A randomized controlled non-inferiority trial of placebo versus macrolide antibiotics for Mycoplasma pneumoniae infection in children with community-acquired pneumonia: trial protocol for the MYTHIC Study.

BACKGROUND: Mycoplasma pneumoniae is a major cause of community-acquired pneumonia (CAP) in school-aged children. Macrolides are the first-line treatment for this infection. However, it is unclear whether macrolides are effective in treating M. pneumoniae CAP, mainly due to limitations in microbiological diagnosis of previous studies. The extensive global use of macrolides has led to increasing antimicrobial resistance. The overall objective of this trial is to produce efficacy data for macrolide treatment in children with M. pneumoniae CAP. METHODS: The MYTHIC Study is a randomized, double-blind, placebo-controlled, multicenter, non-inferiority trial in 13 Swiss pediatric centers. Previously healthy ambulatory and hospitalized children aged 3-17 years with clinically diagnosed CAP will be screened with a sensitive and commercially available M. pneumoniae-specific IgM lateral flow assay from capillary blood. Mycoplasma pneumoniae infection in screened patients will be verified retrospectively by respiratory PCR (reference test) and IgM antibody-secreting cell enzyme-linked immunospot (ELISpot) assay (confirmatory test for distinguishing between carriage and infection). Patients will be randomized 1:1 to receive a 5-day treatment of macrolides (azithromycin) or placebo. The co-primary endpoints are (1) time to normalization of all vital signs, including body temperature, respiratory rate, heart rate, and saturation of peripheral oxygen (efficacy), and (2) CAP-related change in patient care status (i.e., admission, re-admission, or intensive care unit transfer) within 28 days (safety). Secondary outcomes include adverse events (AEs), as well as antimicrobial and anti-inflammatory effects. For both co-primary endpoints, we aim to show non-inferiority of placebo compared to macrolide treatment. We expect no macrolide effect (hazard ratio of 1, absolute risk difference of 0) and set the corresponding non-inferiority margins to 0.7 and -7.5%. The "at least one" success criterion is used to handle multiplicity with the two co-primary endpoints. With a power of 80% to reject at least one null hypothesis at a one-sided significance level of 1.25%, 376 patients will be required. DISCUSSION: This trial will produce efficacy data for macrolide treatment in children with M. pneumoniae CAP that might help to reduce the prescription of antibiotics and therefore contribute to the global efforts toward reducing antimicrobial resistance. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06325293. Registered on 24 April 2024.

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.

Inpatient burden of respiratory syncytial virus (RSV) in Switzerland, 2003 to 2021: an analysis of administrative data.

BackgroundRespiratory syncytial virus (RSV) is a leading cause of acute respiratory infections and hospitalisations in infants (age < 1 year) and young children. Little is known on RSV epidemiology and related inpatient healthcare resource use (HCRU) in Switzerland.AimTo explore RSV-related hospitalisations, inpatient HCRU and medical costs in all age groups, and risk factors for infant hospitalisations in Switzerland.MethodsWe used national hospital registry data from 2003 to 2021 identifying RSV cases with ICD-10-GM codes, and described demographic characteristics, HCRU and associated medical costs of RSV inpatients. The effect of risk factors on infant hospitalisation was estimated with logistic regression.ResultsWe observed a general increase and biannual pattern in RSV hospitalisations between 2003/04 and 2018/19, with 3,575 hospitalisations in 2018/19 and 2,487 in 2019/20 before numbers declined in 2020/21 (n = 902). Around two thirds of all hospitalisations occurred in infants. Mean (median) age was 118 (85) days in hospitalised infants and 74 (77) years in hospitalised adult patients (> 18 years); 7.2% of cases required intensive care unit stay. Mean inpatient medical costs were estimated at EUR 8,046. Most (90.8%) hospitalised infants with RSV were born after 35 weeks of gestation without bronchopulmonary dysplasia or congenital heart disease. Low birth weight, gestational age and congenital disorders were associated with a higher risk for hospitalisation.ConclusionsRSV leads to a substantial number of hospitalisations and peaks in hospital capacity utilisation. Measures to protect all infants from an RSV hospitalisation are essential in addressing this public health challenge.

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.

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.

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.

Preadmission course and management of severe pediatric group A streptococcal infections during the 2022-2023 outbreak: a single-center experience.

PURPOSE: The massive increase of infections with Group A Streptococcus (GAS) in 2022-2023 coincided in Switzerland with a change of the recommendations for the management of GAS pharyngitis. Therefore, the objective of the present study was to investigate whether the clinical manifestations and management before hospitalization for GAS infection differed in 2022-2023 compared with 2013-2022. METHODS: Retrospective study of GAS infections requiring hospitalization in patients below 16 years. Preadmission illness (modified McIsaac score), oral antibiotic use, and outcome in 2022-2023 were compared with 2013-2022. Time series were compared with surveillance data for respiratory viruses. RESULTS: In 2022-2023, the median modified McIsaac score was lower (2 [IQR 2-3] vs. 3 [IQR 2-4], p = < 0.0001) and the duration of preadmission illness was longer (4 days [3-7] vs. 3 [2-6], p = 0.004) than in 2013-2022. In both periods, withholding of preadmission oral antibiotics despite a modified McIsaac score ≥ 3 (12% vs. 18%, n.s.) or ≥ 4 (2.4% vs. 10.0%, p = 0.027) was rare. Respiratory disease, skeletal/muscle infection, and invasive GAS disease were significantly more frequent in 2022-2023, but there were no differences in clinical outcome. The time course of GAS cases in 2022-2023 coincided with the activity of influenza A/B. CONCLUSION: We found no evidence supporting the hypothesis that the 2022-2023 GAS outbreak was associated with a change in preadmission management possibly induced by the new recommendation for GAS pharyngitis. However, clinical manifestations before admission and comparative examination of time-series strongly suggest that viral co-circulation played an important role in this outbreak.

Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children From Other Pediatric Infectious and Inflammatory Diseases.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious hyperinflammatory complication following infection with severe acute respiratory syndrome coronavirus 2. The mechanisms underpinning the pathophysiology of MIS-C are poorly understood. Moreover, clinically distinguishing MIS-C from other childhood infectious and inflammatory conditions, such as Kawasaki disease or severe bacterial and viral infections, is challenging due to overlapping clinical and laboratory features. We aimed to determine a set of plasma protein biomarkers that could discriminate MIS-C from those other diseases. METHODS: Seven candidate protein biomarkers for MIS-C were selected based on literature and from whole blood RNA sequencing data from patients with MIS-C and other diseases. Plasma concentrations of ARG1, CCL20, CD163, CORIN, CXCL9, PCSK9 and ADAMTS2 were quantified in MIS-C (n = 22), Kawasaki disease (n = 23), definite bacterial (n = 28) and viral (n = 27) disease and healthy controls (n = 8). Logistic regression models were used to determine the discriminatory ability of individual proteins and protein combinations to identify MIS-C and association with severity of illness. RESULTS: Plasma levels of CD163, CXCL9 and PCSK9 were significantly elevated in MIS-C with a combined area under the receiver operating characteristic curve of 85.7% (95% confidence interval: 76.6%-94.8%) for discriminating MIS-C from other childhood diseases. Lower ARG1 and CORIN plasma levels were significantly associated with severe MIS-C cases requiring inotropes, pediatric intensive care unit admission or with shock. CONCLUSION: Our findings demonstrate the feasibility of a host protein biomarker signature for MIS-C and may provide new insight into its pathophysiology.

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.

Epidemiology and Clinical Characteristics of Human Metapneumovirus Infections in Hospitalized Children in Two Consecutive Postpandemic Years.

We assessed human metapneumovirus infections in children hospitalized between 2011 and 2023 and compared the strongest pre- and postpandemic seasons. After the COVID-19 pandemic, we observed offseason cases and loss of the alternating pattern of the human metapneumovirus season magnitude. Incidence rate ratio of 0- to 11-month-old versus 12- to 23-month-old children was 2.1 (95% CI: 1.0-4.8) before and 1.3 (95% CI: 0.6-2.9) after the pandemic.

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.

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.

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study.

BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. INTERPRETATION: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics. FUNDING: European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation.

Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature.

BACKGROUND: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood. METHODS: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children. FINDINGS: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures. CONCLUSIONS: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis. FUNDING: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC.

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study.

Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics. Funding: EU Horizon 2020 grant 668303.

External validation of a multivariable prediction model for identification of pneumonia and other serious bacterial infections in febrile immunocompromised children.

OBJECTIVE: To externally validate and update the Feverkids tool clinical prediction model for differentiating bacterial pneumonia and other serious bacterial infections (SBIs) from non-SBI causes of fever in immunocompromised children. DESIGN: International, multicentre, prospective observational study embedded in PErsonalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union (PERFORM). SETTING: Fifteen teaching hospitals in nine European countries. PARTICIPANTS: Febrile immunocompromised children aged 0-18 years. METHODS: The Feverkids clinical prediction model predicted the probability of bacterial pneumonia, other SBI or no SBI. Model discrimination, calibration and diagnostic performance at different risk thresholds were assessed. The model was then re-fitted and updated. RESULTS: Of 558 episodes, 21 had bacterial pneumonia, 104 other SBI and 433 no SBI. Discrimination was 0.83 (95% CI 0.71 to 0.90) for bacterial pneumonia, with moderate calibration and 0.67 (0.61 to 0.72) for other SBIs, with poor calibration. After model re-fitting, discrimination improved to 0.88 (0.79 to 0.96) and 0.71 (0.65 to 0.76) and calibration improved. Predicted risk <1% ruled out bacterial pneumonia with sensitivity 0.95 (0.86 to 1.00) and negative likelihood ratio (LR) 0.09 (0.00 to 0.32). Predicted risk >10% ruled in bacterial pneumonia with specificity 0.91 (0.88 to 0.94) and positive LR 6.51 (3.71 to 10.3). Predicted risk <10% ruled out other SBIs with sensitivity 0.92 (0.87 to 0.97) and negative LR 0.32 (0.13 to 0.57). Predicted risk >30% ruled in other SBIs with specificity 0.89 (0.86 to 0.92) and positive LR 2.86 (1.91 to 4.25). CONCLUSION: Discrimination and calibration were good for bacterial pneumonia but poorer for other SBIs. The rule-out thresholds have the potential to reduce unnecessary investigations and antibiotics in this high-risk group.

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.

Sensitivity of ICD coding for sepsis in children-a population-based study.

Background: International Classification of Diseases 10th edition (ICD-10) is widely used to describe the burden of disease. Aim: To describe how well ICD-10 coding captures sepsis in children admitted to the hospital with blood culture-proven bacterial or fungal infection and systemic inflammatory response syndrome. Methods: Secondary analysis of a population-based, multicenter, prospective cohort study on children with blood culture-proven sepsis of nine tertiary pediatric hospitals in Switzerland. We compared the agreement of validated study data on sepsis criteria with ICD-10 coding abstraction obtained at the participating hospitals. Results: We analyzed 998 hospital admissions of children with blood culture-proven sepsis. The sensitivity of ICD-10 coding abstraction was 60% (95%-CI 57-63) for sepsis; 35% (95%-CI 31-39) for sepsis with organ dysfunction, using an explicit abstraction strategy; and 65% (95%-CI 61-69) using an implicit abstraction strategy. For septic shock, the sensitivity of ICD-10 coding abstraction was 43% (95%-CI 37-50). Agreement of ICD-10 coding abstraction with validated study data varied by the underlying infection type and disease severity (p < 0.05). The estimated national incidence of sepsis, inferred from ICD-10 coding abstraction, was 12.5 per 100,000 children (95%-CI 11.7-13.5) and 21.0 per 100,000 children (95%-CI 19.8-22.2) using validated study data. Conclusions: In this population-based study, we found a poor representation of sepsis and sepsis with organ dysfunction by ICD-10 coding abstraction in children with blood culture-proven sepsis when compared against a prospective validated research dataset. Sepsis estimates in children based on ICD-10 coding may thus severely underestimate the true prevalence of the disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s44253-023-00006-1.

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.