) 2.3; 95% confidence interval (CI): 1.3-4.2], and second-generation [aOR 2.0; 95% CI: 1.02-4.3] and third-generation [aOR 2.2; 95% CI: 1.1-5.0] cephalosporins., Conclusions: Pathogen profile of EOS changed with the implementation of universal GBS screening. S. bovis has emerged as a more common pathogen associated with the risk of meningitis. IAP may not be as effective in reducing EOS rate among infants born <34 weeks as compared with those ≥34 weeks, and newer strategies may be needed., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Prognostic biomarker research neonatal sepsis is lacking. We assessed the utility of a validated pediatric prognostic tool called PERSEVERE II that uses decision tree methodology to predict mortality at discharge in neonates who experienced sepsis., Methods: Prospective study in a dual-center cohort of neonates with sepsis admitted between June 2020 and December 2021. Biomarker analysis was done on serum samples obtained at the time of evaluation for the event., Results: In a cohort of 59 neonates with a mortality rate of 15.3%, PERSEVERE II was 67% sensitive and 59% specific for mortality, p 0.27. Amongst PERSEVERE II biomarkers, IL-8 showed good prognostic performance for mortality prediction with a cutoff of 300 pg/mL (sensitivity 100%, specificity 65%, negative predictive value 100%, AUC 0.87, p 0.0003). We derived a new decision tree that is neonate specific (nPERSEVERE) with improved performance compared to IL-8 (sensitivity 100%, specificity 86%, negative predictive value 100%, AUC 0.95, p < 0.0001)., Conclusions: IL-8 and nPERSEVERE demonstrated good prognostic performance in a small cohort of neonates with sepsis. Moving toward precision medicine in sepsis, our study proposes an important tool for clinical trial prognostic enrichment that needs to be validated in larger studies., Impact: Prognostic and predictive biomarker research is lacking in the newborn intensive care unit. Biomarkers can be used at the time of evaluation for neonatal sepsis (blood culture acquisition) to identify neonates with high baseline mortality risk. Stratification is an important step toward precision medicine in neonatal sepsis., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Being an important cause of early-onset neonatal sepsis, clinical chorioamnionitis in the mother results in frequent laboratory workup and antibiotic use for the neonate. Neonatal intensive care units (NICUs) in Qatar follow the categorical approach recommended by the Centers for Disease Control and Prevention, USA, and all chorioamnionitis-exposed neonates receive antibiotics.Our project aimed to reduce antibiotic use among chorioamnionitis-exposed, asymptomatic term babies by adopting the early-onset sepsis calculator (EOSCAL). Reduction of blood culture and NICU stay duration were added as secondary objectives later.The Institute of Healthcare Improvement Model of Improvement was used. Antibiotic use rate was the primary outcome measure. Blood culture rate and early transfer to the postnatal ward were added after 1 year. The process measures included the EOSCAL use rate and calculation error rate. The rate of positive culture among untreated babies within the first week was taken as a balancing measure. Monthly data were collected from February 2020 and entered as run charts. Calculation errors were dealt by multiple PDSAs. Additional outcome measures were added in January 2021. Data collection and monitoring continued till December 2022.Among 3837 inborn NICU admissions, 464 (12 %) were chorioamnionitis-exposed babies. Of them, 341 (74%) cases were eligible for inclusion. Among eligible cases, 270 (79%) did not receive antibiotics. Blood culture could be avoided among 106 (97% of low-risk babies) and NICU stay was reduced among 45 (92% of eligible low-risk babies). None of the untreated babies developed sepsis during the first week.Implementation of this project effectively and safely reduced the antibiotic use and blood culture rate among term, well-appearing babies exposed to chorioamnionitis. The project resulted in enhanced patient safety, experience and flow and reduced cost. It is recommendable to other NICU settings in Qatar., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Early-onset sepsis (EOS) is one of the leading causes of neonatal death and morbidity worldwide and timely initiation of antibiotic therapy is, therefore, of paramount importance. This study aimed to evaluate the predictive effect of lactate and base excess (BE) values in the cord arterial blood gas and the 6th hour of life venous blood gas analysis on clinical sepsis in newborns. This is a cohort case-control study. In this study, 104 cases were divided into clinical and suspected sepsis groups according to the evaluation at the 24th hour after delivery. Lactate and BE values were evaluated in the cord arterial blood gas analysis (ABGA) and at the postnatal 6th-hour venous blood gas. The cord ABGA and postnatal 6th-hour results were compared in the clinical and suspected sepsis groups. Clinical sepsis was found to be associated with a lactate value above 2 mMol/L at postnatal 6th-hour venous blood gas (p = 0.041). This association was the highest when the clinical sepsis group's postnatal 6th-hour lactate cut-off value was determined as 3.38 mMol/L (sensitivity 57.9% and specificity 68.5%) (p = 0.032). However, no association was found between clinical sepsis diagnosis and venous BE's value in cord ABGA at the postnatal 6th hour. We found that a venous lactate value above 3.38 mMol/L at the postnatal 6th hour was the cut-off value that could indicate early-onset clinical sepsis. However, none of the biomarkers used in diagnosing EOS can accurately show all cases., (© 2023. Springer Nature Limited.)

Background: In 2017, a new Dutch neonatal early-onset sepsis (EOS) guideline was implemented. It is an adaptation from the United Kingdom National Institute for Health and Care Excellence guideline and focuses on maternal and neonatal risk factors. We aim to assess if this guideline performs better at reducing the rate of antibiotic treatment for EOS than the old Dutch categorical EOS guideline, which focused primarily on group B streptococcus (GBS) testing and prophylaxis., Methods: We performed a single-center retrospective cohort study in the Netherlands. Data were collected from two 12-month epochs (2015 vs. 2019). Neonates were included when treated for suspected EOS or when observed for an elevated EOS risk., Results: The empirical antibiotic rate was 4.6% in both years. Prolonged antibiotic treatment (>48 u) increased from 24% in 2015 to 39% in 2019 ( P = 0.021). Adherence to the guideline decreased from 98% in 2015 to 84% in 2019 ( P < 0.001). Strict adherence in 2019 would have led to more antibiotic treatment (5.1% instead of 4.6%). The EOS incidence rate was comparable, namely 0.6% in 2015 and 0.0% in 2019 ( P = 0.480). The change in the definition of risk factors in 2019 led to less antibiotic treatment in case of a maternal fever during birth, from 48% in 2015 to 26% in 2019 ( P < 0.001)., Conclusions: The new Dutch categorical EOS guideline does not achieve its intended purpose of reducing empiric antibiotic therapy for suspected EOS. We advocate the need for a new screening strategy., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: (i) To compare perfusion index (PI) and plethysmography variability index (PVI) between neonates with proven or probable sepsis versus no-sepsis, (ii) to examine an association of PI and PVI with in-hospital mortality., Methods: We enrolled neonates with clinically presumed sepsis. Culture-proven or probable sepsis were categorised as 'cases' and no-sepsis as 'controls'. PI and PVI were recorded hourly for 120 h and averaged in 20-time epochs (0-6 h to 115-120 h)., Results: We analysed 148 neonates with sepsis (proven sepsis = 77, probable sepsis = 71) and 126 with no-sepsis. Neonates with proven/probable sepsis and no-sepsis had comparable PI and PVI values. Among 148 neonates with sepsis, 43 (29%) died. Non-survivors had significantly lower PI values than survivors (mean difference 0.21 [95% CI 0.14-0.29], p-value <0.001). PI had a significant but modest discriminative ability to identify non-survivors. However, PI did not independently predict mortality., Conclusion: Neonates with proven/probable sepsis and no-sepsis had comparable PI and PVI values in the first 120 h of sepsis. PI but not PVI values were significantly lower in non-survivors than survivors. PI did not independently predict in-hospital mortality. Due to modest discriminative ability, PI should be interpreted along with other vital signs to take clinical decisions., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background and Objectives : Early detection of neonatal sepsis is critical because it is potentially fatal. Therefore, sepsis biomarkers of sufficient sensitivity and specificity are needed. This study aimed to evaluate the utility of peripheral blood parameters as neonatal sepsis biomarkers and the diagnostic performance of the monocyte distribution width (MDW) in sepsis in a neonatal intensive care unit. Materials and Methods : A cross-sectional study was conducted from September 2019 to August 2020 at the King Saud University Medical City in Riyadh, Saudi Arabia. Samples were collected and organised as follows: 77 study cases were subdivided into two subgroups (other health complication (49) and sepsis (28)), and there were 70 controls. The causative microorganisms of neonatal sepsis were isolated. Peripheral blood samples were collected from each neonate in an ethylenediaminetetraacetic acid tube for a complete blood count and a leukocyte differential count. Moreover, the receiver operating characteristic (ROC) curve analysis was used to measure the diagnostic performance of the MDW. Results : The haematological parameters and neonatal sepsis cases had a considerable correlation. The MDW was the most significant haematological parameter. The ROC analysis of the MDW demonstrated that the area under the curve was 0.89 (95% confidence interval: 0.867 to 0.998) with a sensitivity of 89.3%, a specificity of 88.2%, and a negative predictive value of 97.2% at the cut-off point of 23. Conclusions : The use of haematological parameters is feasible and can be performed rapidly. Neonatal sepsis showed a strong correlation with leukopenia, anaemia, thrombocytopenia, and an elevated MDW value. Moreover, the ROC curve analysis confirmed the high diagnostic ability of the MDW in neonatal sepsis prediction.

The purpose of this study was to investigate the diagnostic value of combined detection of PCT, IL-6, CRP, and WBC in neonatal sepsis. The study selected 50 neonatal sepsis patients treated in Pucheng County Hospital from April 2018 to June 2020 as the patient group, and 50 healthy newborns as the control group. Before treatment, white blood cell count (WBC) was performed on all neonates, and serum PCT, IL-6, and CRP levels were detected by ELISA. After treatment, serum levels of these four biomarkers in the effective/non-effective groups were observed. The results noted higher levels of these four biomarkers in the patient group rather than the control group before treatment, and in the effective group rather than the non-effective group after treatment. ROC analysis found that the area under curve (AUC), specificity and sensitivity of the combined detection were better than those of the single detection. In short, combined detection of these four biomarkers has a high diagnostic value for neonatal sepsis.

Objective: This study aimed to examine the epidemiology of antibiotic exposure and early onset sepsis (EOS) in late preterm and term infants born via cesarean section with rupture of membranes less than 10 minutes., Study Design: Retrospective review of 1,187 late preterm and term infants born at Brooke Army Medical Center between January 1, 2012 and August 29, 2019. Subjects were assessed for factors related to antibiotic treatment. Statistical analysis was performed to compare infants treated with antibiotics versus observation., Result: An early blood culture was obtained from 234 (19.7%) infants; 170 (14.3%) were treated with antibiotics. Infants treated with antibiotics were significantly younger ( p  < 0.0001), smaller ( p  < 0.0001), more often diagnosed with respiratory distress ( p  < 0.0001), and were more frequently admitted to the neonatal intensive care unit ( p  < 0.0001). There were no cases of culture proven EOS., Conclusion: Although this population lacks risk factors for the development of EOS, a significant percentage was treated with antibiotics. This population may benefit from future antibiotic stewardship efforts., Key Points: · This population is at risk for respiratory morbidity.. · There were no cases of culture proven early onset sepsis.. · This is a group of interest for antibiotic stewardship.., Competing Interests: None declared. The views expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense, or the U.S. Government., (Thieme. All rights reserved.)

Objective: To develop a clinical prediction model to diagnose neonatal sepsis in low-resource settings., Design: Secondary analysis of data collected by the Neotree digital health system from 1 February 2019 to 31 March 2020. We used multivariable logistic regression with candidate predictors identified from expert opinion and literature review. Missing data were imputed using multivariate imputation and model performance was evaluated in the derivation cohort., Setting: A tertiary neonatal unit at Sally Mugabe Central Hospital, Zimbabwe., Patients: We included 2628 neonates aged <72 hours, gestation ≥32 +0 weeks and birth weight ≥1500 g., Interventions: Participants received standard care as no specific interventions were dictated by the study protocol., Main Outcome Measures: Clinical early-onset neonatal sepsis (within the first 72 hours of life), defined by the treating consultant neonatologist., Results: Clinical early-onset sepsis was diagnosed in 297 neonates (11%). The optimal model included eight predictors: maternal fever, offensive liquor, prolonged rupture of membranes, neonatal temperature, respiratory rate, activity, chest retractions and grunting. Receiver operating characteristic analysis gave an area under the curve of 0.74 (95% CI 0.70-0.77). For a sensitivity of 95% (92%-97%), corresponding specificity was 11% (10%-13%), positive predictive value 12% (11%-13%), negative predictive value 95% (92%-97%), positive likelihood ratio 1.1 (95% CI 1.0-1.1) and negative likelihood ratio 0.4 (95% CI 0.3-0.6)., Conclusions: Our clinical prediction model achieved high sensitivity with low specificity, suggesting it may be suited to excluding early-onset sepsis. Future work will validate and update this model before considering implementation within the Neotree., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objective: We sought to compare the incidence of early-onset sepsis (EOS) in infants ≥34 weeks' gestation identified >24 hours after birth, in hospitals using the Kaiser Permanente Sepsis Risk Calculator (SRC) with hospitals using the National Institute for Health and Care Excellence (NICE) guidance., Design and Setting: Prospective observational population-wide cohort study involving all 26 hospitals with neonatal units colocated with maternity services across London (10 using SRC, 16 using NICE)., Participants: All live births ≥34 weeks' gestation between September 2020 and August 2021., Outcome Measures: EOS was defined as isolation of a bacterial pathogen in the blood or cerebrospinal fluid (CSF) culture from birth to 7 days of age . We evaluated the incidence of EOS identified by culture obtained >24 hours to 7 days after birth. We also evaluated the rate empiric antibiotics were commenced >24 hours to 7 days after birth, for a duration of ≥5 days, with negative blood or CSF cultures., Results: Of 99 683 live births, 42 952 (43%) were born in SRC hospitals and 56 731 (57%) in NICE hospitals. The overall incidence of EOS (<72 hours) was 0.64/1000 live births. The incidence of EOS identified >24 hours was 2.3/100 000 (n=1) for SRC vs 7.1/100 000 (n=4) for NICE (OR 0.5, 95% CI (0.1 to 2.7)). This corresponded to (1/20) 5% (SRC) vs (4/45) 8.9% (NICE) of EOS cases (χ=0.3, p=0.59). Empiric antibiotics were commenced >24 hours to 7 days after birth in 4.4/1000 (n=187) for SRC vs 2.9/1000 (n=158) for NICE (OR 1.5, 95% CI (1.2 to 1.9)). 3111 (7%) infants received antibiotics in the first 24 hours in SRC hospitals vs 8428 (15%) in NICE hospitals., Conclusion: There was no significant difference in the incidence of EOS identified >24 hours after birth between SRC and NICE hospitals. SRC use was associated with 50% fewer infants receiving antibiotics in the first 24 hours of life., Competing Interests: Competing interests: CB reports grants and personal awards funded by the National Institute for Health Research, personal fees from Chiesi Pharmaceuticals and AbbVie Pharmaceuticals and is deputy chair of the NIHR Health Technology Assessment Prioritisation Committee for hospital-based care. PTH was a member of NICE CG149 guideline committee and deputy chair of NICE CG195 guideline committee. The other authors do not have any conflicts of interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To evaluate the effect of implementation of the Kaiser Permanente (KP) early onset sepsis (EOS) calculator in infants born at 34 week's gestation or more on antibiotic utilization and length of hospitalization. A single center, retrospective cohort study included all neonates born in Soroka Medical Center at 34 weeks gestation or more between January 1 st , 2015, and January 1 st , 2019, with a predefined maternal risk factor for EOS. Two cohorts of neonates were compared during two time periods, before and after the implementation of the KP calculator. Multivariable logistic and linear regressions were performed to assess the effect of the KP calculator on antibiotic treatment and length of hospitalization. Also, an interrupted time series (ITS) analysis was used to assess the time trends of the two periods. The study included 3858 neonates in the pre-implementation period and 3081 neonates in the post-implementation cohort. The use of the calculator resulted in a significant reduction (46%) in antibiotics treatment for suspected EOS (5.1 vs. 9.4%, P < 0.001). The ITS analysis demonstrated a sharp decline in the slope of antibiotic treatment in the post intervention period: (b = -0.14, p-value = 0.08). The length of hospitalization was significantly reduced in the post-implementation cohort from 62 to 60 h (p-value < 0.001) with no clinical significance. The incidence of EOS was similar in both groups.    Conclusion: A significant reduction in antibiotic treatment was demonstrated after the implementation of the KP calculator without an increase incidence of EOS. The calculator is a powerful accessory decision-making tool that can be used safely in combination with, but not replacing, thorough clinical assessment. What is Known: • The EOS calculator is a useful tool that leads to a significant reduction in preemptive antibiotic utilization. What is New: • The EOS calculator is sensitive when applied to the whole-nursery. • The calculator is useful in different populations, also when women are not routinely screened for GBS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To investigate the relation between autonomic regulation, measured using heart rate variability (HRV), body weight and degree of prematurity in infants. Further to assess utility to include body weight in a machine learning-based sepsis prediction algorithm., Methods: Longitudinal cohort study including 378 infants hospitalised in two neonatal intensive care units. Continuous vital sign data collection was performed prospectively from the time of NICU admission to discharge. Clinically relevant events were annotated retrospectively. HRV described using sample entropy of inter-beat intervals and assessed for its correlation with body weight measurements and age. Weight values were then added to a machine learning-based algorithm for neonatal sepsis detection., Results: Sample entropy showed a positive correlation with increasing body weight and postconceptual age. Very low birth weight infants exhibited significantly lower HRV compared to infants with a birth weight >1500 g. This persisted when reaching similar weight and at the same postconceptual age. Adding body weight measures improved the algorithm's ability to predict sepsis in the overall population., Conclusion: We revealed a positive correlation of HRV with increasing body weight and maturation in infants. Restricted HRV, proven helpful in detecting acute events such as neonatal sepsis, might reflect prolonged impaired development of autonomic control., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Neonatal sepsis is one of the most serious complications in neonatal intensive care units. Due to the often immature immune system, sepsis-related comorbidities are the major contributors to increased neonatal mortality. The rapid progression of the disease makes early treatment critical for patient survival. However, early diagnosis of sepsis remains difficult due to its non-specific symptoms. In recent years, Machine Learning-based techniques have been used in various medical applications to predict diseases using clinical data. In this work, we optimized and evaluated four prediction models with different architectural concepts. Two public datasets containing clinical data from adults and neonates were used for training. The adult data were collected to pre-train the models. Since neonatal data with sepsis diagnosis are very limited, we propose an augmentation method to generate synthetic clinical data. For the final evaluation, the real data of neonatal patients were defined as a test set. An AUROC of 0.91 and an AUPRC of 0.38 were obtained. These results are promising for early prediction of neonatal sepsis using artificial data for augmentation.Clinical relevance- This work demonstrates the potential of Machine Learning-based prediction models for the detection of sepsis to improve the early diagnosis of life-threatening conditions in neonatal intensive care units.

Purpose: To compare the performance of Neutrophil-to-Lymphocyte Ratio (NLR) with that of Platelet-to-Lymphocyte Ratio (PLR) in diagnosing neonatal sepsis (NS)., Methods: PubMed and Embase were searched for relevant studies from the inception of the databases to May, 2022. The pooled sensitivity (SEN), specificity (SPE), and area under the receiver operator characteristic curve (AUC) were measured., Results: Thirteen studies involving 2610 participants were included. The SEN, SPE, and AUC of NLR were 0.76 (95%CI: 0.61-0.87), 0.82 (95%CI: 0.68-0.91), and 0.86 (95%CI: 0.83-0.89), respectively, and those of PLR were 0.82 (95%CI: 0.63-0.92), 0.80 (95%CI: 0.24-0.98), and 0.87 (95%CI: 0.83-0.89), respectively. Significant heterogeneity was observed among the studies. Subgroup analysis and meta-regression showed that types of sepsis (p = 0.01 for SEN), gold standard (p = 0.03 for SPE), and pre-set threshold (p<0.05 for SPE) might be the sources of heterogeneity for NLR, whereas the pre-set threshold (p<0.05 for SPE) might be the source of heterogeneity for PLR., Conclusions: NLR and PLR would be of great accuracy for the diagnosis of NS, and the two indicators have similar diagnostic performance. However, the overall risk of bias was high, and significant heterogeneity was identified among the included studies. The results of this study should be interpreted prudently, and the normal or cut-off values and the type of sepsis should be considered. More prospective studies are needed to further support the clinical application of these findings., (© 2023. The Author(s).)

Introduction: Neonatal sepsis is a major cause of health loss and mortality worldwide. Without proper treatment, neonatal sepsis can quickly develop into multisystem organ failure. However, the signs of neonatal sepsis are non-specific, and treatment is labour-intensive and expensive. Moreover, antimicrobial resistance is a significant threat globally, and it has been reported that over 70% of neonatal bloodstream infections are resistant to first-line antibiotic treatment. Machine learning is a potential tool to aid clinicians in diagnosing infections and in determining the most appropriate empiric antibiotic treatment, as has been demonstrated for adult populations. This review aimed to present the application of machine learning on neonatal sepsis treatment., Methods: PubMed, Embase, and Scopus were searched for studies published in English focusing on neonatal sepsis, antibiotics, and machine learning., Results: There were 18 studies included in this scoping review. Three studies focused on using machine learning in antibiotic treatment for bloodstream infections, one focused on predicting in-hospital mortality associated with neonatal sepsis, and the remaining studies focused on developing machine learning prediction models to diagnose possible sepsis cases. Gestational age, C-reactive protein levels, and white blood cell count were important predictors to diagnose neonatal sepsis. Age, weight, and days from hospital admission to blood sample taken were important to predict antibiotic-resistant infections. The best-performing machine learning models were random forest and neural networks., Conclusion: Despite the threat antimicrobial resistance poses, there was a lack of studies focusing on the use of machine learning for aiding empirical antibiotic treatment for neonatal sepsis., (© 2023. The Author(s).)

Background: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design., Methods and Findings: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability., Conclusion: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis., Trial Registration: ClinicalTrials.gov, (NCT03721302)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Members of the funder (MB, NK, SE) participated as authors on the study, reviewed the manuscript, and approved the final manuscript as submitted. All other authors have declared that no competing interests exist., (Copyright: © 2023 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Heart rate characteristics aid early detection of late-onset sepsis (LOS), but respiratory data contain additional signatures of illness due to infection. Predictive models using cardiorespiratory data may improve early sepsis detection. We hypothesized that heart rate (HR) and oxygenation (SpO 2 ) data contain signatures that improve sepsis risk prediction over HR or demographics alone., Methods: We analyzed cardiorespiratory data from very low birth weight (VLBW, <1500 g) infants admitted to three NICUs. We developed and externally validated four machine learning models to predict LOS using features calculated every 10 m: mean, standard deviation, skewness, kurtosis of HR and SpO 2 , and cross-correlation. We compared feature importance, discrimination, calibration, and dynamic prediction across models and cohorts. We built models of demographics and HR or SpO 2 features alone for comparison with HR-SpO 2 models., Results: Performance, feature importance, and calibration were similar among modeling methods. All models had favorable external validation performance. The HR-SpO 2 model performed better than models using either HR or SpO 2 alone. Demographics improved the discrimination of all physiologic data models but dampened dynamic performance., Conclusions: Cardiorespiratory signatures detect LOS in VLBW infants at 3 NICUs. Demographics risk-stratify, but predictive modeling with both HR and SpO 2 features provides the best dynamic risk prediction., Impact: Heart rate characteristics aid early detection of late-onset sepsis, but respiratory data contain signatures of illness due to infection. Predictive models using both heart rate and respiratory data may improve early sepsis detection. A cardiorespiratory early warning score, analyzing heart rate from electrocardiogram or pulse oximetry with SpO 2 , predicts late-onset sepsis within 24 h across multiple NICUs and detects sepsis better than heart rate characteristics or demographics alone. Demographics risk-stratify, but predictive modeling with both HR and SpO 2 features provides the best dynamic risk prediction. The results increase understanding of physiologic signatures of neonatal sepsis., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Introduction: Neonatal sepsis accounts for 0.97% of all disability-adjusted life years worldwide. Interleukin-6 has been used in sepsis diagnosis, but cut-off values are missing., Methods: Neonates admitted to the neonatal wards with measurements of serum interleukin-6 born between September 2015 and September 2019 were retrospectively analysed. Mean serum interleukin-6 values of patients who never had increased laboratory parameters of infection nor died during their stay and mean interleukin-6 values on the day of blood sampling for a later positive culture in patients with culture-confirmed sepsis were analysed for each time period., Results: In all, 8.488 values in 1.695 neonates, including 752 very-preterm-infants and 701 very-low-birthweight infants, were analysed. The AUC for interleukin-6 was 0.84-0.91 in all neonates, 0.88-0.89 in very-preterm and 0.89-0.91 in very-low-birthweight infants. Using interleukin-6 cut-off values of 80 pg/ml on day of life 1, 40 pg/ml on day of life 2-7 and 30 pg/ml after day of life 7, a sensitivity of 75% and a specificity of 81% for culture-confirmed sepsis were achieved. In very-preterm infants, the corresponding values were 74% for sensitivity and 83% for specificity and in very-low-birthweight infants 74% and 86%, respectively., Conclusion: Serum interleukin-6 has high accuracy for the detection of neonatal sepsis., Impact: Serum interleukin-6 can be used with high accuracy to detect sepsis in neonates with the cut-off values of 80 pg/ml on day of life 1, 40 pg/ml on day of life 2-7 and 30 pg/ml after day of life 7. Serum interleukin-6 can be used with high accuracy to detect sepsis in neonates and very-preterm as well as very-low-birthweight infants. Interleukin-6 values display distinct cut-off values depending on the chronological age of the infant. Our article provides the first cut-off values for interleukin-6 in the first days of life in neonates., (© 2022. The Author(s).)

Objective: Late-onset sepsis (LOS) is a significant cause of mortality in preterm infants. The neonatal sequential organ failure assessment (nSOFA) provides an objective assessment of sepsis risk but requires manual calculation. We developed an EMR pipeline to automate nSOFA calculation for more granular analysis of score performance and to identify optimal alerting thresholds., Methods: Infants born <33 weeks of gestation with LOS were included. A SQL-based pipeline calculated hourly nSOFA scores 48 h before/after sepsis evaluation. Sensitivity analysis identified the optimal timing and threshold of nSOFA for LOS mortality., Results: Eighty episodes of LOS were identified (67 survivors, 13 non-survivor). Non-survivors had persistently elevated nSOFA scores, markedly increasing 12 h prior to culture. At sepsis evaluation, the AUC for nSOFA >2 was 0.744 (p = 0.0047); thresholds of >3 and >4 produced lower AUCs., Conclusions: nSOFA is persistently elevated for infants with LOS mortality compared to survivors with an optimal alert threshold >2., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: We studied neonates with suspected early-onset sepsis (EOS, sepsis developing in the first 72 hours after delivery) in Malawi to (1) describe clinical characteristics and microbiological findings, (2) identify which patient characteristics may be associated with pathogen positivity on blood culture, and (3) describe mortality and its potential determinants., Design: Prospective observational study (May 2018-June 2019)., Setting: Neonatal ward in Queen Elizabeth Central Hospital, the largest government hospital in Malawi., Patients: All neonates with suspected EOS in whom a blood culture was obtained., Results: Out of 4308 neonatal admissions, 1244 (28.9%) had suspected EOS. We included 1149 neonates, of which 109 blood cultures had significant growth (9.5%). The most commonly isolated pathogens were Staphylococcus aureus , Klebsiella pneumoniae , Enterobacter cloacae , Escherichia coli and Acinetobacter baumanii . Many of the Gram negatives were extended-spectrum beta lactamase-producing Enterobacteriaceae, and these were 40-100% resistant to first-line and second-line antimicrobials. Gestational age (GA) of <32 weeks was associated with pathogen-positive blood cultures (<28 weeks: adjusted OR (AOR) 2.72, 95% CI 1.04 to 7.13; 28-32 weeks: AOR 2.26, 95% CI 1.21 to 4.21; p=0.005). Mortality was 17.6% (202/1149) and associated with low birth weight (<1000 g: AOR 47.57, 95% CI 12.59 to 179.81; 1000-1500 g: AOR 11.31, 95% CI 6.97 to 18.36; 1500-2500 g: AOR 2.20, 95% CI 1.42 to 3.39; p<0.001), low Apgar scores at 5 min (0-3: AOR 18.60, 95% CI 8.81 to 39.27; 4-6: AOR 4.41, 95% CI 2.81 to 6.93; p<0.001), positive maternal venereal disease research laboratory status (AOR 2.53, 95% CI 1.25 to 5.12; p=0.001) and congenital anomalies (AOR 7.37, 95% CI 3.61 to 15.05; p<0.001). Prolonged rupture of membranes was inversely associated with mortality (AOR 0.43, 95% CI 0.19 to 0.98; p 0.007)., Conclusion: In Malawi, EOS was suspected in nearly a third of neonatal admissions and had a high mortality. Ten per cent were culture-confirmed and predicted by low GA. To reduce the impact of suspected neonatal sepsis in least developed countries, improved maternal and antenatal care and development of rapid point of care methods to more accurately guide antimicrobial use could simultaneously improve outcome and reduce antimicrobial resistance., Competing Interests: Competing interests: PI has received investigator-initiated research grant support from Bill & Melinda Gates Foundation. MN has received grant support from Roche. The remaining authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)