Imperial College London

DrJethroHerberg

Faculty of MedicineDepartment of Infectious Disease

Clinical Reader in Paediatric Infectious Disease
 
 
 
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j.herberg

 
 
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231Wright Fleming WingSt Mary's Campus

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Summary

 

Publications

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105 results found

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

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, 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

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

Pennisi I, Moniri A, Miscourides N, Miglietta L, Moser N, Habgood-Coote D, Herberg J, 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-a-chip technology, Publisher: MedRxiv

<h4>ABSTRACT</h4> The unmet clinical need for accurate point-of-care (POC) diagnostic tests able to discriminate bacterial from viral infection demands a solution that can be used both within healthcare settings and in the field and that can also stem the tide of antimicrobial resistance. Our approach to solve this problem is to combine the use of Host-gene signatures with our Lab-on-a-chip (LoC) technology enabling low-cost LoC expression analysis to detect Infectious Disease.Host-gene expression signatures have been extensively study as a potential tool to be implemented in the diagnosis of infectious disease. On the other hand LoC technologies using Ion-sensitive field-effect transistor (ISFET) arrays, in conjunction with isothermal chemistries, are offering a promising alternative to conventional lab-based nucleic acid amplification instruments, owing to their portable and affordable nature. Currently, the data analysis of ISFET arrays are restricted to established methods by averaging the output of every sensor to give a single time-series. This simple approach makes unrealistic assumptions, leading to insufficient performance for applications that require accurate quantification such as RNA host transcriptomics. In order to reliably quantify host-gene expression on our LoC platform enabling the classification of bacterial and viral infection on chip, we propose a novel data-driven algorithm for extracting time-to-positive values from ISFET arrays. The algorithm proposed is based on modelling sensor drift with adaptive signal processing and clustering sensors based on their behaviour with unsupervised learning methods. Results show that the approach correctly outputs a time-to-positive for all the reactions, with a high correlation to RT-qLAMP (0.85, R2 = 0.98, p < 0.01), resulting in a classification accuracy of 100 % (CI, 95 - 100). By leveraging more advanced data processing methods for ISFET arrays, this work aims to bridge the gap between tr

Working paper

Jackson H, Calle IR, Broderick C, Habgood-Coote D, dSouza G, Nichols S, Gómez-Rial J, Rivero-Velasco C, Rodríguez-Núñez N, Barbeito-Castiñeiras G, Pérez-Freixo H, Acosta MB-D, Cunnington AJ, Herberg JA, Wright VJ, Gómez-Carballa A, Salas A, Levin M, Martinon-Torres F, Kaforou Met al., 2022, Characterisation of the blood RNA host response underpinning severity in COVID-19 patients, Scientific Reports, Vol: 12, ISSN: 2045-2322

Infection with SARS-CoV-2 has highly variable clinical manifestations, ranging from asymptomatic infection through to life-threatening disease. Host whole blood transcriptomics can offer unique insights into the biological processes underpinning infection and disease, as well as severity. We performed whole blood RNA Sequencing of individuals with varying degrees of COVID-19 severity. We used differential expression analysis and pathway enrichment analysis to explore how the blood transcriptome differs between individuals with mild, moderate, and severe COVID-19, performing pairwise comparisons between groups. Increasing COVID-19 severity was characterised by an abundance of inflammatory immune response genes and pathways, including many related to neutrophils and macrophages, in addition to an upregulation of immunoglobulin genes. Our insights into COVID-19 severity reveal the role of immune dysregulation in the progression to severe disease and highlight the need for further research exploring the interplay between SARS-CoV-2 and the inflammatory immune response.

Journal article

Borensztajn DM, Hagedoorn NN, Carrol ED, von Both U, 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, van der Velden FJS, Vermont C, Zavadska D, Zenz W, Zachariasse JM, Moll HAet al., 2022, Febrile children with comorbidities at the emergency department - a multicentre observational study, European Journal of Pediatrics, Vol: 181, Pages: 3491-3500, ISSN: 0340-6199

We aimed to describe characteristics and management of children with comorbidities attending European emergency departments (EDs) with fever. MOFICHE (Management and Outcome of Fever in children in Europe) is a prospective multicentre study (12 European EDs, 8 countries). Febrile children with comorbidities were compared to those without in terms of patient characteristics, markers of disease severity, management, and diagnosis. Comorbidity was defined as a chronic underlying condition that is expected to last > 1 year. We performed multivariable logistic regression analysis, displaying adjusted odds ratios (aOR), adjusting for patient characteristics. We included 38,110 patients, of whom 5906 (16%) had comorbidities. Most common comorbidities were pulmonary, neurologic, or prematurity. Patients with comorbidities more often were ill appearing (20 versus 16%, p < 0.001), had an ED-Paediatric Early Warning Score of > 15 (22 versus 12%, p < 0.001), or a C-reactive protein > 60 mg/l (aOR 1.4 (95%CI 1.3–1.6)). They more often required life-saving interventions (aOR 2.7, 95% CI 2.2–3.3), were treated with intravenous antibiotics (aOR 2.3, 95%CI 2.1–2.5), and were admitted to the ward (aOR 2.2, 95%CI 2.1–2.4) or paediatric intensive care unit (PICU) (aOR 5.5, 95% CI 3.8–7.9). They were more often diagnosed with serious bacterial infections (aOR 1.8, 95%CI 1.7–2.0), including sepsis/meningitis (aOR 4.6, 95%CI 3.2–6.7). Children most at risk for sepsis/meningitis were children with malignancy/immunodeficiency (aOR 14.5, 8.5–24.8), while children with psychomotor delay/neurological disease were most at risk for life-saving interventions (aOR 5.3, 4.1–6.9) or PICU admission (aOR 9.7, 6.1–15.5).

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., 2022, Bridging a diagnostic Kawasaki disease classifier from a microarray platform to a qRT-PCR assay, Pediatric Research, 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

Trobisch A, Schweintzger NA, Kohlfurst DS, Sagmeister MG, Sperl M, Grisold AJ, Feierl G, Herberg JA, Carrol ED, Paulus SC, Emonts M, van der Flier M, de Groot R, Cebey-Lopez M, Rivero-Calle I, Boeddha NP, Agapow P-M, Secka F, Anderson ST, Behrends U, Wintergerst U, Reiter K, Martinon-Torres F, Levin M, Zenz Wet al., 2022, Osteoarticular infections in pediatric hospitals in Europe: a prospective cohort study from the EUCLIDS consortium, Frontiers in Pediatrics, Vol: 10, Pages: 1-12, ISSN: 2296-2360

Background: Pediatric osteoarticular infections (POAIs) are serious diseases requiring early diagnosis and treatment.Methods: In this prospective multicenter cohort study, children with POAIs were selected from the European Union Childhood Life-threatening Infectious Diseases Study (EUCLIDS) database to analyze their demographic, clinical, and microbiological data.Results: A cohort of 380 patients with POAIs, 203 with osteomyelitis (OM), 158 with septic arthritis (SA), and 19 with both OM and SA, was analyzed. Thirty-five patients were admitted to the Pediatric Intensive Care Unit; out of these, six suffered from shock, one needed an amputation of the right foot and of four left toes, and two had skin transplantation. According to the Pediatric Overall Performance Score, 36 (10.5%) showed a mild overall disability, 3 (0.8%) a moderate, and 1 (0.2%) a severe overall disability at discharge. A causative organism was detected in 65% (247/380) of patients. Staphylococcus aureus (S. aureus) was identified in 57.1% (141/247) of microbiological confirmed cases, including 1 (0.7%) methicillin-resistant S. aureus (MRSA) and 6 (4.2%) Panton-Valentine leukocidin (PVL)-producing S. aureus, followed by Group A Streptococcus (18.2%) and Kingella kingae (8.9%). K. kingae and PVL production in S. aureus were less frequently reported than expected from the literature.Conclusion: POAIs are associated with a substantial morbidity in European children, with S. aureus being the major detected pathogen. In one-third of patients, no causative organism is identified. Our observations show an urgent need for the development of a vaccine against S. aureus and for the development of new microbiologic diagnostic guidelines for POAIs in European pediatric hospitals.

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, Pages: 1-17, 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, Zachariasse JM, Borensztajn D, Adriaansens E, von Both U, Carrol ED, Eleftheriou I, Emonts M, van der Flier M, de Groot R, Herberg JA, Kohlmaier B, Lim E, Maconochie I, Martinón-Torres F, Nijman RG, Pokorn M, Rivero-Calle I, Tsolia M, Zavadska D, Zenz W, Levin M, Vermont C, Moll HA, PERFORM consortiumet al., 2022, Shock Index in the early assessment of febrile children at the emergency department: a prospective multicentre study, Archives of Disease in Childhood, Vol: 107, Pages: 116-122, ISSN: 0003-9888

OBJECTIVE: (1) To derive reference values for the Shock Index (heart rate/systolic blood pressure) based on a large emergency department (ED) population of febrile children and (2) to determine the diagnostic value of the Shock Index for serious illness in febrile children. DESIGN/SETTING: Observational study in 11 European EDs (2017-2018). PATIENTS: Febrile children with measured blood pressure. MAIN OUTCOME MEASURES: Serious bacterial infection (SBI), invasive bacterial infection (IBI), immediate life-saving interventions (ILSIs) and intensive care unit (ICU) admission. The association between high Shock Index (>95th centile) and each outcome was determined by logistic regression adjusted for age, sex, referral, comorbidity and temperature. Additionally, we calculated sensitivity, specificity and negative/positive likelihood ratios (LRs). RESULTS: Of 5622 children, 461 (8.2%) had SBI, 46 (0.8%) had IBI, 203 (3.6%) were treated with ILSI and 69 (1.2%) were ICU admitted. High Shock Index was associated with SBI (adjusted OR (aOR) 1.6 (95% CI 1.3 to 1.9)), ILSI (aOR 2.5 (95% CI 2.0 to 2.9)), ICU admission (aOR 2.2 (95% CI 1.4 to 2.9)) but not with IBI (aOR: 1.5 (95% CI 0.6 to 2.4)). For the different outcomes, sensitivity for high Shock Index ranged from 0.10 to 0.15, specificity ranged from 0.95 to 0.95, negative LRs ranged from 0.90 to 0.95 and positive LRs ranged from 1.8 to 2.8. CONCLUSIONS: High Shock Index is associated with serious illness in febrile children. However, its rule-out value is insufficient which suggests that the Shock Index is not valuable as a screening tool for all febrile children at the ED.

Journal article

Borensztajn D, Hagedoorn NN, Carrol E, von Both U, Dewez JE, Emonts M, van der Flier M, de Groot R, Herberg J, Kohlmaier B, Levin M, Lim E, Maconochie I, Martinon Torres F, Nijman R, Pokorn M, Rivero-Calle I, Tsolia M, Vermont C, Zavadska D, Zenz W, Zachariasse J, Moll HAet al., 2022, Characteristics and management of adolescents attending the ED with fever: a prospective multicentre study, BMJ Open, Vol: 12, ISSN: 2044-6055

Objective Most studies on febrile children have focused on infants and young children with serious bacterial infection (SBI). Although population studies have described an increased risk of sepsis in adolescents, little is known about febrile adolescents attending the emergency department (ED). We aimed to describe patient characteristics and management of febrile adolescents attending the ED.Design and setting The MOFICHE/PERFORM study (Management and Outcome of Febrile Children in Europe/Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union), a prospective multicentre study, took place at 12 European EDs. Descriptive and multivariable regression analyses were performed, comparing febrile adolescents (12–18 years) with younger children in terms of patient characteristics, markers of disease severity (vital signs, clinical alarming signs), management (diagnostic tests, therapy, admission) and diagnosis (focus, viral/bacterial infection).Results 37 420 encounters were included, of which 2577 (6.9%) were adolescents. Adolescents were more often triaged as highly urgent (38.9% vs 34.5%) and described as ill appearing (23.1% vs 15.6%) than younger children. Increased work of breathing and a non-blanching rash were present less often in adolescents, while neurological signs were present more often (1% vs 0%). C reactive protein tests were performed more frequently in adolescents and were more often abnormal (adjusted OR (aOR) 1.7, 95% CI 1.5 to 1.9). Adolescents were more often diagnosed with SBI (OR 1.8, 95% CI 1.6 to 2.0) and sepsis/meningitis (OR 2.3, 95% CI 1.1 to 5.0) and were more frequently admitted (aOR 1.3, 95% CI 1.2 to 1.4) and treated with intravenous antibiotics (aOR 1.7, 95% CI 1.5 to 2.0).Conclusions Although younger children presented to the ED more frequently, adolescents were more often diagnosed with SBI and sepsis/meningitis. Our data emphasise the importance of awareness of severe infections

Journal article

Tan CD, Hagedoorn NN, Dewez JE, Borensztajn DM, 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, Strle F, Tsolia M, Vermont CL, Yeung S, Zachariasse JM, Zenz W, Zavadska D, Moll HA, Consortium Pet al., 2022, Rapid Viral Testing and Antibiotic Prescription in Febrile Children With Respiratory Symptoms Visiting Emergency Departments in Europe, PEDIATRIC INFECTIOUS DISEASE JOURNAL, Vol: 41, Pages: 39-44, ISSN: 0891-3668

Journal article

Hoggart C, Shimizu C, Galassini R, Wright VJ, Shailes H, Bellos E, Herberg JA, Pollard AJ, O'Connor D, Choi SW, Seaby EG, Menikou S, Hibberd M, Sallah N, Burgner D, Brogan P, Patel H, Kim J, Tremoulet AH, Salo E, van Stijn D, Kuijpers T, Burns JC, Levin Met al., 2021, Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease, European Journal of Human Genetics, Vol: 29, Pages: 1734-1744, ISSN: 1018-4813

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

Journal article

Li HK, Kaforou M, Rodriguez-Manzano J, Channon-Wells S, Monir A, Habgood-Coote D, Gupta RK, Mills EA, Lin J, Chiu Y-H, Pennisi I, Miglietta L, Mehta R, Obaray N, Herberg JA, Wright VJ, Georgiou P, Shallcross LJ, Mentzer AJ, Levin M, Cooke GS, Noursadeghi M, Sriskandan Set al., 2021, Discovery and validation of a 3-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations; a case-control then observational cohort study, The Lancet Microbe, Vol: 2, Pages: 594-603, ISSN: 2666-5247

Background: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We sought to derive and validate a blood transcriptional signature to detect viral infections including COVID-19 among adults with suspected infection presenting to the Emergency Department (ED).Methods: Blood RNA sequencing was performed on a discovery cohort of adults attending the ED with suspected infection who had subsequently-confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes were subjected to feature selection to derive the most parsimonious discriminating signature. RT-qPCR validation of the signature was then performed in a prospective cohort of ED patients presenting with undifferentiated fever, and a second case-control cohort of ED patients with COVID-19 or bacterial infection. Signature performance was assessed by calculating area under receiver-operating characteristic curves (AUC-ROCs), sensitivities, and specificities.Findings: A 3-gene transcript signature was derived from the discovery cohort of 56 bacterial and 27 viral infection cases. In the validation cohort of 200 cases, the signature differentiated bacterial from viral infections with an AUC-ROC of 0.976 (95% CI: 0.919-1.000), sensitivity 97.3% and specificity of 100%. The AUC-ROC for C-reactive protein (CRP) and leucocyte count (WCC) was 0.833 (95% CI: 0.694-0.944) and 0.938 (95% CI: 0.840-0.986) respectively. The signature achieved higher net benefit in decision curve analysis than either CRP or WCC for discriminating viral infections from all other cases. In the second validation analysis the signature discriminated 35 bacterial infections from 34 SARS-CoV-2 positive COVID-19 infections with AUC-ROC of 0.953 (95% CI: 0.893-0.992), sensitivity 88.6% and specificity of 94.1%.Interpretation: This novel 3-gene signature discriminates viral i

Journal article

Boeddha NP, Driessen GJ, Hagedoorn NN, Kohlfuerst DS, Hoggart CJ, van Rijswijk AL, Ekinci E, Priem D, Schlapbach LJ, Herberg JA, de Groot R, Anderson ST, Fink CG, Carrol ED, van der Flier M, Martinón-Torres F, Levin M, Leebeek FW, Zenz W, de Maat MPM, Hazelzet JA, Emonts M, Dik WAet al., 2021, Detectable a disintegrin and metalloproteinase with thrombospondin motifs-1 in serum is associated with adverse outcome in pediatric sepsis., Critical Care Explorations, Vol: 3, Pages: 1-12, ISSN: 2639-8028

IMPORTANCE: A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 is hypothesized to play a role in the pathogenesis of invasive infection, but studies in sepsis are lacking. OBJECTIVES: To study A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 protein level in pediatric sepsis and to study the association with outcome. DESIGN: Data from two prospective cohort studies. SETTING AND PARTICIPANTS: Cohort 1 is from a single-center study involving children admitted to PICU with meningococcal sepsis (samples obtained at three time points). Cohort 2 includes patients from a multicenter study involving children admitted to the hospital with invasive bacterial infections of differing etiologies (samples obtained within 48 hr after hospital admission). MAIN OUTCOMES AND MEASURES: Primary outcome measure was mortality. Secondary outcome measures were PICU-free days at day 28 and hospital length of stay. RESULTS: In cohort 1 (n = 59), nonsurvivors more frequently had A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels above the detection limit than survivors at admission to PICU (8/11 [73%] and 6/23 [26%], respectively; p = 0.02) and at t = 24 hours (2/3 [67%] and 3/37 [8%], respectively; p = 0.04). In cohort 2 (n = 240), A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels in patients within 48 hours after hospital admission were more frequently above the detection limit than in healthy controls (110/240 [46%] and 14/64 [22%], respectively; p = 0.001). Nonsurvivors more often had detectable A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels than survivors (16/21 [76%] and 94/219 [43%], respectively; p = 0.003), which was mostly attributable to patients with Neisseria meningitidis. CONCLUSIONS AND RELEVANCE: In children with bacterial infection, detection of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 within 48 hours after hospital admission is associated with deat

Journal article

Borenzstajn D, Hagedoorn N, Carrol ED, von Both U, Dewez JE, Emonts M, Van Der Flier M, de Groot R, Herberg J, Kohlmaier B, Lim E, Maconochie IK, Martinon-Torres F, Nieboer D, Nijman R, Oostenbrink R, Pokorn M, Rivero Calle I, Strle F, Tsolia M, Vermont CL, Yeung S, Zavadska D, Zenz W, Levin M, Moll HAet al., 2021, A NICE combination for predicting hospitalisation at the Emergency Department: a European multicentre observational study of febrile children, The Lancet Regional Health - Europe, Vol: 8, ISSN: 2666-7762

BackgroundProlonged Emergency Department (ED) stay causes crowding and negatively impacts quality of care. We developed and validated a prediction model for early identification of febrile children with a high risk of hospitalisation in order to improve ED flow.MethodsThe MOFICHE study prospectively collected data on febrile children (0–18 years) presenting to 12 European EDs. A prediction models was constructed using multivariable logistic regression and included patient characteristics available at triage. We determined the discriminative values of the model by calculating the area under the receiver operating curve (AUC).FindingsOf 38,424 paediatric encounters, 9,735 children were admitted to the ward and 157 to the PICU. The prediction model, combining patient characteristics and NICE alarming, yielded an AUC of 0.84 (95%CI 0.83-0.84).The model performed well for a rule-in threshold of 75% (specificity 99.0% (95%CI 98.9-99.1%, positive likelihood ratio 15.1 (95%CI 13.4-17.1), positive predictive value 0.84 (95%CI 0.82-0.86)) and a rule-out threshold of 7.5% (sensitivity 95.4% (95%CI 95.0-95.8), negative likelihood ratio 0.15 (95%CI 0.14-0.16), negative predictive value 0..95 (95%CI 0.95-9.96)). Validation in a separate dataset showed an excellent AUC of 0.91 (95%CI 0.90- 0.93). The model performed well for identifying children needing PICU admission (AUC 0.95, 95%CI 0.93-0.97). A digital calculator was developed to facilitate clinical use.InterpretationPatient characteristics and NICE alarming signs available at triage can be used to identify febrile children at high risk for hospitalisation and can be used to improve ED flow.FundingEuropean Union, NIHR, NHS.

Journal article

Thayyil S, Pant S, Montaldo P, Shukla D, Oliveira V, Ivain P, Bassett P, Swami R, Mendoza J, Moreno-Morales M, Lally PJ, Benakappa N, Bandiya P, Shivarudhrappa I, Somanna J, Kantharajanna UB, Rajvanshi A, Krishnappa S, Joby PK, Jayaraman K, Chandramohan R, Kamalarathnam CN, Sebastian M, Tamilselvam I, Rajendran U, Soundrarajan R, Kumar V, Sudarsanan Het al., 2021, Hypothermia for moderate or severe neonatal encephalopathy in low and middle-income countries (HELIX): a randomised control trial in India, Sri Lanka and Bangladesh, The Lancet Global Health, Vol: 9, Pages: e1273-e1285, ISSN: 2214-109X

Background: Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low- and middle-income countries (LMICs) remains unclear. We examined if therapeutic hypothermia alongside optimal supportive intensive care reduces death or disability after neonatal encephalopathy in South Asia. Methods: We conducted a multi-country open label randomised controlled trial involving seven tertiary neonatal intensive care units in India, Sri Lanka and Bangladesh, between August 2015 and September 2020. We allocated infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy into whole body hypothermia (33·5 0 C) for 72 hours using a servo-controlled cooling device, or usual care (control group), within six hours of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support and access to 3 Telsa magnetic resonance imaging and spectroscopy. The primary outcome was a combined end point of death or moderate or severe disability at 18 to 22 months of age, assessed by Bayley scales of infant development (Version III).Findings: Of 576 eligible infants, we assigned 202 to hypothermia and 206 to control group. Primary outcome data were available for 394 (96·5%) infants, and occurred in 98(50·3%) of the hypothermia and 94 (47·2%) of the control group (Risk Ratio (RR) 1·06;95% confidence intervals (CI) 0·87 to 1·30 (p = 0·55). Eighty-four infants (42·4%) in the hypothermia group and 63 (31·3%) (p = 0·02) infants in the control group died, of whom 72 (35·6%) and 49 (23·8%) (p = 0·009) died during neonatal hospitalisation. Interpretation: Therapeutic hypothermia did not reduce the combined outcome of death or disability at18 months after neonatal encephalopathy in LMICs, but significantly increased mortality. Therapeutic hypothermia should not

Journal article

Nijman R, Oostenbrink R, Moll HA, Casals-Pascual C, von Both U, Cunnington A, De T, Eleftheriou I, Emonts M, Fink C, Van Der Flier M, de Groot R, Kaforou M, Kohlmaier B, Kuijpers TW, Lim E, Maconochie I, Paulus S, Martinon-Torres F, Pokorn M, Romaine S, Rivero Calle I, Schlapbach L, Smit FJ, Tsolia M, Usuf E, Wright V, Yeung S, Zavadska D, Zenz W, Levin M, Herberg J, Carrol EDet al., 2021, A novel framework for phenotyping children with suspected or confirmed infection for future biomarker studies, Frontiers in Pediatrics, Vol: 9, Pages: 1-18, ISSN: 2296-2360

Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI.Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0– <16 years: the Alder Hey emergency department (n = 1,120), Alder Hey pediatric intensive care unit (n = 355), Erasmus emergency department (n = 1,993), Maasstad emergency department (n = 714) and St. Mary's hospital (n = 200) cohorts. Biomarkers including procalcitonin (PCT) (4 cohorts), neutrophil gelatinase-associated lipocalin-2 (NGAL) (3 cohorts) and resistin (2 cohorts) were compared for their ability to classify patients according to current standards (dichotomous classification of SBI vs. non-SBI), vs. a proposed PERFORM classification algorithm that assign patients to one of eleven categories. These categories were based on clinical phenotype, test outcomes and C-reactive protein level and accounted for the uncertainty of final diagnosis in many febrile children. The success of the biomarkers was measured by the Area under the receiver operating Curves (AUCs) when they were used individually or in combination.Results: Using the new PERFORM classification system, patients with clinically confident bacterial diagnosis (“definite bacterial” category) had significantly higher levels of PCT, NGAL and resistin compared with those with a clinically confident viral diagnosis (“definite viral” category). Patients with diagnostic uncertainty had biomarker concentrations that varied across the spectrum. AUCs were higher for classification of “definite bacterial” vs. “definite viral” following the PERFORM algorithm than using the “SBI” vs. “non-SBI” c

Journal article

McArdle AJ, Vito O, Patel H, Seaby EG, Shah P, Wilson C, Broderick C, Nijman R, Tremoulet AH, Munblit D, Ulloa-Gutierrez R, Carter MJ, De T, Hoggart C, Whittaker E, Herberg JA, Kaforou M, Cunnington AJ, Levin Met al., 2021, Treatment of multisystem inflammatory syndrome in children, New England Journal of Medicine, Vol: 385, Pages: 11-22, ISSN: 0028-4793

BACKGROUNDEvidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.METHODSWe performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.RESULTSData were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.CONCLUSIONSWe found n

Journal article

Hagedoorn N, Borensztajn D, Nijman R, Nieboer D, Herberg J, Balode A, von Both U, Carroll E, Eleftheriou I, Emonts M, Van Der Flier M, de Groot R, Kohlmaier B, Lim E, Maconochie I, Martinon-Torres F, Pokorn M, Strle F, Tsolia M, Zavadska D, Zenz W, Levin M, Vermont C, Moll Het al., 2021, Development and validation of a prediction model for invasive bacterial infections in febrile children at European Emergency Departments: MOFICHE a prospective observational study, Archives of Disease in Childhood, Vol: 106, Pages: 641-647, ISSN: 0003-9888

Objectives To develop and cross-validate a multivariable clinical prediction model to identify invasive bacterial infections (IBI) and to identify patient groups who might benefit from new biomarkers.Design Prospective observational study.Setting 12 emergency departments (EDs) in 8 European countries.Patients Febrile children aged 0–18 years.Main outcome measures IBI, defined as bacteraemia, meningitis and bone/joint infection. We derived and cross-validated a model for IBI using variables from the Feverkidstool (clinical symptoms, C reactive protein), neurological signs, non-blanching rash and comorbidity. We assessed discrimination (area under the receiver operating curve) and diagnostic performance at different risk thresholds for IBI: sensitivity, specificity, negative and positive likelihood ratios (LRs).Results Of 16 268 patients, 135 (0.8%) had an IBI. The discriminative ability of the model was 0.84 (95% CI 0.81 to 0.88) and 0.78 (95% CI 0.74 to 0.82) in pooled cross-validations. The model performed well for the rule-out threshold of 0.1% (sensitivity 0.97 (95% CI 0.93 to 0.99), negative LR 0.1 (95% CI 0.0 to 0.2) and for the rule-in threshold of 2.0% (specificity 0.94 (95% CI 0.94 to 0.95), positive LR 8.4 (95% CI 6.9 to 10.0)). The intermediate thresholds of 0.1%–2.0% performed poorly (ranges: sensitivity 0.59–0.93, negative LR 0.14–0.57, specificity 0.52–0.88, positive LR 1.9–4.8) and comprised 9784 patients (60%).Conclusions The rule-out threshold of this model has potential to reduce antibiotic treatment while the rule-in threshold could be used to target treatment in febrile children at the ED. In more than half of patients at intermediate risk, sensitive biomarkers could improve identification of IBI and potentially reduce unnecessary antibiotic prescriptions.

Journal article

Sancho-Shimizu V, Brodin P, Cobat A, Biggs CM, Toubiana J, Lucas CL, Henrickson SE, Belot A, Haddad E, Beland K, Pujol A, Schlüter A, Planas-Serra L, Aguilera-Albesa S, Valencia-Ramos J, Rodríguez-Palmero A, Gut M, Rivière JG, Colobran R, Soler-Palacin P, Rodriguez-Gallego C, Perez De Diego R, Flores C, Alsina L, Blazquez-Gamero D, Jordan I, Keles S, Emiroglu M, Akcan OM, Alkan G, Aytekin SE, Gul Y, Tüter Öz ŞK, Bozdemir SE, Bayhan GI, Yüksek SK, Parlakay AÖ, Gülhan B, Yahşi A, Kilic AO, Karbuz A, Erdeniz EH, Özkan EA, Orbak Z, Aydemir Ş, Celik JB, Kandemir B, Aytekin G, Kapakli H, Yarar V, Yosunkaya A, Vatansev H, Aytekin C, Torun SH, Nepesov S, Coskuner T, Sözeri B, Demirkol YK, Kasapcopur O, Yıldız M, Sevketoglu E, Hatipoğlu N, Özçelik T, Yesilbas O, Gayretli Aydin ZG, Sediva A, Klocperk A, Bloomfield M, Meyts I, Delafontaine S, Haerynck F, Hoste L, Shahrooei M, Marque L, Neves JF, Novelli G, Novelli A, Aiuti A, Casari G, Bousfiha AA, Almuhsen SZ, Sobh A, Gagro A, Bajolle F, Bonnet D, Lebon P, Lei W, Lee D, Seeleuthner Y, Zhang P, Maglorius M, Philippot Q, Pelham S, Bastard P, Zhang Q, Jouanguy E, Puel A, Herberg J, Kuijpers TW, Bellos E, Kaforou M, Menikou S, Pan-Hammarström Q, Hammarström L, Abolhassani H, Bryceson Y, Condino-Neto A, Prando C, Bando SY, Cavalcanti A, Fellay J, Blanchard-Hohner G, Mansouri D, Mahmoudi S, Boyarchuk O, Volokha A, Bondarenko A, Stepanovskiy Y, Mogensen T, van de Beek D, Andreakos E, Papadaki M, Abou Tayoun A, Halwani R, Al-Mulla F, Franco JL, Lau Y-L, Kwan M, Imai K, Okada S, Bolze A, Butte MJ, Hsieh E, Drolet BA, Arkin L, Itan Y, Maniatis T, Arditi M, Cooper M, Schmitt E, Chakravorty S, Anderson MS, Su HC, Notarangelo LD, Tangye SG, Milner JD, Levin M, Abel L, Bogunovic D, Casanova J-L, Zhang S-Yet al., 2021, SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?, Journal of Experimental Medicine, Vol: 218, Pages: 1-16, ISSN: 0022-1007

Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

Journal article

Jackson H, Menikou S, Hamilton M, McArdle A, Shimizu C, Galassini R, Huang H, Kim J, Tremoulet A, de Jonge M, Kuijpers T, Wright V, Burns J, Casals-Pascual C, Herberg J, Levin M, Kaforou Met al., 2021, Kawasaki Disease patient stratification and pathway analysis based on host transcriptomic and proteomic profiles, International Journal of Molecular Sciences, Vol: 11, Pages: 1-24, ISSN: 1422-0067

The aetiology of Kawasaki Disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host ‘omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple ‘omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infection at the transcriptomic and proteomic levels through comparison of ‘omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both ‘omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both ‘omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition.

Journal article

Argiz L, Infante S, Machinena A, Bracamonte T, Echeverria L, Prieto A, Garriga T, Vila L, Gonzalez-Delgado P, Garcia-Magan C, Garcia E, Carballeira I, Vazquez-Cortes S, Mori F, Barni S, Arasi S, Pascal M, Boyle RJ, Vazquez-Ortiz Met al., 2021, Children with acute food protein-induced enterocolitis syndrome from Spain and Italy usually tolerate all other food groups, Clinical and Experimental Allergy, Vol: 51, Pages: 1238-1241, ISSN: 0954-7894

Journal article

Hagedoorn N, Wagenaar J, Nieboer D, Bath D, von Both U, Carrol E, Eleftheriou I, Emonts M, Van Der Flier M, de Groot R, Herberg J, Kohlmaier B, Levin M, Lim E, Maconochie I, Martinon-Torres F, Nijman R, Pokorn M, Rivero Calle I, Tsolia M, Yeung S, Zavadska D, Zenz W, Vermont C, Oostenbrink R, Moll Het al., 2021, Impact of a clinical decision rule on antibiotic prescription for children with suspected lower respiratory tract infections presenting to European emergency departments: a simulation study based on routine data, Journal of Antimicrobial Chemotherapy, Vol: 76, Pages: 1349-1357, ISSN: 0305-7453

Background: Discriminating viral from bacterial lower respiratory tract infections (LRTIs) in children is challenging thus commonly resulting in antibiotic overuse. The Feverkidstool, a validated clinical decision rule including clinical symptoms and C-reactive protein, safely reduced antibiotic use in children at low/intermediate risk for bacterial LRTIs in a multicentre trial at emergency departments (EDs) in the Netherlands.Objectives: Using routine data from an observational study, we simulated the impact of the Feverkidstool on antibiotic prescriptions compared with observed antibiotic prescriptions in children with suspected LRTIs at 12 EDs in eight European countries.Methods: We selected febrile children aged 1 month to 5 years with respiratory symptoms and excluded upper respiratory tract infections. Using the Feverkidstool, we calculated individual risks for bacterial LRTI retrospectively. We simulated antibiotic prescription rates under different scenarios: (1) applying effect estimates on antibiotic prescription from the trial; and (2) varying both usage (50%–100%) and compliance (70%–100%) with the Feverkidstool’s advice to withhold antibiotics in children at low/intermediate risk for bacterial LRTI (≤10%).Results: Of 4938 children, 4209 (85.2%) were at low/intermediate risk for bacterial LRTI. Applying effect estimates from the trial, the Feverkidstool reduced antibiotic prescription from 33.5% to 24.1% [pooled risk difference: 9.4% (95% CI: 5.7%–13.1%)]. Simulating 50%–100% usage with 90% compliance resulted in risk differences ranging from 8.3% to 15.8%. Our simulations suggest that antibiotic prescriptions would be reduced in EDs with high baseline antibiotic prescription rates or predominantly (>85%) low/intermediate-risk children.Conclusions: Implementation of the Feverkidstool could reduce antibiotic prescriptions in children with suspected LRTIs in European EDs.

Journal article

Sabatino J, Borrelli N, Fraisse A, Herberg J, Karagadova E, Avesani M, Bucciarelli V, Josen M, Paredes J, Piccinelli E, Spada M, Krupickova S, Indolfi C, Di Salvo Get al., 2021, Abnormal myocardial work in children with Kawasaki disease, Scientific Reports, Vol: 11, ISSN: 2045-2322

Kawasaki disease (KD) can be associated with high morbidity and mortality due to coronary artery aneurysms formation and myocardial dysfunction. Aim of this study was to evaluate the diagnostic performance of non-invasive myocardial work in predicting subtle myocardial abnormalities in Kawasaki disease (KD) children with coronary dilatation (CADL). A total of 100 patients (age 8.7 ± 5 years) were included: 45 children with KD and CADL (KD/CADL) (Z-score > 2.5), 45 age-matched controls (CTRL) and, finally, an additional group of 10 children with KD in absence of coronary dilatation (KD group). Left ventricular (LV) systolic function and global longitudinal strain (GLS) were assessed. Global myocardial work index (MWI) was calculated as the area of the LV pressure-strain loops. From MWI, global Constructive Work (MCW), Wasted Work (MWW) and Work Efficiency (MWE) were estimated. Despite normal LV systolic function by routine echocardiography, KD/CADL patients had lower MWI (1433.2 ± 375.8 mmHg% vs 1752.2 ± 265.7 mmHg%, p < 0.001), MCW (1885.5 ± 384.2 mmHg% vs 2175.9 ± 292.4 mmHg%, p = 0.001) and MWE (994.0 ± 4.8% vs 95.9 ± 2.0%, p = 0.030) compared to CTRL. Furthermore, MWI was significantly reduced in children belonging to the KD group in comparison with controls (KD: 1498.3 ± 361.7 mmHg%; KD vs CTRL p = 0.028) and was comparable between KD/CADL and KD groups (KD/CADL vs KD p = 0.896). Moreover, KD/CADL patients with normal GLS (n = 38) preserved significant differences in MWI and MCW in comparison with CTRL. MWI, MCW and MWE were significantly reduced in KD children despite normal LVEF and normal GLS. These abnormalities seems independent from CADL. Thus, in KD with norm

Journal article

van Aerde KJ, de Haan L, van Leur M, Gerrits GP, Schers H, Moll HA, Hagedoorn NN, Herberg JA, Levin M, Rivero-Calle I, de Jonge MI, de Groot R, van der Flier M, PERFORM Consortiumet al., 2021, Respiratory tract Infection management and antibiotic prescription in children: a unique study comparing three levels of healthcare in the Netherlands., The Pediatric Infectious Disease Journal, Vol: 40, Pages: e100-e105, ISSN: 0891-3668

BACKGROUND: Respiratory tract infections (RTIs) are common in children with febrile illness visiting the general practitioner (GP) or emergency department. We studied the management of children with fever and RTI at 3 different levels of healthcare in The Netherlands, focusing on antibiotic prescription. METHODS: This prospective observational study is part of the Management and Outcome of Febrile children in Europe study. Data were used from face-to-face patient contacts of children with febrile illness in three healthcare settings in Nijmegen, The Netherlands during 2017. These settings were primary (GP), secondary (general hospital) and tertiary care (university hospital). RESULTS: Of 892 cases with RTI without complex comorbidities, overall antibiotic prescription rates were 29% with no differences between the 3 levels of healthcare, leading to an absolute number of 5031 prescriptions per 100,000 children per year in primary care compared with 146 in secondary and tertiary care combined. The prescription rate in otitis media was similar in all levels: 60%. In cases with lower RTI who received nebulizations prescription rates varied between 19% and 55%. CONCLUSIONS: Antibiotic prescription rates for RTIs in children were comparable between the 3 levels of healthcare, thus leading to a majority of antibiotics being prescribed in primary care. Relatively high prescription rates for all foci of RTIs were found, which was not in agreement with the national guidelines. Antibiotic stewardship needs improvement at all 3 levels of healthcare. Guidelines to prescribe small spectrum antibiotics for RTIs need to be better implemented in hospital care settings.

Journal article

Piccinelli E, Herberg J, Kang H, Fraisse A, Krupickova S, Altamar IB, Sabatino J, Singh Y, Bautista-Rodriguez C, Di Salvo Get al., 2021, Segmental and global longitudinal strain differences between children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 pandemic and Kawasaki disease, EACVI – Best of Imaging 2020, Publisher: Oxford University Press (OUP), Pages: 1-1, ISSN: 2047-2404

Conference paper

Li HK, Kaforou M, Rodriguez-Manzano J, Channon-Wells S, Moniri A, Habgood-Coote D, Gupta RK, Mills EA, Arancon D, Lin J, Chiu Y-H, Pennisi I, Miglietta L, Obaray N, Mehta R, Herberg JA, Wright VJ, Georgiou P, Shallcross L, Mentzer AJ, Levin M, Cooke G, Noursadeghi M, Sriskandan Set al., 2021, Discovery and Validation of a 3-Gene Transcriptional Signature to Distinguish COVID-19 and Other Viral Infections from Bacterial Sepsis in Adults; A Case-Control then Observational Cohort Study, Publisher: Elsevier BV

Working paper

Gómez-Carballa A, Barral-Arca R, Cebey-López M, Currás-Tuala MJ, Pischedda S, Gómez-Rial J, Habgood-Coote D, Herberg JA, Kaforou M, Martinón-Torres F, Salas Aet al., 2021, Host transcriptomic response following administration of rotavirus vaccine in infants' mimics wild type infection, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224

Background: Rotavirus (RV) is an enteric pathogen that has devastating impact on childhood morbidity and mortality worldwide. The immunologic mechanism underlying the protection achieved after RV vaccination is not yet fully understood. Methods: We compared the transcriptome of children affected by community-acquired RV infection and children immunized with a live attenuated RV vaccine (RotaTeq®). Results: RV vaccination mimics the wild type infection causing similar changes in children's transcriptome, including transcripts associated with cell cycle, diarrhea, nausea, vomiting, intussusception, and abnormal morphology of midgut. A machine learning approach allowed to detect a combination of nine-transcripts that differentiates vaccinated from convalescent-naturally infected children (AUC: 90%; 95%CI: 70-100) and distinguishes between acute-infected and healthy control children (in both cases, AUC: 100%; 95%CI: 100-100). We identified a miRNA hsa-mir-149 that seems to play a role in the host defense against viral pathogens and may have an antiviral role. Discussion: Our findings might shed further light in the understanding of RV infection, its functional link to intussusception causes, as well as guide development of antiviral treatments and safer and more effective vaccines. The nine-transcript signature may constitute a marker of vaccine protection and helps to differentiate vaccinated from naturally infected or susceptible children.

Journal article

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