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
Year
to

299 results found

McArdle AJ, Cunnington AJ, Levin M, 2021, Therapy for Multisystem Inflammatory Syndrome in Children. Reply., N Engl J Med

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

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, 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

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 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., 2021, Shock Index in the early assessment of febrile children at the emergency department: a prospective multicentre study, Archives of Disease in Childhood, 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

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

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, 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

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

Schlapbach LJ, Andre MC, Grazioli S, Schobi N, Ritz N, Aebi C, Agyeman P, Albisetti M, Bailey DGN, Berger C, Blanchard-Rohner G, Bressieux-Degueldre S, Hofer M, L'Huillier AG, Marston M, Meyer Sauteur PM, Pachlopnik Schmid J, Perez M-H, Rogdo B, Truck J, Woerner A, Wutz D, Zimmermann P, Levin M, Whittaker E, Rimensberger PCet al., 2021, Best practice recommendations for the diagnosis and management of children with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS; multisystem inflammatory syndrome in children, MIS-C) in Switzerland, Frontiers in Pediatrics, Vol: 9, Pages: 1-14, ISSN: 2296-2360

Background: Following the spread of the coronavirus disease 2019 (COVID-19) pandemic a new disease entity emerged, defined as Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C). In the absence of trials, evidence for treatment remains scarce.Purpose: To develop best practice recommendations for the diagnosis and treatment of children with PIMS-TS in Switzerland. It is acknowledged that the field is changing rapidly, and regular revisions in the coming months are pre-planned as evidence is increasing.Methods: Consensus guidelines for best practice were established by a multidisciplinary group of Swiss pediatric clinicians with expertise in intensive care, immunology/rheumatology, infectious diseases, hematology, and cardiology. Subsequent to literature review, four working groups established draft recommendations which were subsequently adapted in a modified Delphi process. Recommendations had to reach >80% agreement for acceptance.Results: The group achieved agreement on 26 recommendations, which specify diagnostic approaches and interventions across anti-inflammatory, anti-infectious, and support therapies, and follow-up for children with suspected PIMS-TS. A management algorithm was derived to guide treatment depending on the phenotype of presentation, categorized into PIMS-TS with (a) shock, (b) Kawasaki-disease like, and (c) undifferentiated inflammatory presentation.Conclusion: Available literature on PIMS-TS is limited to retrospective or prospective observational studies. Informed by these cohort studies and indirect evidence from other inflammatory conditions in children and adults, as well as guidelines from international health authorities, the Swiss PIMS-TS recommendations represent best practice guidelines based on currently available knowledge to standardize treatment of children with suspected PIMS-TS. Given the absence of high-grade evidence, regular up

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

Halliday A, Jain P, Hoang L, Parker R, Tolosa-Wright M, Masonou T, Green N, Boakye A, Takwoingi Y, Hamilton S, Mandagere V, Fries A, Coin L, Deeks J, White PJ, Levin M, Beverley P, Kon OM, Lalvani Aet al., 2021, New technologies for diagnosing active TB: the VANTDET diagnostic accuracy study

<h4>Background</h4>Tuberculosis (TB) is a devastating disease for which new diagnostic tests are desperately needed.<h4>Objective</h4>To validate promising new technologies [namely whole-blood transcriptomics, proteomics, flow cytometry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR)] and existing signatures for the detection of active TB in samples obtained from individuals with suspected active TB.<h4>Design</h4>Four substudies, each of which used samples from the biobank collected as part of the interferon gamma release assay (IGRA) in the Diagnostic Evaluation of Active TB study, which was a prospective cohort of patients recruited with suspected TB.<h4>Setting</h4>Secondary care.<h4>Participants</h4>Adults aged ≥ 16 years presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham, with suspected active TB.<h4>Interventions</h4>New tests using genome-wide gene expression microarray (transcriptomics), surface-enhanced laser desorption ionisation time-of-flight mass spectrometry/liquid chromatography–mass spectrometry (proteomics), flow cytometry or qRT-PCR.<h4>Main outcome measures</h4>Area under the curve (AUC), sensitivity and specificity were calculated to determine diagnostic accuracy. Positive and negative predictive values were calculated in some cases. A decision tree model was developed to calculate the incremental costs and quality-adjusted life-years of changing from current practice to using the novels tests.<h4>Results</h4>The project, and four substudies that assessed the previously published signatures, measured each of the new technologies and performed a health economic analysis in which the best-performing tests were evaluated for cost-effectiveness. The diagnostic accuracy of the transcriptomic tests ranged from an AUC of 0.81 to 0.84 for detecting al

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, 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

Gliddon H, Kaforou M, Alikian M, Coote D, Zhou C, Oni T, Anderson ST, Brent AJ, Crampin AC, Eley B, Heyderman R, Langford PR, Kern F, Ottenhoff THM, Hibberd ML, French N, Wright V, Dockrell HM, Coin L, Wilkinson R, Levin Met al., 2021, Identification of reduced host transcriptomic signatures for tuberculosis disease and digital PCR-based validation and quantification, Frontiers in Immunology, Vol: 12, ISSN: 1664-3224

Recently, host whole blood gene expression signatures have been identified for diagnosis of tuberculosis (TB). Absolute quantification of the concentrations of signature transcripts in blood have not been reported, but would facilitate diagnostic test development. To identify minimal transcript signatures, we applied a transcript selection procedure to microarray data from African adults comprising 536 patients with TB, other diseases (OD) and latent TB (LTBI), divided into training and test sets. Signatures were further investigated using reverse transcriptase (RT)—digital PCR (dPCR). A four-transcript signature (GBP6, TMCC1, PRDM1, and ARG1) measured using RT-dPCR distinguished TB patients from those with OD (area under the curve (AUC) 93.8% (CI95% 82.2–100%). A three-transcript signature (FCGR1A, ZNF296, and C1QB) differentiated TB from LTBI (AUC 97.3%, CI95%: 93.3–100%), regardless of HIV. These signatures have been validated across platforms and across samples offering strong, quantitative support for their use as diagnostic biomarkers for TB.

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

Morris TC, Hoggart CJ, Chegou NN, Kidd M, Oni T, Goliath R, Wilkinson KA, Dockrell HM, Sichali L, Banda L, Crampin AC, French N, Walzl G, Levin M, Wilkinson RJ, Hamilton MSet al., 2021, Evaluation of host serum protein biomarkers of tuberculosis in sub-Saharan Africa, Frontiers in Immunology, Vol: 12, Pages: 1-12, ISSN: 1664-3224

Accurate and affordable point-of-care diagnostics for tuberculosis (TB) are needed. Host serum protein signatures have been derived for use in primary care settings, however validation of these in secondary care settings is lacking. We evaluated serum protein biomarkers discovered in primary care cohorts from Africa reapplied to patients from secondary care. In this nested case-control study, concentrations of 22 proteins were quantified in sera from 292 patients from Malawi and South Africa who presented predominantly to secondary care. Recruitment was based upon intention of local clinicians to test for TB. The case definition for TB was culture positivity for Mycobacterium tuberculosis; and for other diseases (OD) a confirmed alternative diagnosis. Equal numbers of TB and OD patients were selected. Within each group, there were equal numbers with and without HIV and from each site. Patients were split into training and test sets for biosignature discovery. A nine-protein signature to distinguish TB from OD was discovered comprising fibrinogen, alpha-2-macroglobulin, CRP, MMP-9, transthyretin, complement factor H, IFN-gamma, IP-10, and TNF-alpha. This signature had an area under the receiver operating characteristic curve in the training set of 90% (95% CI 86–95%), and, after adjusting the cut-off for increased sensitivity, a sensitivity and specificity in the test set of 92% (95% CI 80–98%) and 71% (95% CI 56–84%), respectively. The best single biomarker was complement factor H [area under the receiver operating characteristic curve 70% (95% CI 64–76%)]. Biosignatures consisting of host serum proteins may function as point-of-care screening tests for TB in African hospitals. Complement factor H is identified as a new biomarker for such signatures.

Journal article

van Beek AE, Pouw RB, Wright VJ, Sallah N, Inwald D, Hoggart C, Brouwer MC, Galassini R, Thomas J, Calvo-Bado L, Fink C, Jongerius I, Hibberd M, Wouters D, Levin M, Kuijpers TWet al., 2021, Loss of Factor H family proteins associates with meningococcal disease severity

<jats:title>ABSTRACT</jats:title><jats:p><jats:italic>Neisseria meningitidis</jats:italic>, the causative agent of meningococcal disease (MD), evades complement-mediated clearance upon infection by ‘hijacking’ the human complement regulator factor H (FH). The FH protein family also comprises the homologous FH-related (FHR) proteins, hypothesized to act as antagonists of FH, and FHR-3 has recently been implicated to play a major role in MD susceptibility. Here, we show that, next to FH and FHR-3, the circulating levels of all FH family proteins are equally decreased during pediatric MD. We did not observe a specific consumption of FH or FHR-3 by <jats:italic>N. meningitidis</jats:italic> during the first days of infection and the levels recovered over time. MD severity associated predominantly with a loss of FH. Strikingly, loss of FH and FHRs associated strongly with renal failure, suggesting insufficient protection of host tissue by the FH protein family. Retaining higher levels of FH family proteins may thus limit tissue injury during MD.</jats:p>

Journal article

Harwood R, Allin B, Jones CE, Whittaker E, Ramnarayan P, Ramanan A, Kaleem M, Tulloh R, Peters MJ, Almond S, Davis PJ, Levin M, Tometzki A, Faust SN, Knight M, Kenny Set al., 2021, A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process, LANCET CHILD & ADOLESCENT HEALTH, Vol: 5, Pages: 133-141, ISSN: 2352-4642

Journal article

Borensztajn D, Hagedoorn N, Rivero Calle I, Maconochie I, von Both U, Carrol E, Dewez J, Emonts M, Van Der Flier M, de Groot R, Herberg J, Kohlmaier B, Lim E, Martinon-Torres F, Nieboer D, Nijman R, Pokorn M, Strle F, Tsolia M, Vermont C, Yeung S, Zavadska D, Zenz W, Levin M, Moll Het al., 2021, Variation in hospital admission in febrile children evaluated at the Emergency Department (ED) in Europe: PERFORM, a multicentre prospective observational study, PLoS One, Vol: 16, ISSN: 1932-6203

ObjectivesHospitalisation is frequently used as a marker of disease severity in observational Emergency Department (ED) studies. The comparison of ED admission rates is complex in potentially being influenced by the characteristics of the region, ED, physician and patient. We aimed to study variation in ED admission rates of febrile children, to assess whether variation could be explained by disease severity and to identify patient groups with large variation, in order to use this to reduce unnecessary health care utilization that is often due to practice variation.DesignMOFICHE (Management and Outcome of Fever in children in Europe, part of the PERFORM study, www.perform2020.org), is a prospective cohort study using routinely collected data on febrile children regarding patient characteristics (age, referral, vital signs and clinical alarming signs), diagnostic tests, therapy, diagnosis and hospital admission.Setting and participantsData were collected on febrile children aged 0–18 years presenting to 12 European EDs (2017–2018).Main outcome measuresWe compared admission rates between EDs by using standardised admission rates after adjusting for patient characteristics and initiated tests at the ED, where standardised rates >1 demonstrate higher admission rates than expected and rates <1 indicate lower rates than expected based on the ED patient population.ResultsWe included 38,120 children. Of those, 9.695 (25.4%) were admitted to a general ward (range EDs 5.1–54.5%). Adjusted standardised admission rates ranged between 0.6 and 1.5. The largest variation was seen in short admission rates (0.1–5.0), PICU admission rates (0.2–2.2), upper respiratory tract infections (0.4–1.7) and fever without focus (0.5–2.7). Variation was small in sepsis/meningitis (0.9–1.1).ConclusionsLarge variation exists in admission rates of febrile children evaluated at European EDs, however, this variation is largely reduced after correc

Journal article

Pennisi I, Rodriguez Manzano J, Moniri A, Kaforou M, Herberg J, Levin M, Georgiou Pet al., 2021, Translation of a host blood RNA Signature distinguishing bacterial from viral infection into a platform suitable for development as a point-of-care test, JAMA Pediatrics, Vol: 175, Pages: 417-419, ISSN: 2168-6203

Journal article

Bautista-Rodriguez C, Sanchez-de-Toledo J, Clark BC, Herberg J, Bajolle F, Randanne PC, Salas-Mera D, Foldvari S, Chowdhury D, Munoz R, Bianco F, Singh Y, Levin M, Bonnet D, Fraisse Aet al., 2021, Multisystem inflammatory syndrome in children: an international survey., Pediatrics, ISSN: 0031-4005

Objective. To describe presentation, hospital course and predictors of bad outcome in MultisystemInflammatory Syndrome in Children (MIS-C).Methods. Retrospective data review of a case series of children meeting published definition forMIS-C discharged/died between March 1st and June 15th, 2020, from 33 participating European,Asian and American hospitals. Data was collected through a web-based survey and includedclinical, laboratory, electrocardiographic and echocardiographic findings and treatmentmanagement.Results. We included 183 patients (109 males [59.6%]; mean age 7.0±4.7 years; black race,56[30.6%]; obesity, 48[26.2%]) with MIS-C. Overall, 114/183(62.3%) had evidence of SARSCoV-2 infection. All presented with fever, 117/183 (63.9%) with gastrointestinal symptoms and79/183 (43.2%) with shock, that was associated with black race, higher inflammation and imagingabnormalities. Twenty-seven patients (14.7%) fulfilled criteria for Kawasaki disease. They wereyounger with no shock, fewer gastrointestinal, cardio-respiratory and neurological symptoms. Theremaining 77 patients (49.3%) had mainly fever and inflammation. Inotropic support, mechanicalventilation and ECMO were indicated in 72 (39.3%), 43 (23.5%) and 4 (2.2%) patients,respectively. A shorter duration of symptoms prior to admission was found to be associated withpoor patient outcome and for ECMO/death, with 72.3% (95% CI 0.56-0.90, p=0.006) increasedrisk per day reduction and with 63.3% (95% CI 0.47-0.82, p<0.0001) increased risk per dayreduction respectively.Conclusion. In this case series, children with MIS-C presented with a wide clinical spectrum,including KD-like, life-threatening shock and milder forms with mainly fever and inflammation.A shorter duration of symptoms prior to admission was associated with worse outcome.

Journal article

Menikou S, McArdle AJ, Li M-S, Kaforou M, Langford PR, Levin Met al., 2020, A proteomics-based method for identifying antigens within immune complexes, PLoS One, Vol: 15, ISSN: 1932-6203

A novel approach to recover and identify immune complexes (ICs) was developed using size exclusion chromatography (SEC) and affinity chromatography on immunoglobulin binding columns (HiTrap Protein G). The purification process was monitored by 1D SDS-PAGE, protein staining, Western blotting and, finally, liquid chromatography tandem mass spectrometry (LC MS/MS) was used to identify the recovered antigens. This approach was applied to serum with artificially created immune complexes (ICs) comprising vaccine antigen (influenza) and antibody, which led to recovery and identification of influenza peptides within the recovered ICs. This approach was compared with the established method for IC detection and recovery, polyethylene glycol (PEG) precipitation, followed by LC MS/MS. Both approaches successfully enabled capture, recovery and characterization of immunoglobulins and influenza antigen(s) in complex with the immunoglobulins. However, PEG precipitation has the advantage of simplicity and is more suited for large scale studies.

Journal article

Willems E, Lores-Motta L, Zanichelli A, Suffritti C, van der Flier M, van der Molen RG, Langereis JD, van Drongelen J, van den Heuvel LP, Volokhina E, van de Kar NCAJ, Keizer-Garritsen J, Levin M, Herberg JA, Martinon-Torres F, Wessels HJTC, de Breuk A, Fauser S, Hoyng CB, den Hollander A, de Groot R, van Gool AJ, Gloerich J, de Jonge Met al., 2020, Quantitative multiplex profiling of the complement system to diagnose complement-mediated diseases, Clinical & Translational Immunology, Vol: 9, Pages: 1-12, ISSN: 2050-0068

ObjectivesComplement deficiencies are difficult to diagnose because of the variability of symptoms and the complexity of the diagnostic process. Here, we applied a novel ‘complementomics’ approach to study the impact of various complement deficiencies on circulating complement levels.MethodsUsing a quantitative multiplex mass spectrometry assay, we analysed 44 peptides to profile 34 complement proteins simultaneously in 40 healthy controls and 83 individuals with a diagnosed deficiency or a potential pathogenic variant in 14 different complement proteins.ResultsApart from confirming near or total absence of the respective protein in plasma of complement‐deficient patients, this mass spectrometry‐based profiling method led to the identification of additional deficiencies. In many cases, partial depletion of the pathway up‐ and/or downstream of the absent protein was measured. This was especially found in patients deficient for complement inhibitors, such as angioedema patients with a C1‐inhibitor deficiency. The added value of complementomics was shown in three patients with poorly defined complement deficiencies.ConclusionOur study shows the potential clinical utility of profiling circulating complement proteins as a comprehensive read‐out of various complement deficiencies. Particularly, our approach provides insight into the intricate interplay between complement proteins due to functional coupling, which contributes to the better understanding of the various disease phenotypes and improvement of care for patients with complement‐mediated diseases.

Journal article

O'Connor D, Pinto MV, Sheerin D, Tomic A, Drury RE, Channon-Wells S, Galal U, Dold C, Robinson H, Kerridge S, Plested E, Hughes H, Stockdale L, Sadarangani M, Snape MD, Rollier CS, Levin M, Pollard AJet al., 2020, Gene expression profiling reveals insights into infant immunological and febrile responses to group B meningococcal vaccine, Molecular Systems Biology, Vol: 16, Pages: 1-19, ISSN: 1744-4292

Neisseria meningitidis is a major cause of meningitis and septicaemia. A MenB vaccine (4CMenB) was licensed by the European Medicines Agency in January 2013. Here we describe the blood transcriptome and proteome following infant immunisations with or without concomitant 4CMenB, to gain insight into the molecular mechanisms underlying post-vaccination reactogenicity and immunogenicity. Infants were randomised to receive control immunisations (PCV13 and DTaP-IPV-Hib) with or without 4CMenB at 2 and 4 months of age. Blood gene expression and plasma proteins were measured prior to, then 4 h, 24 h, 3 days or 7 days post-vaccination. 4CMenB vaccination was associated with increased expression of ENTPD7 and increased concentrations of 4 plasma proteins: CRP, G-CSF, IL-1RA and IL-6. Post-vaccination fever was associated with increased expression of SELL, involved in neutrophil recruitment. A murine model dissecting the vaccine components found the concomitant regimen to be associated with increased gene perturbation compared with 4CMenB vaccine alone with enhancement of pathways such as interleukin-3, -5 and GM-CSF signalling. Finally, we present transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine.

Journal article

Borghesi A, Trück J, Asgari S, Sancho-Shimizu V, Agyeman PKA, Bellos E, Giannoni E, Stocker M, Posfay-Barbe KM, Heininger U, Bernhard-Stirnemann S, Niederer-Loher A, Kahlert CR, Natalucci G, Relly C, Riedel T, Kuehni CE, Thorball CW, Chaturvedi N, Martinon-Torres F, Kuijpers TW, Coin L, Wright V, Herberg J, Levin M, Aebi C, Berger C, Fellay J, Schlapbach LJ, EUCLIDS consortium and the Swiss Paediatric Sepsis Studyet al., 2020, Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study., Clinical Infectious Diseases, Vol: 71, Pages: e614-e623, ISSN: 1058-4838

BACKGROUND: The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes. METHODS: Multicenter population-based prospective study including previously healthy children ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported. RESULTS: 176 children presenting with 185 sepsis episodes underwent WES (median age 52 months, IQR 15.4-126.4). 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) were found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants which were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants. CONCLUSIONS: Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected Variants of Uncertain Significance in PID genes in one out of five children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.

Journal article

Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, Klein JD, Bhutta ZAet al., 2020, COVID-19 and multisystem inflammatory syndrome in children and adolescents, LANCET INFECTIOUS DISEASES, Vol: 20, Pages: E276-E288, ISSN: 1473-3099

Journal article

Tregoning J, Busse D, Kaforou M, Levin M, Herberg J, Kellam P, Bassano Iet al., 2020, Interferon-induced Protein-44 and Interferon-induced Protein 44-like restrict replication of Respiratory Syncytial Virus, Journal of Virology, Vol: 94, Pages: 1-15, ISSN: 0022-538X

Cellular intrinsic immunity, mediated by the expression of an array of interferon-stimulated antiviral genes, is a vital part of host defence. We have previously used a bioinformatic screen to identify two interferon stimulated genes (ISG) with poorly characterised function, Interferon-induced protein 44 (IFI44) and interferon-induced protein 44-like (IFI44L), as potentially being important in Respiratory Syncytial Virus (RSV) infection. Using overexpression systems, CRISPR-Cas9-mediated knockout, and a knockout mouse model we investigated the antiviral capability of these genes in the control of RSV replication. Over-expression of IFI44 or IFI44L was sufficient to restrict RSV infection at an early time post infection. Knocking out these genes in mammalian airway epithelial cells increased levels of infection. Both genes express antiproliferative factors that have no effect on RSV attachment but reduce RSV replication in a minigenome assay. The loss of Ifi44 was associated with a more severe infection phenotype in a mouse model of infection. These studies demonstrate a function for IFI44 and IFI44L in controlling RSV infection.

Journal article

Nijman R, Joergensen R, Levin M, Herberg J, Maconochie Iet al., 2020, Management of children with fever at risk for paediatric sepsis: a prospective study in paediatric emergency care, Frontiers in Pediatrics, Vol: 8, Pages: 1-17, ISSN: 2296-2360

Objective: To study warning signs of serious infections in febrile children presenting to PED, ascertain their risk of having sepsis, and evaluate their management.Design: Prospective observational study.Setting: A single pediatric emergency department (PED).Participants: Febrile children, aged 1 month−16 years, with >= 1 warning signs of sepsis.Interventions and Main outcome measures: Clinical characteristics, including different thresholds for tachycardia and tachypnoea, and their association with (1) delivery of pediatric sepsis 6 (PS6) interventions, (2) final diagnosis of invasive bacterial infection (IBI), (3) the risk for pediatric intensive care unit (PICU) admission, and (4) death.Results: Forty-one percent of 5,156 febrile children had warning signs of sepsis. 1,606 (34%) children had tachypnoea and 1,907 (39%) children had tachycardia when using APLS threshold values. Using the NICE sepsis guidelines thresholds resulted in 1,512 (32%) children having tachypnoea (kappa 0.56) and 2,769 (57%) children having tachycardia (kappa 0.66). Of 1,628 PED visits spanning 1,551 disease episodes, six children (0.4%) had IBI, with one death (0.06%), corresponding with 256 children requiring escalation of care according to sepsis guideline recommendations for each child with IBI. There were five additional PICU admissions (0.4%). 121 (7%) had intravenous antibiotics in PED; 39 children (2%) had an intravenous fluid bolus, inotrope drugs were started in one child. 440 children (27%) were reviewed by a senior clinician. In 4/11 children with IBI or PICU admission or death, PS6 interventions were delivered within 60 min after arriving. 1,062 (65%) visits had no PS6 interventions. Diagnostic performance of vital signs or sepsis criteria for predicting serious illness yielded a large proportion of false positives. Lactataemia was not associated with giving iv fluid boluses (p = 0.19) or presence of serious bacterial infections (p = 0.128).Conclusion: Many febrile chi

Journal article

Pennisi I, Rodriguez Manzano J, Miscourides N, Moniri A, Moser N, Habgood Coote D, Kaforou M, Herberg J, Levin M, Georgiou Pet al., 2020, A method for determining a diagnostic outcome

Patent

Hagedoorn N, Borensztajn D, Nijman R, Balode A, von Both U, Carrol E, Eleftheriou I, Emonts M, Van Der Flier M, de Groot R, Herberg J, Kohlmaier B, Lim E, Maconochie I, Martinon-Torres F, Nieboer D, Pokorn M, Strle F, Tsolia M, Yeung S, Zavadska D, Zenz W, Vermont C, Levin M, Moll Het al., 2020, Variation in antibiotic prescription rates in febrile children presenting to Emergency Departments across Europe (MOFICHE): a multicentre observational study, PLoS Medicine, Vol: 17, ISSN: 1549-1277

BackgroundThe prescription rate of antibiotics is high for febrile children visiting the emergency department (ED), contributing to antimicrobial resistance. Large studies at European EDs covering diversity in antibiotic and broad-spectrum prescriptions in all febrile children are lacking. A better understanding of variability in antibiotic prescriptions in EDs and its relation with viral or bacterial disease is essential for the development and implementation of interventions to optimise antibiotic use. As part of the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union) project, the MOFICHE (Management and Outcome of Fever in Children in Europe) study aims to investigate variation and appropriateness of antibiotic prescription in febrile children visiting EDs in Europe.Methods and findingsBetween January 2017 and April 2018, data were prospectively collected on febrile children aged 0–18 years presenting to 12 EDs in 8 European countries (Austria, Germany, Greece, Latvia, the Netherlands [n = 3], Spain, Slovenia, United Kingdom [n = 3]). These EDs were based in university hospitals (n = 9) or large teaching hospitals (n = 3). Main outcomes were (1) antibiotic prescription rate; (2) the proportion of antibiotics that were broad-spectrum antibiotics; (3) the proportion of antibiotics of appropriate indication (presumed bacterial), inappropriate indication (presumed viral), or inconclusive indication (unknown bacterial/viral or other); (4) the proportion of oral antibiotics of inappropriate duration; and (5) the proportion of antibiotics that were guideline-concordant in uncomplicated urinary and upper and lower respiratory tract infections (RTIs). We determined variation of antibiotic prescription and broad-spectrum prescription by calculating standardised prescription rates using multilevel logistic regression and adjusted for general characteristics (e.g., age, sex, comorbidity, referral), diseas

Journal article

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