Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study
Authors: Luregn J Schlapbach, Devika Ganesamoorthy, Clare Wilson, Sainath Raman, Shane George, Peter J Snelling, Natalie Phillips, Adam Irwin, Natalie Sharp, Renate Le Marsney, Arjun Chavan, Allison Hempenstall, Seweryn Bialasiewicz, Anna D MacDonald, Keith Grimwood, Jessica C Kling, Stephen J McPherson, Antje Blumenthal, Myrsini Kaforou, Michael Levin, Jethro A Herberg, Kristen S Gibbons, Lachlan J M Coin, Michael Levin, Lachlan Coin, Stuart Gormley, Shea Hamilton, Clive Hoggart, Myrsini Kaforou, Vanessa Sancho-Shimizu, Victoria Wright, Amina Abdulla, Paul Agapow, Maeve Bartlett, Hariklia Eleftherohorinou, Rachel Galassini, David Inwald, Meg Mashbat, Stephanie Menikou, Sobia Mustafa, Simon Nadel, Rahmeen Rahman, Hannah Shailes, Clare Thakker, S. Bokhandi, Sue Power, Heather Barham, N. Pathan, Jenna Ridout, Deborah White, Sarah Thurston, S. Faust, S. Patel, Jenni McCorkell, P. Davies, Lindsey Crate, Helen Navarra, Stephanie Carter, R. Ramaiah, Rekha Patel, Catherine Tuffrey, Andrew Gribbin, Sharon McCready, Mark Peters, Katie Hardy, Fran Standing, Lauren O'Neill, Eugenia Abelake, Akash Deep, Eniola Nsirim, Andrew Pollard, Louise Willis, Zoe Young, C. Royad, Sonia White, Peter-Marc Fortune, Phil Hudnott, Federico Martinón-Torres, Antonio Salas, Fernando Álvez González, Ruth Barral-Arca, Miriam Cebey-López, María José Curras-Tuala, Natalia García, Luisa García Vicente, Alberto Gómez-Carballa, Jose Gómez Rial, Andrea Grela Beiroa, Antonio Justicia Grande, Pilar Leboráns Iglesias, Alba Elena Martínez Santos, Nazareth Martinón-Torres, José María Martinón Sánchez, Beatriz Morillo Gutiérrez, Belén Mosquera Pérez, Pablo Obando Pacheco, Jacobo Pardo-Seco, Sara Pischedda, Irene Rivero-Calle, Carmen Rodríguez-Tenreiro, Lorenzo Redondo-Collazo, Antonio Salas Ellacuriaga, Sonia Serén Fernández, María del Sol Porto Silva, Ana Vega, Lucía Vilanova Trillo, Susana Beatriz Reyes, María Cruz León León, Álvaro Navarro Mingorance, Xavier Gabaldó Barrio, Eider Oñate Vergara, Andrés Concha Torre, Ana Vivanco, Reyes Fernández, Francisco Giménez Sánchez, Miguel Sánchez Forte, Pablo Rojo, J. Ruiz Contreras, Alba Palacios, Cristina Epalza Ibarrondo, Elizabeth Fernández Cooke, Marisa Navarro, Cristina Álvarez Álvarez, María José Lozano, Eduardo Carreras, Sonia Brió Sanagustín, Olaf Neth, Mª del Carmen Martínez Padilla, Luis Manuel Prieto Tato, Sara Guillén, Laura Fernández Silveira, David Moreno, R. de Groot, A.M. Tutu van Furth, M. van der Flier, N.P. Boeddha, G.J.A. Driessen, M. Emonts, J.A. Hazelzet, T.W. Kuijpers, D. Pajkrt, E.A.M. Sanders, D. van de Beek, A. van der Ende, H.L.A. Philipsen, A.O.A. Adeel, M.A. Breukels, D.M.C. Brinkman, C.C.M.M. de Korte, E. de Vries, W.J. de Waal, R. Dekkers, A. Dings-Lammertink, R.A. Doedens, A.E. Donker, M. Dousma, T.E. Faber, G.P.J.M. Gerrits, J.A.M. Gerver, J. Heidema, J. Homan-van der Veen, M.A.M. Jacobs, N.J.G. Jansen, P. Kawczynski, K. Klucovska, M.C.J. Kneyber, Y. Koopman-Keemink, V.J. Langenhorst, J. Leusink, B.F. Loza, I.T. Merth, C.J. Miedema, C. Neeleman, J.G. Noordzij, C.C. Obihara, A.L.T. van Overbeek- van Gils, G.H. Poortman, S.T. Potgieter, J. Potjewijd, P.P.R. Rosias, T. Sprong, G.W. ten Tussher, B.J. Thio, G.A. Tramper-Stranders, M. van Deuren, H. van der Meer, A.J.M. van Kuppevelt, A.M. van Wermeskerken, W.A. Verwijs, T.F.W. Wolfs, Luregn J. Schlapbach, Philipp Agyeman, Christoph Aebi, Eric Giannoni, Martin Stocker, Klara M. Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian Kahlert, Paul Hasters, Christa Relly, Walter Baer, Christoph Berger, Enitan D. Carrol, Stéphane Paulus, Hannah Frederick, Rebecca Jennings, Joanne Johnston, Rhian Kenwright, Colin G Fink, Elli Pinnock, Marieke Emonts, Rachel Agbeko, Suzanne Anderson, Fatou Secka, Kalifa Bojang, Isatou Sarr, Ngange Kebbeh, Gibbi Sey, Momodou Saidykhan, Fatoumata Cole, Gilleh Thomas, Martin Antonio, Werner Zenz, Daniela S. Kohlfürst, Alexander Binder, Nina A. Schweintzger, Manfred Sagmeister, Hinrich Baumgart, Markus Baumgartner, Uta Behrends, Ariane Biebl, Robert Birnbacher, Jan-Gerd Blanke, Carsten Boelke, Kai Breuling, Jürgen Brunner, Maria Buller, Peter Dahlem, Beate Dietrich, Ernst Eber, Johannes Elias, Josef Emhofer, Rosa Etschmaier, Sebastian Farr, Ylenia Girtler, Irina Grigorow, Konrad Heimann, Ulrike Ihm, Zdenek Jaros, Hermann Kalhoff, Wilhelm Kaulfersch, Christoph Kemen, Nina Klocker, Bernhard Köster, Benno Kohlmaier, Eleni Komini, Lydia Kramer, Antje Neubert, Daniel Ortner, Lydia Pescollderungg, Klaus Pfurtscheller, Karl Reiter, Goran Ristic, Siegfried Rödl, Andrea Sellner, Astrid Sonnleitner, Matthias Sperl, Wolfgang Stelzl, Holger Till, Andreas Trobisch, Anne Vierzig, Ulrich Vogel, Christina Weingarten, Stefanie Welke, Andreas Wimmer, Uwe Wintergerst, Daniel Wüller, Andrew Zaunschirm, Ieva Ziuraite, Veslava Žukovskaja, Martin L. Hibberd, Sonia Davila, Isabel Delany, Luregn J Schlapbach, Sainath Raman, Nathalie Sharp, Natalie Phillips, Adam Irwin, Ross Balch, Amanda Harley, Kerry Johnson, Zoe Sever, Shane George, Keith Grimwood, Peter J Snelling, Arjun Chavan, Eleanor Kitcatt, Luke Lawton, Allison Hempenstall, Pelista Pilot, Kristen S Gibbons, Renate Le Marsney, Antje Blumenthal, Devika Ganesamoorthy, Carolyn Pardo, Jessica Kling, Stephen McPherson, Anna D MacDonald, Seweryn Bialasiewicz, Trang Pham, Lachlan Coin
Journal: The Lancet Child & Adolescent Health (2024)

Background Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection. Methods This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI. Findings Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease class signature that achieved an AUC of 94·1% (95% CI 90·6–97·7) in distinguishing bacterial from viral infections in the RAPIDS validation cohort. A ten-gene disease severity signature achieved an AUC of 82·2% (95% CI 76·3–88·1) in predicting organ dysfunction within 24 h of sampling in the RAPIDS validation cohort. Used in tandem, the disease class and disease severity signatures predicted organ dysfunction within 24 h of sampling with an AUC of 90·5% (95% CI 83·3–97·6) for patients with predicted bacterial infection and 94·7% (87·8–100·0) for patients with predicted viral infection. In the external EUCLIDS validation dataset (n=362), the disease class and disease severity predicted organ dysfunction at time of sampling with an AUC of 70·1% (95% CI 44·1–96·2) for patients with predicted bacterial infection and 69·6% (53·1–86·0) for patients with predicted viral infection. Interpretation In children evaluated for sepsis, novel host transcriptomic signatures specific for bacterial and viral infection can identify dysregulated host response leading to organ dysfunction. Funding Australian Government Medical Research Future Fund Genomic Health Futures Mission, Children's Hospital Foundation Queensland, Brisbane Diamantina Health Partners, Emergency Medicine Foundation, Gold Coast Hospital Foundation, Far North Queensland Foundation, Townsville Hospital and Health Services SERTA Grant, and Australian Infectious Diseases Research Centre.