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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)322-331
Number of pages10
JournalJournal of the Pediatric Infectious Diseases Society
Volume12
Issue number6
DOIs
Publication statusPublished - 1 Jun 2023

Bibliographical note

Financial support. This work was supported by the European Union’s Horizon 2020 Program under grants (848196 DIAMONDS, 668303 PERFORM, 279185 EUCLIDS, Prof Levin), by the Imperial Biomedical Research Centre (BRC) of the National Institute for Health Research (NIHR), grants (206508/Z/17/Z and MRF-160-0008-ELP-KAFO-C0801 to Dr Kaforou) from the Wellcome Trust and the Medical Research Foundation, a grant (215214/Z/19/Z to Dr Jackson) from the Wellcome Trust, a grant (R61HD105590-01 PreVAIL kIds to Dr. Burns) from the National Institutes of Health, and grants (WDPI_G28062 and WDPI_P89720 to Drs Herberg and Georgiou) from the Community Jameel Imperial College COVID-19 Excellence Fund and the Rosetrees Trust. This work has been supported by the Imperial Confidence in Concept Scheme, funded by MRC Confidence in Concept, Wellcome Trust Institutional Strategic Support Fund, NIHR Imperial BRC, and Rosetrees Trust (to Rodriguez-Manzano and Kaforou).

Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.

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