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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. Correction to: Febrile illness in high-risk children: a prospective, international observational study (European Journal of Pediatrics, (2022), 182, 2, (543-554), 10.1007/s00431-022-04642-1)

Author: van der Velden, F.J.S. de Vries, G. Martin, A. Lim, E. von Both, U. Kolberg, L. Carrol, E.D. Khanijau, A. Herberg, J.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. de Groot, R. Levin, M. van der Flier, M. Emonts, M. Cunnington, A. Herberg, J. Kaforou, M. Wright, V. Baumard, L. Bellos, E. D’Souza, G. Habgood-Coote, D. Hamilton, S. Hoggart, C. Hourmat, S. Jackson, H. Maconochie, I. Menikou, S. Lin, N. Nichols, S. Nijman, R. Powell, O. Pena Paz, I. Shah, P. Shen, C.-F. Vito, O. Wilson, C. Abdulla, A. Ali, L. Darnell, S. Jorgensen, R. Mustafa, S. Persand, S. Stevens, M.M. Kim, N. Kim, E. Fidler, K. Dudley, J. Richmond, V. Tavliavini, E. Shen, C.-F. Liu, C.-C. Wang, S.-M. Salas, A. González, F.Á. Farto, C.B. Barral-Arca, R. Castro, M.´B. Bello, X. García, M.B. Carnota, S. Cebey-López, M. Curras-Tuala, M.J. Suárez, C.D. Vicente, L.G. Gómez-Carballa, A. Rial, J.G. Iglesias, P.L. Martinón-Torres, N. Sánchez, J.M.M. Pérez, B.M. Pardo-Seco, J. Rodríguez, L.P. Pischedda, S. Vázquez, S.R. Calle, I.R. Rodríguez-Tenreiro, C. Redondo-Collazo, L. Ora, M.S. Salas, A. Fernández, S.S. Trasorras, C.S. Iglesias, M.V. Balode, A. Barzdina, A. Deksne, D. Gardovska, D. Gravele, D. Grope, I. Meiere, A. Nokalna, I. Pavare, J. Pucuka, Z. Selecka, K. Rudzate, A. Svile, D. Urbane, U.N. Bojang, K. Zaman, S.M.A. Anderson, S. Sarr, A.R.I. Saidykhan, M. Darboe, S. Ceesay, S. D’alessandro, U. Moll, H.A. Vermont, C.L. Borensztajn, D.M. Tan, C. Zachariasse, J. Dik, W. Agyeman, P.K. Berger, C. Giannoni, E. Stocker, M. Posfay-Barbe, K.M. Heininger, U. Bernhard-Stirnemann, S. Niederer-Loher, A. Kahlert, C.R. Natalucci, G. Relly, C. Riedel, T. Aebi, C. Schlapbach, L.J. Carrol, E.D. Cocklin, E. Jennings, R. Johnston, J. Leigh, S. Lewis-Burke, N. Newall, K. Romaine, S. Eleftheriou, I. and van der Velden, F.J.S. de Vries, G. Martin, A. Lim, E. von Both, U. Kolberg, L. Carrol, E.D. Khanijau, A. Herberg, J.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. de Groot, R. Levin, M. van der Flier, M. Emonts, M. Cunnington, A. Herberg, J. Kaforou, M. Wright, V. Baumard, L. Bellos, E. D’Souza, G. Habgood-Coote, D. Hamilton, S. Hoggart, C. Hourmat, S. Jackson, H. Maconochie, I. Menikou, S. Lin, N. Nichols, S. Nijman, R. Powell, O. Pena Paz, I. Shah, P. Shen, C.-F. Vito, O. Wilson, C. Abdulla, A. Ali, L. Darnell, S. Jorgensen, R. Mustafa, S. Persand, S. Stevens, M.M. Kim, N. Kim, E. Fidler, K. Dudley, J. Richmond, V. Tavliavini, E. Shen, C.-F. Liu, C.-C. Wang, S.-M. Salas, A. González, F.Á. Farto, C.B. Barral-Arca, R. Castro, M.´B. Bello, X. García, M.B. Carnota, S. Cebey-López, M. Curras-Tuala, M.J. Suárez, C.D. Vicente, L.G. Gómez-Carballa, A. Rial, J.G. Iglesias, P.L. Martinón-Torres, N. Sánchez, J.M.M. Pérez, B.M. Pardo-Seco, J. Rodríguez, L.P. Pischedda, S. Vázquez, S.R. Calle, I.R. Rodríguez-Tenreiro, C. Redondo-Collazo, L. Ora, M.S. Salas, A. Fernández, S.S. Trasorras, C.S. Iglesias, M.V. Balode, A. Barzdina, A. Deksne, D. Gardovska, D. Gravele, D. Grope, I. Meiere, A. Nokalna, I. Pavare, J. Pucuka, Z. Selecka, K. Rudzate, A. Svile, D. Urbane, U.N. Bojang, K. Zaman, S.M.A. Anderson, S. Sarr, A.R.I. Saidykhan, M. Darboe, S. Ceesay, S. D’alessandro, U. Moll, H.A. Vermont, C.L. Borensztajn, D.M. Tan, C. Zachariasse, J. Dik, W. Agyeman, P.K. Berger, C. Giannoni, E. Stocker, M. Posfay-Barbe, K.M. Heininger, U. Bernhard-Stirnemann, S. Niederer-Loher, A. Kahlert, C.R. Natalucci, G. Relly, C. Riedel, T. Aebi, C. Schlapbach, L.J. Carrol, E.D. Cocklin, E. Jennings, R. Johnston, J. Leigh, S. Lewis-Burke, N. Newall, K. Romaine, S. Eleftheriou, I.
Abstract: In the original published version of the above article, the names of members of the PERFORM consortium were not introduced in the authorship section. The names are now properly displayed. The complete consortium list has been added as Supplementary material to the original article. The original article has been corrected. © 2023, The Author(s).
Published: 2023

3. 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

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. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

Author: Jackson, H.R., Miglietta, L., Habgood-Coote, D., D'Souza, G., Shah, P., Nichols, S., Vito, O., Powell, O., Davidson, M.S., Shimizu, C., Agyeman, P.K.A., Beudeker, C.R., Brengel-Pesce, K., Carrol, E.D., Carter, M.J., De, T., Eleftheriou, I., Emonts, M., Epalza, C., Georgiou, P., Groot, R. de, Fidler, K., Fink, C., Keulen, D. van, Kuijpers, T., Moll, H., Papatheodorou, I., Paulus, S., Pokorn, M., Pollard, A.J., Rivero-Calle, I., Rojo, P., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Tsolia, M., Usuf, E., Flier, M. van der, Both, U. von, Vermont, C., Yeung, S., Zavadska, D., Zenz, W., Coin, L.J.M., Cunnington, A., Burns, J.C., Wright, V., Martinon-Torres, F., Herberg, Jethro A., Rodriguez-Manzano, J., Kaforou, M., Levin, M., Jackson, H.R., Miglietta, L., Habgood-Coote, D., D'Souza, G., Shah, P., Nichols, S., Vito, O., Powell, O., Davidson, M.S., Shimizu, C., Agyeman, P.K.A., Beudeker, C.R., Brengel-Pesce, K., Carrol, E.D., Carter, M.J., De, T., Eleftheriou, I., Emonts, M., Epalza, C., Georgiou, P., Groot, R. de, Fidler, K., Fink, C., Keulen, D. van, Kuijpers, T., Moll, H., Papatheodorou, I., Paulus, S., Pokorn, M., Pollard, A.J., Rivero-Calle, I., Rojo, P., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Tsolia, M., Usuf, E., Flier, M. van der, Both, U. von, Vermont, C., Yeung, S., Zavadska, D., Zenz, W., Coin, L.J.M., Cunnington, A., Burns, J.C., Wright, V., Martinon-Torres, F., Herberg, Jethro A., Rodriguez-Manzano, J., Kaforou, M., and Levin, M.
Abstract: Contains fulltext : 294537.pdf (Publisher’s version ) (Open Access), BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.
Published: 2023

7. 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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8. Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study

Author: Tan, C.D. van der Walle, E.E.P.L. Vermont, C.L. von Both, U. Carrol, E.D. Eleftheriou, I. Emonts, M. van der Flier, M. de Groot, R. Herberg, J. Kohlmaier, B. Levin, M. Lim, E. Maconochie, I.K. Martinon-Torres, F. Nijman, R.G. Pokorn, M. Rivero-Calle, I. Tsolia, M. Yeung, S. Zenz, W. Zavadska, D. Moll, H.A. Levin, M. Cunnington, A. De, T. Herberg, J. Kaforou, M. Wright, V. Baumard, L. Bellos, E. D’Souza, G. Galassini, R. Habgood-Coote, D. Hamilton, S. Hoggart, C. Hourmat, S. Jackson, H. Maconochie, I. Menikou, S. Lin, N. Nichols, S. Nijman, R. Pena Paz, I. Shah, P. Shen, C.-F. Vito, O. Wilson, C. Abdulla, A. Ali, L. Darnell, S. Jorgensen, R. Mustafa, S. Persand, S. Stevens, M. Kim, E. Pierce, B. Fidler, K. Dudley, J. Richmond, V. Tavliavini, E. Liu, C.-C. Wang, S.-M. Martinón-Torres, F. Salas, A. Álvez González, F. Balo Farto, C. Barral-Arca, R. Barreiro Castro, M. Bello, X. García, M.B. Carnota, S. Cebey-López, M. Curras-Tuala, M.J. Durán Suárez, C. García Vicente, L. Gómez-Carballa, A. Gómez Rial, J. Leboráns Iglesias, P. Martinón-Torres, F. Martinón-Torres, N. Martinón Sánchez, J.M. Mosquera Pérez, B. Pardo-Seco, J. Piñeiro Rodríguez, L. Pischedda, S. Vázquez, S.R. Rivero Calle, I. Rodríguez-Tenreiro, C. Redondo-Collazo, L. Sadiki Ora, M. Salas, A. Serén Fernández, S. Serén Trasorras, C. Vilas Iglesias, M. Zavadska, D. Balode, A. Bārzdiņa, A. Deksne, D. Gardovska, D. Grāvele, D. Grope, I. Meiere, A. Nokalna, I. Pavāre, J. Pučuka, Z. Selecka, K. Sidorova, A. Svile, D. Urbāne, U.N. Usuf, E. Bojang, K. Zaman, S.M.A. Secka, F. Anderson, S. Roca, A. Sarr, I. Saidykhan, M. Darboe, S. Ceesay, S. D’alessandro, U. Moll, H.A. Borensztajn, D.M. Hagedoorn, N.N. Tan, C. Vermont, C.L. Zachariasse, J. Dik, W. Agyeman, P. Schlapbach, L.J. Aebi, C. Wyss, V. Usman, M. Agyeman, P. Schlapbach, L.J. Giannoni, E. Stocker, M. Posfay-Barbe, K.M. Heininger, U. Bernhard-Stirnemann, S. Niederer-Loher, A. Kahlert, C. Natalucci, G. Relly, C. Riedel, T. Aebi, C. Berger, C. Carrol, E.D. Paulus and Tan, C.D. van der Walle, E.E.P.L. Vermont, C.L. von Both, U. Carrol, E.D. Eleftheriou, I. Emonts, M. van der Flier, M. de Groot, R. Herberg, J. Kohlmaier, B. Levin, M. Lim, E. Maconochie, I.K. Martinon-Torres, F. Nijman, R.G. Pokorn, M. Rivero-Calle, I. Tsolia, M. Yeung, S. Zenz, W. Zavadska, D. Moll, H.A. Levin, M. Cunnington, A. De, T. Herberg, J. Kaforou, M. Wright, V. Baumard, L. Bellos, E. D’Souza, G. Galassini, R. Habgood-Coote, D. Hamilton, S. Hoggart, C. Hourmat, S. Jackson, H. Maconochie, I. Menikou, S. Lin, N. Nichols, S. Nijman, R. Pena Paz, I. Shah, P. Shen, C.-F. Vito, O. Wilson, C. Abdulla, A. Ali, L. Darnell, S. Jorgensen, R. Mustafa, S. Persand, S. Stevens, M. Kim, E. Pierce, B. Fidler, K. Dudley, J. Richmond, V. Tavliavini, E. Liu, C.-C. Wang, S.-M. Martinón-Torres, F. Salas, A. Álvez González, F. Balo Farto, C. Barral-Arca, R. Barreiro Castro, M. Bello, X. García, M.B. Carnota, S. Cebey-López, M. Curras-Tuala, M.J. Durán Suárez, C. García Vicente, L. Gómez-Carballa, A. Gómez Rial, J. Leboráns Iglesias, P. Martinón-Torres, F. Martinón-Torres, N. Martinón Sánchez, J.M. Mosquera Pérez, B. Pardo-Seco, J. Piñeiro Rodríguez, L. Pischedda, S. Vázquez, S.R. Rivero Calle, I. Rodríguez-Tenreiro, C. Redondo-Collazo, L. Sadiki Ora, M. Salas, A. Serén Fernández, S. Serén Trasorras, C. Vilas Iglesias, M. Zavadska, D. Balode, A. Bārzdiņa, A. Deksne, D. Gardovska, D. Grāvele, D. Grope, I. Meiere, A. Nokalna, I. Pavāre, J. Pučuka, Z. Selecka, K. Sidorova, A. Svile, D. Urbāne, U.N. Usuf, E. Bojang, K. Zaman, S.M.A. Secka, F. Anderson, S. Roca, A. Sarr, I. Saidykhan, M. Darboe, S. Ceesay, S. D’alessandro, U. Moll, H.A. Borensztajn, D.M. Hagedoorn, N.N. Tan, C. Vermont, C.L. Zachariasse, J. Dik, W. Agyeman, P. Schlapbach, L.J. Aebi, C. Wyss, V. Usman, M. Agyeman, P. Schlapbach, L.J. Giannoni, E. Stocker, M. Posfay-Barbe, K.M. Heininger, U. Bernhard-Stirnemann, S. Niederer-Loher, A. Kahlert, C. Natalucci, G. Relly, C. Riedel, T. Aebi, C. Berger, C. Carrol, E.D. Paulus
Abstract: Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. There is practice variation in management due to differences in guidelines and their usage and adherence. We aimed to assess whether management in febrile children below 3 months attending European Emergency Departments (EDs) was according to the guidelines for fever. This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0–18 years) attending twelve EDs in eight European countries. In febrile children below 3 months (excluding bronchiolitis), we analyzed actual management compared to the guidelines for fever. Ten EDs applied the (adapted) NICE guideline, and two EDs applied local guidelines. Management included diagnostic tests, antibiotic treatment, and admission. We included 913 children with a median age of 1.7 months (IQR 1.0–2.3). Management per ED varied as follows: use of diagnostic tests 14–83%, antibiotic treatment 23–54%, admission 34–86%. Adherence to the guideline was 43% (374/868) for blood cultures, 29% (144/491) for lumbar punctures, 55% (270/492) for antibiotic prescriptions, and 67% (573/859) for admission. Full adherence to these four management components occurred in 15% (132/868, range 0–38%), partial adherence occurred in 56% (484/868, range 35–77%). Conclusion: There is large practice variation in management. The guideline adherence was limited, but highest for admission which implies a cautious approach. Future studies should focus on guideline revision including new biomarkers in order to optimize management in young febrile children.What is Known:• Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment.• There is practice variation in management of young febrile children due to differences in guidelines and their usage and adherence.What is New
Published: 2022

9. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Author: Kumar, Vikrant, Pouw, R.B., Autio, M.I., Sagmeister, M.G., Phua, Z. Yang, Borghini, L., Wright, V.J., Hoggart, C., Pan, B., Tan, A., Binder, A., Brouwer, M.C.T., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Reiter, K., Nöthen, M.M., Hoffmann, P., consortium, E., Schlapbach, L.J., Bellos, E., Anderson, S., Secka, F., Martinón-Torres, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Zenz, W., Wouters, D., Ang, L. Teng, Hibberd, M.L., Levin, M., Kuijpers, T.W., Davila, S., Kumar, Vikrant, Pouw, R.B., Autio, M.I., Sagmeister, M.G., Phua, Z. Yang, Borghini, L., Wright, V.J., Hoggart, C., Pan, B., Tan, A., Binder, A., Brouwer, M.C.T., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Reiter, K., Nöthen, M.M., Hoffmann, P., consortium, E., Schlapbach, L.J., Bellos, E., Anderson, S., Secka, F., Martinón-Torres, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Zenz, W., Wouters, D., Ang, L. Teng, Hibberd, M.L., Levin, M., Kuijpers, T.W., and Davila, S.
Abstract: Contains fulltext : 282924.pdf (Publisher’s version ) (Open Access)
Published: 2022

10. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Author: Kumar, V, Pouw, RB, Autio, M, Sagmeister, MG, Phua, ZY, Borghini, L, Wright, VJ, Hoggart, C, Pan, B, Tan, AKY, Binder, A, Brouwer, MC, Pinnock, E, De Groot, R, Hazelzet, J, Emonts, M, van der Flier, M, Reiter, K, Nothen, MM, Hoffmann, P, Schlapbach, LJ, Bellos, E, Anderson, S, Secka, F, Martinon-Torres, F, Salas, A, Fink, C, Carrol, ED, Pollard, AJ, Coin, LJ, Zenz, W, Wouters, D, Ang, LT, Hibberd, ML, Levin, M, Kuijpers, TW, Davila, S, Kumar, V, Pouw, RB, Autio, M, Sagmeister, MG, Phua, ZY, Borghini, L, Wright, VJ, Hoggart, C, Pan, B, Tan, AKY, Binder, A, Brouwer, MC, Pinnock, E, De Groot, R, Hazelzet, J, Emonts, M, van der Flier, M, Reiter, K, Nothen, MM, Hoffmann, P, Schlapbach, LJ, Bellos, E, Anderson, S, Secka, F, Martinon-Torres, F, Salas, A, Fink, C, Carrol, ED, Pollard, AJ, Coin, LJ, Zenz, W, Wouters, D, Ang, LT, Hibberd, ML, Levin, M, Kuijpers, TW, and Davila, S
Abstract: Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10-16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10-11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.
Published: 2022

11. Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

Author: Secka, F, Herberg, J A, Sarr, I, Darboe, S, Sey, G, Saidykhan, M, Wathuo, M, Kaforou, M, Antonio, M, Roca, A, Zaman, S M A, Cebey-López, M, Boeddha, N P, Paulus, S, Kohlfürst, D S, Emonts, M, Zenz, W, Carrol, E D, de Groot, R, Schlapbach, L, Martinon-Torres, F, Bojang, K, Levin, M, van der Flier, M, Anderson, S T, Pediatrics, European Commission, Imperial College London, Wellcome Trust, and Imperial College Healthcare NHS Trust- BRC Funding
Subjects: Oncology, children, antibiotic, Major Article, Clinical Neurology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Gambia, bacteremia, mortality
Abstract: Contains fulltext : 215757.pdf (Publisher’s version ) (Open Access) Background: The limited availability of microbiology services in sub-Saharan Africa impedes accurate diagnosis of bacterial pathogens and understanding of trends in prevalence and antibiotic sensitivities. We aimed to characterize bacteremia among hospitalized children in The Gambia and to identify factors associated with bacteremia and mortality. Methods: We prospectively studied children presenting with suspected severe infection to 2 urban hospitals in The Gambia, between January 2013 and September 2015. Demographic and anthropometric data, clinical features, management, and blood culture results were documented. Urine screens for antibiotic activity were performed in a subset of participants. Results: Of 411 children enrolled (median age, 29 months; interquartile range, 11-82), 79.5% (325 of 409) reported prehospital antibiotic use. Antimicrobial activity by urinary screen for antibiotic activity was detected in 70.8% (n = 80 of 113). Sixty-six bacterial pathogens were identified in 65 (15.8%) participants and Staphylococcus aureus predominated. Gram-positive organisms were more commonly identified than Gram-negative (P < .01). Antibiotic resistance against first-line antimicrobials (ampicillin and gentamicin) was common among Gram-negative bacteria (39%; range, 25%-100%). Factors significantly associated with bacteremia included the following: gender, hydration status, musculoskeletal examination findings, admission to the Medical Research Council The Gambia at London School of Hygiene & Tropical Medicine hospital, and meeting sepsis criteria. Those associated with increased mortality were presence of a comorbidity, clinical pallor, tachypnea, and altered consciousness. Tachycardia was associated with reduced mortality. Conclusions: The bacteremia rate in children with suspected childhood life-threatening infectious diseases in The Gambia is high. The pattern of pathogen prevalence and antimicrobial resistance has changed over time compared with previous studies illustrating the importance of robust bacterial surveillance programs in resource-limited settings.
Published: 2019

12. Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

Author: Secka, F., Herberg, J.A., Sarr, I., Darboe, S., Sey, G., Saidykhan, M., Wathuo, M., Kaforou, M., Antonio, M., Roca, A., Zaman, S.M.A., Cebey-Lopez, M., Boeddha, N.P., Paulus, S., Kohlfurst, D.S., Emonts, M., Zenz, W., Carrol, E.D., Groot, R. de, Schlapbach, L., Martinon-Torres, F., Bojang, K., Levin, M., Flier, M. van der, Anderson, S.T., Secka, F., Herberg, J.A., Sarr, I., Darboe, S., Sey, G., Saidykhan, M., Wathuo, M., Kaforou, M., Antonio, M., Roca, A., Zaman, S.M.A., Cebey-Lopez, M., Boeddha, N.P., Paulus, S., Kohlfurst, D.S., Emonts, M., Zenz, W., Carrol, E.D., Groot, R. de, Schlapbach, L., Martinon-Torres, F., Bojang, K., Levin, M., Flier, M. van der, and Anderson, S.T.
Abstract: Contains fulltext : 215757.pdf (publisher's version ) (Open Access), Background: The limited availability of microbiology services in sub-Saharan Africa impedes accurate diagnosis of bacterial pathogens and understanding of trends in prevalence and antibiotic sensitivities. We aimed to characterize bacteremia among hospitalized children in The Gambia and to identify factors associated with bacteremia and mortality. Methods: We prospectively studied children presenting with suspected severe infection to 2 urban hospitals in The Gambia, between January 2013 and September 2015. Demographic and anthropometric data, clinical features, management, and blood culture results were documented. Urine screens for antibiotic activity were performed in a subset of participants. Results: Of 411 children enrolled (median age, 29 months; interquartile range, 11-82), 79.5% (325 of 409) reported prehospital antibiotic use. Antimicrobial activity by urinary screen for antibiotic activity was detected in 70.8% (n = 80 of 113). Sixty-six bacterial pathogens were identified in 65 (15.8%) participants and Staphylococcus aureus predominated. Gram-positive organisms were more commonly identified than Gram-negative (P < .01). Antibiotic resistance against first-line antimicrobials (ampicillin and gentamicin) was common among Gram-negative bacteria (39%; range, 25%-100%). Factors significantly associated with bacteremia included the following: gender, hydration status, musculoskeletal examination findings, admission to the Medical Research Council The Gambia at London School of Hygiene & Tropical Medicine hospital, and meeting sepsis criteria. Those associated with increased mortality were presence of a comorbidity, clinical pallor, tachypnea, and altered consciousness. Tachycardia was associated with reduced mortality. Conclusions: The bacteremia rate in children with suspected childhood life-threatening infectious diseases in The Gambia is high. The pattern of pathogen prevalence and antimicrobial resistance has changed over time compared with previous studie
Published: 2019

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

Author: Borghini, L., Png, E., Binder, A., Wright, V.J., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Philipsen, H.L.A., Schlapbach, L.J., Anderson, S., Secka, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Kuijpers, T.W., Martinon-Torres, F., Zenz, W., Levin, M., Hibberd, M.L., Davila, S., Neeleman, C., Deuren, M. van, Kunze, W., Schermann, P., Borghini, L., Png, E., Binder, A., Wright, V.J., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Philipsen, H.L.A., Schlapbach, L.J., Anderson, S., Secka, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Kuijpers, T.W., Martinon-Torres, F., Zenz, W., Levin, M., Hibberd, M.L., Davila, S., Neeleman, C., Deuren, M. van, Kunze, W., and Schermann, P.
Abstract: Contains fulltext : 204148.pdf (publisher's version ) (Open Access), 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

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
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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. Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

Author: MS Mondziekten/Kaakchirurgie, Infectieziekten patientenzorg, Secka, F, Herberg, J A, Sarr, I, Darboe, S, Sey, G, Saidykhan, M, Wathuo, M, Kaforou, M, Antonio, M, Roca, A, Zaman, S M A, Cebey-López, M, Boeddha, N P, Paulus, S, Kohlfürst, D S, Emonts, M, Zenz, W, Carrol, E D, de Groot, R, Schlapbach, L, Martinon-Torres, F, Bojang, K, Levin, M, van der Flier, M, Anderson, S T, MS Mondziekten/Kaakchirurgie, Infectieziekten patientenzorg, Secka, F, Herberg, J A, Sarr, I, Darboe, S, Sey, G, Saidykhan, M, Wathuo, M, Kaforou, M, Antonio, M, Roca, A, Zaman, S M A, Cebey-López, M, Boeddha, N P, Paulus, S, Kohlfürst, D S, Emonts, M, Zenz, W, Carrol, E D, de Groot, R, Schlapbach, L, Martinon-Torres, F, Bojang, K, Levin, M, van der Flier, M, and Anderson, S T
Published: 2019

18. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS)

Author: Boeddha, N.P., Schlapbach, L.J., Driessen, G.J., Herberg, J.A., Rivero-Calle, I., Cebey-Lopez, M., Klobassa, D.S., Philipsen, R., Groot, R. de, Inwald, D.P., Nadel, S., Paulus, S., Pinnock, E., Secka, F., Anderson, S.T., Agbeko, R.S., Berger, C., Fink, C.G., Carrol, E.D., Zenz, W., Levin, M., Flier, M. van der, Martinon-Torres, F., Hazelzet, J.A., Emonts, M., Boeddha, N.P., Schlapbach, L.J., Driessen, G.J., Herberg, J.A., Rivero-Calle, I., Cebey-Lopez, M., Klobassa, D.S., Philipsen, R., Groot, R. de, Inwald, D.P., Nadel, S., Paulus, S., Pinnock, E., Secka, F., Anderson, S.T., Agbeko, R.S., Berger, C., Fink, C.G., Carrol, E.D., Zenz, W., Levin, M., Flier, M. van der, Martinon-Torres, F., Hazelzet, J.A., and Emonts, M.
Abstract: Contains fulltext : 193243.pdf (publisher's version ) (Open Access), BACKGROUND: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability. METHODS: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis. RESULTS: Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1-16.0, P = 0.04; disability OR 5.4, 95% CI 1.8-15.8, P < 0.01) and illness severity as measured by Pediatric Index of Mortality (PIM2) score (mortality OR 2.8, 95% CI 1.3-6.1, P < 0.01; disability OR 3.4, 95% CI 1.8-6.4, P < 0.001). CONCLUSIONS: Despite widespread immunization campaigns, invasive bacterial disease remains responsible for substantial morbidity and mortality in critically ill
Published: 2018

19. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units

Author: Boeddha, N.P. (Navin), Schlapbach, L.J. (Luregn), Driessen, G.J.A. (Gertjan), Herberg, J.A. (Jethro A.), Rivero-Calle, I. (Irene), Cebey-López, M. (Miriam), Klobassa, D.S. (Daniela S.), Philipsen, R. (Ria), Groot, R. (Ronald) de, Inwald, D. (David), Nadel, S. (Simon), Paulus, S. (Stéphane), Pinnock, E. (Eleanor), Secka, F. (Fatou), Anderson, S.T. (Suzanne T.), Agbeko, R.S. (Rachel S.), Berger, C. (Christoph), Fink, C.G. (Colin G.), Carrol, E.D. (Enitan), Zenz, W. (Werner), Levin, M. (Michael), Flier, M. (Michiel) van der, Martinón-Torres, F. (Federico), Hazelzet, J.A. (Jan), Emonts, M. (Marieke), Boeddha, N.P. (Navin), Schlapbach, L.J. (Luregn), Driessen, G.J.A. (Gertjan), Herberg, J.A. (Jethro A.), Rivero-Calle, I. (Irene), Cebey-López, M. (Miriam), Klobassa, D.S. (Daniela S.), Philipsen, R. (Ria), Groot, R. (Ronald) de, Inwald, D. (David), Nadel, S. (Simon), Paulus, S. (Stéphane), Pinnock, E. (Eleanor), Secka, F. (Fatou), Anderson, S.T. (Suzanne T.), Agbeko, R.S. (Rachel S.), Berger, C. (Christoph), Fink, C.G. (Colin G.), Carrol, E.D. (Enitan), Zenz, W. (Werner), Levin, M. (Michael), Flier, M. (Michiel) van der, Martinón-Torres, F. (Federico), Hazelzet, J.A. (Jan), and Emonts, M. (Marieke)
Abstract: Background: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability. Methods: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital dea
Published: 2018
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20. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS)

Author: Boeddha, Navin, Schlapbach, LJ, Driessen, Gertjan, Herberg, JA, Rivero-Calle, I, Cebey-Lopez, M, Klobassa, DS, Philipsen, R, Groot, Ronald, Inwald, DP, Nadel, S, Paulus, S, Pinnock, E, Secka, F, Anderson, ST, Agbeko, RS, Berger, C, Fink, CG, Carrol, ED, Zenz, W, Levin, M, Flier, Michiel, Martinon-Torres, F, Hazelzet, Jan, Emonts, Marieke, Boeddha, Navin, Schlapbach, LJ, Driessen, Gertjan, Herberg, JA, Rivero-Calle, I, Cebey-Lopez, M, Klobassa, DS, Philipsen, R, Groot, Ronald, Inwald, DP, Nadel, S, Paulus, S, Pinnock, E, Secka, F, Anderson, ST, Agbeko, RS, Berger, C, Fink, CG, Carrol, ED, Zenz, W, Levin, M, Flier, Michiel, Martinon-Torres, F, Hazelzet, Jan, and Emonts, Marieke
Published: 2018

21. The impact of pre-hospital antibiotics on blood culture yields in a low resource setting

Author: Sarr, I., primary, Jarju, S., additional, kebbeh, N., additional, Sey, G., additional, Saidykhan, M., additional, Thomas, G., additional, Secka, F., additional, Antonio, M., additional, and Bojang, K., additional
Published: 2016
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22. Immunogenicity and Vaccine Shedding After 1 or 2 Doses of rVSVΔG-ZEBOV-GP Ebola Vaccine (ERVEBO®): Results From a Phase 2, Randomized, Placebo-controlled Trial in Children and Adults.

Author: Lee AW, Liu K, Lhomme E, Blie J, McCullough J, Onorato MT, Connor L, Simon JK, Dubey S, VanRheenen S, Deutsch J, Owens A, Morgan A, Welebob C, Hyatt D, Nair S, Hamzé B, Guindo O, Sow SO, Beavogui AH, Leigh B, Samai M, Akoo P, Serry-Bangura A, Fleck S, Secka F, Lowe B, Watson-Jones D, Roy C, Hensley LE, Kieh M, and Coller BG
Subjects: Adult, Child, Humans, Antibodies, Viral, Viral Envelope Proteins, Vaccines, Synthetic, Vaccination methods, Vaccines, Attenuated, Immunogenicity, Vaccine, Hemorrhagic Fever, Ebola, Ebola Vaccines, Ebolavirus
Abstract: Background: The rVSVΔG-ZEBOV-GP vaccine (ERVEBO®) is a single-dose, live-attenuated, recombinant vesicular stomatitis virus vaccine indicated for the prevention of Ebola virus disease (EVD) caused by Zaire ebolavirus in individuals 12 months of age and older., Methods: The Partnership for Research on Ebola VACcination (PREVAC) is a multicenter, phase 2, randomized, double-blind, placebo-controlled trial of 3 vaccine strategies in healthy children (ages 1-17) and adults, with projected 5 years of follow-up (NCT02876328). Using validated assays (GP-ELISA and PRNT), we measured antibody responses after 1-dose rVSVΔG-ZEBOV-GP, 2-dose rVSVΔG-ZEBOV-GP (given on Day 0 and Day 56), or placebo. Furthermore, we quantified vaccine virus shedding in a subset of children's saliva using RT-PCR., Results: In total, 819 children and 783 adults were randomized to receive rVSVΔG-ZEBOV-GP (1 or 2 doses) or placebo. A single dose of rVSVΔG-ZEBOV-GP increased antibody responses by Day 28 that were sustained through Month 12. A second dose of rVSVΔG-ZEBOV-GP given on Day 56 transiently boosted antibody concentrations. In vaccinated children, GP-ELISA titers were superior to placebo and non-inferior to vaccinated adults. Vaccine virus shedding was observed in 31.7% of children, peaking by Day 7, with no shedding observed after Day 28 post-dose 1 or any time post-dose 2., Conclusions: A single dose of rVSVΔG-ZEBOV-GP induced robust antibody responses in children that was non-inferior to the responses induced in vaccinated adults. Vaccine virus shedding in children was time-limited and only observed after the first dose. Overall, these data support the use of rVSVΔG-ZEBOV-GP for the prevention of EVD in at-risk children. Clinical Trials Registration. The study is registered at ClinicalTrials.gov (NCT02876328), the Pan African Clinical Trials Registry (PACTR201712002760250), and the European Clinical Trials Register (EudraCT number: 2017-001798-18)., Competing Interests: Potential conflicts of interest. K. L., M. T. O., L. C., S. D., S. V., A. O., C. W., D .H., S. N., and B.-A. C. G. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ USA, who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. A. W. L., J. K. S., J. D., and A. M. were employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and may own/have owned stock and/or hold/held stock options in Merck & Co., Inc., Rahway, NJ, USA at the time the study was conducted. E. L., B. H., and C. R. report provision of vaccines from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA to the academic sponsors for the PREVAC trial, but no funding directly to themselves or their institution. J. M. reports provision of sample collection kits for the study sites, provision and support of lab software, technical support and supervision of lab activities, and lab data management. S. O. S. reports payments from Leidos to his institution. P. A. reports support for attending meetings and/or travel including Air tickets and accommodations for attending study related meetings during the conduct of the study. D. W.-J reports funding from Innovative Medicines Initiative 2 Joint Undertaking, additionally D. W.-J. reports funding and donations of an HPV vaccine (Gardasil®) from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA for another unrelated study. 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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23. Validation of the Emergency Department-Paediatric Early Warning Score (ED-PEWS) for use in low- and middle-income countries: A multicentre observational study.

Author: Kemps N, Holband N, Boeddha NP, Faal A, Juliana AE, Kavishe GA, Keitel K, van 't Kruys KH, Ledger EV, Moll HA, Prentice AM, Secka F, Tan R, Usuf E, Unger SA, and Zachariasse JM
Abstract: Early recognition of children at risk of serious illness is essential in preventing morbidity and mortality, particularly in low- and middle-income countries (LMICs). This study aimed to validate the Emergency Department-Paediatric Early Warning Score (ED-PEWS) for use in acute care settings in LMICs. This observational study is based on previously collected clinical data from consecutive children attending four diverse settings in LMICs. Inclusion criteria and study periods (2010-2021) varied. We simulated the ED-PEWS, consisting of patient age, consciousness, work of breathing, respiratory rate, oxygen saturation, heart rate, and capillary refill time, based on the first available parameters. Discrimination was assessed by the area under the curve (AUC), sensitivity and specificity (previously defined cut-offs < 6 and ≥ 15). The outcome measure was for each setting a composite marker of high urgency. 41,917 visits from Gambia rural, 501 visits from Gambia urban, 2,608 visits from Suriname, and 1,682 visits from Tanzania were included. The proportion of high urgency was variable (range 4.6% to 24.9%). Performance ranged from AUC 0.80 (95%CI 0.70-0.89) in Gambia urban to 0.62 (95%CI 0.55-0.67) in Tanzania. The low-urgency cut-off showed a high sensitivity in all settings ranging from 0.83 (95%CI 0.81-0.84) to 1.00 (95%CI 0.97-1.00). The high-urgency cut-off showed a specificity ranging from 0.71 (95%CI 0.66-0.75) to 0.97 (95%CI 0.97-0.97). The ED-PEWS has a moderate to good performance for the recognition of high urgency children in these LMIC settings. The performance appears to have potential in improving the identification of high urgency children in LMICs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kemps et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Published: 2024
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24. 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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25. 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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26. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

Author: Jackson HR, Miglietta L, Habgood-Coote D, D'Souza G, Shah P, Nichols S, Vito O, Powell O, Davidson MS, Shimizu C, Agyeman PKA, Beudeker CR, Brengel-Pesce K, Carrol ED, Carter MJ, De T, Eleftheriou I, Emonts M, Epalza C, Georgiou P, De Groot R, Fidler K, Fink C, van Keulen D, Kuijpers T, Moll H, Papatheodorou I, Paulus S, Pokorn M, Pollard AJ, Rivero-Calle I, Rojo P, Secka F, Schlapbach LJ, Tremoulet AH, Tsolia M, Usuf E, Van Der Flier M, Von Both U, Vermont C, Yeung S, Zavadska D, Zenz W, Coin LJM, Cunnington A, Burns JC, Wright V, Martinon-Torres F, Herberg JA, Rodriguez-Manzano J, Kaforou M, and Levin M
Subjects: Child, Humans, COVID-19 Testing, Hospitals, Systemic Inflammatory Response Syndrome diagnosis, Systemic Inflammatory Response Syndrome genetics, COVID-19 diagnosis, COVID-19 genetics, COVID-19 complications, Mucocutaneous Lymph Node Syndrome diagnosis, Mucocutaneous Lymph Node Syndrome genetics
Abstract: Background: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections., Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39)., Results: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV., Conclusions: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)
Published: 2023
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27. 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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28. 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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29. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations.

Author: Kumar V, Pouw RB, Autio MI, Sagmeister MG, Phua ZY, Borghini L, Wright VJ, Hoggart C, Pan B, Tan AKY, Binder A, Brouwer MC, Pinnock E, De Groot R, Hazelzet J, Emonts M, Van Der Flier M, Reiter K, Nöthen MM, Hoffmann P, Schlapbach LJ, Bellos E, Anderson S, Secka F, Martinón-Torres F, Salas A, Fink C, Carrol ED, Pollard AJ, Coin LJ, Zenz W, Wouters D, Ang LT, Hibberd ML, Levin M, Kuijpers TW, and Davila S
Subjects: Blood Proteins genetics, Complement System Proteins genetics, Genetic Predisposition to Disease, Genotype, Humans, Complement Factor H genetics, Meningococcal Infections genetics
Abstract: Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10 -16 ) by decreasing the concentration of FH in the blood (p value = 1.4 × 10 -11 ). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing., Competing Interests: Declaration of interests R.B.P., M.C.B., D.W., and T.W.K. are co-inventors of patents or patent applications describing FH potentiating antibodies and uses thereof. A.J.P. is chair of the UK Department of Health and Social Care’s Joint Committee on Vaccination and Immunisation. F.M.-T. has received honoraria from GSK group of companies, Pfizer Inc, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. F.M.-T. has also acted as principal investigator in randomized controlled trials of the above-mentioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. All other authors declare no relevant competing interest related to the contents of this manuscript., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2022
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30. Osteoarticular Infections in Pediatric Hospitals in Europe: A Prospective Cohort Study From the EUCLIDS Consortium.

Author: Trobisch A, Schweintzger NA, Kohlfürst DS, Sagmeister MG, Sperl M, Grisold AJ, Feierl G, Herberg JA, Carrol ED, Paulus SC, Emonts M, van der Flier M, de Groot R, Cebey-López M, Rivero-Calle I, Boeddha NP, Agapow PM, Secka F, Anderson ST, Behrends U, Wintergerst U, Reiter K, Martinon-Torres F, Levin M, and Zenz W
Abstract: Background: Pediatric osteoarticular infections (POAIs) are serious diseases requiring early diagnosis and treatment., Methods: In this prospective multicenter cohort study, children with POAIs were selected from the European Union Childhood Life-threatening Infectious Diseases Study (EUCLIDS) database to analyze their demographic, clinical, and microbiological data., Results: A cohort of 380 patients with POAIs, 203 with osteomyelitis (OM), 158 with septic arthritis (SA), and 19 with both OM and SA, was analyzed. Thirty-five patients were admitted to the Pediatric Intensive Care Unit; out of these, six suffered from shock, one needed an amputation of the right foot and of four left toes, and two had skin transplantation. According to the Pediatric Overall Performance Score, 36 (10.5%) showed a mild overall disability, 3 (0.8%) a moderate, and 1 (0.2%) a severe overall disability at discharge. A causative organism was detected in 65% (247/380) of patients. Staphylococcus aureus ( S. aureus ) was identified in 57.1% (141/247) of microbiological confirmed cases, including 1 (0.7%) methicillin-resistant S. aureus (MRSA) and 6 (4.2%) Panton-Valentine leukocidin (PVL)-producing S. aureus , followed by Group A Streptococcus (18.2%) and Kingella kingae (8.9%). K. kingae and PVL production in S. aureus were less frequently reported than expected from the literature., Conclusion: POAIs are associated with a substantial morbidity in European children, with S. aureus being the major detected pathogen. In one-third of patients, no causative organism is identified. Our observations show an urgent need for the development of a vaccine against S. aureus and for the development of new microbiologic diagnostic guidelines for POAIs in European pediatric hospitals., Competing Interests: The 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 Trobisch, Schweintzger, Kohlfürst, Sagmeister, Sperl, Grisold, Feierl, Herberg, Carrol, Paulus, Emonts, van der Flier, de Groot, Cebey-López, Rivero-Calle, Boeddha, Agapow, Secka, Anderson, Behrends, Wintergerst, Reiter, Martinon-Torres, Levin, Zenz and the EUCLIDS consortium.)
Published: 2022
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31. 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, and Davila S
Subjects: Case-Control Studies, Cohort Studies, Genetic Association Studies, Genomics, High-Throughput Nucleotide Sequencing, Humans, Hypopharyngeal Neoplasms microbiology, Hypopharyngeal Neoplasms pathology, Meningococcal Infections epidemiology, Meningococcal Infections microbiology, Neisseria meningitidis isolation & purification, Phenotype, Tumor Cells, Cultured, Genetic Predisposition to Disease, Hypopharyngeal Neoplasms genetics, Meningococcal Infections genetics, Neisseria meningitidis genetics, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid
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
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32. Complement Factor H Levels Associate With Plasmodium falciparum Malaria Susceptibility and Severity.

Author: van Beek AE, Sarr I, Correa S, Nwakanma D, Brouwer MC, Wouters D, Secka F, Anderson STB, Conway DJ, Walther M, Levin M, Kuijpers TW, and Cunnington AJ
Abstract: Background: Plasmodium falciparum may evade complement-mediated host defense by hijacking complement Factor H (FH), a negative regulator of the alternative complement pathway. Plasma levels of FH vary between individuals and may therefore influence malaria susceptibility and severity., Methods: We measured convalescent FH plasma levels in 149 Gambian children who had recovered from uncomplicated or severe P. falciparum malaria and in 173 healthy control children. We compared FH plasma levels between children with malaria and healthy controls, and between children with severe (n = 82) and uncomplicated malaria (n = 67). We determined associations between FH plasma levels and laboratory features of severity and used multivariate analyses to examine associations with FH when accounting for other determinants of severity., Results: FH plasma levels differed significantly between controls, uncomplicated malaria cases, and severe malaria cases (mean [95% confidence interval], 257 [250 to 264], 288 [268 to 309], and 328 [313 to 344] µg/mL, respectively; analysis of variance P < .0001). FH plasma levels correlated with severity biomarkers, including lactate, parasitemia, and parasite density, but did not correlate with levels of PfHRP2, which represent the total body parasite load. Associations with severity and lactate remained significant when adjusting for age and parasite load., Conclusions: Natural variation in FH plasma levels is associated with malaria susceptibility and severity. A prospective study will be needed to strengthen evidence for causation, but our findings suggest that interfering with FH binding by P. falciparum might be useful for malaria prevention or treatment.
Published: 2018
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33. Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study.

Author: Martinón-Torres F, Salas A, Rivero-Calle I, Cebey-López M, Pardo-Seco J, Herberg JA, Boeddha NP, Klobassa DS, Secka F, Paulus S, de Groot R, Schlapbach LJ, Driessen GJ, Anderson ST, Emonts M, Zenz W, Carrol ED, Van der Flier M, and Levin M
Subjects: Algorithms, Child, Preschool, Cohort Studies, Cost of Illness, Europe epidemiology, Female, Humans, Infant, Infant, Newborn, Male, Prospective Studies, Severity of Illness Index, Bacterial Infections epidemiology, Sepsis epidemiology
Abstract: Background: Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe., Methods: The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures., Findings: 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4-93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0-80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8-100·4; p<0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%]), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%]), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admission to a paediatric intensive care unit. Of 2469 patients with outcome data, 57 (2·2%) deaths occurred: seven were in patients with severe focal infections and 50 in those with sepsis., Interpretation: Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients., Funding: European Union's Seventh Framework programme., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
Published: 2018
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34. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS).

Author: Boeddha NP, Schlapbach LJ, Driessen GJ, Herberg JA, Rivero-Calle I, Cebey-López M, Klobassa DS, Philipsen R, de Groot R, Inwald DP, Nadel S, Paulus S, Pinnock E, Secka F, Anderson ST, Agbeko RS, Berger C, Fink CG, Carrol ED, Zenz W, Levin M, van der Flier M, Martinón-Torres F, Hazelzet JA, and Emonts M
Subjects: Adolescent, Analysis of Variance, Chi-Square Distribution, Child, Child, Preschool, Cohort Studies, Community-Acquired Infections epidemiology, Europe epidemiology, Female, Humans, Infant, Intensive Care Units, Pediatric organization & administration, Intensive Care Units, Pediatric statistics & numerical data, Male, Prospective Studies, Sepsis epidemiology, Statistics, Nonparametric, Community-Acquired Infections mortality, Sepsis mortality
Abstract: Background: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability., Methods: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis., Results: Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1-16.0, P = 0.04; disability OR 5.4, 95% CI 1.8-15.8, P < 0.01) and illness severity as measured by Pediatric Index of Mortality (PIM2) score (mortality OR 2.8, 95% CI 1.3-6.1, P < 0.01; disability OR 3.4, 95% CI 1.8-6.4, P < 0.001)., Conclusions: Despite widespread immunization campaigns, invasive bacterial disease remains responsible for substantial morbidity and mortality in critically ill children in high-income countries. Almost one third of sepsis survivors admitted to the PICU were discharged with some disability. More research is required to delineate the long-term outcome of pediatric sepsis and to identify interventional targets. Our findings emphasize the importance of improved early sepsis-recognition programs to address the high burden of disease.
Published: 2018
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35. Evaluation of waning of IgG antibody responses after rVSVΔG-ZEBOV-GP and Ad26.ZEBOV, MVA-BN-Filo Ebola virus disease vaccines: a modelling study from the PREVAC randomized trial.

Author: Valayer S, Alexandre M, Prague M, Beavogui AH, Doumbia S, Kieh M, Greenwood B, Leigh B, Poupelin M, Schwimmer C, Sow SO, Berry IM, Kuhn JH, Fusco D, Cauwelaert ND, Watson-Jones D, Thiébaut R, Lévy Y, Yazdanpanah Y, Richert L, Lhomme E, Aboulhab J, Aguirre-MacKenzie M BS, Akoo P MB, ChB, Akpa E MSN, MPH, RN, Akpata R, Albert S BA, MPH, Ale BM MD, MSc, MPH, Alimamy-Bangura S MB, ChB, Andong P MSt, Andrews BC, Anoma S, Atri N MPH, CPH, Augier A MCom, Awuondo K MSc, Ayouba A, Badio M MSc, Bagayoko A, Balde A MPH, Balssa J PharmD, Bangura LM BSc, Barrington K MPA, Barte de Saint Fare E BA, Baseler B MS, Bauder A BA, PMP, Bauduin C MSc, Bawo L MSc, Beavogui AH MD, PhD, Belson M BS, Ben-Farhat S MEng, Bererd M BS, Bernaud N MSc, Beyslow T PharmD, Biai N MSc, Billioux J, Billouin-Frazier S MSc, Binachon B MD, MPH, Blie J MSc, Bockstal V, Boison P MS, Bolay F, Boly A MM, Bonawitz RE MD, MS, Borg AG MCM, Bosompem S PharmD, MSc, Bozman C MSc, Brady T MPH, Browne S RN, BSN, Bullis R, Cagniard B, Cahill K RN, MSc, CCRC, RAC, Cai Y, Camara AA MSc, Camara AK, Camara AM, Campagne A, Campion C MSc, Cantan A BSc, Cash J BS, Chai SP BBio-MedSc, Chambelin F MHist, Chea M BSc, Chêne G MD, PhD, Choi E, Chouinard M MSW, Chung F, Chung L PharmD, Ciancia S MJ, Cisse PN, Cline-Cole E MA, Colin C MSc, Coller BA, Conde DS, Cone K, Cone K MSW, LCSW-C, C-SWHC, Connor L MS, Connor N MSc, Cooper JB MSc, Couffin-Cardiergues S, Coulibaly F BS, Coulibaly M PharmD, MSc, Crew P PharmD, MPH, BCPS, Dabakuyo-Yonli S PharmD, PhD, Dabitao D PharmD, PhD, Damerval T, Davis B MPH, Deen GF MD, MSc, Dekeyster E, Delfraissy JF MD, PhD, Delmas C MSc, Diakite M PharmD, DPhil, Diallo A MD, MPH, Diallo FA, Diallo MS MD, MPH, Diarra A MSc, Diarra S MSc, PhD, Diawara O BS, Dighero-Kemp B BSc, Diop S MSc, PhD, Diouf W, Dixit S, Djenabou B MSc, Doepel L BA, D’Ortenzio E MD, MPH, Doumbia S MD, PhD, Doumbia MM, Douoguih M MD, MPH, Dozier N MSc, Cauwelaert ND, DuChêne A BS, Duvenhage M NDIPIT, Eckes R RN, Elliott E MSc, Enria L, Espérou H, Etienne C MSc, Eyler A HSD, Fakoli L MSc, Fallah M, Fauvel MA MSc, Faye S, Fayiah J MSc, Fleck S, Fofana V BComp, Tchos KF MD, MPH, Franklin K MPhil, MSc, Fusco D, Gaddah A, Gaignet M MSc, Gallagher K, Gardner J BS, Gichini H MSc, Gozalbes JG, Grandits G MS, Gray M BPharm, Greenwood B, Grobler N, Gross R MSc, Grue L RN, BS, BSN, Grund B, Guindo O MSc, PharmD, Gupta S DrPH, MPH, Haidara F, Hamz B PharmD, Hancox E MSc, Hébert JC MSL, Hendriks J, Hensley P MPh, Hensley LE PhD, MSPH, Herpin B MSN, Higgs E MD, DTMH, MIA, Hilton T BPharm, MSc, Hneino M, Höeltermann TA BSc, MPH, Holley HP, Hoover M, Howard N, Hughes M BA, MBA, CPM, PMP, Ilo D MD, MPH, Irvine S BS, Ishola D MD, PhD, Jato Y MPH, Joe M MSc, Johnson M MSc, Kaba AS, Kagan J, Kallon K MSc, Kamara M MBChB, MSc, Kante M BS, Katoudi J MD, MPH, Keita CM, Keita S, Keita S, Kennedy SB MD, MSc, Keshinro B MBBS, FWACP, Kiawu H MSc, Kieh M MD, MSMHC, Killinger B BA, Kinda M MD, MBA, Kirchoff M PharmD, MSc, MBA, Kocher G MSc, Kodio M PharmD, Kohn B BSc, Koivogui L PharmD, PhD, Kojan R, Koli CF é, PharmD, Koli JS é, MD, Kollie D BSc, Kopka S MS, Koroma B BPharm, Kowuor D BSc, MSc, PhD, Kpayieli-Freeman C MSc, Kwast L MSc, Lacabaratz C, Lacarra B, Lambert L BS, Lambeth C BS, Lancrey-javal S PharmD, Lane HC, Langba S BSc, Lawal B MSc, Lee AW, Lee S, Lees S, Lefevre A, Leigh B MD, MSc, Lemarcis F, Lévy Y MD, PhD, Levy-Marchal C, Leyssen M MD, PhD, Lhomme E MD, PhD, Liang J MSc, Linga M MSc, Liu K, Lowe B MPhil, Lysander J MSc, Mahamadou I PharmD, Maljkovic-Berry I, Mambiah M ASc, Manno D MD, PhD, Marchand J MS, Marron L MSc, Massaquoi MB MD, MSc, Masson L MIBL, Matard C BS, Mazur S BS, McCullough J BS, McFadyen K MPH, McLean C, Mercier N PharmD, Michavila P BBus, Miller T RN, BSN, Millimouno NP, Miranda A MS, Mohamed S BJ, Mooney T BA, Muamba D, Mulbah J BPharm, Ndamenyaa RL MD, MSc, Neaton J, Neboua D, Nelson M BSN, MS, Newell K MPH, MEd, Nguyen VK, Njie Y BSc, Njoh W MSN, Novotney-Barry A MSC, Onorato M BS, Onwuchekwa U BSc, Orsega S MSN, FNP-BC, Ortega-Perez I PhD, MPH, Osborne C BS, Otieno T MSC, Oulaï D MS, PMP, Patel S BS, Peart D, Peeters M MSc, Pettitt J MD, PhD, Peiffer-Smadja N MSc, Phillips R, Pierson J, Piot P MD, PhD, Piziali M JD, MSc, Pong S PharmD, Postnikova E, Proffitt C MA, Quach A, Quigley S MSSc, Randunu N BSc, MBA, Richert L MD, PhD, Rivière P MSc, Robinson C, Roy C, Russell AF MS, Sahr P, Saliba K MSc, PhD, Samai M MBBS, PhD, Samake S PharmD, MSc, Sandrus J AA, Sanogo I MsP, MD, Sarro YS PharmD, PhD, Sawadogo S MD, MSc, Sayadi S MD, MPH, Schvartz M, Schwimmer C, Secka F BSc, MSc, MBChB, Sharma H MSc, Shelley D MS, Shobayo B MSc, Siddiqui S MD, MPH, Simon J, Simpson S MS, Sivahera BM, Slater K, Smolskis M BSN, MA, Smout E MD, MSc, Snowden E MA, Soutthiphong AA MSc, Sow A MSc, Sow SO MD, MSc, Sow Y MD, MPH, Stirratt M, Stoop J, Subramaniam G MSc, Surugue L MJ, Swales N MSc, Tamba S RN, BSN, Tang C BSc, Tangara C MSc, Tapia MD, Teahton J MSc, Tegli J MSc, Termote M MSc, Thaurignac G MSC, Thiebaut R MD, PhD, Thompson G BS, Tierney J BSN, MPM, Tindanbil D MSc, Tour A é, PharmD, MPH, PhD, Towalid E BPharm, Traina S BS, Traore A PharmD, Tyee T PharmD, Vallée D PharmD, Vatrinet R, Vincent C MSc, Vogel S RN, BSN, Wallet C MSc, Warren T, Watson-Jones D MD, PhD, Weaver W MSc, Wentworth D MPH, Wesseh C BSc, Whitworth H, Whitworth J, Wiedemann A, Willems W, Wilson B MSc, Wolf J, Wurie A MD, MSc, Yamadjako D MS, Yaradouno M MSc, Yarmie Q MSc, Yazdanpanah Y MD, PhD, Yu S BS, Zeggani Z MSc, and Zhou H BS
Subjects: Humans, Adult, Double-Blind Method, Child, Adolescent, Female, Male, Young Adult, Vaccination, Middle Aged, Child, Preschool, Antibody Formation, Ebola Vaccines immunology, Ebola Vaccines administration & dosage, Hemorrhagic Fever, Ebola immunology, Hemorrhagic Fever, Ebola prevention & control, Hemorrhagic Fever, Ebola virology, Antibodies, Viral blood, Antibodies, Viral immunology, Ebolavirus immunology, Ebolavirus genetics, Immunoglobulin G blood, Immunoglobulin G immunology
Abstract: rVSVΔG-ZEBOV-GP and Ad26.ZEBOV, MVA-BN-Filo are WHO-prequalified vaccination regimens against Ebola virus disease (EVD). Challenges associated with measuring long-term clinical protection warrant the evaluation of immune response kinetics after vaccination. Data from a large phase 2 randomized double-blind clinical trial (PREVAC) were used to evaluate waning of anti-Ebola virus (EBOV) glycoprotein (GP 1,2 ) antibody concentrations after rVSVΔG-ZEBOV-GP or Ad26.ZEBOV, MVA-BN-Filo vaccination with linear mixed-effect regression models. After a post-vaccination peak, each vaccination strategy was associated with a decrease of anti-EBOV GP 1,2 antibody concentrations with distinct kinetics, highlighting a less-rapid decline in antibody levels after vaccination by rVSVΔG-ZEBOV-GP. One year after administration of the vaccine, antibody concentrations were higher in children compared to adults for both vaccines, although with different effect sizes: 1.74-fold higher concentrations (95% confidence interval [CI] [1.48; 2.02]) for children 12-17 years old to 3.10-fold higher concentrations (95% CI [2.58; 3.69]) for those 1-4 years old compared to adults for Ad26.ZEBOV, MVA-BN-Filo versus 1.36-fold (95% CI [1.12; 1.61]) to 1.41-fold (95% CI [1.21; 1.62]) higher than these values for adults, with relatively small changes from one age category of children to another, for rVSVΔG-ZEBOV-GP. Antibody concentrations also differed according to geographical location, pre-vaccination antibody concentration, and sex. In combination with knowledge on memory response, characterization of the major determinants of immune response durability of both vaccinations may guide future EVD control protocols. Trial registration: ClinicalTrials.gov identifier: NCT02876328.
Published: 2025
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35 results on '"Secka F"'

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

2. Correction to: Febrile illness in high-risk children: a prospective, international observational study (European Journal of Pediatrics, (2022), 182, 2, (543-554), 10.1007/s00431-022-04642-1)

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

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

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

6. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

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

8. Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study

9. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

10. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

11. Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

12. Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

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

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

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

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

17. Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

18. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS)

19. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units

20. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS)

21. The impact of pre-hospital antibiotics on blood culture yields in a low resource setting

22. Immunogenicity and Vaccine Shedding After 1 or 2 Doses of rVSVΔG-ZEBOV-GP Ebola Vaccine (ERVEBO®): Results From a Phase 2, Randomized, Placebo-controlled Trial in Children and Adults.

23. Validation of the Emergency Department-Paediatric Early Warning Score (ED-PEWS) for use in low- and middle-income countries: A multicentre observational study.

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

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

26. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

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

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

29. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations.

30. Osteoarticular Infections in Pediatric Hospitals in Europe: A Prospective Cohort Study From the EUCLIDS Consortium.

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

32. Complement Factor H Levels Associate With Plasmodium falciparum Malaria Susceptibility and Severity.

33. Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study.

34. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS).

35. Evaluation of waning of IgG antibody responses after rVSVΔG-ZEBOV-GP and Ad26.ZEBOV, MVA-BN-Filo Ebola virus disease vaccines: a modelling study from the PREVAC randomized trial.

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