Publications by authors named "Jethro A Herberg"

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.

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  • The study assesses the effectiveness of white blood cell count (WBC) in predicting serious bacterial infections (SBI) in children compared to C reactive protein (CRP) and absolute neutrophil count (ANC).
  • After analyzing data from over 17,000 febrile children across multiple European emergency departments, WBC showed poor predictive value with a sensitivity of 56% and specificity of 74% for WBC >15.
  • The findings suggest that CRP is a better marker for identifying SBI in children, and WBC should only be used for specific cases rather than as a routine diagnostic tool.
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Background: Whole blood host transcript signatures show great potential for diagnosis of infectious and inflammatory illness, with most published signatures performing binary classification tasks. Barriers to clinical implementation include validation studies, and development of strategies that enable simultaneous, multiclass diagnosis of febrile illness based on gene expression.

Methods: We validated five distinct diagnostic signatures for paediatric infectious diseases in parallel using a single NanoString nCounter® experiment.

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Background: Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection.

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  • Induced hypothermia, a common treatment for hypoxic-ischemic encephalopathy (HIE), is less effective in South Asia despite the region having a high disease burden compared to high-income countries.
  • This study aimed to compare blood genome expression profiles of neonates with HIE from high-income countries (Italy) and low-income countries (India, Sri Lanka, and Bangladesh) to understand differences in outcomes.
  • The findings revealed variations in blood expression profiles at birth linked to adverse outcomes and highlighted differing responses to treatment in the two cohorts of neonates.
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  • Differentiating between self-resolving viral infections and bacterial infections in children with fever is challenging and can lead to improper use of antibiotics; this study aims to identify host protein biomarkers that could help distinguish between these infections.
  • The research used a multi-cohort approach and high-dimensional proteomic datasets from various European studies to shortlist potential protein biomarkers by performing several analyses and tests on collected samples.
  • A sparse protein signature was successfully identified, which distinguishes between bacterial and viral infections, and its effectiveness was validated through Luminex assays and disease risk score calculations.
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  • A novel autoinflammatory syndrome named NASA has been identified, characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia, caused by bi-allelic mutations in the IRAK-4 gene.
  • Five patients from two families exhibited severe symptoms including massive splenomegaly and anemia, with some also experiencing neuroinflammation and seizures, linked to specific IRAK-4 mutations affecting its catalytic and regulatory domains.
  • Immunological findings revealed elevated pro-inflammatory cytokines in both serum and cerebrospinal fluid, suggesting that dysfunction in IRAK-4 leads to uncontrolled inflammation despite changes in immune signaling pathways.
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  • The study aimed to validate and update the Feverkids tool, a clinical prediction model designed to help differentiate between bacterial pneumonia, serious bacterial infections (SBIs), and non-SBI causes of fever in immunocompromised children.
  • Conducted in 15 hospitals across nine European countries, the study involved observational data from febrile immunocompromised children aged 0-18 years.
  • Results showed improved accuracy in predicting bacterial pneumonia and SBIs after model updates, indicating effective thresholds that can help minimize unnecessary medical interventions and antibiotic use.
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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.

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Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection.

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Background: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections.

Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138).

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Objectives: To describe the characteristics and clinical outcomes of children with fever ≥5 days presenting to emergency departments (EDs).

Design: Prospective observational study.

Setting: 12 European EDs.

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Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments.

Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort.

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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.

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The unmet clinical need for accurate point-of-care (POC) diagnostic tests able to discriminate bacterial from viral infection demands a solution that can be used both within healthcare settings and in the field, and that can also stem the tide of antimicrobial resistance. Our approach to solve this problem combine the use of host gene signatures with our Lab-on-a-Chip (LoC) technology enabling low-cost POC expression analysis to detect Infectious Disease. Transcriptomics have been extensively investigated as a potential tool to be implemented in the diagnosis of infectious disease.

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Infection with SARS-CoV-2 has highly variable clinical manifestations, ranging from asymptomatic infection through to life-threatening disease. Host whole blood transcriptomics can offer unique insights into the biological processes underpinning infection and disease, as well as severity. We performed whole blood RNA Sequencing of individuals with varying degrees of COVID-19 severity.

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Background: Kawasaki disease (KD) is a systemic vasculitis that mainly affects children under 5 years of age. Up to 30% of patients develop coronary artery abnormalities, which are reduced with early treatment. Timely diagnosis of KD is challenging but may become more straightforward with the recent discovery of a whole-blood host response classifier that discriminates KD patients from patients with other febrile conditions.

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Background: Pediatric osteoarticular infections (POAIs) are serious diseases requiring early diagnosis and treatment.

Methods: In this prospective multicenter cohort study, children with POAIs were selected from the European Union Childhood Life-threatening Infectious Diseases Study (EUCLIDS) database to analyze their demographic, clinical, and microbiological data.

Results: A cohort of 380 patients with POAIs, 203 with osteomyelitis (OM), 158 with septic arthritis (SA), and 19 with both OM and SA, was analyzed.

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Importance: A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 is hypothesized to play a role in the pathogenesis of invasive infection, but studies in sepsis are lacking.

Objectives: To study A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 protein level in pediatric sepsis and to study the association with outcome.

Design: Data from two prospective cohort studies.

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Background: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We aimed to derive and validate a blood transcriptional signature to detect viral infections, including COVID-19, among adults with suspected infection who presented to the emergency department.

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The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI. We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0- <16 years: the Alder Hey emergency department ( = 1,120), Alder Hey pediatric intensive care unit ( = 355), Erasmus emergency department ( = 1,993), Maasstad emergency department ( = 714) and St.

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Background: Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low-income and middle-income countries is unclear. We aimed to examine whether therapeutic hypothermia alongside optimal supportive intensive care reduces death or moderate or severe disability after neonatal encephalopathy in south Asia.

Methods: We did a multicountry open-label, randomised controlled trial in seven tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh.

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Objective: (1) To derive reference values for the Shock Index (heart rate/systolic blood pressure) based on a large emergency department (ED) population of febrile children and (2) to determine the diagnostic value of the Shock Index for serious illness in febrile children.

Design/setting: Observational study in 11 European EDs (2017-2018).

Patients: Febrile children with measured blood pressure.

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