Imperial College London

DrJethroHerberg

Faculty of MedicineDepartment of Infectious Disease

Clinical Reader in Paediatric Infectious Disease
 
 
 
//

Contact

 

j.herberg

 
 
//

Location

 

231Wright Fleming WingSt Mary's Campus

//

Summary

 

Publications

Publication Type
Year
to

88 results found

McArdle AJ, Vito O, Patel H, Seaby EG, Shah P, Wilson C, Broderick C, Nijman R, Tremoulet AH, Munblit D, Ulloa-Gutierrez R, Carter MJ, De T, Hoggart C, Whittaker E, Herberg JA, Kaforou M, Cunnington AJ, Levin Met al., 2021, Treatment of Multisystem Inflammatory Syndrome in Children, New England Journal of Medicine, ISSN: 0028-4793

Journal article

Jackson H, Menikou S, Hamilton S, McArdle A, Shimizu C, Galassini R, Huang H, Kim J, Tremoulet A, Thorne A, Fischer R, de Jonge MI, Kuijpers T, Wright V, Burns JC, Casals-Pascual C, Herberg J, Levin M, Kaforou M, On Behalf Of The Perform Consortiumet al., 2021, Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles., Int J Mol Sci, Vol: 22

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

Journal article

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

Journal article

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

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

Journal article

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

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

Journal article

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

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

Journal article

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

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

Journal article

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

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

Journal article

Piccinelli E, Herberg J, Kang H, Fraisse A, Krupickova S, Altamar IB, Sabatino J, Singh Y, Bautista-Rodriguez C, Di Salvo Get al., 2021, Segmental and global longitudinal strain differences between children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 pandemic and Kawasaki disease, European Heart Journal - Cardiovascular Imaging, Vol: 22, ISSN: 2047-2404

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Funding Acknowledgements</jats:title> <jats:p>Type of funding sources: None.</jats:p> </jats:sec> <jats:sec> <jats:title>Introduction</jats:title> <jats:p> The paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and Kawasaki disease (KD) have overlapping features. This study aimed to describe the strain segmental analysis among both entities.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Retrospective review of strain segmental analysis within 4 weeks of presentation of symptoms among children diagnosed with PIMS-TS between April and June 2020 and a historic cohort of typical KD from the Royal Brompton Hospital, London.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We included 33 PIMS-TS patients (23 males, 69.7%) at a mean age of 8 ± 4,9 years old and 45 KD patients (31 males, 68,9%) at a mean age of 5,8 ± 4,5 years old. PIMS-TS patients were older at presentation (p = 0.038). Left ventricle ejection fraction (LVEF) was normal in both groups (63,3% vs 63,5%; p= 0,89), 4/33 PIMS-TS children (12,1%) had coronary arteries abnormalities (CAA), whereas 100% of KD cohort had CAA. Both groups had a normal global longitudinal strain (GLS),but in PIMS-TS it was significantly reduced compared to the KD group (-20% vs -22%; p = 0,008). Basal segments were the most affected in PIMS-TS with significant difference in the basal anterior and anterolateral strain compared to KD (respectively -18,2% vs -23,4%; p &amp;lt; 0,001

Journal article

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

Journal article

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

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

Journal article

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

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

Journal article

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

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

Journal article

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

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

Journal article

Hagedoorn N, Borensztajn D, Nijman R, Nieboer D, Herberg J, Balode A, von Both U, Carroll E, Eleftheriou I, Emonts M, Van Der Flier M, de Groot R, Kohlmaier B, Lim E, Maconochie I, Martinon-Torres F, Pokorn M, Strle F, Tsolia M, Zavadska D, Zenz W, Levin M, Vermont C, Moll Het al., 2020, Development and validation of a prediction model for invasive bacterial infections in febrile children at European Emergency Departments: MOFICHE a prospective observational study, Archives of Disease in Childhood, ISSN: 0003-9888

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

Journal article

Altamar IB, Whittaker E, Herberg J, Fraisse A, Bautista C, Kang H, Giselle R, Wage R, Lane M, Piccinelli E, Di Salvo G, Mohiaddin R, Pennell DJ, Krupickova SJet al., 2020, Short-term Sequalae of Children With Paediatric Inflammatory Multisystem Syndrome Temporarily Associated With Sars-cov-2 Infection (pims-ts) Assessed by Cardiovascular Magnetic Resonance, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

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

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

Journal article

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

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

Journal article

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

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

Journal article

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

Patent

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

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

Journal article

Montaldo P, Cunnington A, Oliveira V, Swamy R, Bandya P, Pant S, Lally P, Ivain P, Mendoza J, Atreja G, Padmesh V, Baburaj M, Sebastian M, Yasashwi I, Kamalarathnam C, Chandramohan R, Mangalabharathi S, Kumaraswami K, Kumar S, Benakappa N, Manerkar S, Mondhkar J, Prakash V, Sajjid M, Seeralar A, Jahan I, Choudhury Moni S, Shahidullah M, Sujatha R, Chandrasekaran M, Ramji S, Shankaran S, Kaforou M, Herberg J, Thayyil Set al., 2020, Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy, Scientific Reports, Vol: 10, Pages: 1-7, ISSN: 2045-2322

A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth,predicts adverse neurodevelopmental outcomeeighteenmonths after neonatal encephalopathy.We performed next generation sequencing on whole blood ribonucleic acid obtained within sixhours of birth from the first 47encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX)trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1and SMC4 werethe most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatoninand polo-like kinase in babieswith adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanismsand identify novel therapeutic targetsfor neuroprotection.

Journal article

Vergnano S, Bamford A, Bandi S, Chappel F, Demirjian A, Doerholt K, Emonts M, Ferreras-Antolin L, Goenka A, Jones L, Herberg JA, Hinds L, McGarrity O, Moriarty P, O'Riordan S, Patel M, Paulus S, Porter D, Stock K, Patel Set al., 2020, Paediatric antimicrobial stewardship programmes in the UK's regional children's hospitals, JOURNAL OF HOSPITAL INFECTION, Vol: 105, Pages: 736-740, ISSN: 0195-6701

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

Background: Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication—the development of coronary artery aneurysms (CAA)—can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases.Methods and Results: The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients (n = 48) from patients with infection (n = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients (n = 26) from those with infections (n = 150), with an AUC of 0.78. The second validation cohort of acute KD patients (n = 25) and febrile controls (n = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included.Conclusion: When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.

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, Vol: 324, Pages: 259-269, 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

Mashbat B, Bellos E, Hodeib S, Bidmos F, Thwaites RS, Lu Y, Wright VJ, Herberg JA, Klobassa DS, Zenz W, Hansel TT, Nadel S, Langford PR, Schlapbach LJ, Li M-S, Redinbo MR, Di YP, Levin M, Sancho-Shimizu Vet al., 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

Vazquez-Ortiz M, Argiz L, Machinena A, Echeverria L, Blasco C, Prieto A, Infante S, Vila L, Garcia E, Gonzalez-Delgado P, Vazquez-Cortes S, Barni S, Martinon-Torres Fet al., 2020, Diagnostic criteria for acute FPIES: What are we missing?, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, Vol: 8, Pages: 1717-+, ISSN: 2213-2198

Journal article

Venkatesan S, Myles PR, Bolton KJ, Muthuri SG, Al Khuwaitir T, Anovadiya AP, Azziz-Baumgartner E, Bajjou T, Bassetti M, Beovic B, Bertisch B, Bonmarin I, Booy R, Borja-Aburto VH, Burgmann H, Cao B, Carratala J, Chinbayar T, Cilloniz C, Denholm JT, Dominguez SR, Duarte PAD, Dubnov-Raz G, Fanella S, Gao Z, Gérardin P, Giannella M, Gubbels S, Herberg J, Higuera Iglesias AL, Hoeger PH, Hu XY, Islam QT, Jiménez MF, Keijzers G, Khalili H, Kusznierz G, Kuzman I, Langenegger E, Lankarani KB, Leo Y-S, Libster RP, Linko R, Madanat F, Maltezos E, Mamun A, Manabe T, Metan G, Mickiene A, Mikić D, Mohn KGI, Oliva ME, Ozkan M, Parekh D, Paul M, Rath BA, Refaey S, Rodríguez AH, Sertogullarindan B, Skręt-Magierło J, Somer A, Talarek E, Tang JW, To K, Tran D, Uyeki TM, Vaudry W, Vidmar T, Zarogoulidis P, PRIDE Consortium Investigators, Nguyen-Van-Tam JSet al., 2020, Neuraminidase inhibitors and hospital length of stay: a meta-analysis of individual participant data to determine treatment effectiveness among patients hospitalized with nonfatal 2009 pandemic iInfluenza A(H1N1) virus infection, Journal of Infectious Diseases, Vol: 221, Pages: 356-266, ISSN: 0022-1899

BACKGROUND: The effect of neuraminidase inhibitor (NAI) treatment on length of stay (LoS) in patients hospitalized with influenza is unclear. METHODS: We conducted a one-stage individual participant data (IPD) meta-analysis exploring the association between NAI treatment and LoS in patients hospitalized with 2009 influenza A(H1N1) virus (A[H1N1]pdm09) infection. Using mixed-effects negative binomial regression and adjusting for the propensity to receive NAI, antibiotic, and corticosteroid treatment, we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Patients with a LoS of <1 day and those who died while hospitalized were excluded. RESULTS: We analyzed data on 18 309 patients from 70 clinical centers. After adjustment, NAI treatment initiated at hospitalization was associated with a 19% reduction in the LoS among patients with clinically suspected or laboratory-confirmed influenza A(H1N1)pdm09 infection (IRR, 0.81; 95% CI, .78-.85), compared with later or no initiation of NAI treatment. Similar statistically significant associations were seen in all clinical subgroups. NAI treatment (at any time), compared with no NAI treatment, and NAI treatment initiated <2 days after symptom onset, compared with later or no initiation of NAI treatment, showed mixed patterns of association with the LoS. CONCLUSIONS: When patients hospitalized with influenza are treated with NAIs, treatment initiated on admission, regardless of time since symptom onset, is associated with a reduced LoS, compared with later or no initiation of treatment.

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

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00476387&limit=30&person=true