Cerebrospinal fluid inflammatory markers to differentiate between neonatal bacterial meningitis and sepsis: A prospective study of diagnostic accuracy.

OBJECTIVES: We evaluated the diagnostic accuracy of cerebrospinal fluid (CSF) inflammatory markers for diagnosing bacterial meningitis in neonates with sepsis and/or meningitis. METHODS: Cases were identified from a prospective multicenter study including patients aged 0-3 months with Group B Streptococcal (GBS) or Escherichia coli culture positive sepsis/meningitis. CSF CXCL10, MDC, IL-6, IL-8, IL-10, TNF- α, MIF, IL-1RA, CXCL13, IL-1ß, CRP and procalcitonin concentrations were measured with Luminex technology. RESULTS: In 61/373 patients (17%) residual CSF from the lumbar puncture was available, of whom 16 (26%) had definitive meningitis, 15 (25%) probable meningitis and 30 (49%) had sepsis. All biomarkers were detectable in CSF and showed significantly higher concentrations in definitive meningitis versus sepsis patients and six biomarkers in probable meningitis versus sepsis patients. Discrimination between definitive meningitis and sepsis was excellent for IL-1RA (area under the receiver operating characteristic curve [AUC] 0.93), TNF-α (AUC 0.92), CXCL10 (AUC 0.90), IL-1ß (AUC 0.92), IL-6 (AUC 0.94), IL-10 (AUC 0.93) and a combination of IL-1RA, TNF-α, CXCL-10 and CSF leukocyte count (AUC 0.95). CSF leukocyte count remained the predictor with the highest diagnostic accuracy (AUC 0.96). CONCLUSION: CSF inflammatory markers can be used to differentiate between neonatal sepsis and meningitis.

Recurrent bacterial meningitis in children in the Netherlands: a nationwide surveillance study.

OBJECTIVES: This study aimed to estimate the recurrence rate of culture-positive bacterial meningitis in children in the Netherlands. DESIGN: Nationwide surveillance study, using the database of the Netherlands Reference Laboratory for Bacterial Meningitis to identify patients with culture-positive bacterial meningitis during childhood. SETTING: The study was based in the Netherlands. PARTICIPANTS: A total of 9731 children with a first bacterial meningitis episode between 1 July 1987 and 30 June 2019 were identified. PRIMARY AND SECONDARY OUTCOME MEASURES: Recurrence was defined as a subsequent episode >28 days, or caused by a different pathogen. Annual incidence and incidence rate ratios (IRRs) comparing the periods 1988-2003 and 2004-2019 were calculated. Predictors of recurrent meningitis were assessed using Cox proportional hazards regression. RESULTS: Sixty-three (0.6%) of the 9731 children with a first bacterial meningitis episode contracted recurrent meningitis. Neisseria meningitidis was the leading pathogen for first meningitis episodes (52%) and Streptococcus pneumoniae for recurrent episodes (52%). The median annual incidence of first episodes per 100 000 children decreased from 11.81 (IQR 11.26-17.60) in 1988-2003 to 2.60 (IQR 2.37-4.07) in 2004-2019 (IRR 0.25, 95% CI 0.23 to 0.26). The incidence of recurrences did not change: 0.06 (IQR 0.02-0.11) in 1988-2003 to 0.03 (IQR 0.00-0.06) in 2004-2019 (IRR 0.65, 95% CI 0.39 to 1.1). Age above 5 years (OR 3.6 (95% CI 1.5 to 8.3)) and a first episode due to Escherichia coli (OR 25.7 (95% CI 7.2 to 92.0)) were associated with higher risks of recurrence. CONCLUSION: The recurrence rate of childhood bacterial meningitis in the Netherlands was 0.6%. While the incidence rate of first episodes decreased substantially, this was not the case for recurrent episodes. Older age and a first episode due to E. coli were associated with higher recurrence risks.

Meeting report: Towards better risk stratification, prevention and therapy of invasive GBS disease, ESPID research meeting May 2022.

The European Society of Pediatric Infectious Diseases (ESPID) hosted the third Group B Streptococcus (GBS) Research Session in Athens on 11th May 2022, providing researchers and clinicians from around the world an opportunity to share and discuss recent advances in GBS pathophysiology, molecular and genetic epidemiology and how these new insights can help in improving prevention and control of early- and late-onset GBS disease. The meeting provided a state-of-the-art overview of the existing GBS prevention strategies and their limitations, and an opportunity to share the latest research findings. The first presentation provided an overview of current GBS prevention and treatment strategies. In the second presentation, the genomic and antimicrobial resistance profiles of invasive and colonizing GBS strains were presented. The third presentation explained the association of intrapartum antibiotic prophylaxis (IAP) with the development of late-onset disease (LOD) and the interplay of host innate immunity and GBS. The fourth presentation evaluated the role of genomics in understanding horizontal GBS transmission. The fifth presentation focused on the zoonotic links for certain GBS lineages and the last presentation described the protective role of breastmilk. Talks were followed with interactive discussions and concluded with recommendations on what is needed to further GBS clinical research; these included: (i) the development of better risk stratification methods by combining GBS virulence factors, serological biomarkers and clinical risk factors; (ii) further studies on the interplay of perinatal antimicrobials, disturbances in the development of host immunity and late-onset GBS disease; (iii) routine submission of GBS isolates to reference laboratories to help in detecting potential clusters by using genomic sequencing; (iv) collaboration in animal and human GBS studies to detect and prevent the emergence of new pathogenic sequence types; and (v) harnessing the plethora of immune factors in the breastmilk to develop adjunct therapies.

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.

Short-term and long-term risk of mortality and neurodevelopmental impairments after bacterial meningitis during infancy in children in Denmark and the Netherlands: a nationwide matched cohort study.

BACKGROUND: Few studies have reported the long-term consequences of bacterial meningitis during infancy, and studies that have been done usually do not include a comparison cohort. We aimed to assess short-term and long-term risk of mortality, neurodevelopmental impairment (NDI), and health-care use and household income in cohorts of children with and without a history of bacterial meningitis during infancy in Denmark and the Netherlands. METHODS: In this nationwide cohort study, infants with a history of bacterial meningitis before age 1 year were identified through the Danish Medical Birth Registry and Danish National Patient Registry using International Classification of Diseases (ICD)-10 codes and through the Netherlands Reference Laboratory for Bacterial Meningitis. Infants were matched (1:10) by sex and birth month and year to a comparison cohort of the general population without a history of bacterial meningitis. We analysed mortality using Cox proportional hazards regression. In Denmark, diagnoses of NDIs were based on ICD-10 codes; in the Netherlands, special educational needs were used as a functional NDI outcome. Risk ratios (RRs) of NDIs were estimated using modified Poisson regression. We also analysed long-term health-care use in Denmark and household income in both countries. All regression analyses were adjusted for sex and year of birth, and stratified by pathogen whenever sample size allowed. FINDINGS: We included 2216 children with a history of bacterial meningitis (570 [25·7%] in Denmark between Jan 1, 1997, and Dec 31, 2018, and 1646 [74·3%] in the Netherlands between Jan 1, 1995, and Dec 31, 2018), matched to 22 127 comparison cohort members. Median age at diagnosis was 2·8 months (IQR 0·4-7·1) in Denmark and 4·3 months (0·7-7·4) in the Netherlands. Mortality risks within 3 months after disease onset were 3·9% (95% CI 2·6-5·8%) in Denmark and 5·9% (4·7-7·0) in the Netherlands, compared with 0·0% (p<0·0001) and 0·1% (p<0·0001) in the comparison cohorts. Survivors had an increased risk of moderate or severe NDIs at age 10 years (RR 5·0 [95% CI 3·5-7·1] in Denmark and 4·9 [4·0-6·2] in the Netherlands) compared to children in the comparison cohort, particularly after pneumococcal and group B streptococcal meningitis. In Denmark, a history of bacterial meningitis was associated with increased health-care use in the 10 years following diagnosis (rate ratio 4·5 [95% CI 3·9-5·2] for outpatient visits and 4·1 [3·6-4·7] for hospital admissions). INTERPRETATION: Our study shows increased risk of mortality in the short and long term, a five times increase in risk of NDIs, and increased health-care use after bacterial meningitis during infancy. Together with context-specific incidence data, our results can advance pathogen-specific estimation of the meningitis burden and inform service provision at the individual and population level. FUNDING: Bill & Melinda Gates Foundation, the Stichting Remmert Adriaan Laan Fonds, and the Netherlands Organisation for Health Research and Development.

Neonatal early-onset infections: Comparing the sensitivity of the neonatal early-onset sepsis calculator to the Dutch and the updated NICE guidelines in an observational cohort of culture-positive cases.

BACKGROUND: The early-onset sepsis calculator (EOSC) reduces unnecessary antibiotic treatment in newborns. However, its performance in identifying cases with early-onset disease (EOD) is unclear. We compared the sensitivity of the EOSC to the current Dutch and National Institute for Health and Care Excellence (NICE) guidelines when applied to a cohort of newborns with culture-positive early-onset sepsis and meningitis. METHODS: Culture-positive Streptococcus agalactiae (GBS) and Escherichia coli (E. coli) sepsis and meningitis patients ≤3 days old with a gestational age ≥34 weeks, identified between 1/1/2018 and 31/1/2021 in a Dutch prospective nationwide cohort study were included. Cases were identified by treating physicians and microbiological surveillance. Primary outcome was the proportion of patients that would have been treated according to the EOSC, the Dutch, and the NICE EOD prevention guidelines. Differences between proportions were analysed using McNemar's test. FINDINGS: We included 81 GBS and 7 E. coli EOD cases. At 4 h after birth, the EOSC would have recommended antibiotic treatment in 32 (36%) patients, compared to 44 (50%) by the Dutch (p<0·01) and 48 (55%) by the NICE guideline (p<0·01). The EOSC would have initially recommended routine care for 52% of patients compared to 31% and 30% for the Dutch and NICE guidelines (p<0·01). At 24 h after birth, the EOSC would have recommended antibiotic treatment in 54 (61%) infants compared to 64 (73%) by the Dutch (p = 0·02) and 63 (72%) by the NICE guidelines (p = 0·06). INTERPRETATION: The sensitivity of the EOSC in identifying cases of EOD is lower compared to both Dutch and NICE guidelines, especially directly after birth. The EOSC relies more on clinical symptoms and results in less overtreatment of healthy newborns at the cost of later antibiotic treatment in initially well-appearing EOD patients. FUNDING: This work was supported by grants received from Netherlands Organization for Health Research and Development (ZonMw; NWO-Vidi-Grant (grant number 917·17·308); NWO-Vici-Grant (grant number 918·19·627)), the Academic Medical Centre (AMC Innovative Impulse Grant) and Steun Emma Foundation Grant.

Sex Differences in Long-term Outcomes After Group B Streptococcal Infections During Infancy in Denmark and the Netherlands: National Cohort Studies of Neurodevelopmental Impairments and Mortality.

BACKGROUND: Male infants have a higher incidence of invasive group B Streptococcus disease (iGBS) compared with female infants; however, data on sex differences in mortality and long-term outcomes after iGBS are lacking. We assessed whether a child's sex influences the effects of iGBS on mortality and risk of neurodevelopmental impairments (NDIs). METHODS: We used Danish and Dutch registry data to conduct a nationwide cohort study of infants with a history of iGBS. A comparison cohort, children without a history of iGBS, was randomly selected and matched on relevant factors. Effect modification by sex was assessed on additive and multiplicative scales. RESULTS: Our analyses included data from children with a history of iGBS in Denmark (period 1997 -2017; n = 1432) and the Netherlands (2000 -2017; n = 697) and from 21 172 children without iGBS. There was no clear evidence of between-sex heterogeneity in iGBS-associated mortality. Boys had a higher risk of NDI, with evidence for effect modification on additive scale at the age of 5 years for any NDI (relative excess risk due to interaction = 1.28; 95% confidence interval [CI], -0.53 to 3.09 in Denmark and 1.14; 95% CI, -5.13 to 7.41 in the Netherlands). A similar pattern was observed for moderate/severe NDI at age 5 years in Denmark and age 10 years in the Netherlands. CONCLUSION: Boys are at higher risk of NDI ; our results suggest this is disproportionally increased in those who develop iGBS. Future studies should investigate mechanisms of this effect modification by sex.

Prematurity Modifies the Risk of Long-term Neurodevelopmental Impairments After Invasive Group B Streptococcus Infections During Infancy in Denmark and the Netherlands.

BACKGROUND: Preterm birth and neonatal infections are both associated with mortality and long-term neurodevelopmental impairments (NDIs). We examined whether the effect of invasive group B Streptococcus disease (iGBS) on mortality and long-term NDI differs for preterm and term infants, and whether co-occurrence of iGBS and prematurity leads to worse outcome. METHODS: Nationwide cohort studies of children with a history of iGBS were conducted using Danish and Dutch medical databases. Comparison cohorts of children without iGBS were matched on birth year/month, sex, and gestational age. Effects of iGBS on all-cause mortality and NDI were analyzed using Cox proportional hazards and logistic regression. Effect modification by prematurity was evaluated on additive and multiplicative scales. RESULTS: We identified 487 preterm and 1642 term children with a history of iGBS and 21 172 matched comparators. Dutch preterm children exposed to iGBS had the highest mortality rate by 3 months of age (671/1000 [95% CI, 412-929/1000] person-years). Approximately 30% of this mortality rate could be due to the common effect of iGBS and prematurity. Preterm children with iGBS had the highest NDI risk (8.8% in Denmark, 9.0% in the Netherlands). Of this NDI risk 36% (Denmark) and 60% (the Netherlands) might be due to the combined effect of iGBS and prematurity. CONCLUSIONS: Prematurity is associated with iGBS development. Our study shows that it also negatively impacts outcomes of children who survive iGBS. Preterm infants would benefit from additional approaches to prevent maternal GBS colonization, as this decreases risk of both preterm birth and iGBS.