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1. Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study

Author: Herberg, J, Shah, P, Voice, M, Calvo-Bado, L, Rivero Calle, I, Morris, S, Nijman, R, Broderick, C, De, T, Eleftheriou, I, Galassini, R, Khanijau, A, Kolberg, L, Kolnik, M, Rudzate, A, Sagmeister, M, Schweintzger, N, Secka, F, Thakker, C, Van der Velden, F, Vermont, C, Vincek, K, Agyeman, P, Cunnington, A, De Groot, R, Emonts, M, Fidler, K, Kuijpers, T, Mommert-Tripon, M, Brengel-Pesce, K, Mallet, F, Moll, H, Paulus, S, Pokorn, M, Pollard, A, Schlapbach, L, Shen, C-F, Tsolia, M, Usuf, E, Van Der Flier, M, Von Both, U, Yeung, S, Zavadska, D, Zenz, W, Wright, V, Carrol, E, Kaforou, M, Martinon-Torres, F, Fink, C, Levin, M, and PERFORM consortium
Abstract: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods. Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings. Of 4,611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3,477 (75%) had uncertain aetiology. 1,061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N.meningitidis (OR: 3.37, 95% CI: 1.92 – 5.99), S.pneumoniae (OR: 3.89, 95% CI: 2.07 – 7.59), Group A streptococcus (OR 2.73, 95% CI 1.13 – 6.09) and E.coli (OR 2.7, 95% CI 1.02 – 6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11 – 0.46), Influenza B (OR 0.12, 95% CI 0.02 – 0.37) and RSV (OR 0.16, 95% CI: 0.06 – 0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23 – 0.72) and EBV (OR 0.71, 95% CI 0.56 – 0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation. Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics.
Published: 2023

2. Febrile illness in high-risk children: a prospective, international observational study.

Author: Velden, F.J.S. van der, Vries, G de, Martin, A., Lim, E., Both, U. von, Kolberg, L., Carrol, E.D., Khanijau, A., Herberg, Jethro A., De, T., Galassini, R., Kuijpers, T.W., Martinón-Torres, F., Rivero-Calle, I., Vermont, C.L., Hagedoorn, N.N., Pokorn, M., Pollard, A.J., Schlapbach, L.J., Tsolia, M., Elefhteriou, I., Yeung, S., Zavadska, D., Fink, C., Voice, M., Zenz, W., Kohlmaier, B., Agyeman, P.K.A., Usuf, E., Secka, F., Groot, R. de, Levin, M., Flier, M. van der, Emonts, M., Velden, F.J.S. van der, Vries, G de, Martin, A., Lim, E., Both, U. von, Kolberg, L., Carrol, E.D., Khanijau, A., Herberg, Jethro A., De, T., Galassini, R., Kuijpers, T.W., Martinón-Torres, F., Rivero-Calle, I., Vermont, C.L., Hagedoorn, N.N., Pokorn, M., Pollard, A.J., Schlapbach, L.J., Tsolia, M., Elefhteriou, I., Yeung, S., Zavadska, D., Fink, C., Voice, M., Zenz, W., Kohlmaier, B., Agyeman, P.K.A., Usuf, E., Secka, F., Groot, R. de, Levin, M., Flier, M. van der, and Emonts, M.
Abstract: 01 februari 2023, Item does not contain fulltext, To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the 'Biomarker Validation in HR patients' database in PERFORM, were analysed. Immunocompromised children (< 18 years old) presented to fifteen European hospitals in nine countries, and one Gambian hospital, with fever or suspected infection and clinical indication for blood investigations. Febrile episodes were assigned clinical phenotypes using the validated PERFORM algorithm. Logistic regression was used to assess the effect size of predictive features of proven/presumed bacterial or viral infection. A total of 599 episodes in 482 children were analysed. Seventy-eight episodes (13.0%) were definite bacterial, 67 episodes probable bacterial (11.2%), and 29 bacterial syndrome (4.8%). Fifty-five were definite viral (9.2%), 49 probable viral (8.2%), and 23 viral syndrome (3.8%). One hundred ninety were unknown bacterial or viral infections (31.7%), and 108 had inflammatory or other non-infectious causes of fever (18.1%). Predictive features of proven/presumed bacterial infection were ill appearance (OR 3.1 (95% CI 2.1-4.6)) and HIV (OR 10.4 (95% CI 2.0-54.4)). Ill appearance reduced the odds of having a proven/presumed viral infection (OR 0.5 (95% CI 0.3-0.9)). A total of 82.1% had new empirical antibiotics started on admission (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522). Conclusion: The aetiology of febrile illness in immunocompromised children is diverse. In one-third of cases, no cause for the fever will be identified. Justification for standard
Published: 2023

3. Group A streptococcal disease in paediatric inpatients: a European perspective.

Author: Boeddha, N.P., Atkins, L., Groot, R. de, Driessen, G., Hazelzet, J., Zenz, W., Carrol, E.D., Anderson, S.T., Martinon-Torres, F., Agyeman, P.K.A., Galassini, R., Herberg, J., Levin, M., Schlapbach, L.J., Emonts, M., Boeddha, N.P., Atkins, L., Groot, R. de, Driessen, G., Hazelzet, J., Zenz, W., Carrol, E.D., Anderson, S.T., Martinon-Torres, F., Agyeman, P.K.A., Galassini, R., Herberg, J., Levin, M., Schlapbach, L.J., and Emonts, M.
Abstract: 01 februari 2023, Item does not contain fulltext, Group A streptococcal (GAS) disease shows increasing incidence worldwide. We characterised children admitted with GAS infection to European hospitals and studied risk factors for severity and disability. This is a prospective, multicentre, cohort study (embedded in EUCLIDS and the Swiss Pediatric Sepsis Study) including 320 children, aged 1 month to 18 years, admitted with GAS infection to 41 hospitals in 6 European countries from 2012 to 2016. Demographic, clinical, microbiological and outcome data were collected. A total of 195 (61%) patients had sepsis. Two hundred thirty-six (74%) patients had GAS detected from a normally sterile site. The most common infection sites were the lower respiratory tract (LRTI) (22%), skin and soft tissue (SSTI) (23%) and bone and joint (19%). Compared to patients not admitted to PICU, patients admitted to PICU more commonly had LRTI (39 vs 8%), infection without a focus (22 vs 8%) and intracranial infection (9 vs 3%); less commonly had SSTI and bone and joint infections (p < 0.001); and were younger (median 40 (IQR 21-83) vs 56 (IQR 36-85) months, p = 0.01). Six PICU patients (2%) died. Sequelae at discharge from hospital were largely limited to patients admitted to PICU (29 vs 3%, p < 0.001; 12% overall) and included neurodisability, amputation, skin grafts, hearing loss and need for surgery. More patients were recruited in winter and spring (p < 0.001). CONCLUSION: In an era of observed marked reduction in vaccine-preventable infections, GAS infection requiring hospital admission is still associated with significant severe disease in younger children, and short- and long-term morbidity. Further advances are required in the prevention and early recognition of GAS disease. WHAT IS KNOWN: • Despite temporal and geographical variability, there is an increase of incidence of infection with group A streptococci. However, data on the epidemiology of group A streptococcal infections in European children is limited. WHAT IS NEW: • In a lar
Published: 2023

4. Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature.

Author: Habgood-Coote, D., Wilson, C., Shimizu, C., Barendregt, A.M., Philipsen, R., Galassini, R., Calle, I.R., Workman, L., Agyeman, P.K.A., Ferwerda, G., Anderson, S.T., Berg, J.M. van den, Emonts, M., Carrol, E.D., Fink, C.G., Groot, R. de, Hibberd, M.L., Kanegaye, J., Nicol, M.P., Paulus, S., Pollard, A.J., Salas, A., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Walther, M., Zenz, W., Flier, M. van der, Zar, H.J., Kuijpers, T., Burns, J.C., Martinón-Torres, F., Wright, V.J., Coin, L.J.M., Cunnington, A.J., Herberg, Jethro A., Levin, M., Kaforou, M., Habgood-Coote, D., Wilson, C., Shimizu, C., Barendregt, A.M., Philipsen, R., Galassini, R., Calle, I.R., Workman, L., Agyeman, P.K.A., Ferwerda, G., Anderson, S.T., Berg, J.M. van den, Emonts, M., Carrol, E.D., Fink, C.G., Groot, R. de, Hibberd, M.L., Kanegaye, J., Nicol, M.P., Paulus, S., Pollard, A.J., Salas, A., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Walther, M., Zenz, W., Flier, M. van der, Zar, H.J., Kuijpers, T., Burns, J.C., Martinón-Torres, F., Wright, V.J., Coin, L.J.M., Cunnington, A.J., Herberg, Jethro A., Levin, M., and Kaforou, M.
Abstract: Contains fulltext : 296516.pdf (Publisher’s version ) (Open Access), BACKGROUND: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood. METHODS: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children. FINDINGS: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures. CONCLUSIONS: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis. FUNDING: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC.
Published: 2023

5. Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study.

Author: Shah, P., Voice, M., Calvo-Bado, L., Rivero-Calle, I., Morris, S., Nijman, R., Broderick, C., De, T., Eleftheriou, I., Galassini, R., Khanijau, A., Kolberg, L., Kolnik, M., Rudzate, A., Sagmeister, M.G., Schweintzger, N.A., Secka, F., Thakker, C., Velden, F. van der, Vermont, C., Vincek, K., Agyeman, P.K.A., Cunnington, A.J., Groot, R. de, Emonts, M., Fidler, K., Kuijpers, T.W., Mommert-Tripon, M., Brengel-Pesce, K., Mallet, F., Moll, H., Paulus, S., Pokorn, M., Pollard, A., Schlapbach, L.J., Shen, C.F., Tsolia, M., Usuf, E., Flier, M. van der, Both, U. von, Yeung, S., Zavadska, D., Zenz, W., Wright, V., Carrol, E.D., Kaforou, M., Martinon-Torres, F., Fink, C., Levin, M., Herberg, J., Shah, P., Voice, M., Calvo-Bado, L., Rivero-Calle, I., Morris, S., Nijman, R., Broderick, C., De, T., Eleftheriou, I., Galassini, R., Khanijau, A., Kolberg, L., Kolnik, M., Rudzate, A., Sagmeister, M.G., Schweintzger, N.A., Secka, F., Thakker, C., Velden, F. van der, Vermont, C., Vincek, K., Agyeman, P.K.A., Cunnington, A.J., Groot, R. de, Emonts, M., Fidler, K., Kuijpers, T.W., Mommert-Tripon, M., Brengel-Pesce, K., Mallet, F., Moll, H., Paulus, S., Pokorn, M., Pollard, A., Schlapbach, L.J., Shen, C.F., Tsolia, M., Usuf, E., Flier, M. van der, Both, U. von, Yeung, S., Zavadska, D., Zenz, W., Wright, V., Carrol, E.D., Kaforou, M., Martinon-Torres, F., Fink, C., Levin, M., and Herberg, J.
Abstract: 01 september 2023, Contains fulltext : 295917.pdf (Publisher’s version ) (Open Access), BACKGROUND: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. METHODS: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. FINDINGS: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. INTERPRETATION: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which feb
Published: 2023

6. Correction to: Febrile illness in high-risk children: a prospective, international observational study

Author: Van der Velden, FJS, De Vries, G, Martin, A, Lim, E, Von Both, U, Kolberg, L, Carrol, ED, Khanijau, A, Herberg, JA, De, T, Galassini, R, Kuijpers, TW, Martinón-Torres, F, Rivero-Calle, I, Vermont, CL, Hagedoorn, NN, Pokorn, M, Pollard, AJ, Schlapbach, LJ, Tsolia, M, Elefhteriou, I, Yeung, S, Zavadska, D, Fink, C, Voice, M, Zenz, W, Kohlmaier, B, Agyeman, PKA, Usuf, E, Secka, F, De Groot, R, Levin, M, Van der Flier, M, Emonts, M, and PERFORM consortium
Subjects: Pediatrics, Perinatology and Child Health, 610 Medicine & health, 610 Medizin und Gesundheit
Published: 2023
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7. Group A streptococcal disease in paediatric inpatients: a European perspective

Author: Boeddha, N.P., Atkins, L., Groot, R. de, Driessen, G., Hazelzet, J., Zenz, W., Carrol, E.D., Anderson, S.T., Martinon-Torres, F., Agyeman, P.K.A., Galassini, R., Herberg, J., Levin, M., Neeleman, C., Schlapbach, L.J., Emonts, M., University of Zurich, Emonts, Marieke, Pediatrics, Public Health, AII - Infectious diseases, MUMC+: MA Kindergeneeskunde (3), Kindergeneeskunde, MUMC+: VPK Flexteam (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, and consortium, EUCLIDS
Subjects: All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, 10036 Medical Clinic, Pediatrics, Perinatology and Child Health, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 610 Medicine & health, 2735 Pediatrics, Perinatology and Child Health, 610 Medizin und Gesundheit
Abstract: Item does not contain fulltext Group A streptococcal (GAS) disease shows increasing incidence worldwide. We characterised children admitted with GAS infection to European hospitals and studied risk factors for severity and disability. This is a prospective, multicentre, cohort study (embedded in EUCLIDS and the Swiss Pediatric Sepsis Study) including 320 children, aged 1 month to 18 years, admitted with GAS infection to 41 hospitals in 6 European countries from 2012 to 2016. Demographic, clinical, microbiological and outcome data were collected. A total of 195 (61%) patients had sepsis. Two hundred thirty-six (74%) patients had GAS detected from a normally sterile site. The most common infection sites were the lower respiratory tract (LRTI) (22%), skin and soft tissue (SSTI) (23%) and bone and joint (19%). Compared to patients not admitted to PICU, patients admitted to PICU more commonly had LRTI (39 vs 8%), infection without a focus (22 vs 8%) and intracranial infection (9 vs 3%); less commonly had SSTI and bone and joint infections (p
Published: 2022

8. Group A streptococcal disease in paediatric inpatients: a European perspective

Author: Boeddha NP, Atkins L, de Groot R, Driessen G, Hazelzet J, Zenz W, Carrol ED, Anderson ST, Martinon-Torres F, Agyeman PKA, Galassini R, Herberg J, Levin M, Schlapbach LJ, Emonts M, EUCLIDS Consortium
Published: 2022
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9. Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles

Author: Jackson, H., Menikou, S., Hamilton, S., McArdle, A., Shimizu, C., Galassini, R., Huang, H., Kim, J., Tremoulet, A., Thorne, A., Fischer, R., Jonge, M.I. de, Kuijpers, T., Wright, V., Burns, J.C., Casals-Pascual, C., Herberg, J., Levin, M., Kaforou, M., Perform, C. On Behalf Of Th, Jackson, H., Menikou, S., Hamilton, S., McArdle, A., Shimizu, C., Galassini, R., Huang, H., Kim, J., Tremoulet, A., Thorne, A., Fischer, R., Jonge, M.I. de, Kuijpers, T., Wright, V., Burns, J.C., Casals-Pascual, C., Herberg, J., Levin, M., Kaforou, M., and Perform, C. On Behalf Of Th
Abstract: Contains fulltext : 234041.pdf (Publisher’s version ) (Open Access), 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.
Published: 2021

10. Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease.

Author: 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, M, International Kawasaki Disease Genetics Consortium, UK Kawasaki Disease Genetics Consortium, EUCLIDS Consortium, 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, M, International Kawasaki Disease Genetics Consortium, UK Kawasaki Disease Genetics Consortium, and EUCLIDS Consortium
Abstract: 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.
Published: 2021

11. Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood

Author: Zandstra, J. van de Geer, A. Tanck, M.W.T. van Stijn-Bringas Dimitriades, D. Aarts, C.E.M. Dietz, S.M. van Bruggen, R. Schweintzger, N.A. Zenz, W. Emonts, M. Zavadska, D. Pokorn, M. Usuf, E. Moll, H.A. Schlapbach, L.J. Carrol, E.D. Paulus, S. Tsolia, M. Fink, C. Yeung, S. Shimizu, C. Tremoulet, A. Galassini, R. Wright, V.J. Martinón-Torres, F. Herberg, J. Burns, J. Levin, M. Kuijpers, T.W. EUCLIDS Consortium, PERFORM Consortium UK Kawasaki Disease Genetics Study Network
Abstract: 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. © Copyright © 2020 Zandstra, van de Geer, Tanck, van Stijn-Bringas Dimitriades, Aarts, Dietz, van Bruggen, Schweintzger, Zenz, Emonts, Zavadska, Pokorn, Usuf, Moll, Schlapbach, Carrol, Paulus, Tsolia, Fink, Yeung, Shimizu, Tremoulet, Galassini, Wright, Martinón-Torres, Herberg, Burns, Levin, Kuijpers, EUCLIDS Consortium, PERFORM Consortium and UK Kawasaki Disease Genetics Study Network.
Published: 2020

12. Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood

Author: Zandstra, J. (Judith), van de Geer, A. (Annemarie), Tanck, M.W.T. (Michael), van Stijn-Bringas Dimitriades, D. (Diana), Aarts, C.E.M. (Cathelijn E. M.), Dietz, S.M. (Sanne M.), Bruggen, R. (Robin) van, Schweintzger, N.A. (Nina A.), Zenz, W. (Werner), Emonts, M. (Marieke), Zavadska, D. (Dace), Pokorn, M. (Marko), Usuf, E. (Effua), Moll, H.A. (Henriëtte), Schlapbach, L.J. (Luregn), Carrol, E.D. (Enitan), Paulus, S. (Stephane), Tsolia, M. (Maria), Fink, C. (Colin), Yeung, S. (Shunmay), Shimizu, C. (Chisato), Tremoulet, A. (Adriana), Galassini, R. (Rachel), Wright, V.J. (Victoria), Martinón-Torres, F. (Federico), Herberg, J. (Jethro), Burns, J. (Jane), Levin, M. (Michael), Kuijpers, T.W. (Taco W.), Zandstra, J. (Judith), van de Geer, A. (Annemarie), Tanck, M.W.T. (Michael), van Stijn-Bringas Dimitriades, D. (Diana), Aarts, C.E.M. (Cathelijn E. M.), Dietz, S.M. (Sanne M.), Bruggen, R. (Robin) van, Schweintzger, N.A. (Nina A.), Zenz, W. (Werner), Emonts, M. (Marieke), Zavadska, D. (Dace), Pokorn, M. (Marko), Usuf, E. (Effua), Moll, H.A. (Henriëtte), Schlapbach, L.J. (Luregn), Carrol, E.D. (Enitan), Paulus, S. (Stephane), Tsolia, M. (Maria), Fink, C. (Colin), Yeung, S. (Shunmay), Shimizu, C. (Chisato), Tremoulet, A. (Adriana), Galassini, R. (Rachel), Wright, V.J. (Victoria), Martinón-Torres, F. (Federico), Herberg, J. (Jethro), Burns, J. (Jane), Levin, M. (Michael), and Kuijpers, T.W. (Taco W.)
Abstract: 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, t
Published: 2020
Full Text: View/download PDF

13. Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood

Author: Zandstra, J, van de Geer, A, Tanck, MW, Dimitriades, DVB, Aarts, CEM, Dietz, SM, van Bruggen, R, Schweintzger, NA, Zenz, W, Emonts, Marieke, Zavadska, D, Pokorn, M, Usuf, E, Moll, Henriette, 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, TWJ, Zandstra, J, van de Geer, A, Tanck, MW, Dimitriades, DVB, Aarts, CEM, Dietz, SM, van Bruggen, R, Schweintzger, NA, Zenz, W, Emonts, Marieke, Zavadska, D, Pokorn, M, Usuf, E, Moll, Henriette, 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, and Kuijpers, TWJ
Published: 2020

14. Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Author: Wang, X. (Xinzhu), Nijman, R.G. (Ruud), Camuzeaux, S. (Stephane), Sands, C. (Caroline), Jackson, H. (Heather), Kaforou, M. (Myrsini), Emonts, M. (Marieke), Herberg, J.A. (Jethro A.), MacOnochie, I.K. (Ian), Carrol, E.D. (Enitan), Paulus, S.C. (Stephane C.), Zenz, W. (Werner), Flier, M. (Michiel) van der, Groot, R. (Ronald) de, Martinon-Torres, F. (Federico), Schlapbach, L.J. (Luregn), Pollard, A.J. (Andrew J.), Fink, C. (Colin), Kuijpers, T.T. (Taco T.), Anderson, S. (Suzanne), Lewis, M.R. (Matthew R.), Levin, M. (Michael), McClure, M. (Myra), Gormley, S. (Stuart), Hamilton, S. (Shea), Hourmat, B. (Bernardo), Hoggart, C. (Clive), Sancho-Shimizu, V. (Vanessa), Wright, V.J. (Victoria), Abdulla, A. (Amina), Agapow, P. (Paul), Bartlett, M. (Maeve), Bellos, E. (Evangelos), Eleftherohorinou, H. (Hariklia), Galassini, R. (Rachel), Inwald, D. (David), Mashbat, M. (Meg), Menikou, S. (Stefanie), Mustafa, S. (Sobia), Nadel, S. (Simon), Rahman, R. (Rahmeen), Thakker, C. (Clare), Coin, L.M.J. (Lachlan M. J.), Bokhandi, S. (S.), Power, S. (Sue), Barham, H. (Heather), Pathan, D.N. (Dr N), Ridout, J. (Jenna), White, D. (Deborah), Thurston, S. (Sarah), Faust, D. (Dominik), Patel, S.Y. (Smita Y.), McCorkell, J. (Jenni), Davies, P. (P.), Crate, L. (Lindsey), Navarra, H. (Helen), Carter, S. (Stephanie), Ramaiah, R. (R.), Patel, R. (Rekha), Tuffrey, C. (Catherine), Gribbin, A. (Andrew), McCready, S. (Sharon), Peters, M. (Mark), Hardy, K. (Katie), Standing, F. (Fran), O’Neill, L. (Lauren), Abelake, E. (Eugenia), Deep, A. (Akash), Nsirim, E. (Eniola), Willis, L. (Louise), Young, Z. (Zoe), Royad, C. (C.), White, S. (Sonia), Fortune, P.M. (P. M.), Hudnott, P. (Phil), González, F.Á. (Fernando Álvez), Barral-Arca, R. (Ruth), Cebey-López, M. (Miriam), Curras-Tuala, M.J. (María José), García, N. (Natalia), Vicente, L.G. (Luisa García), Gómez-Carballa, A. (Alberto), Rial, J.G. (Jose Gómez), Beiroa, A.G. (Andrea Grela), Grande, A.J. (Antonio Justicia), Iglesias, P.L. (Pilar Leboráns), Santos, A.E.M. (Alba Elena Martínez), Martinón-Torres, F. (Federico), MartinónTorres, N. (Nazareth), Sánchez, J.M.M. (José María Martinón), Gutiérrez, B.M. (Beatriz Morillo), Pérez, B.M. (Belén Mosquera), Pacheco, P.O. (Pablo Obando), Pardo-Seco, J. (Jacobo), Pischedda, S. (Sara), RiveroCalle, I. (Irene), Rodríguez-Tenreiro, C. (Carmen), Redondo-Collazo, L. (Lorenzo), Ellacuriagal, A.S. (Antonio Salas), Fernández, S.S. (Sonia Serén), Silva, M.S.P. (María del Sol Porto), Vega, A. (Ana), Trillo, L.V. (Lucía Vilanova), Salas, A. (Antonio), Reyes, S.B. (Susana Beatriz), León, M.C.L. (María Cruz León), Mingorance, Á.N. (Álvaro Navarro), Barrios, X.G. (Xavier Gabaldó), Vergara, E.O. (Eider Oñate), Torre, A.C. (Andrés Concha), Vivanco, A. (Ana), Fernández, R. (Reyes), Sánchez, F.G. (Francisco Giménez), Forte, M.S. (Miguel Sánchez), Rojo, P. (Pablo), Contreras, J.R. (J. Ruiz), Palacios, A. (Alba), Ibarrondo, C.E. (Cristina Epalza), Cooke, E.F. (Elizabeth Fernández), Navarro, M. (Marisa), Álvarez, C.Á. (Cristina Álvarez), Lozano, M.J. (María José), Carreras, E. (Eduardo), Sanagustín, S.B. (Sonia Brió), Neth, O. (Olaf), Padilla, M.C.M. (Ma del Carmen Martínez), Tato, L.M.P. (Luis Manuel Prieto), Guillén, S. (Sara), Silveira, L.F. (Laura Fernández), Moreno, D. (David), van Furth, A.M.T. (A. M. Tutu), Boeddha, N.P. (Navin), Driessen, G.J.A. (Gertjan), Hazelzet, J.A. (Jan), Pajkrt, D. (D.), Sanders, E.A.M. (E. A.M.), van de Beek, D. (D.), Ende, A. (A.) van der, Philipsen, H.L.A. (H. L.A.), Adeel, A.O.A. (A. O.A.), Breukels, M.A. (M. A.), Brinkman, D.M.C., de Korte, C.C.M.M. (C. C.M.M.), de Vries, E. (E.), Waal, W.J. (Wouter) de, Dekkers, R. (R.), Dings-Lammertink, A. (A.), Doedens, R.A. (R. A.), Donker, A.E. (A.), Dousma, M. (M.), Faber, T.E. (T. E.), Gerrit, G.P.J.M. (Gerardus), Gerver, J.A.M. (J. A.M.), Heidema, J. (Jojanneke), Veen, J.H.-V. (J. Homan-van der), Jacobs, M.A.M. (M. A.M.), Jansen, N.J.G. (N. J.G.), Kawczynski, P. (P.), Klucovska, K. (K.), Kneyber, M.C.J. (M. C.J.), Koopman-Keemink, Y. (Yvonne), Langenhorst, V.J. (V. J.), Leusink, J. (J.), Loza, B.F. (Bettina F.), Merth, I.T. (I. T.), Miedema, C.J. (C. J.), Neeleman, C. (C.), Noordzij, J.G. (Jeroen), Obihara, C.C. (Charlie C.), van Overbeek – van Gils, A.L.T. (A. L.T.), Poortman, G.H. (G. H.), Potgieter, S.T. (S. T.), Potjewijd, J. (J.), Rosias, P.P.R. (Philippe), Sprong, T. (Tom), ten Tussher, G.W. (G. W.), Thio, B.J. (B. J.), Tramper-Stranders, G.A. (Gerdien), Deuren, M. (Marcel) van, van der Meer, H. (H.), van Kuppevelt, A.J.M. (A. J.M.), van Wermeskerken, A.M. (A. M.), Verwijs, W.A. (W. A.), Wolfs, T.F.W. (T. F.W.), Agyeman, P. (Philipp), Aebi, C. (Christoph), Berger, C. (Christoph), Giannoni, P., Stocker, M. (Martin), Posfay-Barbe, K.M. (Klara M.), Heininger, U. (Ulrich), Bernhard-Stirnemann, S. (Sara), Niederer-Loher, A. (Anita), Kahlert, C. (Christian), Hasters, P. (Paul), Relly, C. (Christa), Baer, W. (Walter), Frederick, H. (Hannah), Jennings, R. (Rebecca), Johnston, J. (Joanne), Kenwright, R. (Rhian), Pinnock, E. (Elli), Agbeko, R. (Rachel), Secka, F. (Fatou), Bojang, K. (Kalifa), Sarr, I. (Isatou), Kebbeh, N. (Ngange), Sey, G. (Gibbi), Momodou, (), khan, S. (Saidy), Cole, F. (Fatoumata), Thomas, G. (Gilleh), Antonio, M. (Martin), Klobassa, D.S. (Daniela S.), Binder, A. (Alexander), Schweintzger, N.A. (Nina A.), Sagmeister, M. (Manfred), Baumgart, H. (Hinrich), Baumgartner, M. (Markus), Behrends, U. (Uta), Biebl, A. (Ariane), Birnbacher, R. (Robert), Blanke, J.-G. (Jan-Gerd), Boelke, C. (Carsten), Breuling, K. (Kai), Brunner, J. (Jürgen), Buller, M. (Maria), Dahlem, P. (Peter), Dietrich, B. (Beate), Eber, E. (Ernst), Elias, J. (Johannes), Emhofer, J. (Josef), Etschmaier, R. (Rosa), Farr, S. (Sebastian), Girtler, Y. (Ylenia), Grigorow, I. (Irina), Heimann, K. (Konrad), Ihm, U. (Ulrike), Jaros, Z. (Zdenek), Kalhoff, H. (Hermann), Kaulfersch, W. (Wilhelm), Kemen, C. (Christoph), Klocker, N. (Nina), Köster, B. (Bernhard), Kohlmaier, B. (Benno), Komini, E. (Eleni), Kramer, L. (Lydia), Neubert, A. (Antje), Ortner, D. (Daniel), Pescollderungg, L. (Lydia), Pfurtscheller, K. (Klaus), Reiter, K. (Karl), Ristic, G. (Goran), Rödl, S. (Siegfried), Sellner, A. (Andrea), Sonnleitner, A. (Astrid), Sperl, M. (Matthias), Stelzl, W. (Wolfgang), Till, H. (Holger), Trobisch, A. (Andreas), Vierzig, A. (Anne), Vogel, U. (Ulrich), Weingarten, C. (Christina), Welke, S. (Stefanie), Wimmer, A. (Andreas), Wintergerst, U. (Uwe), Wüller, D. (Daniel), Zaunschirm, A. (Andrew), Ziuraite, I. (Ieva), Žukovskaja, V. (Veslava), Wang, X. (Xinzhu), Nijman, R.G. (Ruud), Camuzeaux, S. (Stephane), Sands, C. (Caroline), Jackson, H. (Heather), Kaforou, M. (Myrsini), Emonts, M. (Marieke), Herberg, J.A. (Jethro A.), MacOnochie, I.K. (Ian), Carrol, E.D. (Enitan), Paulus, S.C. (Stephane C.), Zenz, W. (Werner), Flier, M. (Michiel) van der, Groot, R. (Ronald) de, Martinon-Torres, F. (Federico), Schlapbach, L.J. (Luregn), Pollard, A.J. (Andrew J.), Fink, C. (Colin), Kuijpers, T.T. (Taco T.), Anderson, S. (Suzanne), Lewis, M.R. (Matthew R.), Levin, M. (Michael), McClure, M. (Myra), Gormley, S. (Stuart), Hamilton, S. (Shea), Hourmat, B. (Bernardo), Hoggart, C. (Clive), Sancho-Shimizu, V. (Vanessa), Wright, V.J. (Victoria), Abdulla, A. (Amina), Agapow, P. (Paul), Bartlett, M. (Maeve), Bellos, E. (Evangelos), Eleftherohorinou, H. (Hariklia), Galassini, R. (Rachel), Inwald, D. (David), Mashbat, M. (Meg), Menikou, S. (Stefanie), Mustafa, S. (Sobia), Nadel, S. (Simon), Rahman, R. (Rahmeen), Thakker, C. (Clare), Coin, L.M.J. (Lachlan M. J.), Bokhandi, S. (S.), Power, S. (Sue), Barham, H. (Heather), Pathan, D.N. (Dr N), Ridout, J. (Jenna), White, D. (Deborah), Thurston, S. (Sarah), Faust, D. (Dominik), Patel, S.Y. (Smita Y.), McCorkell, J. (Jenni), Davies, P. (P.), Crate, L. (Lindsey), Navarra, H. (Helen), Carter, S. (Stephanie), Ramaiah, R. (R.), Patel, R. (Rekha), Tuffrey, C. (Catherine), Gribbin, A. (Andrew), McCready, S. (Sharon), Peters, M. (Mark), Hardy, K. (Katie), Standing, F. (Fran), O’Neill, L. (Lauren), Abelake, E. (Eugenia), Deep, A. (Akash), Nsirim, E. (Eniola), Willis, L. (Louise), Young, Z. (Zoe), Royad, C. (C.), White, S. (Sonia), Fortune, P.M. (P. M.), Hudnott, P. (Phil), González, F.Á. (Fernando Álvez), Barral-Arca, R. (Ruth), Cebey-López, M. (Miriam), Curras-Tuala, M.J. (María José), García, N. (Natalia), Vicente, L.G. (Luisa García), Gómez-Carballa, A. (Alberto), Rial, J.G. (Jose Gómez), Beiroa, A.G. (Andrea Grela), Grande, A.J. (Antonio Justicia), Iglesias, P.L. (Pilar Leboráns), Santos, A.E.M. (Alba Elena Martínez), Martinón-Torres, F. (Federico), MartinónTorres, N. (Nazareth), Sánchez, J.M.M. (José María Martinón), Gutiérrez, B.M. (Beatriz Morillo), Pérez, B.M. (Belén Mosquera), Pacheco, P.O. (Pablo Obando), Pardo-Seco, J. (Jacobo), Pischedda, S. (Sara), RiveroCalle, I. (Irene), Rodríguez-Tenreiro, C. (Carmen), Redondo-Collazo, L. (Lorenzo), Ellacuriagal, A.S. (Antonio Salas), Fernández, S.S. (Sonia Serén), Silva, M.S.P. (María del Sol Porto), Vega, A. (Ana), Trillo, L.V. (Lucía Vilanova), Salas, A. (Antonio), Reyes, S.B. (Susana Beatriz), León, M.C.L. (María Cruz León), Mingorance, Á.N. (Álvaro Navarro), Barrios, X.G. (Xavier Gabaldó), Vergara, E.O. (Eider Oñate), Torre, A.C. (Andrés Concha), Vivanco, A. (Ana), Fernández, R. (Reyes), Sánchez, F.G. (Francisco Giménez), Forte, M.S. (Miguel Sánchez), Rojo, P. (Pablo), Contreras, J.R. (J. Ruiz), Palacios, A. (Alba), Ibarrondo, C.E. (Cristina Epalza), Cooke, E.F. (Elizabeth Fernández), Navarro, M. (Marisa), Álvarez, C.Á. (Cristina Álvarez), Lozano, M.J. (María José), Carreras, E. (Eduardo), Sanagustín, S.B. (Sonia Brió), Neth, O. (Olaf), Padilla, M.C.M. (Ma del Carmen Martínez), Tato, L.M.P. (Luis Manuel Prieto), Guillén, S. (Sara), Silveira, L.F. (Laura Fernández), Moreno, D. (David), van Furth, A.M.T. (A. M. Tutu), Boeddha, N.P. (Navin), Driessen, G.J.A. (Gertjan), Hazelzet, J.A. (Jan), Pajkrt, D. (D.), Sanders, E.A.M. (E. A.M.), van de Beek, D. (D.), Ende, A. (A.) van der, Philipsen, H.L.A. (H. L.A.), Adeel, A.O.A. (A. O.A.), Breukels, M.A. (M. A.), Brinkman, D.M.C., de Korte, C.C.M.M. (C. C.M.M.), de Vries, E. (E.), Waal, W.J. (Wouter) de, Dekkers, R. (R.), Dings-Lammertink, A. (A.), Doedens, R.A. (R. A.), Donker, A.E. (A.), Dousma, M. (M.), Faber, T.E. (T. E.), Gerrit, G.P.J.M. (Gerardus), Gerver, J.A.M. (J. A.M.), Heidema, J. (Jojanneke), Veen, J.H.-V. (J. Homan-van der), Jacobs, M.A.M. (M. A.M.), Jansen, N.J.G. (N. J.G.), Kawczynski, P. (P.), Klucovska, K. (K.), Kneyber, M.C.J. (M. C.J.), Koopman-Keemink, Y. (Yvonne), Langenhorst, V.J. (V. J.), Leusink, J. (J.), Loza, B.F. (Bettina F.), Merth, I.T. (I. T.), Miedema, C.J. (C. J.), Neeleman, C. (C.), Noordzij, J.G. (Jeroen), Obihara, C.C. (Charlie C.), van Overbeek – van Gils, A.L.T. (A. L.T.), Poortman, G.H. (G. H.), Potgieter, S.T. (S. T.), Potjewijd, J. (J.), Rosias, P.P.R. (Philippe), Sprong, T. (Tom), ten Tussher, G.W. (G. W.), Thio, B.J. (B. J.), Tramper-Stranders, G.A. (Gerdien), Deuren, M. (Marcel) van, van der Meer, H. (H.), van Kuppevelt, A.J.M. (A. J.M.), van Wermeskerken, A.M. (A. M.), Verwijs, W.A. (W. A.), Wolfs, T.F.W. (T. F.W.), Agyeman, P. (Philipp), Aebi, C. (Christoph), Berger, C. (Christoph), Giannoni, P., Stocker, M. (Martin), Posfay-Barbe, K.M. (Klara M.), Heininger, U. (Ulrich), Bernhard-Stirnemann, S. (Sara), Niederer-Loher, A. (Anita), Kahlert, C. (Christian), Hasters, P. (Paul), Relly, C. (Christa), Baer, W. (Walter), Frederick, H. (Hannah), Jennings, R. (Rebecca), Johnston, J. (Joanne), Kenwright, R. (Rhian), Pinnock, E. (Elli), Agbeko, R. (Rachel), Secka, F. (Fatou), Bojang, K. (Kalifa), Sarr, I. (Isatou), Kebbeh, N. (Ngange), Sey, G. (Gibbi), Momodou, (), khan, S. (Saidy), Cole, F. (Fatoumata), Thomas, G. (Gilleh), Antonio, M. (Martin), Klobassa, D.S. (Daniela S.), Binder, A. (Alexander), Schweintzger, N.A. (Nina A.), Sagmeister, M. (Manfred), Baumgart, H. (Hinrich), Baumgartner, M. (Markus), Behrends, U. (Uta), Biebl, A. (Ariane), Birnbacher, R. (Robert), Blanke, J.-G. (Jan-Gerd), Boelke, C. (Carsten), Breuling, K. (Kai), Brunner, J. (Jürgen), Buller, M. (Maria), Dahlem, P. (Peter), Dietrich, B. (Beate), Eber, E. (Ernst), Elias, J. (Johannes), Emhofer, J. (Josef), Etschmaier, R. (Rosa), Farr, S. (Sebastian), Girtler, Y. (Ylenia), Grigorow, I. (Irina), Heimann, K. (Konrad), Ihm, U. (Ulrike), Jaros, Z. (Zdenek), Kalhoff, H. (Hermann), Kaulfersch, W. (Wilhelm), Kemen, C. (Christoph), Klocker, N. (Nina), Köster, B. (Bernhard), Kohlmaier, B. (Benno), Komini, E. (Eleni), Kramer, L. (Lydia), Neubert, A. (Antje), Ortner, D. (Daniel), Pescollderungg, L. (Lydia), Pfurtscheller, K. (Klaus), Reiter, K. (Karl), Ristic, G. (Goran), Rödl, S. (Siegfried), Sellner, A. (Andrea), Sonnleitner, A. (Astrid), Sperl, M. (Matthias), Stelzl, W. (Wolfgang), Till, H. (Holger), Trobisch, A. (Andreas), Vierzig, A. (Anne), Vogel, U. (Ulrich), Weingarten, C. (Christina), Welke, S. (Stefanie), Wimmer, A. (Andreas), Wintergerst, U. (Uwe), Wüller, D. (Daniel), Zaunschirm, A. (Andrew), Ziuraite, I. (Ieva), and Žukovskaja, V. (Veslava)
Abstract: Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are
Published: 2019
Full Text: View/download PDF

15. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author: 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, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, P, Aebi, C, Berger, C, Giannoni, E, Stocker, M, Posfay-Barbe, KM, Heininger, U, Bernhard-Stirnemann, S, Niederer-Loher, A, Kahlert, C, Hasters, P, Relly, C, Baer, W, Paulus, S, Frederick, H, Jennings, R, Johnston, J, Kenwright, R, Agbeko, R, Bojang, K, Sarr, I, Kebbeh, N, Sey, G, Saidykhan, M, Cole, F, Thomas, G, Antonio, M, Walcher, W, Geishofer, G, Klobassa, D, Martin, M, Pfurtscheller, K, Reiter, K, Roedl, S, Zobel, G, Zoehrer, B, Toepke, B, Fucik, P, Gabriel, M, Penzien, JM, Diab, G, Miething, R, Deeg, KH, Hammer, J, Varnholt, V, Schmidt, A, Bindl, L, Sillaber, U, Huemer, C, Meier, P, Simic-Schleicher, G, Markart, M, Pfau, E, Broede, H, Ausserer, B, Kalhoff, H, Arpe, V, Schweitzer-Krantz, S, Kasper, J-M, Loranth, K, Bittrich, HJ, Simma, B, Klinge, J, Fedlmaier, M, Weigand, N, Herting, E, Grube, R, Fusch, C, Gruber, A, Schimmel, U, Knaufer-Schiefer, S, Laessig, W, Hennenberger, A, von der Wense, A, Tillmann, R, Schwarick, J, Sitzmann, FC, Streif, W, Mueller, H, Kurnik, P, Groneck, P, Weiss, U, Groeblacher-Roth, H, Bensch, J, Moser, R, Schwarz, R, Lenz, K, Hofmann, T, Goepel, W, Schulz, D, Berger, T, Hauser, E, Foerster, KM, Peters, J, Nicolai, TH, Kumlien, B, Beckmann, R, Seitz, C, Hueseman, D, Schuermann, R, Ta, VH, Weikmann, E, Evert, W, Hautz, J, Seidenberg, J, Wocko, L, Luigs, P, Reiter, H-L, Quietzach, J, Koenig, M, Herrmann, J, Mitter, H, Seidler, E, Maak, B, Sperl, W, Zwiauer, K, Meissl, M, Koch, R, Cremer, M, Breuer, HA, Goerke, W, Nossal, R, Pernice, W, Brangenberg, R, Salzer, HR, Koch, H, Schaller, G, Paky, F, Strasser, F, Eitelberger, F, Sontheimer, D, Lischka, A, Kronberger, M, Dilch, A, Scheibenpflug, C, Bruckner, R, Mahler, K, Runge, K, Kunze, W, Schermann, P, 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, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, P, Aebi, C, Berger, C, Giannoni, E, Stocker, M, Posfay-Barbe, KM, Heininger, U, Bernhard-Stirnemann, S, Niederer-Loher, A, Kahlert, C, Hasters, P, Relly, C, Baer, W, Paulus, S, Frederick, H, Jennings, R, Johnston, J, Kenwright, R, Agbeko, R, Bojang, K, Sarr, I, Kebbeh, N, Sey, G, Saidykhan, M, Cole, F, Thomas, G, Antonio, M, Walcher, W, Geishofer, G, Klobassa, D, Martin, M, Pfurtscheller, K, Reiter, K, Roedl, S, Zobel, G, Zoehrer, B, Toepke, B, Fucik, P, Gabriel, M, Penzien, JM, Diab, G, Miething, R, Deeg, KH, Hammer, J, Varnholt, V, Schmidt, A, Bindl, L, Sillaber, U, Huemer, C, Meier, P, Simic-Schleicher, G, Markart, M, Pfau, E, Broede, H, Ausserer, B, Kalhoff, H, Arpe, V, Schweitzer-Krantz, S, Kasper, J-M, Loranth, K, Bittrich, HJ, Simma, B, Klinge, J, Fedlmaier, M, Weigand, N, Herting, E, Grube, R, Fusch, C, Gruber, A, Schimmel, U, Knaufer-Schiefer, S, Laessig, W, Hennenberger, A, von der Wense, A, Tillmann, R, Schwarick, J, Sitzmann, FC, Streif, W, Mueller, H, Kurnik, P, Groneck, P, Weiss, U, Groeblacher-Roth, H, Bensch, J, Moser, R, Schwarz, R, Lenz, K, Hofmann, T, Goepel, W, Schulz, D, Berger, T, Hauser, E, Foerster, KM, Peters, J, Nicolai, TH, Kumlien, B, Beckmann, R, Seitz, C, Hueseman, D, Schuermann, R, Ta, VH, Weikmann, E, Evert, W, Hautz, J, Seidenberg, J, Wocko, L, Luigs, P, Reiter, H-L, Quietzach, J, Koenig, M, Herrmann, J, Mitter, H, Seidler, E, Maak, B, Sperl, W, Zwiauer, K, Meissl, M, Koch, R, Cremer, M, Breuer, HA, Goerke, W, Nossal, R, Pernice, W, Brangenberg, R, Salzer, HR, Koch, H, Schaller, G, Paky, F, Strasser, F, Eitelberger, F, Sontheimer, D, Lischka, A, Kronberger, M, Dilch, A, Scheibenpflug, C, Bruckner, R, Mahler, K, Runge, K, Kunze, W, and Schermann, P
Abstract: 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.
Published: 2019

16. Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Author: Wang, X, Nijman, R, Camuzeaux, S, Sands, C, Jackson, H, Kaforou, M, Emonts, M, Herberg, JA, Maconochie, I, Carrol, ED, Paulus, SC, Zenz, W, Van der Flier, M, de Groot, R, Martinon-Torres, F, Schlapbach, LJ, Pollard, AJ, Fink, C, Kuijpers, TT, Anderson, S, Lewis, MR, Levin, M, McClure, M, Gormley, S, Hamilton, S, Hourmat, B, Hoggart, C, 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, Coin, LMJ, Bokhand, 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, 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, MartinonTorres, N, Martinon Sanchez, JM, Morillo Gutierrez, B, Mosquera Perez, B, Obando Pacheco, P, Pardo-Seco, J, Pischedda, S, RiveroCalle, I, Rodriguez-Tenreiro, C, Redondo-Collazo, L, Salas Ellacuriagal, A, Seren Fernandez, S, Porto Silva, MDS, Vega, A, Vilanova Trillo, L, Salas, 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, Epalza Ibarrondo, C, Fernandez Cooke, E, 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, Boeddha, NP, Driessen, GJA, Hazelzet, JA, 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, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, P, Aebi, C, Berger, C, Giannoni, E, Stocker, M, Posfay-Barbe, KM, Heininger, U, Bernhard-Stirnemann, S, Niederer-Loher, A, Kahlert, C, Hasters, P, Relly, C, Baer, W, Frederick, H, Jennings, R, Johnston, J, Kenwright, R, Pinnock, E, Agbeko, R, Secka, F, Bojang, K, Sarr, I, Kebbeh, N, Sey, G, Momodou, SK, Cole, F, Thomas, G, Antonio, M, Klobassa, DS, Binder, A, Schweintzger, NA, Sagmeister, M, Baumgart, H, Baumgartner, M, Behrends, U, Biebl, A, Birnbacher, R, Blanke, J-G, Boelke, C, Breuling, K, Brunner, J, Buller, M, Dahlem, P, Dietrich, B, Eber, E, Elias, J, Emhofer, J, Etschmaier, R, Farr, S, Girtler, Y, Grigorow, I, Heimann, K, Ihm, U, Jaros, Z, Kalhoff, H, Kaulfersch, W, Kemen, C, Klocker, N, Koester, B, Kohlmaier, B, Komini, E, Kramer, L, Neubert, A, Ortner, D, Pescollderungg, L, Pfurtscheller, K, Reiter, K, Ristic, G, Roedl, S, Sellner, A, Sonnleitner, A, Sperl, M, Stelzl, W, Till, H, Trobisch, A, Vierzig, A, Vogel, U, Weingarten, C, Welke, S, Wimmer, A, Wintergerst, U, Wueller, D, Zaunschirm, A, Ziuraite, I, Zukovskaja, V, Wang, X, Nijman, R, Camuzeaux, S, Sands, C, Jackson, H, Kaforou, M, Emonts, M, Herberg, JA, Maconochie, I, Carrol, ED, Paulus, SC, Zenz, W, Van der Flier, M, de Groot, R, Martinon-Torres, F, Schlapbach, LJ, Pollard, AJ, Fink, C, Kuijpers, TT, Anderson, S, Lewis, MR, Levin, M, McClure, M, Gormley, S, Hamilton, S, Hourmat, B, Hoggart, C, 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, Coin, LMJ, Bokhand, 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, 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, MartinonTorres, N, Martinon Sanchez, JM, Morillo Gutierrez, B, Mosquera Perez, B, Obando Pacheco, P, Pardo-Seco, J, Pischedda, S, RiveroCalle, I, Rodriguez-Tenreiro, C, Redondo-Collazo, L, Salas Ellacuriagal, A, Seren Fernandez, S, Porto Silva, MDS, Vega, A, Vilanova Trillo, L, Salas, 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, Epalza Ibarrondo, C, Fernandez Cooke, E, 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, Boeddha, NP, Driessen, GJA, Hazelzet, JA, 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, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, P, Aebi, C, Berger, C, Giannoni, E, Stocker, M, Posfay-Barbe, KM, Heininger, U, Bernhard-Stirnemann, S, Niederer-Loher, A, Kahlert, C, Hasters, P, Relly, C, Baer, W, Frederick, H, Jennings, R, Johnston, J, Kenwright, R, Pinnock, E, Agbeko, R, Secka, F, Bojang, K, Sarr, I, Kebbeh, N, Sey, G, Momodou, SK, Cole, F, Thomas, G, Antonio, M, Klobassa, DS, Binder, A, Schweintzger, NA, Sagmeister, M, Baumgart, H, Baumgartner, M, Behrends, U, Biebl, A, Birnbacher, R, Blanke, J-G, Boelke, C, Breuling, K, Brunner, J, Buller, M, Dahlem, P, Dietrich, B, Eber, E, Elias, J, Emhofer, J, Etschmaier, R, Farr, S, Girtler, Y, Grigorow, I, Heimann, K, Ihm, U, Jaros, Z, Kalhoff, H, Kaulfersch, W, Kemen, C, Klocker, N, Koester, B, Kohlmaier, B, Komini, E, Kramer, L, Neubert, A, Ortner, D, Pescollderungg, L, Pfurtscheller, K, Reiter, K, Ristic, G, Roedl, S, Sellner, A, Sonnleitner, A, Sperl, M, Stelzl, W, Till, H, Trobisch, A, Vierzig, A, Vogel, U, Weingarten, C, Welke, S, Wimmer, A, Wintergerst, U, Wueller, D, Zaunschirm, A, Ziuraite, I, and Zukovskaja, V
Abstract: 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.
Published: 2019

17. A double blind, placebo-controlled study to assess the effect of famciclovir on virus replication in patients with chronic hepatitis B virus infection

Author: Main, J., Brown, J. L., Howells, C., Galassini, R., Crossey, M., Karayiannis, P., Georgiou, P., Atkinson, G., and Thomas, H. C.
Published: 1996

18. Morbidity and mortality in compensated cirrhosis C: a retrospective follow-up study of 384 patients

Author: Fattovich, Giovanna, Giustina, G, Degos, F, Tremolada, F, Diodati, G, Almasio, P, Nevens, F, Solinas, A, Mura, D, Brouwer, J. T., Thomas, H, Njapoum, C, Casarin, C, Bonetti, P, Fuschi, P, Basho, J, Tocco, A, Bhalla, A, Galassini, R, Noventa, F, Schalm, S. W., and Realdi, G.
Subjects: Hepatitis C virus, cirrhosis, prognosis
Published: 1997

19. Survival and prognostic indicators in cryptogenic compensated cirrhosis: a multicenter study

Author: Fattovich, Giovanna, Giustina, G., Degos, F., Tremolada, F., Diodati, G., Almasio, P., Nevens, F., Solinas, A., Mura, D., Brouwer, J. T., Thomas, H. C., Njapoum, C., Bonetti, P., Casarin, C., Fuschi, P., Basho, J., Tocco, A., Bhalla, A., Galassini, R., Noventa, F., Schalm, S. W., and Realdi, G.
Subjects: cirrhosis, prognosis, survival
Published: 1995

20. Mortality and morbidity in cryptogenic (type C) compensated cirrhosis: a multicenter study

Author: Fattovich, Giovanna, Giustina, G., Degos, F., Tremolada, F., Diodati, G., Almasio, P., Nevens, F., Solinas, A., Mura, D., Brouwer, J. T., Thomas, H. C., Njapoum, C., Bonetti, P., Casarin, C., Fuschi, P., Basho, J., Tocco, A., Bhalla, A., Galassini, R., Noventa, F., Schalm, S. W., and Realdi, G.
Subjects: cirrhosis, morbidity, mortality
Published: 1995

21. Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients

Author: Fattovich, G, primary, Giustina, G, additional, Degos, F, additional, Tremolada, F, additional, Diodati, G, additional, Almasio, P, additional, Nevens, F, additional, Solinas, A, additional, Mura, D, additional, Brouwer, JT, additional, Thomas, H, additional, Njapoum, C, additional, Casarin, C, additional, Bonetti, P, additional, Fuschi, P, additional, Basho, J, additional, Tocco, A, additional, Bhalla, A, additional, Galassini, R, additional, Noventa, F, additional, Schalm, SW, additional, and Realdi, G, additional
Published: 1997
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22. Chronic hepatitis C virus infections: predictive value of genotype and level of viraemia on disease progression and response to interferon alpha.

Author: Booth, J C, primary, Foster, G R, additional, Kumar, U, additional, Galassini, R, additional, Goldin, R D, additional, Brown, J L, additional, and Thomas, H C, additional
Published: 1995
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23. Assessment of immune response to meningococcal disease: comparison of a whole-blood assay and the serum bactericidal assay

Author: Ison, C.A, Anwar, N, Cole, M.J, Galassini, R, Heyderman, R.S, Klein, N.J, West, J, Pollard, A.J, Morley, S, Levin, M, and Group, Meningococcal Research
Abstract: A whole-blood assay (WBA), which assesses the complete bactericidal activity of blood, was compared with the serum bactericidal assay (SBA), which measures antibody and complement mediated cell lysis. Twenty children infected with serogroup B strains and 25 infected with serogroup C strains were studied 8–12 weeks after disease, and 29 healthy children were used as controls. The infecting strain (convalescent children only) and two reference strains, MC58 (B:15:P1.7, 16) and NCTC 8554 (C:NT:P1.5) were used. In children previously infected with a serogroup B strain, bactericidal activity was detected in 95% and 85% to their infecting strain by the WBA (>50% killing) and the SBA (s), respectively. Bactericidal activity to the reference serogroup B and C strain was detected by WBA in 70 and 75% of children, respectively, and the SBA in 45% and 20%. In contrast bactericidal activity was detected to both serogroup C strains in >80% of children previously infected with a serogroup C strain using either assay and in 48% (WBA) and 20% (SBA) to the reference serogroup B strain. Levels of bactericidal activity were detectable in fewer control children. Children convalescing from meningococcal disease develop an immune response to their infecting strain, detectable by both the WBA and SBA, which is independent of age. However, the WBA appears to be a more sensitive measure of bactericidal activity to heterologous strains than the SBA.
Published: 1999
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24. Cellular immune responses to Neisseria meningitidis in children.

Author: Pollard, A J, Galassini, R, Rouppe van der Voort, E M, Hibberd, M, Booy, R, Langford, P, Nadel, S, Ison, C, Kroll, J S, Poolman, J, and Levin, M
Abstract: There is an urgent need for effective vaccines against serogroup B Neisseria meningitidis. Current experimental vaccines based on the outer membrane proteins (OMPs) of this organism provide a measure of protection in older children but have been ineffective in infants. We postulated that the inability of OMP vaccines to protect infants might be due to age-dependent defects in cellular immunity. We measured proliferation and in vitro production of gamma interferon (IFN-gamma), tumor necrosis factor alpha, and interleukin-10 (IL-10) in response to meningococcal antigens by peripheral blood mononuclear cells (PBMCs) from children convalescing from meningococcal disease and from controls. After meningococcal infection, the balance of cytokine production by PBMCs from the youngest children was skewed towards a TH1 response (low IL-10/IFN-gamma ratio), while older children produced more TH2 cytokine (higher IL-10/IFN-gamma ratio). There was a trend to higher proliferative responses by PBMCs from older children. These responses were not influenced by the presence or subtype of class 1 (PorA) OMP or by the presence of class 2/3 (PorB) or class 4 OMP. Even young infants might be expected to develop adequate cellular immune responses to serogroup B N. meningitidis vaccines if a vaccine preparation can be formulated to mimic the immune stimulus of invasive disease, which may include stimulation of TH2 cytokine production.
Published: 1999

25. Humoral immune responses to Neisseria meningitidis in children.

Author: Pollard, A J, Galassini, R, van der Voort, E M, Booy, R, Langford, P, Nadel, S, Ison, C, Kroll, J S, Poolman, J, and Levin, M
Abstract: An understanding of the nature of immunity to serogroup B meningococci in childhood is necessary in order to establish the reasons for poor responses to candidate vaccines in infancy. We sought to examine the nature of humoral immune responses following infection in relation to age. Serum bactericidal activity was poor in children under 12 months of age despite recent infection with Neisseria meningitidis. The highest levels of bactericidal activity were seen in children over 10 years of age. However, infants produced levels of total immunoglobulin G (IgG) and IgG subclass antibodies similar to those in older children in a meningococcal enzyme-linked immunosorbent assay. Most antibody was of the IgG1 and IgG3 subclasses. This striking age dependency of bactericidal antibody response following infection is not apparently due to failure of class switching in infants but might be due to qualitative differences in antibody specificity or affinity.
Published: 1999

26. [Immediate and long-term results of surgical treatment with extracorporeal circulation in interatrial communication of the ostium secundum type. Clinico-instrumental evaluation with study of the polycardiographic findings]

Author: Puviani, G, Galassini, R, Venezia, L, Manzini, E, Zanni, G, and Sacchi, Stefano
Subjects: Adult, Extracorporeal Circulation, Adolescent, Systole, Phonocardiography, Prognosis, ostium secundum type, Heart Septal Defects, Atrial, Electrocardiography, Carotid Arteries, Child, Preschool, Humans, Kinetocardiography, Female, Child, Pulse, Follow-Up Studies
Published: 1980

27. Integration and validation of host transcript signatures, including a novel 3-transcript tuberculosis signature, to enable one-step multiclass diagnosis of childhood febrile disease.

Author: Channon-Wells S, Habgood-Coote D, Vito O, Galassini R, Wright VJ, Brent AJ, Heyderman RS, Anderson ST, Eley B, Martinón-Torres F, Levin M, Kaforou M, and Herberg JA
Subjects: Humans, Child, Child, Preschool, Female, Male, ROC Curve, Gene Expression Profiling, Reproducibility of Results, Infant, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Messenger blood, Transcriptome genetics, Tuberculosis diagnosis, Tuberculosis genetics, Fever diagnosis, Fever microbiology
Abstract: Background: Whole blood host transcript signatures show great potential for diagnosis of infectious and inflammatory illness, with most published signatures performing binary classification tasks. Barriers to clinical implementation include validation studies, and development of strategies that enable simultaneous, multiclass diagnosis of febrile illness based on gene expression., Methods: We validated five distinct diagnostic signatures for paediatric infectious diseases in parallel using a single NanoString nCounter® experiment. We included a novel 3-transcript signature for childhood tuberculosis, and four published signatures which differentiate bacterial infection, viral infection, or Kawasaki disease from other febrile illnesses. Signature performance was assessed using receiver operating characteristic curve statistics. We also explored conceptual frameworks for multiclass diagnostic signatures, including additional transcripts found to be significantly differentially expressed in previous studies. Relaxed, regularised logistic regression models were used to derive two novel multiclass signatures: a mixed One-vs-All model (MOVA), running multiple binomial models in parallel, and a full-multiclass model. In-sample performance of these models was compared using radar-plots and confusion matrix statistics., Results: Samples from 91 children were included in the study: 23 bacterial infections (DB), 20 viral infections (DV), 14 Kawasaki disease (KD), 18 tuberculosis disease (TB), and 16 healthy controls. The five signatures tested demonstrated cross-platform performance similar to their primary discovery-validation cohorts. The signatures could differentiate: KD from other diseases with area under ROC curve (AUC) of 0.897 [95% confidence interval: 0.822-0.972]; DB from DV with AUC of 0.825 [0.691-0.959] (signature-1) and 0.867 [0.753-0.982] (signature-2); TB from other diseases with AUC of 0.882 [0.787-0.977] (novel signature); TB from healthy children with AUC of 0.910 [0.808-1.000]. Application of signatures outside of their designed context reduced performance. In-sample error rates for the multiclass models were 13.3% for the MOVA model and 0.0% for the full-multiclass model. The MOVA model misclassified DB cases most frequently (18.7%) and TB cases least (2.7%)., Conclusions: Our study demonstrates the feasibility of NanoString technology for cross-platform validation of multiple transcriptomic signatures in parallel. This external cohort validated performance of all five signatures, including a novel sparse TB signature. Two exploratory multi-class models showed high potential accuracy across four distinct diagnostic groups., (© 2024. The Author(s).)
Published: 2024
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28. Enhanced CD95 and interleukin 18 signalling accompany T cell receptor Vβ21.3+ activation in multi-inflammatory syndrome in children.

Author: Zhang Z, Kean IRL, Dratva LM, Clark JA, Syrimi E, Khan N, Daubney E, White D, O'Neill L, Chisholm C, Payne C, Benkenstein S, Kupiec K, Galassini R, Wright V, Winmill H, Robbins C, Brown K, Ramnarayan P, Scholefield B, Peters M, Klein N, Montgomery H, Meyer KB, Teichmann SA, Bryant C, Taylor G, and Pathan N
Subjects: Humans, Child, Inflammasomes metabolism, Inflammasomes immunology, SARS-CoV-2 immunology, Adolescent, Male, Receptors, Antigen, T-Cell, alpha-beta metabolism, Receptors, Antigen, T-Cell, alpha-beta genetics, Female, Child, Preschool, Single-Cell Analysis, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD28 Antigens metabolism, Lymphocyte Activation immunology, Receptors, Interleukin-18 metabolism, Receptors, Interleukin-18 genetics, Receptors, Interleukin-18 immunology, Interleukin-18 metabolism, Signal Transduction, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, fas Receptor metabolism, fas Receptor genetics, Monocytes immunology, Monocytes metabolism, Systemic Inflammatory Response Syndrome immunology, Systemic Inflammatory Response Syndrome metabolism, COVID-19 immunology, COVID-19 virology, COVID-19 metabolism, COVID-19 complications
Abstract: Multisystem inflammatory syndrome in children is a post-infectious presentation SARS-CoV-2 associated with expansion of the T cell receptor Vβ21.3+ T-cell subgroup. Here we apply muti-single cell omics to compare the inflammatory process in children with acute respiratory COVID-19 and those presenting with non SARS-CoV-2 infections in children. Here we show that in Multi-Inflammatory Syndrome in Children (MIS-C), the natural killer cell and monocyte population demonstrate heightened CD95 (Fas) and Interleuking 18 receptor expression. Additionally, TCR Vβ21.3+ CD4+ T-cells exhibit skewed differentiation towards T helper 1, 17 and regulatory T cells, with increased expression of the co-stimulation receptors ICOS, CD28 and interleukin 18 receptor. We observe no functional evidence for NLRP3 inflammasome pathway overactivation, though MIS-C monocytes show elevated active caspase 8. This, coupled with raised IL18 mRNA expression in CD16- NK cells on single cell RNA sequencing analysis, suggests interleukin 18 and CD95 signalling may trigger activation of TCR Vβ21.3+ T-cells in MIS-C, driven by increased IL-18 production from activated monocytes and CD16- Natural Killer cells., (© 2024. The Author(s).)
Published: 2024
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29. Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children From Other Pediatric Infectious and Inflammatory Diseases.

Author: Yeoh S, Estrada-Rivadeneyra D, Jackson H, Keren I, Galassini R, Cooray S, Shah P, Agyeman P, Basmaci R, Carrol E, Emonts M, Fink C, Kuijpers T, Martinon-Torres F, Mommert-Tripon M, Paulus S, Pokorn M, Rojo P, Romani L, Schlapbach L, Schweintzger N, Shen CF, Tsolia M, Usuf E, van der Flier M, Vermont C, von Both U, Yeung S, Zavadska D, Coin L, Cunnington A, Herberg J, Levin M, Kaforou M, and Hamilton S
Subjects: Humans, Child, Blood Proteins, Systemic Inflammatory Response Syndrome diagnosis, Biomarkers, Proprotein Convertase 9, Mucocutaneous Lymph Node Syndrome diagnosis, COVID-19 complications
Abstract: Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious hyperinflammatory complication following infection with severe acute respiratory syndrome coronavirus 2. The mechanisms underpinning the pathophysiology of MIS-C are poorly understood. Moreover, clinically distinguishing MIS-C from other childhood infectious and inflammatory conditions, such as Kawasaki disease or severe bacterial and viral infections, is challenging due to overlapping clinical and laboratory features. We aimed to determine a set of plasma protein biomarkers that could discriminate MIS-C from those other diseases., Methods: Seven candidate protein biomarkers for MIS-C were selected based on literature and from whole blood RNA sequencing data from patients with MIS-C and other diseases. Plasma concentrations of ARG1, CCL20, CD163, CORIN, CXCL9, PCSK9 and ADAMTS2 were quantified in MIS-C (n = 22), Kawasaki disease (n = 23), definite bacterial (n = 28) and viral (n = 27) disease and healthy controls (n = 8). Logistic regression models were used to determine the discriminatory ability of individual proteins and protein combinations to identify MIS-C and association with severity of illness., Results: Plasma levels of CD163, CXCL9 and PCSK9 were significantly elevated in MIS-C with a combined area under the receiver operating characteristic curve of 85.7% (95% confidence interval: 76.6%-94.8%) for discriminating MIS-C from other childhood diseases. Lower ARG1 and CORIN plasma levels were significantly associated with severe MIS-C cases requiring inotropes, pediatric intensive care unit admission or with shock., Conclusion: Our findings demonstrate the feasibility of a host protein biomarker signature for MIS-C and may provide new insight into its pathophysiology., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
Published: 2024
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30. Raising AWaRe-ness of Antimicrobial Stewardship Challenges in Pediatric Emergency Care: Results from the PERFORM Study Assessing Consistency and Appropriateness of Antibiotic Prescribing Across Europe.

Author: Kolberg L, Khanijau A, van der Velden FJS, Herberg J, De T, Galassini R, Cunnington AJ, Wright VJ, Shah P, Kaforou M, Wilson C, Kuijpers T, Martinón-Torres F, Rivero-Calle I, Moll H, Vermont C, Pokorn M, Kolnik M, Pollard AJ, Agyeman PKA, Schlapbach LJ, Tsolia MN, Yeung S, Zavadska D, Zenz W, Schweintzger NA, van der Flier M, de Groot R, Usuf E, Voice M, Calvo-Bado L, Mallet F, Fidler K, Levin M, Carrol ED, Emonts M, and von Both U
Subjects: Child, Humans, Drug Prescriptions, Europe, Emergency Service, Hospital, Fever diagnosis, Fever drug therapy, Penicillins therapeutic use, Anti-Bacterial Agents therapeutic use, Antimicrobial Stewardship methods
Abstract: Background: Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing., Methods: Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification., Results: Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/β-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category., Conclusions: Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship., Competing Interests: Potential conflicts of interest. A. J. C. reports 2 grants from UK Research and Innovation (principal investigator), outside the submitted work, a grant from the National Institute of Health and Care Research (as joint lead of the Global Health Research Group), and a role as chair of the Committee for Scientific Affairs and Awards for European Society for Paediatric Infectious Disease. F. M-T. reports financial support for educational activities from Sanofi, MSD, Moderna, GlaxoSmithKline (GSK), Biofabri, AstraZeneca, Novavax, Janssen, and Pfizer, outside the submitted work; travel expenses and meeting fees covered by Pfizer, MSD, GSK, and Sanofi; participation on a data safety monitoring board or advisory board for Pfizer and Biofabri; ; roles as coordinator of Spanish Pediatric Critical Trials Network and coordinator of the World Health Organization (WHO) Collaborating Centre for Vaccine Safety of Santiago de Compostela; and roles as principal investigator in randomized controlled trials for Ablynx, Abbott, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis and GSK. A. J. P. reports consulting fees from Shionogi, outside the submitted work; grants or contracts paid to the institution from the Bill & Melinda Gates Foundation, the Wellcome Trust, Cepi, the Medical Research Council, and the National Institute for Health and Care Research; royalties or licenses from AstraZeneca (Oxford University has entered into a partnership with AstraZeneca for development of coronavirus disease 2019 [COVID-19] vaccines); and unpaid roles as chair of the Department of Health and Social Care's Joint Committee on Vaccination and Immunisation and as a member of the WHO Strategic Advisory Group of Experts on Immunization (SAGE) until 2022. P. K. A. A. was a member of the Sanofi advisory board for nirsevimab in 2022. M. N. T. reports consulting fees for an MSD advisory board, support for attending IDWeek 2022 from Pfizer and IDWeek 2023 from Janssen, and unpaid participation on the Scientific Advisory Group of Experts for COVID-19 (Greece) and the National Committee for immunization Practices (Greece). U. v. B. reports financial support for educational activities (lectures on antimicrobial stewardship; pediatric educational curricula) from MSD, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
Published: 2024
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31. Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature.

Author: Habgood-Coote D, Wilson C, Shimizu C, Barendregt AM, Philipsen R, Galassini R, Calle IR, Workman L, Agyeman PKA, Ferwerda G, Anderson ST, van den Berg JM, Emonts M, Carrol ED, Fink CG, de Groot R, Hibberd ML, Kanegaye J, Nicol MP, Paulus S, Pollard AJ, Salas A, Secka F, Schlapbach LJ, Tremoulet AH, Walther M, Zenz W, Van der Flier M, Zar HJ, Kuijpers T, Burns JC, Martinón-Torres F, Wright VJ, Coin LJM, Cunnington AJ, Herberg JA, Levin M, and Kaforou M
Subjects: Child, Humans, Diagnosis, Differential, Nucleotide Motifs, Fever diagnosis, Fever genetics, RNA, Benchmarking, Biomedical Research
Abstract: Background: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood., Methods: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children., Findings: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures., Conclusions: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis., Funding: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC., Competing Interests: Declaration of interests The authors declare that a patent application on the method described in this manuscript has been filed (2304229.4/GB/PRV, 23-03-2023)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2023
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32. Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study.

Author: Shah P, Voice M, Calvo-Bado L, Rivero-Calle I, Morris S, Nijman R, Broderick C, De T, Eleftheriou I, Galassini R, Khanijau A, Kolberg L, Kolnik M, Rudzate A, Sagmeister MG, Schweintzger NA, Secka F, Thakker C, van der Velden F, Vermont C, Vincek K, Agyeman PKA, Cunnington AJ, De Groot R, Emonts M, Fidler K, Kuijpers TW, Mommert-Tripon M, Brengel-Pesce K, Mallet F, Moll H, Paulus S, Pokorn M, Pollard A, Schlapbach LJ, Shen CF, Tsolia M, Usuf E, van der Flier M, von Both U, Yeung S, Zavadska D, Zenz W, Wright V, Carrol ED, Kaforou M, Martinon-Torres F, Fink C, Levin M, and Herberg J
Abstract: Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice., Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed., Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively., Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics., Funding: EU Horizon 2020 grant 668303., Competing Interests: AC received research funding from UK-NIHR and EPSRC. He has unpaid roles at ESPID, and the Excellence in Paediatrics Institute. He filed a patent for a new diagnostic method in children. AP received grant funding from Gates Foundation, Wellcome Trust, Cepi, UK-MRC and NIHR. He received consulting fees from Shionogi. He leads the UK Joint Committee on Vaccination and Immunisation, and was a memeber of WHO-SAGE until 2022. Oxford University has entered into a partnership with AZ for development of COVID19 vaccines. CB received UK-NIHR research funding. FMT received funding from Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Referencia Competitiva, and Instituto de Salud Carlos III. MT has unpaid role at the National Committee on Immunization Practices, and at the Scientific Advisory Group of Experts for COVID-19. TK has unpaid roles at the National Working Party on Immunodeficiencies, and the National Advisory Committee on SARS-CoV-2 vaccination. UVB received funding from TeleKasper—Innovationsfonds, German G-BA, and has received funds for lectures at MSD—Workshop Pädiatrie. The other authors have no conflict of interests., (© 2023 The Authors.)
Published: 2023
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33. Biobanking and consenting to research: a qualitative thematic analysis of young people's perspectives in the North East of England.

Author: van der Velden FJS, Lim E, Gills L, Broadey J, Hayes L, Roberts E, Courtney J, Ball J, Herberg J, Galassini R, and Emonts M
Subjects: Child, Humans, Female, Adolescent, Prospective Studies, Parental Consent, Qualitative Research, England, Biological Specimen Banks, Informed Consent
Abstract: Background: Biobanking biospecimens and consent are common practice in paediatric research. We need to explore children and young people's (CYP) knowledge and perspectives around the use of and consent to biobanking. This will ensure meaningful informed consent can be obtained and improve current consent procedures., Methods: We designed a survey, in co-production with CYP, collecting demographic data, views on biobanking, and consent using three scenarios: 1) prospective consent, 2) deferred consent, and 3) reconsent and assent at age of capacity. The survey was disseminated via the Young Person's Advisory Group North England (YPAGne) and participating CYP's secondary schools. Data were analysed using a qualitative thematic approach by three independent reviewers (including CYP) to identify common themes. Data triangulation occurred independently by a fourth reviewer., Results: One hundred two CYP completed the survey. Most were between 16-18 years (63.7%, N = 65) and female (66.7%, N = 68). 72.3% had no prior knowledge of biobanking (N = 73). Acceptability of prospective consent for biobanking was high (91.2%, N = 93) with common themes: 'altruism', 'potential benefits outweigh individual risk', 'frugality', and '(in)convenience'. Deferred consent was also deemed acceptable in the large majority (84.3%, N = 86), with common themes: 'altruism', 'body integrity' and 'sample frugality'. 76.5% preferred to reconsent when cognitively mature enough to give assent (N = 78), even if parental consent was previously in place. 79.2% wanted to be informed if their biobanked biospecimen is reused (N = 80)., Conclusion: Prospective and deferred consent acceptability for biobanking is high among CYP in the UK. Altruism, frugality, body integrity, and privacy are the most important themes. Clear communication and justification are paramount to obtain consent. Any CYP with capacity should be part of the consenting procedure, if possible., (© 2023. The Author(s).)
Published: 2023
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34. Correction to: Febrile illness in high-risk children: a prospective, international observational study.

Author: van der Velden FJS, de Vries G, Martin A, Lim E, von Both U, Kolberg L, Carrol ED, Khanijau A, Herberg JA, De T, Galassini R, Kuijpers TW, Martinón-Torres F, Rivero-Calle I, Vermont CL, Hagedoorn NN, Pokorn M, Pollard AJ, Schlapbach LJ, Tsolia M, Elefhteriou I, Yeung S, Zavadska D, Fink C, Voice M, Zenz W, Kohlmaier B, Agyeman PKA, Usuf E, Secka F, de Groot R, Levin M, van der Flier M, and Emonts M
Published: 2023
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35. Correction to: Group A streptococcal disease in paediatric inpatients: a European perspective.

Author: Boeddha NP, Atkins L, de Groot R, Driessen G, Hazelzet J, Zenz W, Carrol ED, Anderson ST, Martinon-Torres F, Agyeman PKA, Galassini R, Herberg J, Levin M, Schlapbach LJ, and Emonts M
Published: 2023
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36. Group A streptococcal disease in paediatric inpatients: a European perspective.

Author: Boeddha NP, Atkins L, de Groot R, Driessen G, Hazelzet J, Zenz W, Carrol ED, Anderson ST, Martinon-Torres F, Agyeman PKA, Galassini R, Herberg J, Levin M, Schlapbach LJ, and Emonts M
Subjects: Child, Humans, Infant, Cohort Studies, Inpatients, Prospective Studies, Intensive Care Units, Pediatric, Streptococcal Infections diagnosis, Streptococcal Infections epidemiology, Streptococcal Infections complications, Sepsis complications, Community-Acquired Infections complications
Abstract: Group A streptococcal (GAS) disease shows increasing incidence worldwide. We characterised children admitted with GAS infection to European hospitals and studied risk factors for severity and disability. This is a prospective, multicentre, cohort study (embedded in EUCLIDS and the Swiss Pediatric Sepsis Study) including 320 children, aged 1 month to 18 years, admitted with GAS infection to 41 hospitals in 6 European countries from 2012 to 2016. Demographic, clinical, microbiological and outcome data were collected. A total of 195 (61%) patients had sepsis. Two hundred thirty-six (74%) patients had GAS detected from a normally sterile site. The most common infection sites were the lower respiratory tract (LRTI) (22%), skin and soft tissue (SSTI) (23%) and bone and joint (19%). Compared to patients not admitted to PICU, patients admitted to PICU more commonly had LRTI (39 vs 8%), infection without a focus (22 vs 8%) and intracranial infection (9 vs 3%); less commonly had SSTI and bone and joint infections (p < 0.001); and were younger (median 40 (IQR 21-83) vs 56 (IQR 36-85) months, p = 0.01). Six PICU patients (2%) died. Sequelae at discharge from hospital were largely limited to patients admitted to PICU (29 vs 3%, p < 0.001; 12% overall) and included neurodisability, amputation, skin grafts, hearing loss and need for surgery. More patients were recruited in winter and spring (p < 0.001)., Conclusion: In an era of observed marked reduction in vaccine-preventable infections, GAS infection requiring hospital admission is still associated with significant severe disease in younger children, and short- and long-term morbidity. Further advances are required in the prevention and early recognition of GAS disease., What Is Known: • Despite temporal and geographical variability, there is an increase of incidence of infection with group A streptococci. However, data on the epidemiology of group A streptococcal infections in European children is limited., What Is New: • In a large, prospective cohort of children with community-acquired bacterial infection requiring hospitalisation in Europe, GAS was the most frequent pathogen, with 12% disability at discharge, and 2% mortality in patients with GAS infection. • In children with GAS sepsis, IVIG was used in only 4.6% of patients and clindamycin in 29% of patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Published: 2023
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37. Febrile illness in high-risk children: a prospective, international observational study.

Author: van der Velden FJS, de Vries G, Martin A, Lim E, von Both U, Kolberg L, Carrol ED, Khanijau A, Herberg JA, De T, Galassini R, Kuijpers TW, Martinón-Torres F, Rivero-Calle I, Vermont CL, Hagedoorn NN, Pokorn M, Pollard AJ, Schlapbach LJ, Tsolia M, Elefhteriou I, Yeung S, Zavadska D, Fink C, Voice M, Zenz W, Kohlmaier B, Agyeman PKA, Usuf E, Secka F, de Groot R, Levin M, van der Flier M, and Emonts M
Subjects: Child, Humans, Prospective Studies, Fever diagnosis, Fever etiology, Fever drug therapy, Anti-Bacterial Agents therapeutic use, Biomarkers, Bacterial Infections complications, Bacterial Infections diagnosis, Bacterial Infections epidemiology, Virus Diseases complications, Virus Diseases diagnosis, Virus Diseases drug therapy
Abstract: To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the 'Biomarker Validation in HR patients' database in PERFORM, were analysed. Immunocompromised children (< 18 years old) presented to fifteen European hospitals in nine countries, and one Gambian hospital, with fever or suspected infection and clinical indication for blood investigations. Febrile episodes were assigned clinical phenotypes using the validated PERFORM algorithm. Logistic regression was used to assess the effect size of predictive features of proven/presumed bacterial or viral infection. A total of 599 episodes in 482 children were analysed. Seventy-eight episodes (13.0%) were definite bacterial, 67 episodes probable bacterial (11.2%), and 29 bacterial syndrome (4.8%). Fifty-five were definite viral (9.2%), 49 probable viral (8.2%), and 23 viral syndrome (3.8%). One hundred ninety were unknown bacterial or viral infections (31.7%), and 108 had inflammatory or other non-infectious causes of fever (18.1%). Predictive features of proven/presumed bacterial infection were ill appearance (OR 3.1 (95% CI 2.1-4.6)) and HIV (OR 10.4 (95% CI 2.0-54.4)). Ill appearance reduced the odds of having a proven/presumed viral infection (OR 0.5 (95% CI 0.3-0.9)). A total of 82.1% had new empirical antibiotics started on admission (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522). Conclusion: The aetiology of febrile illness in immunocompromised children is diverse. In one-third of cases, no cause for the fever will be identified. Justification for standard intravenous antibiotic treatment for every febrile immunocompromised child is debatable, yet effective. Better clinical decision-making tools and new biomarkers are needed for this population. What is Known: • Immunosuppressed children are at high risk for morbidity and mortality of serious bacterial and viral infection, but often present with fever as only clinical symptom. • Current diagnostic measures in this group are not specific to rule out bacterial infection, and positivity rates of microbiological cultures are low. What is New: • Febrile illness and infectious complications remain a significant cause of mortality and morbidity in HR children, yet management is effective. • The aetiology of febrile illness in immunocompromised children is diverse, and development of pathways for early discharge or cessation of intravenous antibiotics is debatable, and requires better clinical decision-making tools and biomarkers., (© 2023. The Author(s).)
Published: 2023
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38. Low Levels of Factor H Family Proteins During Meningococcal Disease Indicate Systemic Processes Rather Than Specific Depletion by Neisseria meningitidis .

Author: van Beek AE, Pouw RB, Wright VJ, Sallah N, Inwald D, Hoggart C, Brouwer MC, Galassini R, Thomas J, Calvo-Bado L, Fink CG, Jongerius I, Hibberd M, Wouters D, Levin M, and Kuijpers TW
Subjects: Complement Factor H, Complement System Proteins, Humans, Hemolytic-Uremic Syndrome, Meningococcal Infections, Neisseria meningitidis
Abstract: Neisseria meningitidis , the causative agent of meningococcal disease (MD), evades complement-mediated clearance upon infection by 'hijacking' the human complement regulator factor H (FH). The FH protein family also comprises the homologous FH-related (FHR) proteins, hypothesized to act as antagonists of FH, and FHR-3 has recently been implicated to play a major role in MD susceptibility. Here, we show that the circulating levels of all FH family proteins, not only FH and FHR-3, are equally decreased during the acute illness. We did neither observe specific consumption of FH or FHR-3 by N. meningitidis , nor of any of the other FH family proteins, suggesting that the globally reduced levels are due to systemic processes including dilution by fluid administration upon admission and vascular leakage. MD severity associated predominantly with a loss of FH rather than FHRs. Additionally, low FH levels associated with renal failure, suggesting insufficient protection of host tissue by the active protection by the FH protein family, which is reminiscent of reduced FH activity in hemolytic uremic syndrome. Retaining higher levels of FH may thus limit tissue injury during MD., Competing Interests: RP, MB, DW and TK are co-inventors of patents describing the potentiation of FH with monoclonal antibodies and therapeutic uses thereof. JT, LCB and CF are employed by Micropathology Ltd. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Beek, Pouw, Wright, Sallah, Inwald, Hoggart, Brouwer, Galassini, Thomas, Calvo-Bado, Fink, Jongerius, Hibberd, Wouters, Levin and Kuijpers.)
Published: 2022
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39. Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease.

Author: 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, and Levin M
Subjects: Caspase 3 genetics, Humans, Phosphotransferases (Alcohol Group Acceptor) genetics, Proteins genetics, Receptors, IgG genetics, Coronary Aneurysm genetics, Mucocutaneous Lymph Node Syndrome genetics, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Abstract: 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., (© 2021. The Author(s).)
Published: 2021
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40. Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles.

Author: 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, and On Behalf Of The Perform Consortium
Subjects: Adolescent, Child, Child, Preschool, Computational Biology, Female, Humans, Male, Bacterial Infections classification, Bacterial Infections diagnosis, Bacterial Infections metabolism, Gene Expression Profiling, Mucocutaneous Lymph Node Syndrome classification, Mucocutaneous Lymph Node Syndrome diagnosis, Mucocutaneous Lymph Node Syndrome metabolism, Proteomics, Virus Diseases classification, Virus Diseases diagnosis, Virus Diseases metabolism
Abstract: 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.
Published: 2021
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41. Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood.

Author: Zandstra J, van de Geer A, Tanck MWT, van Stijn-Bringas Dimitriades D, 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, Martinón-Torres F, Herberg J, Burns J, Levin M, and Kuijpers TW
Abstract: 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., (Copyright © 2020 Zandstra, van de Geer, Tanck, van Stijn-Bringas Dimitriades, Aarts, Dietz, van Bruggen, Schweintzger, Zenz, Emonts, Zavadska, Pokorn, Usuf, Moll, Schlapbach, Carrol, Paulus, Tsolia, Fink, Yeung, Shimizu, Tremoulet, Galassini, Wright, Martinón-Torres, Herberg, Burns, Levin, Kuijpers, EUCLIDS Consortium, PERFORM Consortium and UK Kawasaki Disease Genetics Study Network.)
Published: 2020
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42. Randomized controlled trial of the effect of selenium supplementation on thyroid function in the elderly in the United Kingdom.

Author: Rayman MP, Thompson AJ, Bekaert B, Catterick J, Galassini R, Hall E, Warren-Perry M, and Beckett GJ
Subjects: Aged, Female, Humans, Hypothyroidism drug therapy, Hypothyroidism epidemiology, Male, Middle Aged, Selenium blood, Thyroid Function Tests, United Kingdom epidemiology, Hypothyroidism blood, Hypothyroidism prevention & control, Selenium Compounds administration & dosage, Thyrotropin blood, Thyroxine blood, Triiodothyronine blood
Abstract: Background: Thyroid function depends on the essential trace mineral selenium, which is at the active center of the iodothyronine deiodinase enzymes that catalyze the conversion of the prohormone thyroxine (T(4)) to the active form of thyroid hormone, triiodothyronine (T(3))., Objective: Because selenium intake in the United Kingdom has fallen during the past 25 y, we wanted to determine whether current selenium status might be limiting conversion of T(4) to T(3) in the elderly, in whom marginal hypothyroidism is relatively common., Design: We investigated the effect of selenium supplementation in a double-blind, placebo-controlled trial in 501 elderly UK volunteers. Similar numbers of men and women from each of 3 age groups, 60-64 y, 65-69 y, and 70-74 y, were randomly allocated to receive 100, 200, or 300 microg Se/d as high-selenium yeast or placebo yeast for 6 mo. As part of the study, plasma selenium, thyroid-stimulating hormone, and total and free T(3) and T(4) were measured. Data from 368 euthyroid volunteers who provided blood samples at baseline and 6 mo were analyzed., Results: Although selenium status at baseline correlated weakly with free T(4) (r = -0.19, P < 0.001) and with the ratio of free T(3) to free T(4) (r = 0.12, P = 0.02), we found no evidence of any effect of selenium supplementation on thyroid function, despite significant increases in plasma selenium. However, baseline plasma selenium in our study (x: 91 microg/L) was somewhat higher than in previous supplementation studies in which apparently beneficial effects were seen., Conclusion: We found no indication for increasing selenium intake to benefit T(4) to T(3) conversion in the elderly UK population.
Published: 2008
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43. Impact of selenium on mood and quality of life: a randomized, controlled trial.

Author: Rayman M, Thompson A, Warren-Perry M, Galassini R, Catterick J, Hall E, Lawrence D, and Bliss J
Subjects: Affect drug effects, Aged, Analysis of Variance, Chi-Square Distribution, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Micronutrients administration & dosage, Middle Aged, Pilot Projects, Reference Values, Selenium administration & dosage, Treatment Outcome, Affect physiology, Dietary Supplements, Micronutrients physiology, Quality of Life, Selenium physiology
Abstract: Background: Selenium is known to be important to the brain. Three small, published studies have suggested an effect of selenium supplementation or deprivation on mood in healthy volunteers. We investigated these findings on a much larger scale., Methods: In this double-blind, placebo-controlled intervention, 501 UK participants aged 60-74 were randomly allocated to receive 100, 200 or 300 microg selenium/d as high-selenium yeast or placebo yeast. Mood (Profile of Moods States - Bipolar Form [POMS-BI] questionnaire), "quality of life" (Short Form 36 [SF-36] questionnaire) and plasma selenium were measured at baseline and six months., Results: Supplementation significantly increased plasma selenium above baseline values: from an overall mean (SD) of 90(19) ng/g to 91(26), 144(27), 191(41) and 227(53) ng/g in the placebo, 100, 200, 300 microg selenium groups respectively (p < .001). Four hundred forty-eight participants completed the POMS-BI questionnaires at both time points, with no significant differences in total mood or mood-subscale scores seen between doses. After six months of supplementation, mean (SD) total mood scores for the four doses were 163(36), 161(37), 162(33), 162(34), F(3,443) = .25, p = .86. Quality of life was similarly unaffected., Conclusions: There was no evidence that selenium supplementation benefited mood or quality of life in these elderly volunteers. Though this is at odds with some previous results, our robust study design, much larger sample size and longer supplementation period, together with the evidence that the brain is a privileged site for selenium retention, suggest that this is a reliable finding.
Published: 2006
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44. [Systolic intervals in interatrial communication before and after surgery].

Author: Puviani G, Venezia L, Galassini R, and Zanni G
Subjects: Adolescent, Adult, Child, Child, Preschool, Follow-Up Studies, Heart Function Tests, Heart Septal Defects, Atrial surgery, Humans, Middle Aged, Heart Septal Defects, Atrial diagnosis, Myocardial Contraction, Systole
Published: 1980

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