C-Reactive Protein, Procalcitonin, and White Blood Count to Rule Out Neonatal Early-onset Sepsis Within 36 Hours: A Secondary Analysis of the Neonatal Procalcitonin Intervention Study.

BACKGROUND: Neonatal early-onset sepsis (EOS) is one of the main causes of global neonatal mortality and morbidity, and initiation of early antibiotic treatment is key. However, antibiotics may be harmful. METHODS: We performed a secondary analysis of results from the Neonatal Procalcitonin Intervention Study, a prospective, multicenter, randomized, controlled intervention study. The primary outcome was the diagnostic accuracy of serial measurements of C-reactive protein (CRP), procalcitonin (PCT), and white blood count (WBC) within different time windows to rule out culture-positive EOS (proven sepsis). RESULTS: We analyzed 1678 neonates with 10 899 biomarker measurements (4654 CRP, 2047 PCT, and 4198 WBC) obtained within the first 48 hours after the start of antibiotic therapy due to suspected EOS. The areas under the curve (AUC) comparing no sepsis vs proven sepsis for maximum values of CRP, PCT, and WBC within 36 hours were 0.986, 0.921, and 0.360, respectively. The AUCs for CRP and PCT increased with extended time frames up to 36 hours, but there was no further difference between start to 36 hours vs start to 48 hours. Cutoff values at 16 mg/L for CRP and 2.8 ng/L for PCT provided a sensitivity of 100% for discriminating no sepsis vs proven sepsis. CONCLUSIONS: Normal serial CRP and PCT measurements within 36 hours after the start of empiric antibiotic therapy can exclude the presence of neonatal EOS with a high probability. The negative predictive values of CRP and PCT do not increase after 36 hours.

Stratification of Culture-Proven Early-Onset Sepsis Cases by the Neonatal Early-Onset Sepsis Calculator: An Individual Patient Data Meta-Analysis.

OBJECTIVES: To provide a comprehensive assessment of case stratification by the Neonatal Early-Onset Sepsis (EOS) Calculator, a novel tool for reducing unnecessary antibiotic treatment. STUDY DESIGN: A systematic review with individual patient data meta-analysis was conducted, extending PROSPERO record CRD42018116188. Cochrane, PubMed/MEDLINE, EMBASE, Web of Science, Google Scholar, and major conference proceedings were searched from 2011 through May 1, 2020. Original data studies including culture-proven EOS case(s) with EOS Calculator application, independent from EOS Calculator development, and including representative birth cohorts were included. Relevant (individual patient) data were extracted from full-text and data queries. The main outcomes were the proportions of EOS cases assigned to risk categories by the EOS Calculator at initial assessment and within 12 hours. Evidence quality was assessed using Newcastle-Ottawa scale, Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies, and GRADE tools. RESULTS: Among 543 unique search results, 18 were included, totaling more than 459 000 newborns. Among 234 EOS cases, EOS Calculator application resulted in initial assignments to (strong consideration of) empiric antibiotic administration for 95 (40.6%; 95% CI, 34.2%-47.2%), more frequent vital signs for 36 (15.4%; 95% CI, 11.0%-20.7%), and routine care for 103 (44.0%; 95% CI, 37.6%-50.6%). By 12 hours of age, these proportions changed to 143 (61.1%; 95% CI, 54.5%-67.4%), 26 (11.1%; 95% CI, 7.4%-15.9%), and 65 (27.8%; 95% CI, 22.1%-34.0%) of 234 EOS cases, respectively. CONCLUSIONS: EOS Calculator application assigns frequent vital signs or routine care to a substantial proportion of EOS cases. Clinical vigilance remains essential for all newborns.

Multicentre study found that adherence to national antibiotic recommendations for neonatal early-onset sepsis was low.

AIM: Our aim was to evaluate adherence to the Dutch neonatal early-onset sepsis (EOS) guidelines, adapted from UK guidance. We also looked at the effect on antibiotic recommendations and duration. METHOD: This was a multicentre, prospective observational cross-sectional study carried out in seven hospitals in the Netherlands between 1 September 2018 and 1 November 2019. We enrolled 1024 neonates born at 32 weeks of gestation or later if they demonstrated at least one EOS risk factor or clinical signs of infection. RESULTS: The Dutch guidelines recommended antibiotic treatment for 438/1024 (42.8%) of the neonates designated at risk, but only 186/438 (42.5%) received antibiotics. The guidelines advised withholding antibiotics for 586/1024 (57.2%) of neonates and in 570/586 (97.3%) cases the clinicians adhered to this recommendation. Blood cultures were obtained for 182/186 (97.8%) infants who started antibiotics and only four were positive, for group B streptococci. Antibiotic treatment was continued for more than 3 days in 56/178 (31.5%) neonates, despite a negative blood culture. CONCLUSION: Low adherence to the Dutch guidelines meant that the majority of neonates did not receive the antibiotic treatment that was recommended, while some antibiotic use was prolonged despite negative blood cultures. The guidelines need to be revised.

Early onset sepsis calculator implementation is associated with reduced healthcare utilization and financial costs in late preterm and term newborns.

The neonatal early onset sepsis (EOS) calculator is a novel tool for antibiotic stewardship in newborns, associated with a reduction of empiric antibiotic treatment for suspected EOS. We studied if implementation of the EOS calculator results in less healthcare utilization and lower financial costs of suspected EOS. For this, we compared two single-year cohorts of hospitalizations within 3 days after birth in a Dutch nonacademic teaching hospital, before and after implementation of the EOS calculator. All admitted newborns born at or after 35 weeks of gestation were eligible for inclusion. We analyzed data from 881 newborns pre-implementation and 827 newborns post-implementation. We found significant reductions in EOS-related laboratory tests performed and antibiotic days, associated with implementation of the EOS calculator. Mean length of hospital stay was shorter, and EOS-related financial costs were lower after implementation among term, but not among preterm newborns.Conclusion: In addition to the well-known positive impact on antibiotic stewardship, implementation of the EOS calculator is also clearly associated with reductions in healthcare utilization related to suspected EOS in late preterm and term newborns and with a reduction in associated financial costs among those born term.What is Known:• The early-onset sepsis (EOS) calculator is a novel tool for antibiotic stewardship in newborns, associated with a reduction in empiric antibiotic treatment for suspected EOS.What is New:• In newborns at risk for EOS, EOS calculator implementation is associated with a significant reduction in laboratory investigations related to suspected EOS and significantly shorter stay in those born term.• EOS calculator implementation in term newborns is associated with a mean reduction of €207 in costs for EOS-related care per admitted newborn.

Sepsis calculator implementation reduces empiric antibiotics for suspected early-onset sepsis.

Significant overtreatment with antibiotics for suspected early onset sepsis (EOS) constitutes a persisting clinical problem, generating unnecessary risks, harms, and costs for many newborns. We aimed to study feasibility and impact of a sepsis calculator to help guide antibiotic for suspected EOS in a European setting. In this single-center study, the sepsis calculator was implemented as an addition to and in accordance with existing protocols. One thousand eight hundred seventy-seven newborns ≥ 35 weeks of gestational age were prospectively evaluated; an analogous retrospective control group (n = 2076) was used for impact analysis. We found that empirical treatment with intravenous antibiotics for suspected EOS was reduced from 4.8 to 2.7% after sepsis calculator implementation (relative risk reduction 44% (95% confidence interval 21.4-59.5%)). No evidence for changes in time to treatment start, treatment duration, or proven sepsis rates was found. Adherence to sepsis calculator recommendation was 91%. CONCLUSION: Pragmatic and feasible implementation of the sepsis calculator yields a 44% reduction of empirical use of antibiotics for EOS, without signs of delay or prolongation of treatment. These findings warrant a multicenter, nation-wide, randomized study evaluating systematic use of the sepsis calculator prediction model and its effects in clinical practice outside of the USA. What is known: • Significant overtreatment with antibiotics for suspected early-onset sepsis results in unnecessary costs, risks, and harms. • Implementation of the sepsis calculator in the USA has resulted in a significant decrease in empirical antibiotic treatment, without apparent adverse events. What is new: • Implementation of the sepsis calculator in daily clinical decision-making in a Dutch teaching hospital is feasible in conjunction with existing protocols, with high adherence. • Antibiotic therapy for suspected early-onset sepsis was reduced by 44% following implementation of the calculator.

Interference Between Respiratory Syncytial Virus and Human Rhinovirus Infection in Infancy.

BACKGROUND: Respiratory syncytial virus (RSV) and human rhinovirus (HRV) are the most common viruses associated with acute respiratory tract infections in infancy. Viral interference is important in understanding respiratory viral circulation and the impact of vaccines. METHODS: To study viral interference, we evaluated cases of RSV and HRV codetection by polymerase chain reaction in 2 prospective birth cohort studies (the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure [INSPIRE] study and the Tennessee Children's Respiratory Initiative [TCRI]) and a double-blinded, randomized, controlled trial (MAKI), using adjusted multivariable regression analyses. RESULTS: Among 3263 respiratory tract samples, 24.5% (798) and 37.3% (1216) were RSV and HRV positive, respectively. The odds of HRV infection were significantly lower in RSV-infected infants in all cohorts, with adjusted odds ratios of 0.30 (95% confidence interval [CI], .22-.40 in the INSPIRE study, 0.18 (95% CI, .11-.28) in the TCRI (adjusted for disease severity), and 0.34 (95% CI, .16-.72) in the MAKI trial. HRV infection was significantly more common among infants administered RSV immunoprophylaxis, compared with infants who did not receive immunoprophylaxis (OR, 1.65; 95% CI, 1.65-2.39). CONCLUSIONS: A negative association of RSV on HRV codetection was consistently observed across populations, seasons, disease severity, and geographical regions. Suppressing RSV infection by RSV immunoprophylaxis might increase the risk of having HRV infection.

Population-Attributable Risk of Risk Factors for Recurrent Wheezing in Moderate Preterm Infants During the First Year of Life.

BACKGROUND: Recurrent wheezing in young infants has a high prevalence, influences quality of life, and generates substantial health care costs. We previously showed that respiratory syncytial virus infection is an important mechanism of recurrent wheezing in moderate preterm infants. We aimed to provide population-attributable risks (PAR) of risk factors for recurrent wheezing during the first year of life in otherwise healthy moderate preterm infants. METHODS: RISK is a multicentre prospective birth cohort study of 4424 moderate preterm infants born at 32-35 weeks gestation. We estimated PAR of risk factors for recurrent wheezing, which was defined as three or more parent-reported wheezing episodes during the first year of life. RESULTS: We evaluated 3952 (89%) children at 1 year of age, of whom 705 infants (18%) developed recurrent wheezing. Fourteen variables were independently associated with recurrent wheezing. Hospitalisation for respiratory syncytial virus bronchiolitis had a strong relationship with recurrent wheezing (RR 2.6; 95% confidence interval, CI, 2.2, 3.1), but a relative modest PAR (8%; 95% CI 6, 11%) which can be explained by a low prevalence (13%). Day-care attendance showed a strong relationship with recurrent wheezing (RR 1.9; 95% CI 1.7, 2.2) and the highest PAR (32%; 95% CI 23, 37%) due to a high prevalence (67%). The combined adjusted PAR for the 14 risk factors associated with recurrent wheezing was 49% (95% CI 46, 52%). CONCLUSIONS: In moderate preterm infants, day-care attendance has the largest PAR for recurrent wheezing. Trial evidence is needed to determine the potential benefit of delayed day-care attendance in this population.

Factors Associated with Prolonged Antibiotic Therapy in Neonates with Suspected Early-Onset Sepsis.

Early-onset sepsis (EOS) is a rare but profoundly serious bacterial infection. Neonates at risk of EOS are often treated with antibiotics. The start of empiric antibiotic therapy can successfully be reduced by the implementation of the EOS calculator. However, once started, antibiotic therapy is often continued despite a negative blood culture. To decrease the burden of antibiotic therapy, it is necessary to know whether the clinician's reasons are based on objective factors. Therefore, we performed a retrospective single-centre cohort study to identify the factors associated with prolongation of antibiotic therapy in neonates with suspected EOS but a negative blood culture. Maternal, clinical, and laboratory data of neonates with a gestational age of ≥32 weeks, admitted between January 2019 and June 2021, were collected. Among neonates with a negative blood culture, we compared neonates with prolonged (≥3 days) to neonates with discontinued (<3 days) antibiotic therapy. The clinician's reported reasons for prolonging therapy were explored. Blood cultures were positive in 4/146 (2.7%), negative in 131/146 (89.7%), and not obtained in 11/146 (7.5%) of the neonates. The incidence of EOS was 0.7 per 1000 neonates. Of the 131 neonates with a negative blood culture, 47 neonates (35.9%) received prolonged antibiotic therapy. In the prolonged group, the mean gestational age was higher (38.9 versus 36.8 weeks), and spontaneous preterm birth was less prevalent (21.3% versus 53.6%). Prolonged treatment was associated with late onset of respiratory distress, respiratory rate, hypoxia, apnoea and bradycardia, pale appearance, behavioural change, and elevated CRP levels. The most reported reasons were clinical appearance (38.3%), elevated CRP levels (36.2%), and skin colour (10.6%). Prolonging empiric antibiotic therapy despite a negative blood culture is common in suspected EOS. Clinical signs associated with prolongation are uncommon and the reported reasons for prolongation contain subjective assessments and arbitrary interpretations that are not supported by the guideline recommendations as arguments for prolonged therapy.

Personalized Infant Risk Prediction for Severe Respiratory Syncytial Virus Lower Respiratory Tract Infection Requiring Intensive Care Unit Admission.

Background: Currently, there are no available tools to identify infants at the highest risk of significant morbidity and mortality from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) who would benefit most from RSV prevention products. The objective was to develop and internally validate a personalized risk prediction tool for use among all newborns that uses readily available birth/postnatal data to predict RSV LRTI requiring intensive care unit (ICU) admission. Methods: We conducted a population-based birth cohort study of infants born from 1995 to 2007, insured by the Tennessee Medicaid Program, and who did not receive RSV immunoprophylaxis during the first year of life. The primary outcome was severe RSV LRTI requiring ICU admission during the first year of life. We built a multivariable logistic regression model including demographic and clinical variables available at or shortly after birth to predict the primary outcome. Results: In a population-based sample of 429 365 infants, 713 (0.2%) had severe RSV LRTI requiring ICU admission. The median age of admission was 66 days (interquartile range, 37-120). Our tool, including 19 variables, demonstrated good predictive accuracy (area under the curve, 0.78; 95% confidence interval, 0.77-0.80) and identified infants who did not qualify for palivizumab, based on American Academy of Pediatrics guidelines, but had higher predicted risk levels than infants who qualified (27% of noneligible infants with >0.16% predicted probabilities [lower quartile for eligible infants]). Conclusions: We developed a personalized tool that identified infants at increased risk for severe RSV LRTI requiring ICU admission, expected to benefit most from immunoprophylaxis.

Incidence of Antibiotic Exposure for Suspected and Proven Neonatal Early-Onset Sepsis between 2019 and 2021: A Retrospective, Multicentre Study.

Management of suspected early-onset sepsis (EOS) is undergoing continuous evolution aiming to limit antibiotic overtreatment, yet current data on the level of overtreatment are only available for a select number of countries. This study aimed to determine antibiotic initiation and continuation rates for suspected EOS, along with the incidence of culture-proven EOS in The Netherlands. In this retrospective study from 2019 to 2021, data were collected from 15 Dutch hospitals, comprising 13 regional hospitals equipped with Level I-II facilities and 2 academic hospitals equipped with Level IV facilities. Data included birth rates, number of neonates started on antibiotics for suspected EOS, number of neonates that continued treatment beyond 48 h and number of neonates with culture-proven EOS. Additionally, blood culture results were documented. Data were analysed both collectively and separately for regional and academic hospitals. A total of 103,492 live-born neonates were included. In 4755 neonates (4.6%, 95% CI 4.5-4.7), antibiotic therapy was started for suspected EOS, and in 2399 neonates (2.3%, 95% CI 2.2-2.4), antibiotic treatment was continued beyond 48 h. Incidence of culture-proven EOS was 1.1 cases per 1000 live births (0.11%, 95% CI 0.09-0.14). Overall, for each culture-proven EOS case, 40.6 neonates were started on antibiotics and in 21.7 neonates therapy was continued. Large variations in treatment rates were observed across all hospitals, with the number of neonates initiated and continued on antibiotics per culture-proven EOS case varying from 4 to 90 and from 4 to 56, respectively. The high number of antibiotic prescriptions compared to the EOS incidence and wide variety in clinical practice among hospitals in The Netherlands underscore both the need and potential for a novel approach to the management of neonates with suspected EOS.

Evaluating safety and effectiveness of the early-onset sepsis calculator to reduce antibiotic exposure in Dutch at-risk newborns: a protocol for a cluster randomised controlled trial.

INTRODUCTION: Newborns are at risk for early-onset sepsis (EOS). In the Netherlands, EOS affects less than 0.2% of newborns, but approximately 5% are treated with empirical antibiotics. These numbers form an example of overtreatment in countries using risk-factor based guidelines for administrating antibiotics. An alternative to these guidelines is the EOS calculator, a tool that calculates an individual EOS risk and provides management recommendation. However, validation outside the North-American setting is limited, especially for safety outcomes. We aim to investigate whether EOS calculator use can safely reduce antibiotic exposure in newborns with suspected EOS compared with the Dutch guideline. METHODS AND ANALYSIS: This protocol describes a cluster randomised controlled trial assessing whether EOS calculator use is non-inferior regarding safety, and superior regarding limiting overtreatment, compared with the Dutch guideline. We will include newborns born at ≥34 weeks' gestation, with at least one risk factor consistent with EOS within 24 hours after birth. After 1:1 randomisation, the 10 participating Dutch hospitals will use either the Dutch guideline or the EOS calculator as standard of care for all newborns at risk for EOS. In total, 1830 newborns will be recruited. The coprimary non-inferiority outcome will be the presence of at least one of four predefined safety criteria. The coprimary superiority outcome will be the proportion of participants starting antibiotic therapy for suspected and, or proven EOS within 24 hours after birth. Secondary outcomes will be the total duration of antibiotic therapy, the percentage of antibiotic therapy started between 24 and 72 hours after birth, and parent-reported quality of life. Analyses will be performed both as intention to treat and per protocol. ETHICS AND DISSEMINATION: This trial has been approved by the Medical Ethics Committee of the Amsterdam UMC (NL78203.018.21). Results will be presented in peer-reviewed journals and at international conferences. TRIAL REGISTRATION NUMBER: NCT05274776.

Barriers and Facilitators to the Implementation of the Early-Onset Sepsis Calculator: A Multicenter Survey Study.

Prior studies demonstrated the neonatal early-onset sepsis (EOS) calculator's potential in drastically reducing antibiotic prescriptions, and its international adoption is increasing rapidly. To optimize the EOS calculator's impact, successful implementation is crucial. This study aimed to identify key barriers and facilitators to inform an implementation strategy. A multicenter cross-sectional survey was carried out among physicians, residents, nurses and clinical obstetricians of thirteen Dutch hospitals. Survey development was prepared through a literature search and stakeholder interviews. Data collection and analysis were based on the Consolidated Framework for Implementation Research (CFIR). A total of 465 stakeholders completed the survey. The main barriers concerned the expectance of the department's capacity problems and the issues with maternal information transfer between departments. Facilitators concerned multiple relative advantages of the EOS calculator, including stakeholder education, EOS calculator integration in the electronic health record and existing positive expectations about the safety and effectivity of the calculator. Based on these findings, tailored implementation interventions can be developed, such as identifying early adopters and champions, conducting educational meetings tailored to the target group, creating ready-to-use educational materials, integrating the EOS calculator into electronic health records, creating a culture of collective responsibility among departments and collecting data to evaluate implementation success and innovation results.

Group B Streptococcus Early-Onset Disease: New Preventive and Diagnostic Tools to Decrease the Burden of Antibiotic Use.

The difficulty in recognizing early-onset neonatal sepsis (EONS) in a timely manner due to non-specific symptoms and the limitations of diagnostic tests, combined with the risk of serious consequences if EONS is not treated in a timely manner, has resulted in a low threshold for starting empirical antibiotic treatment. New guideline strategies, such as the neonatal sepsis calculator, have been proven to reduce the antibiotic burden related to EONS, but lack sensitivity for detecting EONS. In this review, the potential of novel, targeted preventive and diagnostic methods for EONS is discussed from three different perspectives: maternal, umbilical cord and newborn perspectives. Promising strategies from the maternal perspective include Group B Streptococcus (GBS) prevention, exploring the virulence factors of GBS, maternal immunization and antepartum biomarkers. The diagnostic methods obtained from the umbilical cord are preliminary but promising. Finally, promising fields from the newborn perspective include biomarkers, new microbiological techniques and clinical prediction and monitoring strategies. Consensus on the definition of EONS and the standardization of research on novel diagnostic biomarkers are crucial for future implementation and to reduce current antibiotic overexposure in newborns.

An infected urachal cyst--a rare diagnosis in a child with acute abdominal pain.

UNLABELLED: A 2-year-old girl who presented with acute abdominal pain and spiking fever was diagnosed with an infected urachal cyst. Ultrasonography aided the diagnosis and the urachal remnant was removed successfully through a single laparoscopic procedure. Treatment is through removal of the complete structure, to prevent malignant degeneration in adulthood. CONCLUSION: Urachal cysts may cause abdominal complaints when infected. Although rare, they should be added to the differential diagnosis of acute abdominal pain in the paediatric patient, as this case illustrates.

Long-Term Respiratory Consequences of Early-Life Respiratory Viral Infections: A Pragmatic Approach to Fundamental Questions.

Early-life viral infection can have profound effects on the developing lung and immune systems, both important in asthma development. For decades, research has aimed to establish whether there is a causal link between these viral infections as an exposure and asthma later in childhood. Establishing causality will remain important, but new insights regarding early-life viral infection as an exposure, the recognition of asthma as a heterogeneous outcome, and the shared genetic susceptibility to both suggest a refocus from answering the theoretical question of causality toward additional pragmatic approaches focusing on improving patient outcomes across the spectrum of respiratory disease. This Clinical Commentary reviews the evidence on the consequences of early-life viral infection and aims to look beyond the question of causality, suggesting a research agenda specifically aimed at what matters for human development, and for the quality of life of current and future patients with wheezing disorders.

Incidence of Early and Late Onset Neonatal Sepsis in Suriname: A National Tertiary Hospital Birth-cohort Study.

BACKGROUND: Early onset neonatal sepsis (EONS) and late onset neonatal sepsis (LONS) are important causes of neonatal mortality and morbidity. A pressing need for reliable and detailed data of low- and middle-income countries exists. This study aimed to describe the incidence and outcome of neonatal sepsis in the only tertiary hospital of Suriname, a middle-income country in South America. METHODS: Infants born at the Academic Hospital of Paramaribo from May 2017 through December 2018 were prospectively included at birth. Perinatal data, duration of antibiotic treatment, blood culture results and mortality data were gathered. Neonatal sepsis was defined as positive blood culture with a pathogenic microorganism within the first 28 days of life. RESULTS: Of the 2190 infants included, 483 (22%) were admitted to neonatal (intensive) care. The incidence of EONS was 2.1 (95% CI: 0.9-5) per 1000 live births, with no deaths. Antibiotics for suspected EONS were administrated to 189 (8.6%) infants, of whom 155 (82%) were born prematurely. The incidence of LONS cases was 145 (95% CI: 114-176) per 1000 admissions. Gramnegative bacteria accounted for 70% (48 out of 70) of causative organisms. Seventeen deaths were directly caused by sepsis (35 per 1000 admissions). CONCLUSIONS: Findings from this tertiary center birth cohort study in a middle-income setting indicate EONS incidence and outcomes comparable to high-income settings, whereas LONS is a more prevalent and significant challenge with a predominance of gram-negative bacteria, and high mortality.

Fatal Early-onset Sepsis Caused by Intrauterine Transmission of Serogroup Y Meningococcus.

Infections by meningococcal species are extremely rare in the first days of life. We present a fatal case of early-onset sepsis presenting at birth, caused by intrauterine transmission of serogroup Y N. meningitidis, evidenced clinically and histologically by corresponding chorioamnionitis and N. meningitidis-positive amniotic fluid. This case confirms a long-standing suspicion that N. meningitidis can be transmitted in utero.