Imperial College London

ProfessorMichaelLevin

Faculty of MedicineDepartment of Infectious Disease

Chair in Paediatrics & International Child Health
 
 
 
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Contact

 

+44 (0)20 7594 3760m.levin Website

 
 
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Location

 

233Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
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377 results found

Yeoh S, Estrada-Rivadeneyra D, Jackson H, Keren I, Galassini R, Cooray S, Shah P, Agyeman P, Basmaci R, Carrol E, Emonts M, Fink C, Kuijpers T, Martinon-Torres F, Mommert-Tripon M, Paulus S, Pokorn M, Rojo P, Romani L, Schlapbach L, Schweintzger N, Shen C-F, Tsolia M, Usuf E, van der Flier M, Vermont C, von Both U, Yeung S, Zavadska D, Coin L, Cunnington A, Herberg J, Levin M, Kaforou M, Hamilton S, PERFORM, DIAMONDS and UK KD Genetic Consortiaet al., 2024, Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children From Other Pediatric Infectious and Inflammatory Diseases., Pediatr Infect Dis J

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.

Journal article

Sanchez-Pinto LN, Bennett TD, DeWitt PE, Russell S, Rebull MN, Martin B, Akech S, Albers DJ, Alpern ER, Balamuth F, Bembea M, Chisti MJ, Evans I, Horvat CM, Jaramillo-Bustamante JC, Kissoon N, Menon K, Scott HF, Weiss SL, Wiens MO, Zimmerman JJ, Argent AC, Sorce LR, Schlapbach LJ, Watson RS, Society of Critical Care Medicine Pediatric Sepsis Definition Task Force, Biban P, Carrol E, Chiotos K, Flauzino De Oliveira C, Hall MW, Inwald D, Ishimine P, Levin M, Lodha R, Nadel S, Nakagawa S, Peters MJ, Randolph AG, Ranjit S, Souza DC, Tissieres P, Wynn JLet al., 2024, Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock., JAMA

IMPORTANCE: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. OBJECTIVE: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. EXPOSURE: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. MAIN OUTCOMES AND MEASURES: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. RESULTS: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as cr

Journal article

Schlapbach LJ, Watson RS, Sorce LR, Argent AC, Menon K, Hall MW, Akech S, Albers DJ, Alpern ER, Balamuth F, Bembea M, Biban P, Carrol ED, Chiotos K, Chisti MJ, DeWitt PE, Evans I, Flauzino de Oliveira C, Horvat CM, Inwald D, Ishimine P, Jaramillo-Bustamante JC, Levin M, Lodha R, Martin B, Nadel S, Nakagawa S, Peters MJ, Randolph AG, Ranjit S, Rebull MN, Russell S, Scott HF, de Souza DC, Tissieres P, Weiss SL, Wiens MO, Wynn JL, Kissoon N, Zimmerman JJ, Sanchez-Pinto LN, Bennett TD, Society of Critical Care Medicine Pediatric Sepsis Definition Task Forceet al., 2024, International Consensus Criteria for Pediatric Sepsis and Septic Shock., JAMA

IMPORTANCE: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. OBJECTIVE: To update and evaluate criteria for sepsis and septic shock in children. EVIDENCE REVIEW: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. FINDINGS: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coa

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, Vol: 109, Pages: 59-66, 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

Moradi Marjaneh M, Challenger J, salas A, Gómez-Carballa A, Sivananthan A, Rivero-Calle I, Barbeito-Castiñeiras G, Foo C, Wu Y, Liew F, Jackson H, Habgood-Coote D, D'Souza G, Nichols S, Wright V, Levin M, Kaforou M, Thwaites R, Okell L, Martinon-Torres F, Cunnington A, PERFORM Consortium, GEN-COVID Study Groupet al., 2023, Analysis of blood and nasal epithelial transcriptomes to identify mechanisms associated with control of SARS-CoV-2 viral load in the upper respiratory tract, Journal of Infection, Vol: 87, Pages: 538-550, ISSN: 0163-4453

Objectives:The amount of SARS-CoV-2 detected in the upper respiratory tract (URT viral load) is a key driver of transmission of infection. Current evidence suggests that mechanisms constraining URT viral load are different from those controlling lower respiratory tract viral load and disease severity. Understanding such mechanisms may help to develop treatments and vaccine strategies to reduce transmission. Combining mathematical modelling of URT viral load dynamics with transcriptome analyses we aimed to identify mechanisms controlling URT viral load.Methods:COVID-19 patients were recruited in Spain during the first wave of the pandemic. RNA sequencing of peripheral blood and targeted NanoString nCounter transcriptome analysis of nasal epithelium were performed and gene expression analysed in relation to paired URT viral load samples collected within 15 days of symptom onset. Proportions of major immune cells in blood were estimated from transcriptional data using computational differential estimation. Weighted correlation network analysis (adjusted for cell proportions) and fixed transcriptional repertoire analysis were used to identify associations with URT viral load, quantified as standard deviations (z-scores) from an expected trajectory over time.ResultsEighty-two subjects (50% female, median age 54 years (range 3–73)) with COVID-19 were recruited. Paired URT viral load samples were available for 16 blood transcriptome samples, and 17 respiratory epithelial transcriptome samples. Natural Killer (NK) cells were the only blood cell type significantly correlated with URT viral load z-scores (r = −0.62, P = 0.010). Twenty-four blood gene expression modules were significantly correlated with URT viral load z-score, the most significant being a module of genes connected around IFNA14 (Interferon Alpha-14) expression (r = −0.60, P = 1e-10). In fixed repertoire analysis, prostanoid-related gene expression was significantly associated with higher vir

Journal article

Jackson HR, Zandstra J, Menikou S, Hamilton MS, McArdle AJ, Fischer R, Thorne AM, Huang H, Tanck MW, Jansen MH, De T, Agyeman PKA, Von Both U, Carrol ED, Emonts M, Eleftheriou I, Van der Flier M, Fink C, Gloerich J, De Groot R, Moll HA, Pokorn M, Pollard AJ, Schlapbach LJ, Tsolia MN, Usuf E, Wright VJ, Yeung S, Zavadska D, Zenz W, Coin LJM, Casals-Pascual C, Cunnington AJ, Martinon-Torres F, Herberg JA, de Jonge MI, Levin M, Kuijpers TW, Kaforou M, PERFORM consortiumet al., 2023, 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, The Lancet: Digital Health, Vol: 5, Pages: e774-e785, ISSN: 2589-7500

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-

Journal article

Kolberg L, Khanijau A, van der Velden F, Herberg J, De T, Galassini R, Cunnington A, Wright V, Shah P, Kaforou M, Wilson C, Kuijpers T, Martinón-Torres F, Rivero-Calle I, Moll H, Vermont C, Pokorn M, Kolnik M, Pollard A, Agyeman P, Schlapbach L, Tsolia M, Yeung S, Zavadska D, Zenz W, Schweintzger N, Van Der Flier M, de Groot R, Usuf E, Voice M, Calvo-Bado L, Mallet F, Fidler K, Levin M, Carrol E, Emonts M, von Both U, The PERFORM Consortiumet al., 2023, AWaRe-ness of antimicrobial stewardship challenges in pediatric emergency care: results from the PERFORM study assessing consistency and appropriateness of antibiotic prescribing across Europe, Clinical Infectious Diseases, ISSN: 1058-4838

ObjectivesOptimization of antimicrobial stewardship (AMS) is key to tackling antimicrobial resistance (AMR), which is exacerbated by over-prescription of antibiotics in pediatric Emergency Departments (EDs). We described patterns of empiric antibiotic use in European EDs, and characterized appropriateness and consistency of prescribing.MethodsBetween August 2016 and December 2019 febrile children attending the ED in nine 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 WHO AWaRe.ResultsOf 2130 febrile episodes (excluding children with non-bacterial/non-viral phenotypes), 1549 (72.7%) were assigned a ‘bacterial’ and 581 (27.3%) a ‘viral’ phenotype. A total of 1318/1549 (85.1%) episodes with a ‘bacterial’ and 269/581 (46.3%) with a ‘viral’ phenotype received empiric systemic antibiotics (first two days of admission). Of those, the majority (87.8% in ‘bacterial’ and 87.0% in ‘viral’ group) received parenteral antibiotics. The top three antibiotics prescribed were third-generation cephalosporins, penicillins and penicillin/beta-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the ‘viral’ group 216/269 (80.3%) received ≥ one Watch antibiotic.ConclusionsDifferentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial over-prescription 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

Journal article

Wang H, Shimizu C, Bainto E, Hamilton S, Jackson HR, Estrada-Rivadeneyra D, Kaforou M, Levin M, Pancheri JM, Dummer KB, Tremoulet AH, Burns JCet al., 2023, Subgroups of children with Kawasaki disease: a data-driven cluster analysis, LANCET CHILD & ADOLESCENT HEALTH, Vol: 7, Pages: 697-707, ISSN: 2352-4642

Journal article

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

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 MG, Schweintzger NA, Secka F, Thakker C, van der Velden F, Vermont C, Vincek K, Agyeman PKA, Cunnington AJ, De Groot R, Emonts M, Fidler K, Kuijpers TW, Mommert-Tripon M, Brengel-Pesce K, Mallet F, Moll H, Paulus S, Pokorn M, Pollard A, Schlapbach LJ, Shen C-F, Tsolia M, Usuf E, van der Flier M, von Both U, Yeung S, Zavadska D, Zenz W, Wright V, Carrol ED, Kaforou M, Martinon-Torres F, Fink C, Levin M, Herberg Jet al., 2023, Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study, LANCET REGIONAL HEALTH-EUROPE, Vol: 32, ISSN: 2666-7762

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, Vol: 182, Pages: 3939-3947, 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

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

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

Pinto Pereira SM, Mensah A, Nugawela MD, Stephenson T, Ladhani SN, Dalrymple E, Dudley J, McOwat K, Simmons R, Heyman I, Segal T, Semple MG, Xu L, CLoCk Consortium, Shafran Ret al., 2023, Long COVID in children and young after infection or reinfection with the Omicron variant: a prospective observational study, Journal of Pediatrics, Vol: 259, Pages: 113463-113463, ISSN: 0022-3476

To describe the prevalence of long COVID in children infected for the first time (n = 332) or reinfected (n = 243) with Omicron compared with test-negative children (n = 311). Overall, 12%-16% of those infected with Omicron met the research definition of long COVID at 3 and 6 months after infection, with no evidence of difference between cases of first positive and reinfected (Pχ2 = 0.17).

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

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

Ouldali N, Son MBF, McArdle AJ, Vito O, Vaugon E, Belot A, Leblanc CL, Murray NL, Patel MM, Levin M, Randolph AG, Angoulvant Fet al., 2023, Immunomodulatory Therapy for MIS-C, PEDIATRICS, Vol: 152, ISSN: 0031-4005

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

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

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

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

Moradi Marjaneh M, Challenger J, Salas A, Gómez-Carballa A, Sivananthan A, Rivero-Calle I, Barbeito-Castiñeiras G, Foo C, Wu Y, Liew F, Jackson H, Habgood-Coote D, DSouza G, Nichols S, Wright V, Levin M, Kaforou M, Thwaites R, Okell L, Martinón-Torres F, Cunnington A, GEN-COVID Study Group, PERFORM Consortiumet al., 2023, Analysis of blood and nasal epithelial transcriptomes to identify mechanisms associated with control of SARS-CoV-2 viral load in the upper respiratory tract

Working paper

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

Takele Y, Mulaw T, Adem E, Womersley R, Kaforou M, Franssen SU, Michael levin, Taylor GP, Müller I, Cotton JA, Kropf Pet al., 2023, Recurrent visceral leishmaniasis relapses in HIV co-infected patients are characterised by less efficient immune responses and higher parasite load, iScience, Vol: 26, Pages: 1-22, ISSN: 2589-0042

Visceral leishmaniasis (VL) and HIV co-infection (VL/HIV) has emerged as a significant public health problem in Ethiopia, with up to 30% of patients with VL co-infected with HIV. These patients suffer from recurrent VL relapses and increased mortality. Those with a previous history of VL relapses (recurrent VL/HIV) experience increased VL relapses as compared to patients with HIV presenting with their first episode of VL (primary VL/HIV). Our aim was to identify drivers that account for the higher rate of VL relapses in patients with recurrent VL/HIV (n = 28) as compared to primary VL/HIV (n = 21). Our results show that the relapse-free survival in patients with recurrent VL/HIV was shorter, that they had higher parasite load, lower weight gain, and lower recovery of all blood cell lineages. Their poorer prognosis was characterized by lower production of IFN-gamma, lower CD4+ T cell counts, and higher expression of programmed cell death protein 1 (PD1) on T cells.

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., 2023, Febrile illness in high-risk children: a prospective, international observational study, European Journal of Pediatrics, Vol: 182, Pages: 543-554, ISSN: 0340-6199

To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the ‘Biomarker Validation in HR patients’ database in PERFORM, were analysed. Immunocompromised children (< 18 years old) presented to fifteen European hospitals in nine countries, and one Gambian hospital, with fever or suspected infection and clinical indication for blood investigations. Febrile episodes were assigned clinical phenotypes using the validated PERFORM algorithm. Logistic regression was used to assess the effect size of predictive features of proven/presumed bacterial or viral infection. A total of 599 episodes in 482 children were analysed. Seventy-eight episodes (13.0%) were definite bacterial, 67 episodes probable bacterial (11.2%), and 29 bacterial syndrome (4.8%). Fifty-five were definite viral (9.2%), 49 probable viral (8.2%), and 23 viral syndrome (3.8%). One hundred ninety were unknown bacterial or viral infections (31.7%), and 108 had inflammatory or other non-infectious causes of fever (18.1%). Predictive features of proven/presumed bacterial infection were ill appearance (OR 3.1 (95% CI 2.1–4.6)) and HIV (OR 10.4 (95% CI 2.0–54.4)). Ill appearance reduced the odds of having a proven/presumed viral infection (OR 0.5 (95% CI 0.3–0.9)). A total of 82.1% had new empirical antibiotics started on admission (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522).

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, Martinón-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 M, PERFORM consortiumet al., 2023, Correction to: Febrile illness in high-risk children: a prospective, international observational study., European Journal of Pediatrics, Vol: 182, Pages: 555-556, ISSN: 0340-6199

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

Boeddha NP, Atkins L, de Groot R, Driessen G, Hazelzet J, Zenz W, Carrol ED, Anderson ST, Martinon-Torres F, Agyeman PKA, Galassini R, Herberg J, Levin M, Schlapbach LJ, Emonts Met al., 2023, Group A streptococcal disease in paediatric inpatients: a European perspective (Vol 182, pg 697, 2023), EUROPEAN JOURNAL OF PEDIATRICS, ISSN: 0340-6199

Journal article

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