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

275 results found

Harwood R, Allin B, Jones CE, Whittaker E, Ramnarayan P, Ramanan AV, Kaleem M, Tulloh R, Peters MJ, Almond S, Davis PJ, Levin M, Tometzki A, Faust SN, Knight M, Kenny S, PIMS-TS National Consensus Management Study Groupet al., 2020, 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 Adolesc Health

Paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) is a novel condition that was first reported in April, 2020. We aimed to develop a national consensus management pathway for the UK to provide guidance for clinicians caring for children with PIMS-TS. A three-phase online Delphi process and virtual consensus meeting sought consensus over the investigation, management, and research priorities from multidisciplinary clinicians caring for children with PIMS-TS. We used 140 consensus statements to derive a consensus management pathway that describes the initial investigation of children with suspected PIMS-TS, including blood markers to help determine the severity of disease, an echocardiogram, and a viral and septic screen to exclude other infectious causes of illness. The importance of a multidisciplinary team in decision making for children with PIMS-TS is highlighted throughout the guidance, along with the recommended treatment options, including supportive care, intravenous immunoglobulin, methylprednisolone, and biological therapies. These include IL-1 antagonists (eg, anakinra), IL-6 receptor blockers (eg, tocilizumab), and anti-TNF agents (eg, infliximab) for children with Kawasaki disease-like phenotype and non-specific presentations. Use of a rapid online Delphi process has made it possible to generate a national consensus pathway in a timely and cost-efficient manner in the middle of a global pandemic. The consensus statements represent the views of UK clinicians and are applicable to children in the UK suspected of having PIMS-TS. Future evidence will inform updates to this guidance, which in the interim provides a solid framework to support clinicians caring for children with PIMS-TS. This process has directly informed new PIMS-TS specific treatment groups as part of the adaptive UK RECOVERY trial protocol, which is the first formal randomised controlled trial of therapies for PIMS-TS globally.

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

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

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

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Levin M, 2020, Childhood Multisystem Inflammatory Syndrome - A New Challenge in the Pandemic, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 383, Pages: 393-395, ISSN: 0028-4793

Journal article

Zandstra J, van de Geer A, Tanck MWT, Dimitriades DVS-B, Aarts CEM, Dietz SM, van Bruggen R, Schweintzger NA, Zenz W, Emonts M, Zavadska D, Pokorn M, Usuf E, Moll HA, Schlapbach LJ, Carrol ED, Paulus S, Tsolia M, Fink C, Yeung S, Shimizu C, Tremoulet A, Galassini R, Wright VJ, Martinon-Torres F, Herberg J, Burns J, Levin M, Kuijpers TWet al., 2020, Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood, FRONTIERS IN PEDIATRICS, Vol: 8, ISSN: 2296-2360

Journal article

Rodgers E, Bentley SD, Borrow R, Bratcher HB, Brisse S, Brueggemann AB, Caugant DA, Findlow J, Fox L, Glennie L, Harrison LH, Harrison OB, Heyderman RS, van Rensburg MJ, Jolley KA, Kwambana-Adams B, Ladhani S, LaForce M, Levin M, Lucidarme J, MacAlasdair N, Maclennan J, Maiden MCJ, Maynard-Smith L, Muzzi A, Oster P, Rodrigues CMC, Ronveaux O, Serino L, Smith V, van der Ende A, Vázquez J, Wang X, Yezli S, Stuart JMet al., 2020, The global meningitis genome partnership., J Infect

Genomic surveillance of bacterial meningitis pathogens is essential for effective disease control globally, enabling identification of emerging and expanding strains and consequent public health interventions. While there has been a rise in the use of whole genome sequencing, this has been driven predominately by a subset of countries with adequate capacity and resources. Global capacity to participate in surveillance needs to be expanded, particularly in low and middle-income countries with high disease burdens. In light of this, the WHO-led collaboration, Defeating Meningitis by 2030 Global Roadmap, has called for the establishment of a Global Meningitis Genome Partnership that links resources for: N. meningitidis (Nm), S. pneumoniae (Sp), H. influenzae (Hi) and S. agalactiae (Sa) to improve worldwide co-ordination of strain identification and tracking. Existing platforms containing relevant genomes include: PubMLST: Nm (31,622), Sp (15,132), Hi (1935), Sa (9026); The Wellcome Sanger Institute: Nm (13,711), Sp (> 24,000), Sa (6200), Hi (1738); and BMGAP: Nm (8785), Hi (2030). A steering group is being established to coordinate the initiative and encourage high-quality data curation. Next steps include: developing guidelines on open-access sharing of genomic data; defining a core set of metadata; and facilitating development of user-friendly interfaces that represent publicly available data.

Journal article

Pennisi I, Rodriguez Manzano J, Moniri A, Kaforou M, Herberg J, Levin M, Georgiou Pet al., 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, ISSN: 2168-6203

Journal article

Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, Ramnarayan P, Fraisse A, Miller O, Davies P, Kucera F, Brierley J, McDougall M, Carter M, Tremoulet A, Shimizu C, Herberg J, Burns JC, Lyall H, Levin Met al., 2020, Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2, JAMA, Pages: E1-E11, ISSN: 0098-7484

Importance In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation.Objectives To describe the clinical and laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders.Design, Setting, and Participants Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019.Exposures Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization.Main Outcomes and Measures Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders.Results Fifty-eight children (median age, 9 years [interquartile range {IQR}, 5.7-14]; 33 girls [57%]) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including v

Journal article

Hodeib S, Herberg JA, Levin M, Sancho-Shimizu Vet al., 2020, Human genetics of meningococcal infections, Human Genetics, Vol: 139, Pages: 961-980, ISSN: 0340-6717

Neisseria meningitidis is a leading cause of bacterial septicaemia and meningitis worldwide. Meningococcal disease is rare but can be life threatening with a tendency to affect children. Many studies have investigated the role of human genetics in predisposition to N. meningitidis infection. These have identified both rare single-gene mutations as well as more common polymorphisms associated with meningococcal disease susceptibility and severity. These findings provide clues to the pathogenesis of N. meningitidis, the basis of host susceptibility to infection and to the aetiology of severe disease. From the multiple discoveries of monogenic complement deficiencies to the associations of complement factor H and complement factor H-related three polymorphisms to meningococcal disease, the complement pathway is highlighted as being central to the genetic control of meningococcal disease. This review aims to summarise the current understanding of the host genetic basis of meningococcal disease with respect to the different stages of meningococcal infection.

Journal article

Sancho Shimizu V, 2020, A rare mutation in SPLUNC1 underlies meningococcal disease affecting bacterial adherence and invasion, Clinical Infectious Diseases, Vol: 70, Pages: 2045-2053, ISSN: 1058-4838

BackgroundNeisseriameningitidis (Nm) is a nasopharyngeal commensal carried by healthy individuals. However, invasive infections occurs in a minority of individuals, with devastating consequences. There is evidence that common polymorphisms are associated with invasive meningococcal disease (IMD) but the contribution of rare variants other than complement has not been determined.MethodsWe identified familial cases of IMD in the UK meningococcal disease study and the European Union Life-threatening Infectious Disease Study. Candidate genetic variants were identified by whole exome sequencing of two patients with familial IMD. Candidate variants were further validated by in vitro assays.ResultsExomes of two siblings with IMD identified a novel heterozygous missense mutation in BPIFA1/SPLUNC1. Sequencing of 186 other non-familial cases identified another unrelated IMD patient with the same mutation. SPLUNC1 is an innate immune defence protein expressed in the nasopharyngeal epithelia, however, its role in invasive infections is unknown. In vitro assays demonstrated that recombinant SPLUNC1 inhibits biofilm formation by Nm, and impedes Nm adhesion and invasion of human airway cells. The dominant negative mutant rSPLUNC1 (p.G22E) showed reduced anti-biofilm activity, increased meningococcal adhesion and invasion of cells compared with wild type SPLUNC1.ConclusionsA mutation in SPLUNC1 affecting mucosal attachment, biofilm formation and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease.

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, 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

Brogan P, Burns JC, Cornish J, Diwakar V, Eleftheriou D, Gordon JB, Gray HH, Johnson TW, Levin M, Malik I, MacCarthy P, McCormack R, Miller O, Tulloh RMRet al., 2020, Lifetime cardiovascular management of patients with previous Kawasaki disease, HEART, Vol: 106, Pages: 411-420, ISSN: 1355-6037

Journal article

Wang X, Nijman R, Camuzeaux S, Sands C, Jackson H, Kaforou M, Emonts M, Herberg J, Maconochie I, Carrol E, Paulus S, Zenz W, Coin L, Flier MVD, Groot RD, Martinon-Torres F, Schlapbach LJ, Pollard A, Fink C, Kuijpers TT, Anderson S, Lewis M, Levin M, McClure M, EUCLIDS consortiumet al., 2019, Plasma lipid profiles discriminate bacterial from viral infection in febrile children, Scientific Reports, Vol: 9, ISSN: 2045-2322

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The ‘omics’ approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n=20) and confirmed viral infection (n=20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group..A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.

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Levin M, Cunnington AJ, Hoggart CJ, 2019, Secondary re-analysis of the FEAST trial - Authors' reply, The Lancet Respiratory Medicine, Vol: 7, Pages: e31-e31, ISSN: 2213-2600

Journal article

Shimizu C, Kim J, Eleftherohorinou H, Wright VJ, Hoang LT, Tremoulet AH, Franco A, Hibberd ML, Takahashi A, Kubo M, Ito K, Tanaka T, Onouchi Y, Coin LJM, Levin M, Burns JC, Shike H, International Kawasaki Disease Genetic Consortiumet al., 2019, HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease, Human Immunology, Vol: 80, Pages: 731-738, ISSN: 0198-8859

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children.

Journal article

Secka F, Herberg J, Sarr I, Darboe S, Sey G, Saidykhan M, Wathuo M, Kaforou M, Antonio M, Roca A, Zaman SMA, Cebey-Lopez M, Boeddha NP, Paulus S, Kohlfurst D, Emonts M, Zenz W, Carrol E, de Groot R, Schlapbach L, Martinon-Torres F, Bojang K, Levin M, van der Flier M, Anderson Set al., 2019, Bacteremia in childhood life-threatening infections in urban Gambia: EUCLIDS in West Africa, Open Forum Infectious Diseases, Vol: 6, ISSN: 2328-8957

BackgroundThe limited availability of microbiology services in sub-Saharan Africa impedes accurate diagno-sis of bacterial pathogens and understanding of trends in prevalence and antibiotic sensitivities. We aimed to characterize bacteremia amongst hospitalized children in The Gambia and to identi-fy factors associated with bacteremia and mortality. MethodsWe prospectively studied children presenting with suspected severe infection to two urban hos-pitals in The Gambia, between January 2013 and September 2015. Demographic and anthropo-metric data, clinical features, management and blood culture results were documented. Urine screens for antibiotic activity were performed in a subset of participants. ResultsOf 411 children enrolled (median age 29 months; IQR: 11-82), 79.5% (325/409) reported pre-hospital antibiotic use. Antimicrobial activity by urinary screen for antibiotic activity was detected in 70.8% (n=80/113). 66 bacterial pathogens were identified in 65 (15.8%) participants and Staphylococcus aureus predominated. Gram positive organisms were more commonly identified than Gram-negative (p<0.01). Antibiotic resistance against first-line antimicrobials (ampicillin and gentamicin) was common among Gram-negative bacteria (39%; range 25-100%). Factors signif-icantly associated with bacteremia included: gender, hydration status, musculoskeletal examina-tion findings, admission to the MRCG-LSHTM hospital, and meeting sepsis criteria. Those asso-ciated with increased mortality were presence of a comorbidity, clinical pallor, tachypnoea and altered consciousness. Tachycardia was associated with reduced mortality. ConclusionsThe bacteremia rate in children with suspected childhood life-threatening infectious diseases in The Gambia is high. The pattern of pathogen prevalence and antimicrobial resistance has changed over time compared to previous studies illustrating the importance of robust bacterial surveillance programs in resource-limited settings.

Journal article

Rohlwink U, Figaji A, Wilkinson K, Horswell S, Sesay A, Deffur A, Enslin N, Solomons R, Van Toorn R, Eley B, Levin M, Wilkinson R, Lai PJet al., 2019, Tuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity, Nature Communications, Vol: 10, ISSN: 2041-1723

Tuberculous meningitis (TBM) is the most severe form of TB with high rates of mortality and morbidity. We conducted RNA-sequencing on whole blood as well as on ventricular and lumbar cerebrospinal fluid (CSF) of pediatric patients treated for TBM. Differential transcript expression of TBM cases were compared with healthy controls in whole blood and with non-TB cerebral infection controls in CSF. Whole blood RNA-Seq analysis demonstratesa distinct immune response pattern in TBM, with significant increase inboth canonical and non-canonical inflammasome activation and decrease in T-cell activation. In ventricular CSF, a significant enrichment associated with neuronal excitotoxicity and cerebral damage is detected in TBM. Finally, compartmental comparison in TBM indicatesthat the ventricular profile representsbrain injury whereas the lumbar profile representsprotein translation and cytokine signalling. Together, transcriptomic analysis shows thatdisease processes differ between the periphery and the central nervous system, and within brain compartments.

Journal article

Levin M, Cunnington A, Hoggart C, Adverse effects of saline or albumin fluid bolus in resuscitation: response to Maitland et al. and Quartagno et al., Lancet Respiratory Medicine, ISSN: 2213-2600

Journal article

Tulloh RMR, Mayon-White R, Harnden A, Ramanan AV, Tizard EJ, Shingadia D, Michie CA, Lynn RM, Levin M, Franklin OD, Craggs P, Davidson S, Stirzaker R, Danson M, Brogan PAet al., 2019, Kawasaki disease: a prospective population survey in the UK and Ireland from 2013 to 2015, ARCHIVES OF DISEASE IN CHILDHOOD, Vol: 104, Pages: 640-646, ISSN: 0003-9888

Journal article

Levin M, Cunnington AJ, Wilson C, Nadel S, Lang HJ, Ninis N, McCulloch M, Argent A, Buys H, Moxon CA, Best A, Nijman RG, Hoggart CJet al., 2019, Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial, Lancet Respiratory Medicine, Vol: 7, Pages: 581-593, ISSN: 2213-2600

BACKGROUND: Fluid resuscitation is the recommended management of shock, but increased mortality in febrile African children in the FEAST trial. We hypothesised that fluid bolus-induced deaths in FEAST would be associated with detectable changes in cardiovascular, neurological, or respiratory function, oxygen carrying capacity, and blood biochemistry. METHODS: We developed composite scores for respiratory, cardiovascular, and neurological function using vital sign data from the FEAST trial, and used them to compare participants from FEAST with those from four other cohorts and to identify differences between the bolus (n=2097) and no bolus (n=1044) groups of FEAST. We calculated the odds of adverse outcome for each ten-unit increase in baseline score using logistic regression for each cohort. Within FEAST participants, we also compared haemoglobin and plasma biochemistry between bolus and non-bolus patients, assessed the effects of these factors along with the vital sign scores on the contribution of bolus to mortality using Cox proportional hazard models, and used Bayesian clustering to identify subgroups that differed in response to bolus. The FEAST trial is registered with ISRCTN, number ISRCTN69856593. FINDINGS: Increasing respiratory (odds ratio 1·09, 95% CI 1·07-1·11), neurological (1·26, 1·21-1·31), and cardiovascular scores (1·09, 1·05-1·14) were associated with death in FEAST (all p<0·0001), and with adverse outcomes for specific scores in the four other cohorts. In FEAST, fluid bolus increased respiratory and neurological scores and decreased cardiovascular score at 1 h after commencement of the infusion. Fluid bolus recipients had mean 0·33 g/dL (95% CI 0·20-0·46) reduction in haemoglobin concentration after 8 h (p<0·0001), and at 24 h had a decrease of 1·41 mEq/L (95% CI 0·76-2·06; p=0·0002) in mean base excess and increase o

Journal article

Willems E, Alkema W, Keizer-Garritsen J, Suppers A, van der Flier M, Philipsen RHLA, van den Heuvel LP, Volokhina E, van der Molen RG, Herberg JA, Levin M, Wright VJ, Ahout IML, Ferwerda G, Emonts M, Boeddha NP, Rivero-Calle I, Torres FM, Wessels HJCT, de Groot R, van Gool AJ, Gloerich J, de Jonge MIet al., 2019, Biosynthetic homeostasis and resilience of the complement system in health and infectious disease, EBioMedicine, Vol: 45, Pages: 303-313, ISSN: 2352-3964

BACKGROUND: The complement system is a central component of the innate immune system. Constitutive biosynthesis of complement proteins is essential for homeostasis. Dysregulation as a consequence of genetic or environmental cues can lead to inflammatory syndromes or increased susceptibility to infection. However, very little is known about steady state levels in children or its kinetics during infection. METHODS: With a newly developed multiplex mass spectrometry-based method we analyzed the levels of 32 complement proteins in healthy individuals and in a group of pediatric patients infected with bacterial or viral pathogens. FINDINGS: In plasma from young infants we found reduced levels of C4BP, ficolin-3, factor B, classical pathway components C1QA, C1QB, C1QC, C1R, and terminal pathway components C5, C8, C9, as compared to healthy adults; whereas the majority of complement regulating (inhibitory) proteins reach adult levels at very young age. Both viral and bacterial infections in children generally lead to a slight overall increase in complement levels, with some exceptions. The kinetics of complement levels during invasive bacterial infections only showed minor changes, except for a significant increase and decrease of CRP and clusterin, respectively. INTERPRETATION: The combination of lower levels of activating and higher levels of regulating complement proteins, would potentially raise the threshold of activation, which might lead to suppressed complement activation in the first phase of life. There is hardly any measurable complement consumption during bacterial or viral infection. Altogether, expression of the complement proteins appears surprisingly stable, which suggests that the system is continuously replenished. FUND: European Union's Horizon 2020, project PERFORM, grant agreement No. 668303.

Journal article

Borensztajn D, Yeung S, Hagedoorn NN, Balode A, von Both U, Carrol ED, Dewez JE, Eleftheriou I, Emonts M, van der Flier M, de Groot R, Herberg JA, Kohlmaier B, Lim E, Maconochie I, Martinón-Torres F, Nijman R, Pokorn M, Strle F, Tsolia M, Wendelin G, Zavadska D, Zenz W, Levin M, Moll HAet al., 2019, Diversity in the emergency care for febrile children in Europe: a questionnaire study, BMJ Paediatrics Open, Vol: 3, ISSN: 2399-9772

Objective: To provide an overview of care in emergency departments (EDs) across Europe in order to interpret observational data and implement interventions regarding the management of febrile children. Design and setting: An electronic questionnaire was sent to the principal investigators of an ongoing study (PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management), www.perform2020.eu) in 11 European hospitals in eight countries: Austria, Germany, Greece, Latvia, the Netherlands, Slovenia, Spain and the UK. Outcome measures: The questionnaire covered indicators in three domains: local ED quality (supervision, guideline availability, paper vs electronic health records), organisation of healthcare (primary care, immunisation), and local factors influencing or reflecting resource use (availability of point-of-care tests, admission rates). Results: Reported admission rates ranged from 4% to 51%. In six settings (Athens, Graz, Ljubljana, Riga, Rotterdam, Santiago de Compostela), the supervising ED physicians were general paediatricians, in two (Liverpool, London) these were paediatric emergency physicians, in two (Nijmegen, Newcastle) supervision could take place by either a general paediatrician or a general emergency physician, and in one (München) this could be either a general paediatrician or a paediatric emergency physician. The supervising physician was present on site in all settings during office hours and in five out of eleven settings during out-of-office hours. Guidelines for fever and sepsis were available in all settings; however, the type of guideline that was used differed. Primary care was available in all settings during office hours and in eight during out-of-office hours. There were differences in routine immunisations as well as in additional immunisations that were offered; immunisation rates varied between and within countries. Conclusion: Differences in local, regional and national aspects of care exist in th

Journal article

Georgiadou A, Lee HJ, Walther M, van Beek A, Fitriani F, Wouters D, Kuijpers T, Nwakanma D, D'Alessandro U, Riley E, Otto T, Ghani A, Levin M, Coin L, Conway D, Bretscher M, Cunnington Aet al., 2019, Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions, Nature Microbiology, Vol: 4, Pages: 1592-1602, ISSN: 2058-5276

During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of mechanisms of disease and protection. We sought to model the contributions of parasite multiplication rate and host response to observed parasite load in individual subjects with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates. We predicted higher parasite multiplication rates and lower host responsiveness in severe malaria cases, with severe anemia being more insidious than cerebral malaria. We predicted that parasite growth-inhibition was associated with platelet consumption, lower expression of CXCL10 and type-1 interferon-associated genes, but increased cathepsin G and matrix metallopeptidase 9 expression. We found that cathepsin G and matrix metallopeptidase 9 directly inhibit parasite invasion into erythrocytes. Parasite multiplication rate was associated with host iron availability and higher complement factor H levels, lower expression of gametocyte-associated genes but higher expression of translation-associated genes in the parasite. Our findings demonstrate the potential of using explicit modelling of pathogen load dynamics to deepen understanding of host-pathogen interactions and identify mechanistic correlates of protection.

Journal article

Menikou S, Langford P, Levin M, 2019, Kawasaki disease: the role of immune complexes revisited, Frontiers in Immunology, Vol: 10, ISSN: 1664-3224

Kawasaki disease (KD) is an inflammatory disease in children associated with vasculitis affecting predominantly the coronary arteries and is now the most common cause of acquired heart disease in children in developed countries. The etiology of KD is unknown but epidemiological studies implicate an infectious agent or toxin, which causes disease in genetically predisposed individuals. The presence of immune complexes (ICs) in the serum of children with KD was established in numerous studies during the 1970s and 80s. More recent genetic studies have identified variation in Fcγ receptors and genes controlling immunoglobulin production associated with KD. In this review we link the genetic findings and IC studies and suggest a key role for their interaction in pathophysiology of the disease.

Journal article

O'Connor D, Png E, Khor CC, Snape MD, Hil AVS, van der Klis F, Hoggart C, Levin M, Hibberd ML, Pollard AJet al., 2019, Common Genetic Variations Associated with the Persistence of Immunity following Childhood Immunization, CELL REPORTS, Vol: 27, Pages: 3241-+, ISSN: 2211-1247

Journal article

Borghini L, Png E, Binder A, Wright VJ, Pinnock E, de Groot R, Hazelzet J, Emonts M, Van der Flier M, Schlapbach LJ, Anderson S, Secka F, Salas A, Fink C, Carrol ED, Pollard AJ, Coin LJ, Kuijpers TW, Martinon-Torres F, Zenz W, Levin M, Hibberd ML, Davila S, Gormley S, Hamilton S, Herberg J, Hourmat B, Hoggart C, Kaforou M, Sancho-Shimizu V, Abdulla A, Agapow P, Bartlett M, Bellos E, Eleftherohorinou H, Galassini R, Inwald D, Mashbat M, Menikou S, Mustafa S, Nadel S, Rahman R, Thakker C, Bokhandi S, Power S, Barham H, Pathan N, Ridout J, White D, Thurston S, Faust S, Patel S, McCorkell J, Davies P, Cratev L, Navarra H, Carter S, Ramaiah R, Patel R, Tuffrey C, Gribbin A, McCready S, Peters M, Hardy K, Standing F, O'Neill L, Abelake E, Deep A, Nsirim E, Willis L, Young Z, Royad C, White S, Fortune PM, Hudnott P, Alvez Gonzalez F, Barral-Arca R, Cebey-Lopez M, Jose Curras-Tuala M, Garcia N, Garcia Vicente L, Gomez-Carballa A, Gomez Rial J, Grela Beiroa A, Justicia Grande A, Leborans Iglesias P, Martinez Santos AE, Martinon-Torres N, Martinon Sanchez JM, Mosquera Perez B, Obando Pacheco P, Pardo-Seco J, Pischedda S, Rivero Calle I, Rodriguez-Tenreiro C, Redondo-Collazo L, Seren Fernandez S, Porto Silva MDS, Vega A, Beatriz Reyes S, Leon Leon MC, Navarro Mingorance A, Gabaldo Barrios X, Onate Vergara E, Concha Torre A, Vivanco A, Fernandez R, Gimenez Sanchez F, Sanchez Forte M, Rojo P, Ruiz Contreras J, Palacios A, Navarro M, Alvarez Alvarez C, Jose Lozano M, Carreras E, Brio Sanagustin S, Neth O, Martinez Padilla MDC, Prieto Tato LM, Guillen S, Fernandez Silveira L, Moreno D, van Furth AMT, van der Flier M, Boeddha NP, Driessen GJA, Pajkrt D, Sanders EAM, van de Beek D, van der Ende A, Philipsen HLA, Adeel AOA, Breukels MA, Brinkman DMC, de Korte CCMM, de Vries E, de Waal WJ, Dekkers R, Dings-Lammertink A, Doedens RA, Donker AE, Dousma M, Faber TE, Gerrits GPJM, Gerver JAM, Heidema J, Homan-van der Veen J, Jacobs MAM, Jansen NJG, Kawczynski P, Klucovska K, Kneyber MCJ Ket al., 2019, Identification of regulatory variants associated with genetic susceptibility to meningococcal disease, Scientific Reports, Vol: 9, ISSN: 2045-2322

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.

Journal article

Menikou S, McArdle A, Kaforou M, Shimizu C, Wright VJ, Herberg JA, Kanegaye JT, Tremoulet A, Burns JC, Levin Met al., 2019, Characterisation of immune complexes in Kawasaki Disease and other infectious diseases by protein sequencing, 103rd Annual Meeting of the American-Association-of-Immunologists, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767

Conference paper

Nagelkerke SQ, Tacke CE, Breunis WB, Tanck MWT, Geissler J, Png E, Hoang LT, van der Heijden J, Naim ANM, Yeung RSM, Levin ML, Wright VJ, Burgner DP, Ponsonby A-L, Ellis JA, Cimaz R, Shimizu C, Burns JC, Fijnyandraat K, van der Schoot CE, van den Berg TK, de Boer M, Davila S, Hibberd ML, Kuijpers TW, Dahdah N, Kone-Paut Iet al., 2019, Extensive ethnic variation and linkage disequilibrium at the FCGR2/3 locus: Different genetic associations revealed in Kawasaki Disease, Frontiers in Immunology, Vol: 10, ISSN: 1664-3224

The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C-ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C-ORF haplotype showed strong LD with, among others, rs201218628 (FCGR2A-Q27W, r2 = 0.63). LD between these two variants was weaker (r2 = 0.17) in Africans, whereas the FCGR2C-ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The FCGR2C-ORF haplotype and rs1801274 (FCGR2A-H131R) were in weak LD (r2 = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the FCGR2C-ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the FCGR2/3 locus with knowledge of LD and ethnic variation.

Journal article

Ahmad L, Mashbat B, Leung C, Brookes C, Hamad S, Krokowski S, Shenoy A, Lorenzo L, Levin M, O'Hare P, Zhang S-Y, Casanova J-L, Mostowy S, Sancho Shimizu MVet al., 2019, Human TANK-binding kinase 1 is required for early autophagy induction upon herpes simplex virus 1 infection, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 765-769.e7, ISSN: 0091-6749

Journal article

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