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

261 results found

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., 2019, Lifetime cardiovascular management of patients with previous Kawasaki disease., Heart

Kawasaki disease (KD) is an inflammatory disorder of young children, associated with vasculitis of the coronary arteries with subsequent aneurysm formation in up to one-third of untreated patients. Those who develop aneurysms are at life-long risk of coronary thrombosis or the development of stenotic lesions, which may lead to myocardial ischaemia, infarction or death. The incidence of KD is increasing worldwide, and in more economically developed countries, KD is now the most common cause of acquired heart disease in children. However, many clinicians in the UK are unaware of the disorder and its long-term cardiac complications, potentially leading to late diagnosis, delayed treatment and poorer outcomes. Increasing numbers of patients who suffered KD in childhood are transitioning to the care of adult services where there is significantly less awareness and experience of the condition than in paediatric services. The aim of this document is to provide guidance on the long-term management of patients who have vascular complications of KD and guidance on the emergency management of acute coronary complications. Guidance on the management of acute KD is published elsewhere.

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.

Journal article

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

Sancho Shimizu V, A rare mutation in SPLUNC1 underlies meningococcal disease affecting bacterial adherence and invasion, Clinical Infectious Diseases, 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

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

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

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 P, Levin M, Beverley P, Kon O, Lalvani Aet al., Validation of new technologies for the diagnostic evaluation of active tuberculosis (VANTDET), Efficacy and Mechanism Evaluation, ISSN: 2050-4365

Background: Tuberculosis (TB) is a devastating disease for which new diagnostic tests are desperately needed. Objective: To validate promising new technologies (namely whole blood transcriptomics, proteomics, flow cytometry and qRT-PCR) and existing signatures for detection of active TB in samples obtained from individuals suspected of active TB. Design: Four sub-studies, each of which used the samples from biobank collected as part of the IDEA study, which was a prospective cohort of patients recruited with suspected TB. Setting: secondary care Participants: Adults (aged ≥ 16 years old) presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham with suspected active TB. Interventions: New tests using either: genome-wide gene expression microarray (transcriptomics); SELDI TOF/ LC-MS (proteomics), flow cytometry, qRT-PCR. Main outcome measures: 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 (QALYs) of changing from current practice to using the novels tests. Results: The project and 4 sub-studies which assessed the previous published signatures measured using each of the new technologies, and a health economic analysis where the best performing tests were evaluated for cost effectiveness. The diagnostic accuracy of the transcriptomic tests ranged from AUC=0.81-0.84 for detecting all TB in our cohort. The performance for detecting culture confirmed TB or pulmonary TB (PTB) was better than for highly probable TB or extrapulmonary TB (EPTB) respectively, but not high enough to be clinically useful. None of the previously described serum proteomic signatures for active TB provided good diagnostic accuracy, not did the candidate rule-out tests. Four of six previously described cell

Journal article

Feinstein Y, Walker JC, Peters MJ, Nadel S, Pathan N, Edmonds N, Herberg J, Kaforou M, Wright V, Levin M, Ramnarayan Pet al., 2018, Cohort profile of the Biomarkers of Acute Serious Illness in Children (BASIC) study: a prospective multicentre cohort study in critically ill children, BMJ Open, Vol: 8, ISSN: 2044-6055

Purpose Despite significant progress, challenges remain in the management of critically ill children, including early identification of infection and organ failure and robust early risk stratification to predict poor outcome. The Biomarkers of Acute Serious Illness in Children study aims to identify genetic and biological pathways underlying the development of critical illness in infections and organ failure and those leading to poor outcome (death or severe disability) in children requiring emergency intensive care.Participants We recruited a prospective cohort of critically ill children undergoing emergency transport to four paediatric intensive care units (PICUs) in Southeast England between April 2014 and December 2016.Findings to date During the study period, 1017 patients were recruited by the regional PICU transport team, and blood and urine samples were obtained at/around first contact with the patient by the transport team. Consent for participation in the study was deferred until after PICU admission and 674 parents/carers were consented. Further samples (blood, urine, stool and throat swabs) were collected after consent. Samples were processed and stored for genomic, transcriptomic, proteomic and metabolomic analyses. Demographic, clinical and laboratory data at first contact, during PICU stay and at discharge, were collected, as were detailed data regarding infectious or non-infectious aetiology. In addition, 115 families have completed 12-month validated follow-up questionnaires to assess quality of life and child behaviour.The first phase of sample analyses (transcriptomic profiling) is currently in progress.Future plans Stored samples will be analysed using genomic, proteomic and metabolic profiling. Advanced bioinformatics techniques will be used to identify biomarkers for early diagnosis of infection, identification of organ failure and risk stratification to predict poor outcome (death/severe disability).Trial registration number NCT03238040.

Journal article

van Beek A, Pouw R, Sarr I, Correa S, Nwakanma D, Brouwer M, Wouters D, Conway D, Walther M, Levin M, Kuijpers T, Cunnington Aet al., 2018, Complement factor H levels associate with severity of Plasmodium falciparum malaria, 27th International Complement Workshop (ICW), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 234-234, ISSN: 0161-5890

Conference paper

Wright V, Herberg J, Kaforou M, Shimizu C, Eleftherohorinou H, Shailes H, Barendregt A, Menikou S, Gormley S, Berk M, Hoang L, Tremoulet A, Kanegaye J, Coin L, Glode M, Hibberd M, Kuijpers T, Hoggart C, Burns J, Levin Met al., 2018, Diagnosis of Kawasaki disease using a minimal whole blood gene expression signature, JAMA Pediatrics, Vol: 172, ISSN: 2168-6203

Importance There is no diagnostic test for Kawasaki disease (KD). Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed treatment and an increased risk of coronary artery aneurysms. Objective To identify a whole blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.Design Case-control discovery study groups comprising training, test, and validation groups of children with KD or comparator febrile illness. Setting Hospitals in the UK, Spain, Netherlands and USA.Participants The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, 242 bacterial or viral infections) and 55 healthy controls. The independent validation group included 130 febrile children and 102 KD patients, including 72 in the first 7 days of illness.Exposures Whole blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (Parallel Deterministic Model Search).Main outcomes and measures The ability of transcript signatures - implemented as Disease Risk Scores - to discriminate KD cases from controls, was assessed by Area Under the Curve (AUC), sensitivity, and specificity at the optimal cut-point according to Youden’s index. Results A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set with AUC, sensitivity, and specificity (95% confidence intervals (CI)) of 96.2% (92.5-99.9), 81.7% (60.0-94.8), and 92.1% (84.0-97.0), respectively. In the validation set, the signature distinguished KD from febrile controls with AUC, sensitivity, and specificity (95% CI) of 94.6% (91.3-98.0), 85.9% (76.8-92.6), and 89.1% (83.0-93.7) respectively. The signature was applied to clinically defin

Journal article

Sarr I, Correa S, Nwakanma D, Brouwer M, Wouters D, Secka F, Anderson S, Conway D, Walther M, Levin M, Kuijpers T, Cunnington Aet al., 2018, Complement Factor H levels associate with Plasmodium falciparum malaria susceptibility and severity, Open Forum Infectious Diseases, Vol: 5, ISSN: 2328-8957

BackgroundPlasmodium falciparum may evade complement-mediated host defense by hijacking complement Factor H (FH), a negative regulator of the alternative complement pathway. Plasma levels of FH vary between individuals and may therefore influence malaria susceptibility and severity.MethodsWe measured convalescent FH plasma levels in 149 Gambian children who had recovered from uncomplicated or severe P. falciparum malaria and in 173 healthy control children. We compared FH plasma levels between children with malaria and healthy controls, and between children with severe (n = 82) and uncomplicated malaria (n = 67). We determined associations between FH plasma levels and laboratory features of severity and used multivariate analyses to examine associations with FH when accounting for other determinants of severity.ResultsFH plasma levels differed significantly between controls, uncomplicated malaria cases, and severe malaria cases (mean [95% confidence interval], 257 [250 to 264], 288 [268 to 309], and 328 [313 to 344] µg/mL, respectively; analysis of variance P < .0001). FH plasma levels correlated with severity biomarkers, including lactate, parasitemia, and parasite density, but did not correlate with levels of PfHRP2, which represent the total body parasite load. Associations with severity and lactate remained significant when adjusting for age and parasite load.ConclusionsNatural variation in FH plasma levels is associated with malaria susceptibility and severity. A prospective study will be needed to strengthen evidence for causation, but our findings suggest that interfering with FH binding by P. falciparum might be useful for malaria prevention or treatment.

Journal article

Lee HJ, Georgiadou A, Walther M, Nwakanma D, Stewart L, Levin M, Otto T, Conway D, Coin L, Cunnington Aet al., 2018, Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria, Science Translational Medicine, Vol: 10, ISSN: 1946-6234

The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In Plasmodium falciparum malaria, host and parasite processes can be assessed by dual RNA-sequencing of blood from infected patients. Here we performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria. Integrating these transcriptomic data with estimates of parasite load and detailed clinical information allowed consideration of potentially confounding effects due to differing leukocyte proportions in blood, parasite developmental stage, and whole-body pathogen load. We report hundreds of human and parasite genes differentially expressed between severe and uncomplicated malaria, with distinct profiles associated with coma, hyperlactatemia, and thrombocytopenia. High expression of neutrophil granule-related genes was consistently associated with all severe malaria phenotypes. We observed severity-associated variation in the expression of parasite genes which determine cytoadhesion to vascular endothelium, rigidity of infected erythrocytes, and parasite growth rate. Up to 99% of human differential gene expression in severe malaria was driven by differences in parasite load, whereas parasite gene expression showed little association with parasite load. Co-expression analyses revealed interactions between human and P. falciparum, with prominent co-regulation of translation genes in severe malaria between host and parasite. Multivariate analyses suggested that increased expression of granulopoiesis and interferon-γ related genes, together with inadequate suppression of type-1 interferon signalling, best explained severity of infection. These findings provide a framework for understanding the contributions of host and parasite to the pathogenesis of severe malaria and identifying targets for adjunctive therapy.

Journal article

Lee HJ, Georgiadou A, Otto T, Levin M, Coin L, Conway D, Cunnington Aet al., 2018, Transcriptomic studies in malaria – a paradigm for investigation of systemic host-pathogen interactions, Microbiology and Molecular Biology Reviews, Vol: 82, ISSN: 1092-2172

Transcriptomics, the analysis of genome-wide RNA expression, is a common approach to investigate host and pathogen processes in infectious diseases. Technical and bioinformatic advances have permitted increasingly thorough analysis of the association of RNA expression with fundamental biology, immunity, pathogenesis, diagnosis, and prognosis. Transcriptomic approaches can now be used to realize a previously unattainable goal, simultaneous study of RNA expression in host and pathogen, in order to better understand their interactions. This exciting prospect is not without challenges, especially as focus moves from interactions in vitro under tightly controlled conditions to tissue-and systemic-level interactions in animal models and natural and experimental infections in humans. Here we review the contribution of transcriptomic studies to the understanding of malaria, a parasitic disease which has exerted a major influence on human evolution and continues to cause a huge global burden of disease. We consider malaria as a paradigm for transcriptomic assessment of systemic host-pathogen interaction in humans, because much of the direct host-pathogen interaction occurs within the blood–a readily sampled compartment of the body. We illustrate lessons learned from transcriptomic studies of malaria, and how these may guide studies of host-pathogen interaction in other infectious diseases. We propose that the potential of transcriptomic studies to improve understanding of malaria as a disease remains partly untapped because of limitations in study design rather than as a consequence of technological constraints. Further advances will require integration of transcriptomic data with analytical approaches from other scientific disciplines including epidemiology and mathematical modelling.

Journal article

Martinón-Torres F, Salas A, Rivero-Calle I, Cebey-López M, Pardo-Seco J, Herberg JA, Boeddha NP, Klobassa DS, Secka F, Paulus S, de Groot R, Schlapbach LJ, Driessen GJ, Anderson ST, Emonts M, Zenz W, Carrol ED, Van der Flier M, Levin M, Levin M, Coin L, Gormley S, Hamilton S, Herberg J, Hourmat B, Hoggart C, Kaforou M, Sancho-Shimizu V, Wright 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, Crate 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, Pollard A, Willis L, Young Z, Royad C, White S, Fortune PM, Hudnott P, Martinón-Torres F, Salas Ellacuriaga A, Álvez González F, Barral-Arca R, Cebey-López M, Curras-Tuala MJ, García N, García Vicente L, Gómez-Carballa A, Gómez Rial J, Grela Beiroa A, Justicia Grande A, Leboráns Iglesias P, Martínez Santos AE, Martinón-Torres N, Martinón Sánchez JM, Morillo Gutiérrez Bet al., 2018, Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study, Lancet Child and Adolescent Health, Vol: 2, Pages: 404-414, ISSN: 2352-4642

Background: Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods: The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings: 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; p < 0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%] ), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%] ), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admis

Journal article

Boeddha NP, Schlapbach LJ, Driessen GJ, Herberg JA, Rivero-Calle I, Cebey-López M, Klobassa DS, Philipsen R, de Groot R, Inwald DP, Nadel S, Paulus S, Pinnock E, Secka F, Anderson ST, Agbeko RS, Berger C, Fink CG, Carrol ED, Zenz W, Levin M, van der Flier M, Martinón-Torres F, Hazelzet JA, Emonts M, EUCLIDS consortiumet al., 2018, Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS), Critical Care, Vol: 22, ISSN: 1364-8535

BACKGROUND: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability. METHODS: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis. RESULTS: Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1-16.0, P = 0.04; disability OR 5.4, 95% CI 1.8-15.8, P < 0.01) and illness severity as measured by Pediatric Index of Mortality (PIM2) score (mortality OR 2.8, 95% CI 1.3-6.1, P < 0.01; disability OR 3.4, 95% CI 1.8-6.4, P < 0.001). CONCLUSIONS: Despite wide

Journal article

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, Moffatt MF, OGarra A, Openshaw PJMet al., 2018, Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza, Nature Immunology, Vol: 19, Pages: 625-635, ISSN: 1529-2916

Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.

Journal article

Brent AJ, Mugo D, Musyimi R, Mutiso A, Morpeth SC, Levin M, Scott JAGet al., 2018, Bacteriological diagnosis of childhood TB: a prospective observational study (vol 7, 2017), SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322

Journal article

Mashbat B, Bellos E, Bidmos F, Tarran R, Lu Y, Wright V, Herberg J, Langford P, Schlapbach L, Li M-S, Di P, Levin M, Sancho-Shimizu Vet al., 2018, Whole exome sequencing identifies BPIFA1 mutation underlying invasive meningococcal disease, Human Genome Meeting 2018, Publisher: BIOMED CENTRAL LTD, ISSN: 1473-9542

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