Sepsis shapes the human γδ TCR repertoire in an age- and pathogen-dependent manner.

Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T-cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0-16 years) with blood culture-proven bacterial sepsis caused by HMBPP-positive Escherichia coli or by HMBPP-negative Staphylococcus aureus or by HMBPP-negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal-derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens.

Raising AWaRe-ness of Antimicrobial Stewardship Challenges in Pediatric Emergency Care: Results from the PERFORM Study Assessing Consistency and Appropriateness of Antibiotic Prescribing Across Europe.

BACKGROUND: Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing. METHODS: Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification. RESULTS: Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/ß-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category. CONCLUSIONS: Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship.

Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study.

BACKGROUND: Early-life antibiotic exposure is disproportionately high compared to the burden of culture-proven early-onset sepsis (CP-EOS). We assessed the contribution of culture-negative cases to the overall antibiotic exposure in the first postnatal week. METHODS: We conducted a retrospective analysis across eleven countries in Europe, North America, and Australia. All late-preterm and term infants born between 2014 and 2018 who received intravenous antibiotics during the first postnatal week were classified as culture-negative cases treated for ≥5 days (CN ≥ 5d), culture-negative cases treated for <5 days (CN < 5d), or CP-EOS cases. RESULTS: Out of 757,979 infants, 21,703 (2.9%) received intravenous antibiotics. The number of infants classified as CN ≥ 5d, CN < 5d, and CP-EOS was 7996 (37%), 13,330 (61%), and 375 (1.7%). The incidence of CN ≥ 5d, CN < 5d, and CP-EOS was 10.6 (95% CI 10.3-10.8), 17.6 (95% CI 17.3-17.9), and 0.49 (95% CI 0.44-0.54) cases per 1000 livebirths. The median (IQR) number of antibiotic days administered for CN ≥ 5d, CN < 5d, and CP-EOS was 77 (77-78), 53 (52-53), and 5 (5-5) per 1000 livebirths. CONCLUSIONS: CN ≥ 5d substantially contributed to the overall antibiotic exposure, and was 21-fold more frequent than CP-EOS. Antimicrobial stewardship programs should focus on shortening antibiotic treatment for culture-negative cases. IMPACT: In a study of 757,979 infants born in high-income countries, we report a presumed culture-negative early-onset sepsis incidence of 10.6/1000 livebirths with an associated antibiotic exposure of 77 antibiotic days per 1000 livebirths. This study sheds light on the major contribution of presumed culture-negative early-onset sepsis to early-life antibiotic exposure. Given the diagnostic uncertainty surrounding culture-negative early-onset sepsis, the low mortality rate, and the disproportionate antibiotic exposure associated with this condition, our study emphasizes the importance of targeting culture-negative early-onset sepsis in antimicrobial stewardship programs.

Management of neonates at risk of early onset sepsis: a probability-based approach and recent literature appraisal : Update of the Swiss national guideline of the Swiss Society of Neonatology and the Pediatric Infectious Disease Group Switzerland.

In Switzerland and other high-income countries, one out of 3000 to 5000 term and late preterm neonates develops early onset sepsis (EOS) associated with a mortality of around 3%, while incidence and mortality of EOS in very preterm infants are substantially higher. Exposure to antibiotics for suspected EOS is disproportionally high compared to the incidence of EOS with consequences for future health and antimicrobial resistance (AMR). A safe reduction of unnecessary antibiotic treatment has to be a major goal of new management strategies and guidelines. Antibiotics should be administered immediately in situations with clinical signs of septic shock. Group B streptococcus (GBS) and Escherichia coli (E. coli) are the leading pathogens of EOS. Amoxicillin combined with an aminoglycoside remains the first choice for empirical treatment. Serial physical examinations are recommended for all neonates with risk factors for EOS. Neonates without any clinical signs suggestive of EOS should not be treated with antibiotics. In Switzerland, we do not recommend the use of the EOS calculator, a risk stratification tool, due to its unclear impact in a population with an observed antibiotic exposure below 3%. Not all neonates with respiratory distress should be empirically treated with antibiotics. Isolated tachypnea or respiratory distress starting immediately after delivery by elective caesarean section or a clearly assessed alternative explanation than EOS for clinical signs may point towards a low probability of sepsis. On the other hand, unexplained prematurity with risk factors has an inherent higher risk of EOS. Before the start of antibiotic therapy, blood cultures should be drawn with a minimum volume of 1 ml in a single aerobic blood culture bottle. This standard procedure allows antibiotics to be stopped after 24 to 36 h if no pathogen is detected in blood cultures. Current data do not support the use of PCR-based pathogen detection in blood as a standard method. Lumbar puncture is recommended in blood culture-proven EOS, critical illness, or in the presence of neurological symptoms such as seizures or altered consciousness. The accuracy of a single biomarker measurement to distinguish inflammation from infection is low in neonates. Therefore, biomarker guidance is not a standard part of decision-making regarding the start or stop of antibiotic therapy but may be used as part of an algorithm and after appropriate education of health care teams. Every newborn started on antibiotics should be assessed for organ dysfunction with prompt initiation of respiratory and hemodynamic support if needed. An elevated lactate may be a sign of poor perfusion and requires a comprehensive assessment of the clinical condition. Interventions to restore perfusion include fluid boli with crystalloids and catecholamines. Neonates in critical condition should be cared for in a specialized unit. In situations with a low probability of EOS, antibiotics should be stopped as early as possible within the first 24 h after the start of therapy. In cases with microbiologically proven EOS, reassessment and streamlining of antibiotic therapy in neonates is an important step to minimize AMR. CONCLUSION:  This guideline, developed through a critical review of the literature, facilitates a probability-based approach to the management of neonates at risk of early onset sepsis. WHAT IS KNOWN: • Neonatal exposure to antibiotics is disproportionally high compared with the incidence of early onset sepsis with implications for future health and antimicrobial resistance. WHAT IS NEW: • A probability-based approach may facilitate a more balanced management of neonatal sepsis and antibiotic stewardship.

Postpandemic fluctuations of regional respiratory syncytial virus hospitalization epidemiology: potential impact on an immunization program in Switzerland.

RSV hospitalization epidemiology is subject to rapid changes brought about by the COVID-19 pandemic and the prospect of vaccine prevention. The purpose of this report is to characterize recent epidemiologic and clinical fluctuations and to analyze their potential impact on an immunization program with nirsevimab. This is a 2018-2024 retrospective analysis of all hospitalizations caused by RSV in patients below 16 years of age occurring at an academic Children's Hospital that serves a defined population. We simulated the vaccine impact against RSV hospitalization by applying the expected effects of the infant immunization program with nirsevimab proposed in Switzerland to observed case counts. We analyzed 1339 hospitalizations. The consecutive occurrence of two major epidemics in 2022-2023 and 2023-2024 had never been recorded previously. The 2023-2024 season witnessed a major shift to older age. Only 61% of patients were below 12 months of age, while prepandemic long-term surveillance since 1997 found a range between 64 and 85% (median, 73%). Age below 3 months, prematurity, airway anomalies, congenital heart disease, and neuromuscular disorders were independently associated with ICU admission. Simulation of the vaccine impact using two scenarios of coverage and efficacy (scenario 1, 50% and 62%, respectively; scenario 2, 90% and 90%) and three different age distributions resulted in an infant vaccine impact of 31.0% (scenario 1) and 81.0% (scenario 2), respectively. Vaccine impact for all patients below 16 years ranged from 22.7 to 24.9% (scenario 1) and 54.2 to 68.8% (scenario 2). CONCLUSION: RSV hospitalization epidemiology was characterized by substantial variability in patient age on admission. As the proposed RSV immunization program primarily targets infants, year-to-year fluctuation of cases among older children will cause a variability of vaccine impact of approximately 15%. This information may be useful for physicians and hospital administrators when they anticipate the resources needed during the winter season. WHAT IS KNOWN: • RSV hospitalization epidemiology was subject to massive disturbances during the COVID-19 pandemic. • Extended half-life monoclonal antibodies and active maternal immunization offer new means of passive protection of infants against severe RSV disease. WHAT IS NEW: • We demonstrate substantial year-to-year fluctuation of the age distribution at the time of RSV hospitalization. • Up to 40% of annual RSV hospitalizations in a given season occur in children above 12 months of age who do not benefit from maternal RSV immunization and may not be eligible for receipt of a monoclonal antibody.

Organ Dysfunction in Children With Blood Culture-Proven Sepsis: Comparative Performance of Four Scores in a National Cohort Study.

OBJECTIVES: Previous studies applying Sepsis-3 criteria to children were based on retrospective analyses of PICU cohorts. We aimed to compare organ dysfunction criteria in children with blood culture-proven sepsis, including emergency department, PICU, and ward patients, and to assess relevance of organ dysfunctions for mortality prediction. DESIGN: We have carried out a nonprespecified, secondary analysis of a prospective dataset collected from September 2011 to December 2015. SETTING: Emergency departments, wards, and PICUs in 10 tertiary children's hospitals in Switzerland. PATIENTS: Children younger than 17 years old with blood culture-proven sepsis. We excluded preterm infants and term infants younger than 7 days old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the 2005 International Pediatric Sepsis Consensus Conference (IPSCC), Pediatric Logistic Organ Dysfunction-2 (PELOD-2), pediatric Sequential Organ Failure Assessment (pSOFA), and Pediatric Organ Dysfunction Information Update Mandate (PODIUM) scores, measured at blood culture sampling, to predict 30-day mortality. We analyzed 877 sepsis episodes in 807 children, with a 30-day mortality of 4.3%. Percentage with organ dysfunction ranged from 32.7% (IPSCC) to 55.3% (pSOFA). In adjusted analyses, the accuracy for identification of 30-day mortality was area under the curve (AUC) 0.87 (95% CI, 0.82-0.92) for IPSCC, 0.83 (0.76-0.89) for PELOD-2, 0.85 (0.78-0.92) for pSOFA, and 0.85 (0.78-0.91) for PODIUM. When restricting scores to neurologic, respiratory, and cardiovascular dysfunction, the adjusted AUC was 0.89 (0.84-0.94) for IPSCC, 0.85 (0.79-0.91) for PELOD-2, 0.87 (0.81-0.93) for pSOFA, and 0.88 (0.83-0.93) for PODIUM. CONCLUSIONS: IPSCC, PELOD-2, pSOFA, and PODIUM performed similarly to predict 30-day mortality. Simplified scores restricted to neurologic, respiratory, and cardiovascular dysfunction yielded comparable performance.

Prediction of recovery from multiple organ dysfunction syndrome in pediatric sepsis patients.

MOTIVATION: Sepsis is a leading cause of death and disability in children globally, accounting for ∼3 million childhood deaths per year. In pediatric sepsis patients, the multiple organ dysfunction syndrome (MODS) is considered a significant risk factor for adverse clinical outcomes characterized by high mortality and morbidity in the pediatric intensive care unit. The recent rapidly growing availability of electronic health records (EHRs) has allowed researchers to vastly develop data-driven approaches like machine learning in healthcare and achieved great successes. However, effective machine learning models which could make the accurate early prediction of the recovery in pediatric sepsis patients from MODS to a mild state and thus assist the clinicians in the decision-making process is still lacking. RESULTS: This study develops a machine learning-based approach to predict the recovery from MODS to zero or single organ dysfunction by 1 week in advance in the Swiss Pediatric Sepsis Study cohort of children with blood-culture confirmed bacteremia. Our model achieves internal validation performance on the SPSS cohort with an area under the receiver operating characteristic (AUROC) of 79.1% and area under the precision-recall curve (AUPRC) of 73.6%, and it was also externally validated on another pediatric sepsis patients cohort collected in the USA, yielding an AUROC of 76.4% and AUPRC of 72.4%. These results indicate that our model has the potential to be included into the EHRs system and contribute to patient assessment and triage in pediatric sepsis patient care. AVAILABILITY AND IMPLEMENTATION: Code available at https://github.com/BorgwardtLab/MODS-recovery. The data underlying this article is not publicly available for the privacy of individuals that participated in the study. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Group A streptococcal disease in paediatric inpatients: a European perspective.

Group A streptococcal (GAS) disease shows increasing incidence worldwide. We characterised children admitted with GAS infection to European hospitals and studied risk factors for severity and disability. This is a prospective, multicentre, cohort study (embedded in EUCLIDS and the Swiss Pediatric Sepsis Study) including 320 children, aged 1 month to 18 years, admitted with GAS infection to 41 hospitals in 6 European countries from 2012 to 2016. Demographic, clinical, microbiological and outcome data were collected. A total of 195 (61%) patients had sepsis. Two hundred thirty-six (74%) patients had GAS detected from a normally sterile site. The most common infection sites were the lower respiratory tract (LRTI) (22%), skin and soft tissue (SSTI) (23%) and bone and joint (19%). Compared to patients not admitted to PICU, patients admitted to PICU more commonly had LRTI (39 vs 8%), infection without a focus (22 vs 8%) and intracranial infection (9 vs 3%); less commonly had SSTI and bone and joint infections (p < 0.001); and were younger (median 40 (IQR 21-83) vs 56 (IQR 36-85) months, p = 0.01). Six PICU patients (2%) died. Sequelae at discharge from hospital were largely limited to patients admitted to PICU (29 vs 3%, p < 0.001; 12% overall) and included neurodisability, amputation, skin grafts, hearing loss and need for surgery. More patients were recruited in winter and spring (p < 0.001). CONCLUSION: In an era of observed marked reduction in vaccine-preventable infections, GAS infection requiring hospital admission is still associated with significant severe disease in younger children, and short- and long-term morbidity. Further advances are required in the prevention and early recognition of GAS disease. WHAT IS KNOWN: • Despite temporal and geographical variability, there is an increase of incidence of infection with group A streptococci. However, data on the epidemiology of group A streptococcal infections in European children is limited. WHAT IS NEW: • In a large, prospective cohort of children with community-acquired bacterial infection requiring hospitalisation in Europe, GAS was the most frequent pathogen, with 12% disability at discharge, and 2% mortality in patients with GAS infection. • In children with GAS sepsis, IVIG was used in only 4.6% of patients and clindamycin in 29% of patients.

Febrile illness in high-risk children: a prospective, international observational study.

To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the 'Biomarker Validation in HR patients' database in PERFORM, were analysed. Immunocompromised children (< 18 years old) presented to fifteen European hospitals in nine countries, and one Gambian hospital, with fever or suspected infection and clinical indication for blood investigations. Febrile episodes were assigned clinical phenotypes using the validated PERFORM algorithm. Logistic regression was used to assess the effect size of predictive features of proven/presumed bacterial or viral infection. A total of 599 episodes in 482 children were analysed. Seventy-eight episodes (13.0%) were definite bacterial, 67 episodes probable bacterial (11.2%), and 29 bacterial syndrome (4.8%). Fifty-five were definite viral (9.2%), 49 probable viral (8.2%), and 23 viral syndrome (3.8%). One hundred ninety were unknown bacterial or viral infections (31.7%), and 108 had inflammatory or other non-infectious causes of fever (18.1%). Predictive features of proven/presumed bacterial infection were ill appearance (OR 3.1 (95% CI 2.1-4.6)) and HIV (OR 10.4 (95% CI 2.0-54.4)). Ill appearance reduced the odds of having a proven/presumed viral infection (OR 0.5 (95% CI 0.3-0.9)). A total of 82.1% had new empirical antibiotics started on admission (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522).   Conclusion: The aetiology of febrile illness in immunocompromised children is diverse. In one-third of cases, no cause for the fever will be identified. Justification for standard intravenous antibiotic treatment for every febrile immunocompromised child is debatable, yet effective. Better clinical decision-making tools and new biomarkers are needed for this population. What is Known: • Immunosuppressed children are at high risk for morbidity and mortality of serious bacterial and viral infection, but often present with fever as only clinical symptom. • Current diagnostic measures in this group are not specific to rule out bacterial infection, and positivity rates of microbiological cultures are low. What is New: • Febrile illness and infectious complications remain a significant cause of mortality and morbidity in HR children, yet management is effective. • The aetiology of febrile illness in immunocompromised children is diverse, and development of pathways for early discharge or cessation of intravenous antibiotics is debatable, and requires better clinical decision-making tools and biomarkers.

Serum Ascorbic Acid and Thiamine Concentrations in Sepsis: Secondary Analysis of the Swiss Pediatric Sepsis Study.

OBJECTIVES: To determine circulating levels of ascorbic acid (VitC) and thiamine (VitB1) in neonates and children with blood culture-proven sepsis. DESIGN: Nested single-center study of neonates and children prospectively included in the Swiss Pediatric Sepsis Study. SETTING: One tertiary care academic hospital. PATIENTS: Sixty-one neonates and children 0-16 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: VitC and VitB1 were quantified in serum of patients (median age, 10.5 mo; interquartile range [IQR], 0.5-62.1 mo) with blood culture-proven sepsis. Median time between sepsis onset and sampling for measurement of vitamins was 3 days (IQR, 2-4 d). Median serum levels of VitC and VitB1 were 32.4 µmol/L (18.9-53.3 µmol/L) and 22.5 nmol/L (12.6-82 nmol/L); 36% of the patients (22/61) had low VitC and 10% (6/61) had VitC deficiency; and 72% (44/61) had low VitB1 and 13% (8/61) had VitB1 deficiency. Children with low VitC were older (p = 0.007) and had higher C-reactive protein (p = 0.004) compared with children with VitC within the normal range. Children with low VitB1 levels were older (p = 0.0009) and were less frequently receiving enteral or parenteral vitamin supplementation (p = 0.0000003) compared with children with normal VitB1 levels. CONCLUSIONS: In this cohort of newborns and children with sepsis, low and deficient VitC and VitB1 levels were frequently observed. Age, systemic inflammation, and vitamin supplementation were associated with vitamin levels during sepsis.

Predicting fever in neutropenia with safety-relevant events in children undergoing chemotherapy for cancer: The prospective multicenter SPOG 2015 FN Definition Study.

BACKGROUND: Fever in neutropenia (FN) remains a frequent complication in pediatric patients undergoing chemotherapy for cancer. Preventive strategies, like primary antibiotic prophylaxis, need to be evidence-based. PROCEDURE: Data on pediatric patients with any malignancy from the prospective multicenter SPOG 2015 FN Definition Study (NCT02324231) were analyzed. A score predicting the risk to develop FN with safety-relevant events (SRE; bacteremia, severe sepsis, intensive care unit admission, death) was developed using multivariate mixed Poisson regression. Its predictive performance was assessed by internal cross-validation and compared with the performance of published rules. RESULTS: In 238 patients, 318 FN episodes were recorded, including 53 (17%) with bacteremia and 68 (21%) with SRE. The risk-prediction score used three variables: chemotherapy intensity, defined according to the expected duration of severe neutropenia, time since diagnosis, and type of malignancy. Its cross-validated performance, assessed by the time needed to cover (TNC) one event, exceeded the performance of published rules. A clinically useful score threshold of ≥11 resulted in 2.3% time at risk and 4.1 months TNC. Using external information on efficacy and timing of intermittent antibiotic prophylaxis, 4.3 months of prophylaxis were needed to prevent one FN with bacteremia, and 5.2 months to prevent one FN with SRE, using a threshold of ≥11. CONCLUSIONS: This score, based on three routinely accessible characteristics, accurately identifies pediatric patients at risk to develop FN with SRE during chemotherapy. The score can help to design clinical decision rules on targeted primary antibiotic prophylaxis and corresponding efficacy studies.

Whole-exome Sequencing for the Identification of Rare Variants in Primary Immunodeficiency Genes in Children With Sepsis: A Prospective, Population-based Cohort Study.

BACKGROUND: The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes. METHODS: We conducted a multicenter, population-based, prospective study including previously healthy children aged ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported. RESULTS: There were 176 children presenting with 185 sepsis episodes who underwent WES (median age, 52 months; interquartile range, 15.4-126.4). There were 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants that were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories, as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants. CONCLUSIONS: Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected variants of uncertain significance in PID genes in 1 out of 5 children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.

Burden of Streptococcus pneumoniae Sepsis in Children After Introduction of Pneumococcal Conjugate Vaccines: A Prospective Population-based Cohort Study.

BACKGROUND: Population-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on burden of pneumococcal sepsis in children are lacking. We aimed to assess this burden following introduction of PCV-13 in a nationwide cohort study. METHODS: The Swiss Pediatric Sepsis Study (September 2011 to December 2015) prospectively recruited children <17 years of age with blood culture-proven sepsis due to Streptococcus pneumoniae, meeting criteria for systemic inflammatory response syndrome. Infection with vaccine serotype in children up to date with PCV immunization was defined as vaccine failure. Main outcomes were admission to pediatric intensive care unit (PICU) and length of hospital stay (LOS). RESULTS: Children with pneumococcal sepsis (n = 117) accounted for a crude incidence of 2.0 per 100 000 children (95% confidence interval [CI] 1.7-2.4) and 25% of community-acquired sepsis episodes. Case fatality rate was 8%. Forty-two (36%) patients required PICU admission. Children with meningitis (29; 25%) were more often infected by serotypes not included in PCV (69% vs 31%; P < .001). Sixteen (26%) of 62 children up to date with PCV immunization presented with vaccine failure, including 11 infected with serotype 3. In multivariable analyses, children with meningitis (odds ratio [OR] 6.8; 95% CI 2.4-19.3; P < .001) or infected with serotype 3 (OR 2.8; 95% CI 1.1-7.3; P = .04) were more often admitted to PICU. Children infected with serotype 3 had longer LOS (ß coefficient 0.2, 95% CI .1-1.1; P = .01). CONCLUSIONS: The incidence of pneumococcal sepsis in children shortly after introduction of PCV-13 remained substantial. Meningitis mostly due to non-vaccine serotypes and disease caused by serotype 3 represented significant predictors of severity.

Neonatal Sepsis of Early Onset, and Hospital-Acquired and Community-Acquired Late Onset: A Prospective Population-Based Cohort Study.

OBJECTIVE: To assess the epidemiology of blood culture-proven early- (EOS) and late-onset neonatal sepsis (LOS). STUDY DESIGN: All newborn infants admitted to tertiary care neonatal intensive care units in Switzerland and presenting with blood culture-proven sepsis between September 2011 and December 2015 were included in the study. We defined EOS as infection occurring <3 days after birth, and LOS as infection ≥3 days after birth. Infants with LOS were classified as having community-acquired LOS if onset of infection was ≤48 hours after admission, and hospital-acquired LOS, if onset was >48 hours after admission. Incidence was estimated based on the number of livebirths in Switzerland and adjusted for the proportion of admissions at centers participating in the study. RESULTS: We identified 444 episodes of blood culture-proven sepsis in 429 infants; 20% of cases were EOS, 62% hospital-acquired LOS, and 18% community-acquired LOS. The estimated national incidence of EOS, hospital-acquired LOS, and community-acquired LOS was 0.28 (95% CI 0.23-0.35), 0.86 (0.76-0.97), and 0.28 (0.23-0.34) per 1000 livebirths. Compared with EOS, hospital-acquired LOS occurred in infants of lower gestational age and was more frequently associated with comorbidities. Community-acquired LOS was more common in term infants and in male infants. Mortality was 18%, 12%, and 0% in EOS, hospital-acquired LOS, and community-acquired LOS, and was higher in preterm infants, in infants with septic shock, and in those requiring mechanical ventilation. CONCLUSIONS: We report a high burden of sepsis in neonates with considerable mortality and morbidity. EOS, hospital-acquired LOS, and community-acquired LOS affect specific patient subgroups and have distinct clinical presentation, pathogens and outcomes.

Seroepidemiology of Human Tularemia-Systematic Review and Meta-analysis of Seroprevalence Studies.

Background: Seroepidemiologic studies of human tularemia have been conducted throughout the northern hemisphere. The purposes of this study were (1) to provide an overview of Francisella tularensis seroprevalence data, and (2) to generate an estimate of the proportion of study participants whose infection remained subclinical. Methods: We conducted a systematic review of F tularensis seroprevalence studies according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched PubMed, Embase, and Web of Science covering the period from 1951 to 2023. Results: The weighted pooled seroprevalence among 44 486 participants recruited in 52 studies was 3.7% (95% confidence interval [CI], 2.7-5.1). Reported seroprevalences ranged between 0.2% and 31.3%. Occupational activities associated with an increased likelihood of exposure (risk ratio, 3.51 [95% CI, 3.2-3.86]) and studies from North America versus Europe and Asia (4.53 [4.15-4.94]) were associated with significantly increased seropositive rates. Twenty-eight data sets (47%) reported clinical information on a total of 965 seropositive participants. The weighted pooled estimate for subclinical seropositivity was 84.4% (95% CI, 72.9%-991.7%). Studies from F tularensis type A areas (risk ratio, 0.37 [95% CI, .27-.51) and studies from sites where pulmonary tularemia prevailed (0.38 [.28-.51]) reported lower subclinical seropositivity rates than studies from type B areas and from areas of predominance of (ulcero)glandular or oropharyngeal tularemia, respectively. Conclusions: Throughout the northern hemisphere, only a small proportion of study participants showed serologic evidence of exposure to F tularensis. Eight of 10 seropositive participants had no historical evidence of past clinical tularemia.

Ongoing Excess Hospitalizations for Severe Pediatric Group A Streptococcal Disease in 2023-2024-A Single-Center Report.

A Europe-wide outbreak of invasive pediatric group A streptococcal infections (iGAS) began in fall 2022. Here, we report the evolution of GAS hospitalizations in children and adolescents during the second outbreak year in 2023-2024 at a tertiary center in Switzerland. Using prospective monitoring of all in-patient GAS cases below 16 years of age, including those with iGAS, we compared case frequencies and clinical characteristics in three time periods (2013-2020; 2022-2023; 2023-2024). Annual GAS hospitalizations increased from a median of 25 cases (range 11-28) in 2013-2020 to 89 and 63 cases, respectively, in 2022-2023 and 2023-2024. iGAS cases evolved similarly (2013-2020, 4 cases (3-8); 2022-2023, 32 cases; 2023-2024, 21 cases). The decline in cases from 2022-2023 to 2023-2024 included all types of GAS organ involvement, except suppurative infections in the head area, which remained largely unchanged (48 vs. 45 cases). Pleural empyema declined from 13 to 7 cases, possibly explained by a poor overlap of the GAS and influenza curves, respectively, in 2023-2024 compared to 2022-2023. These data document the prolongation of the GAS outbreak into its second winter season in 2023-2024.

Outcome prediction in pediatric fever in neutropenia: Development of clinical decision rules and external validation of published rules based on data from the prospective multicenter SPOG 2015 FN definition study.

BACKGROUND: Fever in neutropenia (FN) remains a serious complication of childhood cancer therapy. Clinical decision rules (CDRs) are recommended to help distinguish between children at high and low risk of severe infection. The aim of this analysis was to develop new CDRs for three different outcomes and to externally validate published CDRs. PROCEDURE: Children undergoing chemotherapy for cancer were observed in a prospective multicenter study. CDRs predicting low from high risk infection regarding three outcomes (bacteremia, serious medical complications (SMC), safety relevant events (SRE)) were developed from multivariable regression models. Their predictive performance was assessed by internal cross-validation. Published CDRs suitable for validation were identified by literature search. Parameters of predictive performance were compared to assess reproducibility. RESULTS: In 158 patients recruited between April 2016 and August 2018, 360 FN episodes were recorded, including 56 (16%) with bacteremia, 30 (8%) with SMC and 72 (20%) with SRE. The CDRs for bacteremia and SRE used four characteristics (type of malignancy, severely reduced general condition, leucocyte count <0.3 G/L, bone marrow involvement), the CDR for SMC two characteristics (severely reduced general condition and platelet count <50 G/L). Eleven published CDRs were analyzed. Six CDRs showed reproducibility, but only one in both sensitivity and specificity. CONCLUSIONS: This analysis developed CDRs predicting bacteremia, SMC or SRE at presentation with FN. In addition, it identified six published CDRs that show some reproducibility. Validation of CDRs is fundamental to find the best balance between sensitivity and specificity, and will help to further improve management of FN.

Estimating antibiotic coverage from linked microbiological and clinical data from the Swiss Paediatric Sepsis Study to support empiric antibiotic regimen selection.

In light of rising antibiotic resistance, better methods for selection of empiric antibiotic treatment based on clinical and microbiological data are needed. Most guidelines target specific clinical infections, and variably adjust empiric antibiotic selection by certain patient characteristics. Coverage estimates reflect the probability that an antibiotic regimen will be active against the causative pathogen once confirmed and can provide an objective basis for empiric regimen selection. Coverage can be estimated for specific infections using a weighted incidence syndromic combination antibiograms (WISCAs) framework. However, no comprehensive data combining clinical and microbiological data for specific clinical syndromes are available in Switzerland. We therefore describe estimating coverage from semi-deterministically linked routine microbiological and cohort data of hospitalised children with sepsis. Coverage estimates were generated for each hospital and separately pooling data across ten contributing hospitals for five pre-defined patient risk groups. Data from 1,082 patients collected during the Swiss Paediatric Sepsis Study (SPSS) 2011-2015 were included. Preterm neonates were the most commonly represented group, and half of infants and children had a comorbidity. 67% of neonatal sepsis cases were hospital-acquired late-onset whereas in children 76% of infections were community-acquired. Escherichia coli, Coagulase-negative staphylococci (CoNS) and Staphylococcus aureus were the most common pathogens. At all hospitals, ceftazidime plus amikacin regimen had the lowest coverage, and coverage of amoxicillin plus gentamicin and meropenem were generally comparable. Coverage was improved when vancomycin was included in the regimen, reflecting uncertainty about the empirically targeted pathogen spectrum. Children with community-acquired infections had high coverage overall. It is feasible to estimate coverage of common empiric antibiotic regimens from linked data. Pooling data by patient risk groups with similar expected pathogen and susceptibility profiles may improve coverage estimate precision, supporting better differentiation of coverage between regimens. Identification of data sources, selection of regimens and consideration of pathogens to target for improved empiric coverage is important.