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

Author

Jackson, Heather R, Miglietta, Luca, Habgood-Coote, Dominic, D'Souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp KA, Beudeker, Coco R, Brengel-Pesce, Karen, Carrol, Enitan D, Carter, Michael J, De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J, Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J, Tremoulet, Adriana H, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan JM, Cunnington, Aubrey, Burns, Jane C, Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A, Rodriguez-Manzano, Jesus, Kaforou, Myrsini, and Levin, Michael

Subjects
Paediatrics, Medical Microbiology, Biomedical and Clinical Sciences, Pediatric, Genetics, Infectious Diseases, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Child, Humans, COVID-19, Systemic Inflammatory Response Syndrome, Hospitals, Mucocutaneous Lymph Node Syndrome, COVID-19 Testing, MIS-C, diagnostic signature, host diagnostics, host response, pediatric infectious diseases, rapid diagnostics, transcriptomics, Medical microbiology
Abstract

BackgroundTo identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections.MethodsChildren 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).ResultsIn 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.ConclusionsMIS-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

6. A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study

Author

Jackson, Heather Ruth, Zandstra, Judith, Menikou, Stephanie, Hamilton, Shea, McArdle, Andrew J, De, Tisham, Agyeman, Philipp K A, Von Both, Ulrich, Carrol, Enitan D, Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, De Groot, Ronald, Moll, Henriette A, Pokorn, Marko, Pollard, Andrew, Schlapbach, Luregn J, Tsolia, Maria, Usuf, Effua, Wright, Victoria, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan JM, Cunnington, Aubrey J, Martinon-Torres, Federico, Herberg, Jethro, De Jonge, Marien I, Levin, Michael, Kuijpers, Taco, Kaforou, Myrsini, Abdulla, Amina, Aebi, Christoph, Agbeko, Rachel, Ali, Ladan, Alkema, Wynand, Allen, Karen, Anderson, Suzanne, Ansari, Imran, Arif, Tasnim, Avramoska, Tanja, Baas, Bryan, Bahovec, Natalija, Balode, Anda, Bãrdzdina, Arta, Barendregt, A M, Barral-Arca, Ruth, Bath, David, Bauchinger, Sebastian, Baumard, Lucas, Baumgart, Hinrich, Baxter, Frances, Bell, Kathryn, Bell, Ashley, Bello, Xabier, Bellos, Evangelos, Benesch, Martin, Bennet, Joshua, Berger, Christoph, Bernhard-Stirnemann, Sara, Bibi, Sagida, Bidlingmaier, Christoph, Binder, Alexander, Binder, Vera, Blackmore, Jennifer, Bojang, Kalifa, Borensztajn, Dorine M, Brengel-Pesce, Karen, Broderick, Claire, Buschbeck, Judith, Calvo-Bado, Leonides, Carnota, Sandra, Carter, Michael J, Castro, María Barreiro, Cebey-López, Miriam, Ceesay, Samba, Ceolotto, Astrid, Chan, Adora, Cocklin, Elizabeth, Collings, Kalvin, Crulley, Stephen, Curras-Tuala, María José, D'alessandro, Umberto, D'Souza, Giselle, Danhauser, Katharina, Darboe, Saffiatou, Darnell, Sarah, De Haan, L, De Vries, Gabriella, Deksne, Dãrta, Devine, Kirsty, Dewez, Juan Emmanuel, Dik, W, Dudley, Julia, Eber, Ernst, Fabian, Daniel, Farto, Cristina Balo, Fernández, Sonia Serén, Fidler, Katy, Fitchett, Elizabeth, Galassini, Rachel, Gallisti, Siegfried, García, Mirian Ben, Gardovska, Dace, Geissler, J, Gerrits, G P J M, Giannoni, Eric, Gloerich, Jolein, Gómez-Carballa, Alberto, González, Fernando Álves, Gores, Gunther, Grãvele, Dagne, Griese, Matthias, Grope, Ilze, Gurung, Meeru, Haas, Nikolaus, Habgood-Coote, Dominic, Hagedoorn, Nienke N, Haidl, Harald, Harrison, Rebekah, Hauer, Almuthe, Heidema, J, Heininger, Ulrich, Henriet, Stefanie, Hibberd, Martin, Hoggart, Cllive, Hösele, Susanne, Hourmat, Sara, Hude, Christa, Huijnen, Martijn, Iglesias, Pilar Leboráns, Iglesias, Marisol Vilas, Jennings, Rebecca, Johnson, Joanne, Jongerius, Ilse, Jorgensen, Rikke, Kahlert, Christian, Kandasamy, Rama, Kappler, Matthias, Keldorfer, Markus, Kelly, Dominic F, Khanijau, Aakash, Kim, Nayoung, Kim, Eunjung, King, Sharon, Kolberg, Laura, Kolnik, Mojca, Kloosterhuis, Lieke, Kohlfürst, Daniela S, Kohlmaier, Benno, Krenn, Larissa, Leigh, Simon, Leitner, Manuel, Leurent, Baptiste, Lim, Emma, Lin, Naomi, Liu, Ching-Chuan, Löffler, Sabine, Lurz, Eberhard, Mackerness, Christine, Maconochie, Ian, Mallet, Francois, Marmarinos, Antonis, Martin, Alex, Martin, Mike, Martinón Sánchez, José María, Martinón-Torres, Nazareth, McAlinden, Paul, McDonald, Sam, McDonell, Anne, Meiere, Anija, Meierford, Anne, Miedema, C J, Miners, Alec, Mistry, Ravi, Mommert, Marine, Morris, Sophie, Muench, Georg, Murdoch, David R, Mustafa, Sobia, Natalucci, Giancarlo, Neeleman, C, Newall, Karen, Nichols, Samuel, Niederer-Loher, Anita, Niedrist, Tobias, Nijman, Ruud, Nokalna, Ieve, Nordberg, Gudrun, O'Connor, Daniel, Obihara, C C, Oliver, Zoe, Oosthoek, Wilma, Ora, Miguel Sadiki, Osterman, Veronika, Pachot, Alexandre, Pajkrt, D, Pardo-Seco, Jacobo, Pavãre, Jana, Paz, Ivonne Pena, Paulus, Stéphane, Pérez, Belén Mosquera, Persand, Salina, Pfleger, Andreas, Pfurtscheller, Klaus, Philipsen, Ria, Pickering, Alisa, Pierce, Benjamin, Pilch, Heidemarie, Pischedda, Sara, Pölz, Lena, Posfay-Barbe, Klara M, Powell, Oliver, Prunk, Petra, Pučuka, Zanda, Rajic, Glorija, Rashid, Aqeela, Redondo-Collazo, Lorenzo, Reiter, Karl, Relly, Christa, Rhodes, Mathew, Rial, Jose Gómez, Richmond, Vivien, Riedel, Thomas, Rivero Calle, Irene, Roca, Anna, Rödl, Siegfried, Rodríguez, Lidia Piñeiro, Rodríguez-Tenreiro, Carmen, Romaine, Sam, Rowlands, Emily, Rudzate, Aleksandra, Sagmeister, Manfred, Saidykhan, Momodou, Sallas, Antonio, Sarr, Isatou, Schoen, Carola, Schonenberg, D, Schweintzger, Nina, Secka, Fatou, Selecka, Katrīna, Shah, Priyen, Shen, Ching-Fen, Shrestha, Shrijana, Skrabl-Baumgartner, Andrea, Soon, Joshua, Sperl, Matthias, Sprenkeler, Evelien, Spyridis, Nikos, Srovin, Tina Plankar, Stampfer, Laura, Stevens, Molly, Stocker, Martin, Strenger, Volker, Suárez, Carlos Durán, Svile, Dace, Syggelou, Kelly, Tal, Chantal, Tambouratzi, Maria, Tavliavini, Emma, Thakker, Clare, Thomson, Evelyn, Throson, Stephen, Till, Holger, Tramper-Stranders, G A, Trasorras, Cristina Serén, Trobisch, Andreas, Urbãne, Urzula Nora, Usman, Mariama, Valentine, Lucille, Van Aerde, Koen, Van den Berg, J M, Van den Broek, Bryan, Van der Giessen, Ilona, Van der Kuip, M, Van der Velden, Fabian, Van Furth, A M, Van Gool, Alain J, Van Leur, M, van Mierlo, G, Vázquez, Sara Ray, Vermont, Clementien, Vicente, Luisa García, Vincek, Katarina, Vito, Ortensia, Voice, Marie, Wallia, Diane, Walsh, Ben, Wang, Shih-Min, Wedderburn, Catherine, Willems, Esther, Wilson, Clare, Wood, Amanda, Woodsford, Phil, Wyss, Verena, Xagorari, Marietta, Zachariasse, Joany, Zaman, Syed M A, Zurl, Christoph, Zwerenz, Manuela, Jackson, Heather R, Hamilton, Melissa Shea, Fischer, Roman, Thorne, Adam M, Huang, Honglei, Tanck, Michael W, Jansen, Machiel H, Pollard, Andrew J, Tsolia, Maria N, Wright, Victoria J, Coin, Lachlan J M, Casals-Pascual, Climent, Herberg, Jethro A, de Jonge, Marien I, and Kuijpers, Taco W

Published
2023
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7. Large-scale association analyses identify host factors influencing human gut microbiome composition

Author

Kurilshikov, Alexander, Medina-Gomez, Carolina, Bacigalupe, Rodrigo, Radjabzadeh, Djawad, Wang, Jun, Demirkan, Ayse, Le Roy, Caroline I, Raygoza Garay, Juan Antonio, Finnicum, Casey T, Liu, Xingrong, Zhernakova, Daria V, Bonder, Marc Jan, Hansen, Tue H, Frost, Fabian, Rühlemann, Malte C, Turpin, Williams, Moon, Jee-Young, Kim, Han-Na, Lüll, Kreete, Barkan, Elad, Shah, Shiraz A, Fornage, Myriam, Szopinska-Tokov, Joanna, Wallen, Zachary D, Borisevich, Dmitrii, Agreus, Lars, Andreasson, Anna, Bang, Corinna, Bedrani, Larbi, Bell, Jordana T, Bisgaard, Hans, Boehnke, Michael, Boomsma, Dorret I, Burk, Robert D, Claringbould, Annique, Croitoru, Kenneth, Davies, Gareth E, van Duijn, Cornelia M, Duijts, Liesbeth, Falony, Gwen, Fu, Jingyuan, van der Graaf, Adriaan, Hansen, Torben, Homuth, Georg, Hughes, David A, Ijzerman, Richard G, Jackson, Matthew A, Jaddoe, Vincent WV, Joossens, Marie, Jørgensen, Torben, Keszthelyi, Daniel, Knight, Rob, Laakso, Markku, Laudes, Matthias, Launer, Lenore J, Lieb, Wolfgang, Lusis, Aldons J, Masclee, Ad AM, Moll, Henriette A, Mujagic, Zlatan, Qibin, Qi, Rothschild, Daphna, Shin, Hocheol, Sørensen, Søren J, Steves, Claire J, Thorsen, Jonathan, Timpson, Nicholas J, Tito, Raul Y, Vieira-Silva, Sara, Völker, Uwe, Völzke, Henry, Võsa, Urmo, Wade, Kaitlin H, Walter, Susanna, Watanabe, Kyoko, Weiss, Stefan, Weiss, Frank U, Weissbrod, Omer, Westra, Harm-Jan, Willemsen, Gonneke, Payami, Haydeh, Jonkers, Daisy MAE, Arias Vasquez, Alejandro, de Geus, Eco JC, Meyer, Katie A, Stokholm, Jakob, Segal, Eran, Org, Elin, Wijmenga, Cisca, Kim, Hyung-Lae, Kaplan, Robert C, Spector, Tim D, Uitterlinden, Andre G, Rivadeneira, Fernando, Franke, Andre, Lerch, Markus M, Franke, Lude, Sanna, Serena, D’Amato, Mauro, and Pedersen, Oluf

Subjects
Microbiology, Biological Sciences, Genetics, Human Genome, Biotechnology, Clinical Research, Digestive Diseases, Nutrition, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Adolescent, Adult, Bifidobacterium, Child, Child, Preschool, Cohort Studies, Female, Gastrointestinal Microbiome, Genetic Variation, Genome-Wide Association Study, Humans, Lactase, Linkage Disequilibrium, Male, Mendelian Randomization Analysis, Metabolism, Quantitative Trait Loci, RNA, Ribosomal, 16S, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P

Published
2021

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

Author

Shah, Priyen, Voice, Marie, Calvo-Bado, Leonides, Calle, Irene Rivero, Morris, Sophie, Nijman, Ruud, Broderick, Claire, De, Tisham, Eleftheriou, Irini, Galassini, Rachel, Khanijau, Aakash, Kolberg, Laura, Kolnik, Mojca, Rudzate, Aleksandra, Sagmeister, Manfred, Schweintzger, Nina, Secka, Fatou, Thakker, Clare, Van der Velden, Fabian, Vermont, Clementien, Vincek, Katarina, Agyeman, Philipp K.A., Cunnington, Aubrey J., De Groot, Ronald, Emonts, Marieke, Fidler, Katy, Kuijpers, Taco, Mommert-Tripon, Marine, Brengel-Pesce, Karen, Mallet, Francois, Moll, Henriette, Paulus, Stéphane, Pokorn, Marko, Pollard, Andrew, Schlapbach, Luregn J., Shen, Ching-Fen, Tsolia, Maria, Usuf, Effua, Van der Flier, Michiel, Von Both, Ulrich, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Wright, Victoria, Carrol, Enitan D., Kaforou, Myrsini, Martinon-Torres, Federico, Fink, Colin, Levin, Michael, Herberg, Jethro, Baumard, Lucas, Bellos, Evangelos, Coin, Lachlan, D'Souza, Giselle, Habgood-Coote, Dominic, Hamilton, Shea, Hoggart, Cllive, Hourmat, Sara, Jackson, Heather, Lin, Naomi, Menikou, Stephanie, Nichols, Samuel, Paz, Ivonne Pena, Powell, Oliver, Vito, Ortensia, Wilson, Clare, Abdulla, Amina, Ali, Ladan, Darnell, Sarah, Jorgensen, Rikke, Maconochie, Ian, Mustafa, Sobia, Persand, Salina, Walsh, Ben, Stevens, Molly, Kim, Nayoung, Kim, Eunjung, Pierce, Benjamin, Dudley, Julia, Richmond, Vivien, Tavliavini, Emma, Liu, Ching-Chuan, Wang, Shih-Min, González, Fernando Álves, Farto, Cristina Balo, Barral-Arca, Ruth, Castro, María Barreiro, Bello, Xabier, Ben García, Mirian, Carnota, Sandra, Cebey-López, Miriam, Curras-Tuala, María José, Suárez, Carlos Durán, Vicente, Luisa García, Gómez-Carballa, Alberto, Rial, Jose Gómez, Iglesias, Pilar Leboráns, Martinón-Torres, Nazareth, Martinón Sánchez, José María, Pérez, Belén Mosquera, Pardo-Seco, Jacobo, Rodríguez, Lidia Piñeiro, Pischedda, Sara, Vázquez, Sara Ray, Rodríguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Ora, Miguel Sadiki, Sallas, Antonio, Fernández, Sonia Serén, Trasorras, Cristina Serén, Iglesias, Marisol Vilas, Balode, Anda, Bãrdzdina, Arta, Deksne, Dãrta, Gardovska, Dace, Grãvele, Dagne, Grope, Ilze, Meiere, Anija, Nokalna, Ieve, Pavãre, Jana, Pučuka, Zanda, Selecka, Katrīna, Svile, Dace, Urbãne, Urzula Nora, Bojang, Kalifa, Zaman, Syed M.A., Anderson, Suzanne, Roca, Anna, Sarr, Isatou, Saidykhan, Momodou, Darboe, Saffiatou, Ceesay, Samba, D'alessandro, Umberto, Borensztajn, Dorine M., Hagedoorn, Nienke N., Tal, Chantal, Zachariasse, Joany, Dik, W., Aebi, Christoph, Berger, Christoph, Wyss, Verena, Usman, Mariama, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M., Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Natalucci, Giancarlo, Relly, Christa, Riedel, Thomas, Cocklin, Elizabeth, Jennings, Rebecca, Johnson, Joanne, Leigh, Simon, Newall, Karen, Romaine, Sam, Tambouratzi, Maria, Marmarinos, Antonis, Xagorari, Marietta, Syggelou, Kelly, Spyridis, Nikos, Blackmore, Jennifer, Harrison, Rebekah, Kohlmaier, Benno, Kohlfürst, Daniela S., Zurl, Christoph, Binder, Alexander, Hösele, Susanne, Leitner, Manuel, Pölz, Lena, Rajic, Glorija, Bauchinger, Sebastian, Baumgart, Hinrich, Benesch, Martin, Ceolotto, Astrid, Eber, Ernst, Gallisti, Siegfried, Gores, Gunther, Haidl, Harald, Hauer, Almuthe, Hude, Christa, Keldorfer, Markus, Krenn, Larissa, Pilch, Heidemarie, Pfleger, Andreas, Pfurtscheller, Klaus, Nordberg, Gudrun, Niedrist, Tobias, Rödl, Siegfried, Skrabl-Baumgartner, Andrea, Sperl, Matthias, Stampfer, Laura, Strenger, Volker, Till, Holger, Trobisch, Andreas, Löffler, Sabine, Dewez, Juan Emmanuel, Hibberd, Martin, Bath, David, Miners, Alec, Fitchett, Elizabeth, Wedderburn, Catherine, Meierford, Anne, Leurent, Baptiste, De Jonge, Marien I., van Aerde, Koen, Alkema, Wynand, van den Broek, Bryan, Gloerich, Jolein, Van Gool, Alain J., Henriet, Stefanie, Huijnen, Martijn, Philipsen, Ria, Willems, Esther, Gerrits, G.P.J.M., Van Leur, M., Heidema, J., De Haan, L., Miedema, C.J., Neeleman, C., Obihara, C.C., Tramper-Stranders, G.A., Kandasamy, Rama, Carter, Michael J., O'Connor, Daniel, Bibi, Sagida, Kelly, Dominic F., Gurung, Meeru, Throson, Stephen, Ansari, Imran, Murdoch, David R., Shrestha, Shrijana, Oliver, Zoe, Lim, Emma, Valentine, Lucille, Allen, Karen, Bell, Kathryn, Chan, Adora, Crulley, Stephen, Devine, Kirsty, Fabian, Daniel, King, Sharon, McAlinden, Paul, McDonald, Sam, McDonell, Anne, Pickering, Alisa, Thomson, Evelyn, Wood, Amanda, Wallia, Diane, Woodsford, Phil, Baxter, Frances, Bell, Ashley, Rhodes, Mathew, Agbeko, Rachel, Mackerness, Christine, Baas, Bryan, Kloosterhuis, Lieke, Oosthoek, Wilma, Arif, Tasnim, Bennet, Joshua, Collings, Kalvin, Van der Giessen, Ilona, Martin, Alex, Rashid, Aqeela, Rowlands, Emily, Soon, Joshua, De Vries, Gabriella, van der Velden, Fabian, Martin, Mike, Mistry, Ravi, Zwerenz, Manuela, Buschbeck, Judith, Bidlingmaier, Christoph, Binder, Vera, Danhauser, Katharina, Haas, Nikolaus, Griese, Matthias, Kappler, Matthias, Lurz, Eberhard, Muench, Georg, Reiter, Karl, Schoen, Carola, Pachot, Alexandre, Mommert, Marine, Srovin, Tina Plankar, Bahovec, Natalija, Prunk, Petra, Osterman, Veronika, Avramoska, Tanja, Jongerius, Ilse, van den Berg, J.M., Schonenberg, D., Barendregt, A.M., Pajkrt, D., van der Kuip, M., van Furth, A.M., Sprenkeler, Evelien, Zandstra, Judith, van Mierlo, G., Geissler, J., Rivero-Calle, Irene, Sagmeister, Manfred G., Schweintzger, Nina A., Kuijpers, Taco W., van der Flier, Michiel, and von Both, Ulrich

Published
2023
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9. Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Author

Abdulla, Amina, Aebi, Christoph, van Aerde, Koen, Agbeko, Rachel, Agyeman, Philipp, D’alessandro, Umberto, Ali, Ladan, Alkema, Wynand, Allen, Karen, González, Fernando Álvez, Anderson, Suzanne, Ansari, Imran, Araf, Tasnim, Avramoska, Tanja, Baas, Bryan, Bahovec, Natalija, Farto, Cristina Balo, Balode, Anda, Barendregt, A.M., Barral-Arca, Ruth, Castro, María Barreiro, Bārzdiņa, Arta, Bath, David, Bauchinger, Sebastian, Baumard, Lucas, Baumgart, Hinrich, Baxter, Frances, Bell, Ashley, Bell, Kathryn, Bello, Xabier, Bellos, Evangelos, Benesch, Martin, Ben García, Mirian, Bennet, Joshua, Berger, Christoph, van den Berg, J.M., Bernhard-Stirnemann, Sara, Bibi, Sagida, Bidlingmaier, Christoph, Binder, Alexander, Binder, Vera, Bojang, Kalifa, Borensztajn, Dorine M., von Both, Ulrich, Brengel-Pesce, Karen, van den Broek, Bryan, Buschbeck, Judith, Calvo-Bado, Leo, Carnota, Sandra, Carrol, Enitan D., Carter, Michael J., Cebey-López, Miriam, Ceesay, Samba, Ceolotto, Astrid, Chan, Adora, Cocklin, Elizabeth, Collings, Kalvin, Crulley, Stephen, Cunnington, Aubrey, Curras-Tuala, María José, Danhauser, Katharina, Darboe, Saffiatou, Darnell, Sarah, De, Tisham, Deksne, Dārta, Devine, Kirsty, Dewez, Juan Emmanuel, Dudley, Julia, Suárez, Carlos Durán, Eber, Ernst, Eleftheriou, Irini, Emonts, Marieke, Fabian, Daniel, Feuchtinger, Tobias, Fidler, Katy, Fink, Colin, van der Flier, Michiel, van Furth, A.M., Galassini, Rachel, Gallistl, Siegfried, Vicente, Luisa García, Gardovska, Dace, Geissler, J., Gerrits, G.P.J.M., Giannoni, Eric, van der Giessen, Ilona, Gloerich, Jolein, Gómez-Carballa, Alberto, Rial, Jose Gómez, van Gool, Alain J., Gores, Gunther, Grāvele, Dagne, Griese, Matthias, Grope, Ilze, de Groot, Ronald, Gurung, Meeru, de Haan, L., Haas, Nikolaus, Habgood-Coote, Dominic, Hagedoorn, Nienke N., Haidl, Harald, Hamilton, Shea, Hauer, Almuthe, Heidema, J., Heininger, Ulrich, Henriet, Stefanie, Herberg, Jethro, Hoggart, Clive, Hösele, Susanne, Hourmat, Sara, Hude, Christa, Huijnen, Martijn, Jackson, Heather, Jennings, Rebecca, Johnston, Joanne, de Jonge, Marien I., Jongerius, Ilse, Jorgensen, Rikke, Kaforou, Myrsini, Kahlert, Christian, Kandasamy, Rama, Kappler, Matthias, Keil, Julia, Keldorfer, Markus, Kell, Dominic F., Kim, Eunjung, King, Sharon, Kloosterhuis, Lieke, Kohlfürst, Daniela S., Kohlmaier, Benno, Kolberg, Laura, Kolnik, Mojca, Krenn, Larissa, Kuijpers, Taco, van der Kuip, M., Iglesias, Pilar Leboráns, Leigh, Simon, Leitner, Manuel, van Leur, M., Lim, Emma, Lin, Naomi, Liu, Ching-Chuan, Löffler, Sabine, Lurz, Eberhard, Maconochie, Ian, Mackerness, Christine, Mallet, François, Martinón-Torres, Federico, Marmarinos, Antonis, Martin, Alex, Martin, Mike, Martinón Sánchez, José María, Martinón-Torres, Nazareth, McAlinden, Paul, McDonnell, Anne, McDonald, Sam, Miedema, C.J., Meiere, Anija, Menikou, Stephanie, van Mierlo, G., Miners, Alec, Mistry, Ravi, Moll, Henriëtte A., Mommert, Marine, Pérez, Belén Mosquera, Murdoch, David R., Mustafa, Sobia, Natalucci, Giancarlo, Neeleman, C., Newall, Karen, Nichols, Samuel, Niedrist, Tobias, Niederer-Loher, Anita, Nijman, Ruud, Nokalna, Ieva, Urbāne, Urzula Nora, Nordberg, Gudrun, Obihara, C.C., O'Connor, Daniel, Oosthoek, Wilma, Osterman, Veronika, Pachot, Alexandre, Pajkrt, D., Pardo-Seco, Jacobo, Paulus, Stéphane, Pavāre, Jana, Paz, Ivonne Pena, Persand, Salina, Pfleger, Andreas, Pfurtscheller, Klaus, Philipsen, Ria, Pickering, Ailsa, Pierce, Benjamin, Pilch, Heidemarie, Rodríguez, Lidia Piñeiro, Pischedda, Sara, Srovin, Tina Plankar, Pokorn, Marko, Pollard, Andrew J., Pölz, Lena, Posfay-Barbe, Klara M., Prunk, Petra, Pučuka, Zanda, Rajic, Glorija, Rashid, Aqeela, Redondo-Collazo, Lorenzo, Relly, Christa, Calle, Irene Rivero, Vázquez, Sara Rey, Rhodes, Mathew, Richmond, Vivien, Riedel, Thomas, RocaIsatou Sarr, Anna, Rödl, Siegfried, Rodríguez-Tenreiro, Carmen, Romaine, Sam, Rowlands, Emily, Ora, Miguel Sadiki, Sagmeister, Manfred G., Saidykhan, Momodou, Salas, Antonio, Schlapbach, Luregn J., Schonenberg, D., Secka, Fatou, Selecka, Katrīna, Fernández, Sonia Serén, Trasorras, Cristina Serén, Shah, Priyen, Shen, Ching-Fen, Shrestha, Shrijana, Sidorova, Aleksandra, Skrabl-Baumgartner, Andrea, D’Souza, Giselle, Sperl, Matthias, Sprenkeler, Evelien, Schweintzger, Nina A., Stampfer, Laura, Stevens, Molly, Stocker, Martin, Strenger, Volker, Svile, Dace, Syggelou, Kelly, Tambouratzi, Maria, Tan, Chantal, Tavliavini, Emma, Thomson, Evelyn, Thorson, Stephen, Till, Holger, Tramper-Stranders, G.A., Trobisch, Andreas, Tsolia, Maria, Usuf, Effua, Valentine, Lucille, Vermont, Clementien L., Iglesias, Marisol Vilas, Vincek, Katarina, Voice, Marie, de Vries, Gabriella, Wallia, Diane, Wang, Shih-Min, Willems, Esther, Wilson, Clare, Wood, Amanda, Woodsford, Phil, Wright, Victoria, Xagorari, Marietta, Yeung, Shunmay, Zachariasse, Joany, Zavadska, Dace, Zaman, Syed M.A., Zandstra, Judith, Zenz, Werner, Zurl, Christoph, Zwerenz, Manuela, Suppers, Anouk, van den Heuvel, Lambert P., van de Kar, Nicole, Philipsen, Ria H.L.A., van Dael, Maurice, Wright, Victoria J., Herberg, Jethro A., Torres, Federico Martinon, Levin, Michael, Lefeber, Dirk J., and Wessels, Hans J.C.T.

Published
2023
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10. Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood

Author

Zandstra, Judith, van de Geer, Annemarie, Tanck, Michael WT, van Stijn-Bringas Dimitriades, Diana, Aarts, Cathelijn EM, Dietz, Sanne M, van Bruggen, Robin, Schweintzger, Nina A, Zenz, Werner, Emonts, Marieke, Zavadska, Dace, Pokorn, Marko, Usuf, Effua, Moll, Henriette A, Schlapbach, Luregn J, Carrol, Enitan D, Paulus, Stephane, Tsolia, Maria, Fink, Colin, Yeung, Shunmay, Shimizu, Chisato, Tremoulet, Adriana, Galassini, Rachel, Wright, Victoria J, Martinón-Torres, Federico, Herberg, Jethro, Burns, Jane, Levin, Michael, Kuijpers, Taco W, and Consortium, PERFORM Consortium and UK Kawasaki Disease Genetics Study Network EUCLIDS

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Infectious Diseases, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Infection, Inflammatory and immune system, Good Health and Well Being, kawasaki disease, infectious disease, vasculitis, coronary aneurysm, biomarker, bacterial infection, viral infection, EUCLIDS Consortium, PERFORM Consortium and UK Kawasaki Disease Genetics Study Network, Paediatrics and Reproductive Medicine, Other Medical and Health Sciences, Paediatrics
Abstract

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

Published
2020

13. Febrile children with comorbidities at the emergency department — a multicentre observational study

Author

Borensztajn, Dorine M., Hagedoorn, Nienke N., Carrol, Enitan D., von Both, Ulrich, Emonts, Marieke, van der Flier, Michiel, de Groot, Ronald, Herberg, Jethro, Kohlmaier, Benno, Levin, Michael, Lim, Emma, Maconochie, Ian K., Martinon-Torres, Federico, Nijman, Ruud G., Pokorn, Marko, Rivero-Calle, Irene, Tsolia, Maria, van der Velden, Fabian J. S., Vermont, Clementien, Zavadska, Dace, Zenz, Werner, Zachariasse, Joany M., and Moll, Henriette A.

Published
2022
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17. Antibiotic prescription for febrile children in European emergency departments: a cross-sectional, observational study

Author

Moll, Henriette A., Oostenbrink, Rianne, van Veen, Mirjam, Noordzij, Jeroen G., Smit, Frank, van Wermeskerken, Anne-Marie, Angoulvant, Francois, Dubos, Francois, Gras-Leguen, Christele, Desmarest, Marie, Aurel, Marie, Gajdos, Vincent, Joffre, Christelle, Mintegi, Santiago, Acedo, Yordana, Herrero Garcia, Laura, Medina, Inmaculada, Cózar, Juan Alonso, Fernandez Arribas, Jose Luis, Pinto, Sara, Sá, Gabriela, Mação, Patrícia, Silva, Daniela, Zarcos, Maria, Seiler, Michelle, Gervaix, Alain, Maconochie, Ian, Olesen, Hanne, Bønnelykke, Christiane, Parri, Niccolò, Fichera, Vito, Arrhigini, Alberto, Bressan, Silvia, Da Dalt, Liviana, Moldovan, Diana, Dreghiciu, Daniela-Maria, Bognar, Zsolt, Yilmaz, Hayri L., Sari Gökay, Sinem, van de Maat, Josephine, van de Voort, Elles, Nieboer, Daan, and Moll, Henriette

Published
2019
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19. Bone health in children with Angelman syndrome at the ENCORE Expertise Center

Author

Bindels-de Heus, Karen G.C.B., Hagenaar, Doesjka A., Mous, Sabine E., Dekker, Ilonka, van der Kaay, Daniëlle C.M., Kerkhof, Gerthe F., Elgersma, Ype, Moll, Henriette A., de Wit, Marie Claire Y., Bindels-de Heus, Karen G.C.B., Hagenaar, Doesjka A., Mous, Sabine E., Dekker, Ilonka, van der Kaay, Daniëlle C.M., Kerkhof, Gerthe F., Elgersma, Ype, Moll, Henriette A., and de Wit, Marie Claire Y.

Abstract

Angelman syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD), or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are observed frequently in our clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. In this prospective cohort study, we describe bone health in 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the bone health index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication use, mobility, body mass index (BMI), and onset of puberty. Children with AS had a mean BHI of −1.77 SDS (SD 1.4). A significantly lower BHI was found in children with a deletion (−2.24 SDS) versus non-deletion (−1.02 SDS). Other factors associated with reduced BHI-SDS were inability to walk and late onset of puberty. Children with a history of one or more fractures (22%) had a significantly lower BHI than children without fractures (−2.60 vs −1.56 SDS). Longitudinal analysis showed a significant decrease in BHI-SDS with age in all genetic subtypes. Conclusions: Children with AS have a reduced bone health. Risk factors are deletion genotype, no independent walking, and late onset of puberty. Bone health decreased significantly with age. (Table presented.)

Published
2024

20. Which low urgent triaged febrile children are suitable for a fast track? An observational European study

Author

Tan, Chantal D., Vermont, Clementien L., Zachariasse, Joany M., von Both, Ulrich, Carrol, Enitan D., Eleftheriou, Irini, Emonts, Marieke, van der Flier, Michiel, Herberg, Jethro, Kohlmaier, Benno, Levin, Michael, Lim, Emma, Maconochie, Ian K., Martinon-Torres, Federico, Nijman, Ruud G., Pokorn, Marko, Rivero-Calle, Irene, Rudzāte, Aleksandra, Tsolia, Maria, Zenz, Werner, Zavadska, Dace, Moll, Henriette A., Tan, Chantal D., Vermont, Clementien L., Zachariasse, Joany M., von Both, Ulrich, Carrol, Enitan D., Eleftheriou, Irini, Emonts, Marieke, van der Flier, Michiel, Herberg, Jethro, Kohlmaier, Benno, Levin, Michael, Lim, Emma, Maconochie, Ian K., Martinon-Torres, Federico, Nijman, Ruud G., Pokorn, Marko, Rivero-Calle, Irene, Rudzāte, Aleksandra, Tsolia, Maria, Zenz, Werner, Zavadska, Dace, and Moll, Henriette A.

Abstract

Background:The number of paediatric patients visiting the ED with non-urgent problems is increasing, leading to poor patient flow and ED crowding. Fast track aims to improve the efficiency of evaluation and discharge of low acuity patients. We aimed to identify which febrile children are suitable for a fast track based on presenting symptoms and management. Methods:This study is part of the Management and Outcome of Fever in children in Europe study, which is an observational study including routine data of febrile children <18 years attending 12 European EDs. We included febrile, low urgent children (those assigned a triage acuity of either’standard’ or’non-urgent’ using the Manchester Triage System) and defined children as suitable for fast track when they have minimal resource use and are discharged home. Presenting symptoms consisted of neurological (n=237), respiratory (n=8476), gastrointestinal (n=1953) and others (n=3473, reference group). Multivariable logistic regression analyses regarding presenting symptoms and management (laboratory blood testing, imaging and admission) were performed with adjustment for covariates: patient characteristics, referral status, previous medical care, previous antibiotic use, visiting hours and ED setting. Results:We included 14 139 children with a median age of 2.7 years (IQR 1.3–5.2). The majority had respiratory symptoms (60%), viral infections (50%) and consisted of self-referrals (69%). The neurological group received imaging more often (adjusted OR (aOR) 1.8, 95% CI 1.1 to 2.9) and were admitted more frequently (aOR 1.9, 95% CI 1.4 to 2.7). The respiratory group had fewer laboratory blood tests performed (aOR 0.6, 95% CI 0.5 to 0.7), were less frequently admitted (aOR 0.6, 95% CI 0.5 to 0.7), but received imaging more often (aOR 1.8, 95% CI 1.6 to 2.0). Lastly, the gastrointestinal group had more laboratory blood tests performed (aOR 1.2. 95% CI 1.1 to 1.4) a

Published
2024

21. Which low urgent triaged febrile children are suitable for a fast track? An observational European study

Author

Infectieziekten patientenzorg, Child Health, Infection & Immunity, Tan, Chantal D., Vermont, Clementien L., Zachariasse, Joany M., Von Both, Ulrich, Carrol, Enitan D., Eleftheriou, Irini, Emonts, Marieke, Van Der Flier, Michiel, Herberg, Jethro, Kohlmaier, Benno, Levin, Michael, Lim, Emma, Maconochie, Ian K., Martinon-Torres, Federico, Nijman, Ruud G., Pokorn, Marko, Rivero-Calle, Irene, RudzÄa Te, Aleksandra, Tsolia, Maria, Zenz, Werner, Zavadska, Dace, Moll, Henriette A., Infectieziekten patientenzorg, Child Health, Infection & Immunity, Tan, Chantal D., Vermont, Clementien L., Zachariasse, Joany M., Von Both, Ulrich, Carrol, Enitan D., Eleftheriou, Irini, Emonts, Marieke, Van Der Flier, Michiel, Herberg, Jethro, Kohlmaier, Benno, Levin, Michael, Lim, Emma, Maconochie, Ian K., Martinon-Torres, Federico, Nijman, Ruud G., Pokorn, Marko, Rivero-Calle, Irene, RudzÄa Te, Aleksandra, Tsolia, Maria, Zenz, Werner, Zavadska, Dace, and Moll, Henriette A.

Published
2024

22. Which low urgent triaged febrile children are suitable for a fast track? An observational European study

Author

Tan, Chantal D, primary, Vermont, Clementien L, additional, Zachariasse, Joany M, additional, von Both, Ulrich, additional, Carrol, Enitan D, additional, Eleftheriou, Irini, additional, Emonts, Marieke, additional, van der Flier, Michiel, additional, Herberg, Jethro, additional, Kohlmaier, Benno, additional, Levin, Michael, additional, Lim, Emma, additional, Maconochie, Ian K, additional, Martinon-Torres, Federico, additional, Nijman, Ruud G, additional, Pokorn, Marko, additional, Rivero-Calle, Irene, additional, Rudzāte, Aleksandra, additional, Tsolia, Maria, additional, Zenz, Werner, additional, Zavadska, Dace, additional, and Moll, Henriette A, additional

Published
2024
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24. Presentations of children to emergency departments across Europe and the COVID-19 pandemic: A multinational observational study

Author

Nijman, Ruud G., Honeyford, Kate, Farrugia, Ruth, Rose, Katy, Bognar, Zsolt, Buonsenso, Danilo, Da Dalt, Liviana, De, Tisham, Maconochie, Ian K., Parri, Niccolo, Roland, Damian, Alfven, Tobias, Aupiais, Camille, Barrett, Michael, Basmaci, Romain, Borensztajn, Dorine, Castanhinha, Susana, Vasilico, Corrine, Durnin, Sheena, Fitzpatrick, Paddy, Fodor, Laszlo, Gomez, Borja, Greber-Platzer, Susanne, Guedj, Romain, Hartshorn, Stuart, Hey, Florian, Jankauskaite, Lina, Kohlfuerst, Daniela, Kolnik, Mojca, Lyttle, Mark D., Mação, Patrícia, Mascarenhas, Maria Inês, Messahel, Shrouk, Özkan, Esra Akyüz, Pucuka, Zanda, Reis, Sofia, Rybak, Alexis, Ryd Rinder, Malin, Teksam, Ozlem, Turan, Caner, Thors, Valtýr Stefánsson, Velasco, Roberto, Bressan, Silvia, Moll, Henriette A., Oostenbrink, Rianne, and Titomanlio, Luigi

Subjects
Epidemics -- Influence, Pediatric emergencies -- Forecasts and trends, Market trend/market analysis, Biological sciences
Abstract

Background During the initial phase of the Coronavirus Disease 2019 (COVID-19) pandemic, reduced numbers of acutely ill or injured children presented to emergency departments (EDs). Concerns were raised about the potential for delayed and more severe presentations and an increase in diagnoses such as diabetic ketoacidosis and mental health issues. This multinational observational study aimed to study the number of children presenting to EDs across Europe during the early COVID-19 pandemic and factors influencing this and to investigate changes in severity of illness and diagnoses. Methods and findings Routine health data were extracted retrospectively from electronic patient records of children aged 18 years and under, presenting to 38 EDs in 16 European countries for the period January 2018 to May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRRs), using predicted counts for each site as offset to adjust for case-mix differences, were used to compare age groups, diagnoses, and outcomes. Reductions in pediatric ED attendances, hospital admissions, and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (IRR 2·26, 95% CI 1·90 to 2·70, p < 0.001) and in children aged Conclusions Reductions in ED attendances were seen across Europe during the first COVID-19 lockdown period. More severely ill children continued to attend hospital more frequently compared to those with minor injuries and illnesses, although absolute numbers fell. Trial registration ISRCTN91495258 https://www.isrctn.com/ISRCTN91495258., Author(s): Ruud G. Nijman 1,2,3,*, Kate Honeyford 4, Ruth Farrugia 5, Katy Rose 1,6, Zsolt Bognar 7, Danilo Buonsenso 8,9, Liviana Da Dalt 10, Tisham De 2, Ian K. Maconochie [...]

Published
2022
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27. Rapid Viral Testing and Antibiotic Prescription in Febrile Children With Respiratory Symptoms Visiting Emergency Departments in Europe

Author

Tan, Chantal D., Hagedoorn, Nienke N., Dewez, Juan E., Borensztajn, Dorine M., von Both, Ulrich, Carrol, Enitan D., Emonts, Marieke, van der Flier, Michiel, de Groot, Ronald, Herberg, Jethro, Kohlmaier, Benno, Levin, Michael, Lim, Emma, Maconochie, Ian K., Martinon-Torres, Federico, Nijman, Ruud G., Pokorn, Marko, Rivero-Calle, Irene, Strle, Franc, Tsolia, Maria, Vermont, Clementien L., Yeung, Shunmay, Zachariasse, Joany M., Zenz, Werner, Zavadska, Dace, and Moll, Henriette A.

Published
2022
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29. Raising AWaRe-ness of Antimicrobial Stewardship Challenges in Pediatric Emergency Care: Results from the PERFORM Study Assessing Consistency and Appropriateness of Antibiotic Prescribing Across Europe.

Author

Kolberg, Laura, Khanijau, Aakash, Velden, Fabian J S van der, Herberg, Jethro, De, Tisham, Galassini, Rachel, Cunnington, Aubrey J, Wright, Victoria J, Shah, Priyen, Kaforou, Myrsini, Wilson, Clare, Kuijpers, Taco, Martinón-Torres, Federico, Rivero-Calle, Irene, Moll, Henriette, Vermont, Clementien, Pokorn, Marko, Kolnik, Mojca, Pollard, Andrew J, and Agyeman, Philipp K A

Subjects
ANTIBIOTICS, THIRD generation cephalosporins, MEDICAL prescriptions, RESEARCH funding, ANTIMICROBIAL stewardship, SCIENTIFIC observation, EMERGENCY medical services, HOSPITAL emergency services, FEVER, DESCRIPTIVE statistics, PEDIATRICS, LONGITUDINAL method, PHYSICIAN practice patterns, RESEARCH, DRUG prescribing, BACTERIAL diseases, VIRUS diseases, BETA lactamases, PHENOTYPES, PENICILLIN
Abstract

Background Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing. Methods Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification. Results Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/β-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category. Conclusions Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship. [ABSTRACT FROM AUTHOR]

Published
2024
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42. Diversity, compositional and functional differences between gut microbiota of children and adults

Author

Radjabzadeh, Djawad, Boer, Cindy G., Beth, Sanne A., van der Wal, Pelle, Kiefte-De Jong, Jessica C., Jansen, Michelle A. E., Konstantinov, Sergey R., Peppelenbosch, Maikel P., Hays, John P., Jaddoe, Vincent W. V., Ikram, M. Arfan, Rivadeneira, Fernando, van Meurs, Joyce B. J., Uitterlinden, André G., Medina-Gomez, Carolina, Moll, Henriette A., and Kraaij, Robert

Published
2020
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46. Are children with prolonged fever at a higher risk for serious illness? A prospective observational study

Author

Nijman, Ruud G, primary, Tan, Chantal D, additional, Hagedoorn, Nienke N, additional, Nieboer, Daan, additional, Herberg, Jethro Adam, additional, Balode, Anda, additional, von Both, Ulrich, additional, Carrol, Enitan D, additional, Eleftheriou, Irini, additional, Emonts, Marieke, additional, van der Flier, Michiel, additional, de Groot, Ronald, additional, Kohlmaier, Benno, additional, Lim, Emma, additional, Martinón-Torres, Federico, additional, Pokorn, Marko, additional, Strle, Franc, additional, Tsolia, Maria, additional, Yeung, Shunmay, additional, Zachariasse, Joany M, additional, Zavadska, Dace, additional, Zenz, Werner, additional, Levin, Michael, additional, Vermont, Clementien L, additional, Moll, Henriette A, additional, and Maconochie, Ian K, additional

Published
2023
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47. A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM):a multi-cohort machine learning study

Author

Jackson, Heather R., Zandstra, Judith, Menikou, Stephanie, Hamilton, Melissa Shea, McArdle, Andrew J., Fischer, Roman, Thorne, Adam M., Huang, Honglei, Tanck, Michael W., Jansen, Machiel H., De, Tisham, Agyeman, Philipp K.A., Von Both, Ulrich, Carrol, Enitan D., Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, Gloerich, Jolein, De Groot, Ronald, Moll, Henriette A., Pokorn, Marko, Pollard, Andrew J., Schlapbach, Luregn J., Tsolia, Maria N., Usuf, Effua, Wright, Victoria J., Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Casals-Pascual, Climent, Cunnington, Aubrey J., Martinon-Torres, Federico, Herberg, Jethro A., de Jonge, Marien I., Levin, Michael, Kuijpers, Taco W., Kaforou, Myrsini, Jackson, Heather R., Zandstra, Judith, Menikou, Stephanie, Hamilton, Melissa Shea, McArdle, Andrew J., Fischer, Roman, Thorne, Adam M., Huang, Honglei, Tanck, Michael W., Jansen, Machiel H., De, Tisham, Agyeman, Philipp K.A., Von Both, Ulrich, Carrol, Enitan D., Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, Gloerich, Jolein, De Groot, Ronald, Moll, Henriette A., Pokorn, Marko, Pollard, Andrew J., Schlapbach, Luregn J., Tsolia, Maria N., Usuf, Effua, Wright, Victoria J., Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Casals-Pascual, Climent, Cunnington, Aubrey J., Martinon-Torres, Federico, Herberg, Jethro A., de Jonge, Marien I., Levin, Michael, Kuijpers, Taco W., and Kaforou, Myrsini

Abstract

BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS:376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma sample

Published
2023

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

Author

Jackson, Heather R., Miglietta, Luca, Habgood-Coote, Dominic, D'souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp K.A., Beudeker, Coco R., Brengel-Pesce, Karen, Carrol, Enitan D., Carter, Michael J., De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, Van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J., Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J., Tremoulet, Adriana H., Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Cunnington, Aubrey, Burns, Jane C., Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A., Rodriguez-Manzano, Jesus, Kaforou, Myrsini, Levin, Michael, Jackson, Heather R., Miglietta, Luca, Habgood-Coote, Dominic, D'souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp K.A., Beudeker, Coco R., Brengel-Pesce, Karen, Carrol, Enitan D., Carter, Michael J., De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, Van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J., Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J., Tremoulet, Adriana H., Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Cunnington, Aubrey, Burns, Jane C., Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A., Rodriguez-Manzano, Jesus, Kaforou, Myrsini, and Levin, Michael

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.

Published
2023

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

Author

Shah, Priyen, Voice, Marie, Calvo-Bado, Leonides, Rivero-Calle, Irene, Morris, Sophie, Nijman, Ruud, Broderick, Claire, De, Tisham, Eleftheriou, Irini, Galassini, Rachel, Khanijau, Aakash, Kolberg, Laura, Kolnik, Mojca, Rudzate, Aleksandra, Sagmeister, Manfred, Schweintzger, Nina, Secka, Fatou, Thakker, Clare, van der Velden, Fabian, Vermont, Clementien, Vincek, Katarina, Agyeman, Philipp K.A., Cunnington, Aubrey J., De Groot, Ronald, Emonts, Marieke, Fidler, Katy, Kuijpers, Taco, Mommert-Tripon, Marine, Brengel-Pesce, Karen, Mallet, Francois, Moll, Henriette, Paulus, Stéphane, Pokorn, Marko, Pollard, Andrew, van der Flier, Michiel, Borensztajn, Dorine M., Hagedoorn, Nienke N., Zachariasse, Joany, Dik, W., Stocker, Martin, Willems, Esther, De Haan, L., Neeleman, C., Tramper-Stranders, G. A., Baas, Bryan, Kloosterhuis, Lieke, Oosthoek, Wilma, De Vries, Gabriella, van den Berg, J. M., Barendregt, A. M., Shah, Priyen, Voice, Marie, Calvo-Bado, Leonides, Rivero-Calle, Irene, Morris, Sophie, Nijman, Ruud, Broderick, Claire, De, Tisham, Eleftheriou, Irini, Galassini, Rachel, Khanijau, Aakash, Kolberg, Laura, Kolnik, Mojca, Rudzate, Aleksandra, Sagmeister, Manfred, Schweintzger, Nina, Secka, Fatou, Thakker, Clare, van der Velden, Fabian, Vermont, Clementien, Vincek, Katarina, Agyeman, Philipp K.A., Cunnington, Aubrey J., De Groot, Ronald, Emonts, Marieke, Fidler, Katy, Kuijpers, Taco, Mommert-Tripon, Marine, Brengel-Pesce, Karen, Mallet, Francois, Moll, Henriette, Paulus, Stéphane, Pokorn, Marko, Pollard, Andrew, van der Flier, Michiel, Borensztajn, Dorine M., Hagedoorn, Nienke N., Zachariasse, Joany, Dik, W., Stocker, Martin, Willems, Esther, De Haan, L., Neeleman, C., Tramper-Stranders, G. A., Baas, Bryan, Kloosterhuis, Lieke, Oosthoek, Wilma, De Vries, Gabriella, van den Berg, J. M., and Barendregt, A. M.

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

Published
2023

50. Hyperphagia, Growth, and Puberty in Children with Angelman Syndrome

Author

Bindels-de Heus, Karen G.C.B., Hagenaar, Doesjka A., Dekker, Ilonka, van der Kaay, Danielle C.M., Kerkhof, Gerthe F., Elgersma, Ype, de Wit, Marie Claire Y., Mous, Sabine E., Moll, Henriette A., Bindels-de Heus, Karen G.C.B., Hagenaar, Doesjka A., Dekker, Ilonka, van der Kaay, Danielle C.M., Kerkhof, Gerthe F., Elgersma, Ype, de Wit, Marie Claire Y., Mous, Sabine E., and Moll, Henriette A.

Abstract

Angelman Syndrome (AS) is a rare genetic disorder caused by lack of maternal UBE3A protein due to a deletion of the chromosome 15q11.2-q13 region, uniparental paternal disomy, imprinting center defect, or pathogenic variant in the UBE3A gene. Characteristics are developmental delay, epilepsy, behavioral, and sleep problems. There is some evidence for hyperphagia, shorter stature, and higher BMI compared to neurotypical children, but longitudinal studies on growth are lacking. In this study, we analyzed prospectively collected data of 145 children with AS, who visited the ENCORE Expertise Center between 2010 and 2021, with a total of 853 visits. Children showed an elevated mean score of 25 on the Dykens Hyperphagia questionnaire (range 11–55) without genotype association. Higher scores were significantly associated with higher body mass index (BMI) standard deviation scores (SDS) (p = 0.004). Mean height was −1.2 SDS (SD 1.3), mean BMI-SDS was 0.6 (SD 1.7); 43% had a BMI-SDS > 1 and 20% had a BMI-SDS > 2. Higher BMI-SDS was significantly associated with non-deletion genotype (p = 0.037) and walking independently (p = 0.023). Height SDS decreased significantly with age (p < 0.001) and BMI-SDS increased significantly with age (p < 0.001. Onset of puberty was normal. In conclusion, children with AS showed moderate hyperphagia, lower height SDS, and higher BMI-SDS compared to norm data, with increasing deviation from the norm with age. It is uncertain how loss of maternal UBE3A function may influence growth. Attention to diet, exercise, and hyperphagia from an early age is recommended to prevent obesity and associated health problems.

Published
2023

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