Imperial College London

DrJethroHerberg

Faculty of MedicineDepartment of Infectious Disease

Clinical Reader in Paediatric Infectious Disease
 
 
 
//

Contact

 

j.herberg

 
 
//

Location

 

231Wright Fleming WingSt Mary's Campus

//

Summary

 

Publications

Publication Type
Year
to

131 results found

Habgood-Coote D, Wilson C, Shimizu C, Barendregt AM, Philipsen R, Galassini R, Calle IR, Workman L, Agyeman PKA, Ferwerda G, Anderson ST, van den Berg JM, Emonts M, Carrol ED, Fink CG, de Groot R, Hibberd ML, Kanegaye J, Nicol MP, Paulus S, Pollard AJ, Salas A, Secka F, Schlapbach LJ, Tremoulet AH, Walther M, Zenz W, Pediatric Emergency Medicine Kawasaki Disease Research Group PEMKDRG, UK Kawasaki Genetics consortium, GENDRES consortium, EUCLIDS consortium, PERFORM consortium, Van der Flier M, Zar HJ, Kuijpers T, Burns JC, Martinón-Torres F, Wright VJ, Coin LJM, Cunnington AJ, Herberg JA, Levin M, Kaforou Met al., 2023, Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature, Med, Vol: 4, Pages: 635-654.e5, ISSN: 2666-6340

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.

Journal article

Cooray S, Price-Kuehne F, Hong Y, Omoyinmi E, Burleigh A, Gilmour KC, Ahmad B, Choi S, Bahar MW, Torpiano P, Gagunashvili A, Jensen B, Bellos E, Sancho-Shimizu V, Herberg JA, Mankad K, Kumar A, Kaliakatsos M, Worth AJJ, Eleftheriou D, Whittaker E, Brogan PAet al., 2023, Neuroinflammation, autoinflammation, splenomegaly and anemia caused by bi-allelic mutations in IRAK4, Frontiers in Immunology, Vol: 14

<jats:p>We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic mutations in <jats:italic>IRAK4</jats:italic>. IRAK-4 is a serine/threonine kinase with a pivotal role in innate immune signaling from toll-like receptors and production of pro-inflammatory cytokines. In humans, bi-allelic mutations in <jats:italic>IRAK4</jats:italic> result in IRAK-4 deficiency and increased susceptibility to pyogenic bacterial infections, but autoinflammation has never been described. We describe 5 affected patients from 2 unrelated families with compound heterozygous mutations in <jats:italic>IRAK4</jats:italic> (c.C877T (p.Q293*)/c.G958T (p.D320Y); and c.A86C (p.Q29P)/c.161 + 1G&amp;gt;A) resulting in severe systemic autoinflammation, massive splenomegaly and severe transfusion dependent anemia and, in 3/5 cases, severe neuroinflammation and seizures. IRAK-4 protein expression was reduced in peripheral blood mononuclear cells (PBMC) in affected patients. Immunological analysis demonstrated elevated serum tumor necrosis factor (TNF), interleukin (IL) 1 beta (IL-1β), IL-6, IL-8, interferon α2a (IFN-α2a), and interferon β (IFN-β); and elevated cerebrospinal fluid (CSF) IL-6 without elevation of CSF IFN-α despite perturbed interferon gene signature. Mutations were located within the death domain (DD; p.Q29P and splice site mutation c.161 + 1G&amp;gt;A) and kinase domain (p.Q293*/p.D320Y) of IRAK-4. Structure-based modeling of the DD mutation p.Q29P showed alteration in the alignment of a loop within the DD with loss of contact distance and hydrogen bond interactions with IRAK-1/2 within the myddosome complex. The kinase domain mutation p.D320Y was predicted to stabilize interactions within the kinase active site. While precise mechanisms of autoinflammation in NASA remain u

Journal article

Herberg J, Shah P, Voice M, Calvo-Bado L, Rivero Calle I, Morris S, Nijman R, Broderick C, De T, Eleftheriou I, Galassini R, Khanijau A, Kolberg L, Kolnik M, Rudzate A, Sagmeister M, Schweintzger N, Secka F, Thakker C, van der Velden F, Vermont C, Vincek K, Agyeman P, Cunnington A, de Groot R, Emonts M, Fidler K, Kuijpers T, Mommert-Tripon M, Brengel-Pesce K, Mallet F, Moll H, Paulus S, Pokorn M, Pollard A, Schlapbach L, Shen C-F, Tsolia M, Usuf E, Van Der Flier M, von Both U, Yeung S, Zavadska D, Zenz W, Wright V, Carrol E, Kaforou M, Martinon-Torres F, Fink C, Levin M, PERFORM consortiumet al., 2023, Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study, The Lancet Regional Health. Europe, Vol: 32, Pages: 1-17, ISSN: 2666-7762

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 4,611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3,477 (75%) had uncertain aetiology. 1,061 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

Journal article

Martin AJ, van der Velden FJS, von Both U, Tsolia MN, Zenz W, Sagmeister M, Vermont C, de Vries G, Kolberg L, Lim E, Pokorn M, Zavadska D, Martinón-Torres F, Rivero-Calle I, Hagedoorn NN, Usuf E, Schlapbach L, Kuijpers TW, Pollard AJ, Yeung S, Fink C, Voice M, Carrol E, Agyeman PKA, Khanijau A, Paulus S, De T, Herberg JA, Levin M, van der Flier M, de Groot R, Nijman R, Emonts Met al., 2023, External validation of a multivariable prediction model for identification of pneumonia and other serious bacterial infections in febrile immunocompromised children, Archives of Disease in Childhood, ISSN: 0003-9888

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.

Journal article

Willems E, Gloerich J, Suppers A, van der Flier M, van den Heuvel LP, van de Kar N, Philipsen RHLA, van Dael M, Kaforou M, Wright VJ, Herberg JA, Torres FM, Levin M, de Groot R, van Gool AJ, Lefeber DJ, Wessels HJCT, de Jonge MI, PERFORM consortiumet al., 2023, Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens, iScience, Vol: 26, ISSN: 2589-0042

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. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection.

Journal article

Jackson H, Menikou S, Hamilton MS, McArdle AJ, De T, Wright VJ, Cunnington AJ, Herberg JA, Levin M, Kaforou Met al., 2023, Using a multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children, The Lancet: Digital Health, ISSN: 2589-7500

Journal article

Nijman RG, Tan CD, Hagedoorn NN, Nieboer D, Herberg JA, Balode A, von Both U, Carrol ED, Eleftheriou I, Emonts M, van der Flier M, de Groot R, Kohlmaier B, Lim E, Martinón-Torres F, Pokorn M, Strle F, Tsolia M, Yeung S, Zachariasse JM, Zavadska D, Zenz W, Levin M, Vermont CL, Moll HA, Maconochie IK, PERFORM consortiumet al., 2023, Are children with prolonged fever at a higher risk for serious illness? A prospective observational study, Archives of Disease in Childhood, Vol: 108, Pages: 632-639, ISSN: 0003-9888

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. PATIENTS: Consecutive febrile children <18 years between January 2017 and April 2018. INTERVENTIONS: Children with fever ≥5 days and their risks for serious bacterial infection (SBI) were compared with children with fever <5 days, including diagnostic accuracy of non-specific symptoms, warning signs and C-reactive protein (CRP; mg/L). MAIN OUTCOME MEASURES: SBI and other non-infectious serious illness. RESULTS: 3778/35 705 (10.6%) of febrile children had fever ≥5 days. Incidence of SBI in children with fever ≥5 days was higher than in those with fever <5 days (8.4% vs 5.7%). Triage urgency, life-saving interventions and intensive care admissions were similar for fever ≥5 days and <5 days. Several warning signs had good rule in value for SBI with specificities >0.90, but were observed infrequently (range: 0.4%-17%). Absence of warning signs was not sufficiently reliable to rule out SBI (sensitivity 0.92 (95% CI 0.87-0.95), negative likelihood ratio (LR) 0.34 (0.22-0.54)). CRP <20 mg/L was useful for ruling out SBI (negative LR 0.16 (0.11-0.24)). There were 66 cases (1.7%) of non-infectious serious illnesses, including 21 cases of Kawasaki disease (0.6%), 28 inflammatory conditions (0.7%) and 4 malignancies. CONCLUSION: Children with prolonged fever have a higher risk of SBI, warranting a careful clinical assessment and diagnostic workup. Warning signs of SBI occurred infrequently but, if present, increased the likelihood of SBI. Although rare, clinicians should consider important non-infectious causes of prolonged fever.

Journal article

Iio K, Hanna H, Beykou M, Gale C, Herberg Jet al., 2023, The role of procalcitonin in predicting complications of Kawasaki disease, Archives of Disease in Childhood, ISSN: 0003-9888

Journal article

van der Velden FJS, Lim E, Gills L, Broadey J, Hayes L, Roberts E, Courtney J, Ball J, Herberg J, Galassini R, Emonts M, DIAMONDS consortiumet al., 2023, Biobanking and consenting to research: a qualitative thematic analysis of young people's perspectives in the North East of England, BMC Medical Ethics, Vol: 24, Pages: 1-11, ISSN: 1472-6939

BACKGROUND: Biobanking biospecimens and consent are common practice in paediatric research. We need to explore children and young people's (CYP) knowledge and perspectives around the use of and consent to biobanking. This will ensure meaningful informed consent can be obtained and improve current consent procedures. METHODS: We designed a survey, in co-production with CYP, collecting demographic data, views on biobanking, and consent using three scenarios: 1) prospective consent, 2) deferred consent, and 3) reconsent and assent at age of capacity. The survey was disseminated via the Young Person's Advisory Group North England (YPAGne) and participating CYP's secondary schools. Data were analysed using a qualitative thematic approach by three independent reviewers (including CYP) to identify common themes. Data triangulation occurred independently by a fourth reviewer. RESULTS: One hundred two CYP completed the survey. Most were between 16-18 years (63.7%, N = 65) and female (66.7%, N = 68). 72.3% had no prior knowledge of biobanking (N = 73). Acceptability of prospective consent for biobanking was high (91.2%, N = 93) with common themes: 'altruism', 'potential benefits outweigh individual risk', 'frugality', and '(in)convenience'. Deferred consent was also deemed acceptable in the large majority (84.3%, N = 86), with common themes: 'altruism', 'body integrity' and 'sample frugality'. 76.5% preferred to reconsent when cognitively mature enough to give assent (N = 78), even if parental consent was previously in place. 79.2% wanted to be informed if their biobanked biospecimen is reused (N = 80). CONCLUSION: Prospective and deferred consent acceptability for biobanking is high among CYP in the UK. Altruism, frugality, body integrity, and privacy are the most important themes. Clear communication and justification are paramount to obtain consent. Any CYP with capacity

Journal article

Tan CD, Vermont CL, Zachariasse JM, von Both U, Eleftheriou I, Emonts M, van der Flier M, Herberg J, Kohlmaier B, Levin M, Lim E, Maconochie IK, Martinon-Torres F, Nijman RG, Pokorn M, Rivero-Calle I, Tsolia M, Zenz W, Zavadska D, Moll HA, Carrol ED, PERFORM consortium Personalised Risk assessment in febrile children tooptimize Real-life Management across the European Unionet al., 2023, Emergency medical services utilisation among febrile children attending emergency departments across Europe: an observational multicentre study, European Journal of Pediatrics, Pages: 1-9, ISSN: 0340-6199

Children constitute 6-10% of all patients attending the emergency department (ED) by emergency medical services (EMS). However, discordant EMS use in children occurs in 37-61% with fever as an important risk factor. We aimed to describe EMS utilisation among febrile children attending European EDs. This study is part of an observational multicentre study assessing management and outcome in febrile children up to 18 years (MOFICHE) attending twelve EDs in eight European countries. Discordant EMS use was defined as the absence of markers of urgency including intermediate/high triage urgency, advanced diagnostics, treatment, and admission in children transferred by EMS. Multivariable logistic regression analyses were performed for the association between (1) EMS use and markers of urgency, and (2) patient characteristics and discordant EMS use after adjusting all analyses for the covariates age, gender, visiting hours, presenting symptoms, and ED setting. A total of 5464 (15%, range 0.1-42%) children attended the ED by EMS. Markers of urgency were more frequently present in the EMS group compared with the non-EMS group. Discordant EMS use occurred in 1601 children (29%, range 1-59%). Age and gender were not associated with discordant EMS use, whereas neurological symptoms were associated with less discordant EMS use (aOR 0.2, 95%CI 0.1-0.2), and attendance out of office hours was associated with more discordant EMS use (aOR 1.6, 95%CI 1.4-1.9). Settings with higher percentage of self-referrals to the ED had more discordant EMS use (p < 0.05).  Conclusion: There is large practice variation in EMS use in febrile children attending European EDs. Markers of urgency were more frequently present in children in the EMS group. However, discordant EMS use occurred in 29%. Further research is needed on non-medical factors influencing discordant EMS use in febrile children across Europe, so that pre-emptive strategies can be implemented. What is Known:

Journal article

Jackson HR, Miglietta L, Habgood-Coote D, D'Souza G, Shah P, Nichols S, Vito O, Powell O, Davidson MS, Shimizu C, Agyeman PKA, Beudeker CR, Brengel-Pesce K, Carrol ED, Carter MJ, De T, Eleftheriou I, Emonts M, Epalza C, Georgiou P, De Groot R, Fidler K, Fink C, van Keulen D, Kuijpers T, Moll H, Papatheodorou I, Paulus S, Pokorn M, Pollard AJ, Rivero-Calle I, Rojo P, Secka F, Schlapbach LJ, Tremoulet AH, Tsolia M, Usuf E, Van Der Flier M, Von Both U, Vermont C, Yeung S, Zavadska D, Zenz W, Coin LJM, Cunnington A, Burns JC, Wright V, Martinon-Torres F, Herberg JA, Rodriguez-Manzano J, Kaforou M, Levin Met al., 2023, Diagnosis of multisystem inflammatory syndrome in children by a whole-blood transcriptional signature, Journal of the Pediatric Infectious Diseases Society, Vol: 12, Pages: 322-331, ISSN: 2048-7207

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). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

Journal article

Morfopoulou S, Buddle S, Torres Montaguth OE, Atkinson L, Guerra-Assunção JA, Moradi Marjaneh M, Zennezini Chiozzi R, Storey N, Campos L, Hutchinson JC, Counsell JR, Pollara G, Roy S, Venturini C, Antinao Diaz JF, Siam A, Tappouni LJ, Asgarian Z, Ng J, Hanlon KS, Lennon A, McArdle A, Czap A, Rosenheim J, Andrade C, Anderson G, Lee JCD, Williams R, Williams CA, Tutill H, Bayzid N, Martin Bernal LM, Macpherson H, Montgomery K-A, Moore C, Templeton K, Neill C, Holden M, Gunson R, Shepherd SJ, Shah P, Cooray S, Voice M, Steele M, Fink C, Whittaker TE, Santilli G, Gissen P, Kaufer BB, Reich J, Andreani J, Simmonds P, Alrabiah DK, Castellano S, Chikowore P, Odam M, Rampling T, Houlihan C, Hoschler K, Talts T, Celma C, Gonzalez S, Gallagher E, Simmons R, Watson C, Mandal S, Zambon M, Chand M, Hatcher J, De S, Baillie K, Semple MG, DIAMONDS Consortium, PERFORM Consortium, ISARIC4C Investigators, Martin J, Ushiro-Lumb I, Noursadeghi M, Deheragoda M, Hadzic N, Grammatikopoulos T, Brown R, Kelgeri C, Thalassinos K, Waddington SN, Jacques TS, Thomson E, Levin M, Brown JR, Breuer Jet al., 2023, Genomic investigations of unexplained acute hepatitis in children, Nature, Vol: 617, Pages: 564-573, ISSN: 0028-0836

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Journal article

Patel H, Sintou A, Chowdhury RA, Rothery S, Iacob AO, Prasad S, Rainer PP, Martinón-Torres F, Sancho-Shimizu V, Shimizu C, Dummer K, Tremoulet AH, Burns JC, Sattler S, Levin M, DIAMONDS consortiumet al., 2023, Evaluation of autoantibody binding to cardiac tissue in multisystem inflammatory syndrome in children and COVID-19 vaccination-induced myocarditis., JAMA Network Open, Vol: 6, Pages: 1-11, ISSN: 2574-3805

IMPORTANCE: Cardiac dysfunction and myocarditis have emerged as serious complications of multisystem inflammatory syndrome in children (MIS-C) and vaccines against SARS-CoV-2. Understanding the role of autoantibodies in these conditions is essential for guiding MIS-C management and vaccination strategies in children. OBJECTIVE: To investigate the presence of anticardiac autoantibodies in MIS-C or COVID-19 vaccine-induced myocarditis. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study included children with acute MIS-C or acute vaccine myocarditis, adults with myocarditis or inflammatory cardiomyopathy, healthy children prior to the COVID-19 pandemic, and healthy COVID-19 vaccinated adults. Participants were recruited into research studies in the US, United Kingdom, and Austria starting January 2021. Immunoglobulin G (IgG), IgM, and IgA anticardiac autoantibodies were identified with immunofluorescence staining of left ventricular myocardial tissue from 2 human donors treated with sera from patients and controls. Secondary antibodies were fluorescein isothiocyanate-conjugated antihuman IgG, IgM, and IgA. Images were taken for detection of specific IgG, IgM, and IgA deposits and measurement of fluorescein isothiocyanate fluorescence intensity. Data were analyzed through March 10, 2023. MAIN OUTCOMES AND MEASURES: IgG, IgM and IgA antibody binding to cardiac tissue. RESULTS: By cohort, there were a total of 10 children with MIS-C (median [IQR] age, 10 [13-14] years; 6 male), 10 with vaccine myocarditis (median age, 15 [14-16] years; 10 male), 8 adults with myocarditis or inflammatory cardiomyopathy (median age, 55 [46-63] years; 6 male), 10 healthy pediatric controls (median age, 8 [13-14] years; 5 male), and 10 healthy vaccinated adults (all older than 21 years, 5 male). No antibody binding above background was observed in human cardiac tissue treated with sera from pediatric patients with MIS-C or vaccine myocarditis. One of the 8 adult patients with myocarditi

Journal article

Ho A, Orton R, Tayler R, Asamaphan P, Herder V, Davis C, Tong L, Smollett K, Manali M, Allan J, Rawlik K, McDonald SE, Vink E, Pollock L, Gannon L, Evans C, McMenamin J, Roy K, Marsh K, Divala T, Holden MTG, Lockhart M, Yirrell D, Currie S, O'Leary M, Henderson D, Shepherd SJ, Jackson C, Gunson R, MacLean A, McInnes N, Bradley-Stewart A, Battle R, Hollenbach JA, Henderson P, Odam M, Chikowore P, Oosthuyzen W, Chand M, Hamilton MS, Estrada-Rivadeneyra D, Levin M, Avramidis N, Pairo-Castineira E, Vitart V, Wilkie C, DIAMONDS Consortium, ISARIC4C Investigators, Palmarini M, Ray S, Robertson DL, da Silva Filipe A, Willett BJ, Breuer J, Semple MG, Turner D, Baillie JK, Thomson ECet al., 2023, Adeno-associated virus 2 infection in children with non-A-E hepatitis., Nature, Vol: 617, Pages: 555-563

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status.

Journal article

Channon-Wells S, Vito O, McArdle AJ, Seaby EG, Patel H, Shah P, Pazukhina E, Wilson C, Broderick C, D'Souza G, Keren I, Nijman RG, Tremoulet A, Munblit D, Ulloa-Gutierrez R, Carter MJ, Ramnarayan P, De T, Hoggart C, Whittaker E, Herberg JA, Kaforou M, Cunnington AJ, Blyuss O, Levin M, Chouli M, Hamadouche N, Ladj MS, Agrimbau Vázquez J, Carmona R, Collia AG, Ellis A, Natta D, Pérez L, Rubiños M, Veliz N, Yori S, Britton PN, Burgner DP, Carey E, Crawford NW, Giuliano H, McMinn A, Wong S, Wood N, Holter W, Krainz M, Ulreich R, Zurl C, Dehoorne J, Haerynck F, Hoste L, Schelstraete P, Vandekerckhove K, Willems J, Almeida Farias CG, Almeida FJ, Alves Leal I, Araujo da Silva AR, Araujo e Silva AE, Barreiro STA, Bomfim Prado da Silva DG, Cervi MC, dos Santos Naja Cardoso MV, Henriques Teixeira C, Jarovsky D, Martins Araujo J, Naaman Berezin E, Palazzi Sáfadi MA, Paternina-de la Ossa RA, Souza Vieira C, Dimitrova A, Ganeva M, Stefanov S, Telcharova-Mihaylovska A, Biggs CM, Lopez A, Scuccimarri R, Tan R, Wasserman S, Withington D, Ampuero C, Aravena J, Bustos B R, Casanova D, Cruces P, Diaz F, García-Salum T, Godoy L, Medina RA, Valenzuela Galaz G, Camacho-Moreno G, Avila-Aguero ML, Brenes-Chacón H, Camacho-Badilla K, Ivankovich-Escoto G, Naranjo-Zuniga G, Soriano-Fallas A, Ulloa-Gutierrez R, Yock-Corrales A, Amer MA, Abdelmeguid Y, Ahmed YHHZ, Badib A, Badreldin K, Elkhashab Y, Heshmat H, Hussein A, Mohamed Hussein AH, Ibrahim S, Shoman W, Yakout RM, Heinonen S, Angoulvant F, Belot A, Ouldali N, Beske F, Heep A, Masjosthusmann K, Reiter K, van den Heuvel I, von Both U, Agrafiotou A, Antachopoulos C, Charisi K, Eleftheriou I, Farmaki E, Fotis L, Kafetzis D, Koletsi P, Kourtesi K, Lampidi S, Liakopoulou T, Maritsi D, Michailidou E, Milioudi M, Mparmpounaki I, Papadimitriou E, Papaevangelou V, Roilides E, Tsiatsiou O, Tsolas G, Tsolia M, Vantsi P, Banegas Pineda LY, Borjas Aguilar KL, Cantillano Quintero EM, Ip P, Kwan MYW, Kwok J, Lau YL, To K, Wong JSC, David M, Farkas D, Kaet al., 2023, Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study, The Lancet Rheumatology, Vol: 5, Pages: e184-e199, ISSN: 2665-9913

BackgroundMultisystem 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.MethodsThe Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370.FindingsWe enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologica

Journal article

Kohlmaier B, Leitner M, Hagedoorn NN, Borensztajn DM, von Both U, Carrol ED, Emonts M, van der Flier M, de Groot R, Herberg J, Levin M, Lim E, Maconochie IK, MartinonTorres F, Nijman RG, Pokorn M, RiveroCalle I, Tan CD, Maria T, Vermont CL, Zachariasse JM, Zavadska D, Moll HA, Zenz Wet al., 2023, European study confirms the combination of fever and petechial rash as an important warning sign for childhood sepsis and meningitis, Acta Paediatrica, ISSN: 0803-5253

Journal article

Wittmann S, Jorgensen R, Oostenbrink R, Moll H, Herberg J, Levin M, Maconochie I, Nijman Ret al., 2023, Heart rate and respiratory rate in predicting risk of serious bacterial infection in febrile children given antipyretics: prospective observational study, European Journal of Pediatrics, Vol: 182, Pages: 2205-2214, ISSN: 0340-6199

Clinical algorithms used in the assessment of febrile children in the Paediatric Emergency Departments are commonly based on threshold values for vital signs, which in children with fever are often outside the normal range. Our aim was to assess the diagnostic value of heart and respiratory rate for serious bacterial infection (SBI) in children after temperature lowering following administration of antipyretics. A prospective cohort of children presenting with fever between June 2014 and March 2015 at the Paediatric Emergency Department of a large teaching hospital in London, UK, was performed. Seven hundred forty children aged 1 month–16 years presenting with a fever and ≥ 1 warning signs of SBI given antipyretics were included. Tachycardia or tachypnoea were defined by different threshold values: (a) APLS threshold values, (b) age-specific and temperature-adjusted centiles charts and (c) relative difference in z-score. SBI was defined by a composite reference standard (cultures from a sterile site, microbiology and virology results, radiological abnormalities, expert panel). Persistent tachypnoea after body temperature lowering was an important predictor of SBI (OR 1.92, 95% CI 1.15, 3.30). This effect was only observed for pneumonia but not other SBIs. Threshold values for tachypnoea > 97th centile at repeat measurement achieved high specificity (0.95 (0.93, 0.96)) and positive likelihood ratios (LR + 3.25 (1.73, 6.11)) and may be useful for ruling in SBI, specifically pneumonia. Persistent tachycardia was not an independent predictor of SBI and had limited value as a diagnostic test.

Journal article

Kuiper R, Wright VJ, Habgood-Coote D, Shimizu C, Huigh D, Tremoulet AH, van Keulen D, Hoggart CJ, Rodriguez-Manzano J, Herberg JA, Kaforou M, Tempel D, Burns JC, Levin Met al., 2023, Bridging a diagnostic Kawasaki disease classifier from a microarray platform to a qRT-PCR assay, Pediatric Research, Vol: 93, Pages: 559-569, ISSN: 0031-3998

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. Here, we bridged this microarray-based classifier to a clinically applicable quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay: the Kawasaki Disease Gene Expression Profiling (KiDs-GEP) classifier. METHODS: We designed and optimized a qRT-PCR assay and applied it to a subset of samples previously used for the classifier discovery to reweight the original classifier. RESULTS: The performance of the KiDs-GEP classifier was comparable to the original classifier with a cross-validated area under the ROC curve of 0.964 [95% CI: 0.924-1.00] vs 0.992 [95% CI: 0.978-1.00], respectively. Both classifiers demonstrated similar trends over various disease conditions, with the clearest distinction between individuals diagnosed with KD vs viral infections. CONCLUSION: We successfully bridged the microarray-based classifier into the KiDs-GEP classifier, a more rapid and more cost-efficient qRT-PCR assay, bringing a diagnostic test for KD closer to the hospital clinical laboratory. IMPACT: A diagnostic test is needed for Kawasaki disease and is currently not available. We describe the development of a One-Step multiplex qRT-PCR assay and the subsequent modification (i.e., bridging) of the microarray-based host response classifier previously described by Wright et al. The bridged KiDs-GEP classifier performs well in discriminating Kawasaki disease patients from febrile controls. This host response clinical test for Kawasaki disease can be adapted to the hospital clinical laboratory.

Journal article

Eleftheriou D, Moraes YC, Purvis C, Pursell M, Morillas MM, Kahn R, Mossberg M, Kucera F, Tulloh R, Standing JF, Swallow V, McCormack R, Herberg J, Levin M, Wan M, Klein N, Connon R, Walker AS, Brogan Pet al., 2023, Multi-centre, randomised, open-label, blinded endpoint assessed, trial of corticosteroids plus intravenous immunoglobulin (IVIG) and aspirin, versus IVIG and aspirin for prevention of coronary artery aneurysms (CAA) in Kawasaki disease (KD): the KD CAA prevention (KD-CAAP) trial protocol, TRIALS, Vol: 24

Journal article

Krupickova S, Voges I, Mohiaddin R, Bautista C, Li W, Herberg J, Daubeney PEF, Pennell DJ, Fraisse Aet al., 2023, Short-term outcome of late gadolinium changes detected on cardiovascular magnetic resonance imaging following coronavirus disease 2019 Pfizer/BioNTech vaccine-related myocarditis in adolescents, PEDIATRIC RADIOLOGY, ISSN: 0301-0449

Journal article

Dewez JE, Pembrey L, Nijman RG, Del Torso S, Grossman Z, Hadjipanayis A, Van Esso D, Lim E, Emonts M, Burns J, Gras-LeGuen C, Kohlfuerst D, Dornbusch HJ, Brengel-Pesce K, Mallet F, von Both U, Tsolia M, Eleftheriou I, Zavadska D, de Groot R, van der Flier M, Moll H, Hagedoorn N, Borensztajn D, Oostenbrink R, Kuijpers T, Pokorn M, Vincek K, Martinón-Torres F, Rivero I, Agyeman P, Carrol ED, Paulus S, Cunnington A, Herberg J, Levin M, Mujkić A, Geitmann K, Da Dalt L, Valiulis A, Lapatto R, Syridou G, Altorjai P, Torpiano P, Størdal K, Illy K, Mazur A, Spreitzer MV, Rios J, Wyder C, Romankevych I, Basmaci R, Ibanez-Mico S, Yeung Set al., 2022, Availability and use of rapid diagnostic tests for the management of acute childhood infections in Europe: A cross-sectional survey of paediatricians., PLoS One, Vol: 17, Pages: 1-22, ISSN: 1932-6203

BACKGROUND: Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability. METHODS AND FINDINGS: A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics. CONCLUSION: There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicia

Journal article

Neumann E, Schreeck F, Herberg J, Aigrain EJ, Maitland-van der Zee AH, Perez-Martinez A, Hawcutt DB, Schaeffeler E, Rane A, de Wildt SN, Schwab Met al., 2022, How paediatric drug development and use could benefit from OMICs: A c4c expert group white paper, British Journal of Clinical Pharmacology, Vol: 88, Pages: 5017-5033, ISSN: 0306-5251

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates and infants, is limited by a paucity of good-quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts by complementary information about targeted and nontargeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis-generating, allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a subdivision into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as are the type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, noninvasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (eg liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, such as artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to the identification complex phenotypes and subpopulations of patients to improve the development of medicines for children with potential economic advantages.

Journal article

Hagedoorn NN, Boeddha NP, Kohlfuerst DS, Anderson S, Carrol ED, Agapow P, van der Flier M, Hazelzet J, Herberg J, Kuijpers T, Levin M, Martinon-Torres F, van Rijswijk A, Schlapbach LJ, Vermont C, Zenz W, Dik WA, Driessen G, Emonts M, EUCLIDS Consortiumet al., 2022, Hemostasis proteins in invasive meningococcal and nonmeningococcal infections: a prospective multicenter study., Pediatric Critical Care Medicine, Vol: 23, Pages: e543-e554, ISSN: 1529-7535

OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens (Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus, and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012-2016) with community-acquired infections due to meningococci (n = 83), pneumococci (n = 64), S. aureus (n = 50), and GAS (n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score). Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens (p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic

Journal article

Boeddha NPP, Atkins L, de Groot R, Driessen G, Hazelzet J, Zenz W, Carrol EDD, Anderson STT, Martinon-Torres F, Agyeman PKA, Galassini R, Herberg J, Levin M, Schlapbach LJJ, Emonts Met al., 2022, Group A streptococcal disease in paediatric inpatients: a European perspective, EUROPEAN JOURNAL OF PEDIATRICS, ISSN: 0340-6199

Journal article

Tan CD, van der Walle EEPL, Vermont CL, von Both U, Carrol ED, Eleftheriou I, Emonts M, van der Flier M, de Groot R, Herberg J, Kohlmaier B, Levin M, Lim E, Maconochie IK, Martinon-Torres F, Nijman RG, Pokorn M, Rivero-Calle I, Tsolia M, Yeung S, Zenz W, Zavadska D, Moll HAet al., 2022, Correction to: Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study, European Journal of Pediatrics, Vol: 181, Pages: 4211-4214, ISSN: 0340-6199

Journal article

van der Velden FJS, de Vries G, Martin A, Lim E, von Both U, Kolberg L, Carrol ED, Khanijau A, Herberg JA, De T, Galassini R, Kuijpers TW, Martinon-Torres F, Rivero-Calle I, Vermont CL, Hagedoorn NN, Pokorn M, Pollard AJ, Schlapbach LJ, Tsolia M, Elefhteriou I, Yeung S, Zavadska D, Fink C, Voice M, Zenz W, Kohlmaier B, Agyeman PKA, Usuf E, Secka F, de Groot R, Levin M, van der Flier M, Emonts Met al., 2022, Febrile illness in high-risk children: a prospective, international observational study, EUROPEAN JOURNAL OF PEDIATRICS, ISSN: 0340-6199

Journal article

Tan CD, van der Walle EEPL, Vermont CL, von Both U, Carrol ED, Eleftheriou I, Emonts M, van der Flier M, de Groot R, Herberg J, Kohlmaier B, Levin M, Lim E, Maconochie IK, Martinon-Torres F, Nijman RG, Pokorn M, Rivero-Calle I, Tsolia M, Yeung S, Zenz W, Zavadska D, Moll HA, PERFORM consortium Personalised Risk assessment in febrile children to optimize Real-life Management across the European Unionet al., 2022, Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study, European Journal of Pediatrics, Vol: 181, Pages: 4199-4209, ISSN: 0340-6199

Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. There is practice variation in management due to differences in guidelines and their usage and adherence. We aimed to assess whether management in febrile children below 3 months attending European Emergency Departments (EDs) was according to the guidelines for fever. This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0-18 years) attending twelve EDs in eight European countries. In febrile children below 3 months (excluding bronchiolitis), we analyzed actual management compared to the guidelines for fever. Ten EDs applied the (adapted) NICE guideline, and two EDs applied local guidelines. Management included diagnostic tests, antibiotic treatment, and admission. We included 913 children with a median age of 1.7 months (IQR 1.0-2.3). Management per ED varied as follows: use of diagnostic tests 14-83%, antibiotic treatment 23-54%, admission 34-86%. Adherence to the guideline was 43% (374/868) for blood cultures, 29% (144/491) for lumbar punctures, 55% (270/492) for antibiotic prescriptions, and 67% (573/859) for admission. Full adherence to these four management components occurred in 15% (132/868, range 0-38%), partial adherence occurred in 56% (484/868, range 35-77%). CONCLUSION: There is large practice variation in management. The guideline adherence was limited, but highest for admission which implies a cautious approach. Future studies should focus on guideline revision including new biomarkers in order to optimize management in young febrile children. WHAT IS KNOWN: • Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. • There is practice variation in management of young febrile children due to differences in guideline

Journal article

Pennisi I, Moniri A, Miscourides N, Miglietta L, Moser N, Habgood-Coote D, Herberg JA, Levin M, Kaforou M, Rodriguez-Manzano J, Georgiou Pet al., 2022, Discrimination of bacterial and viral infection using host-RNA signatures integrated in a lab-on-chip platform, BIOSENSORS & BIOELECTRONICS, Vol: 216, ISSN: 0956-5663

Journal article

Tan CD, El Ouasghiri S, von Both U, Carrol ED, Emonts M, van der Flier M, de Groot R, Herberg J, Kohlmaier B, Levin M, Lim E, Maconochie IK, Martinon-Torres F, Nijman RG, Pokorn M, Rivero-Calle I, Tsolia M, Vermont CL, Zenz W, Zavadska D, Moll HA, Zachariasse JM, PERFORM consortium Personalised Risk assessment in febrile children to optimise Real-life Management across the European Unionet al., 2022, Sex differences in febrile children with respiratory symptoms attending European emergency departments: An observational multicenter study., PLoS One, Vol: 17, Pages: 1-11, ISSN: 1932-6203

OBJECTIVE: To assess sex differences in presentation and management of febrile children with respiratory symptoms attending European Emergency Departments. DESIGN AND SETTING: An observational study in twelve Emergency Departments in eight European countries. PATIENTS: Previously healthy children aged 0-<18 years with fever (≥ 38°C) at the Emergency Department or in the consecutive three days before Emergency Department visit and respiratory symptoms were included. MAIN OUTCOME MEASURES: The main outcomes were patient characteristics and management defined as diagnostic tests, treatment and admission. Descriptive statistics were used for patient characteristics and management stratified by sex. Multivariable logistic regression analyses were performed for the association between sex and management with adjustment for age, disease severity and Emergency Department. Additionally, subgroup analyses were performed in children with upper and lower respiratory tract infections and in children below five years. RESULTS: We included 19,781 febrile children with respiratory symptoms. The majority were boys (54%), aged 1-5 years (58%) and triaged as low urgent (67%). Girls presented less frequently with tachypnea (15% vs 16%, p = 0.002) and increased work of breathing (8% vs 12%, p<0.001) compared with boys. Girls received less inhalation medication than boys (aOR 0.82, 95% CI 0.74-0.90), but received antibiotic treatment more frequently than boys (aOR 1.09, 95% CI 1.02-1.15), which is associated with a higher prevalence of urinary tract infections. Amongst children with a lower respiratory tract infection and children below five years girls received less inhalation medication than boys (aOR 0.77, 95% CI 0.66-0.89; aOR 0.80, 95% CI 0.72-0.90). CONCLUSIONS: Sex differences concerning presentation and management are present in previously healthy febrile children with respiratory symptoms presenting to the Emergency Department. Future research should focus on whethe

Journal article

Piccinelli E, Bautista-Rodriguez C, Herberg J, Kang H, Krupickova S, Altamar IB, Moscatelli S, Sabatino J, Josen M, Paredes J, Whittaker E, Singh Y, Fraisse A, Di Salvo Get al., 2022, Segmental and global longitudinal strain differences between Kawasaki disease and multi-system inflammatory syndrome in children, CARDIOLOGY IN THE YOUNG, ISSN: 1047-9511

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00476387&limit=30&person=true