Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study

Summary: Background: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We aimed to derive and validate a blood transcriptional signature to dete...

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Autores principales:	Ho Kwong Li, MRCP, Myrsini Kaforou, PhD, Jesus Rodriguez-Manzano, PhD, Samuel Channon-Wells, MMath, Ahmad Moniri, MEng, Dominic Habgood-Coote, MSc, Rishi K Gupta, MRCP, Ewurabena A Mills, BSc, Dominique Arancon, BSN, Jessica Lin, MRes, Yueh-Ho Chiu, PhD, Ivana Pennisi, MSc, Luca Miglietta, MSc, Ravi Mehta, MRCP, Nelofar Obaray, PhD, Jethro A Herberg, PhD, Victoria J Wright, PhD, Pantelis Georgiou, PhD, Laura J Shallcross, PhD, Alexander J Mentzer, DPhil, Michael Levin, ProfPhD, Graham S Cooke, ProfDPhil, Mahdad Noursadeghi, ProfPhD, Shiranee Sriskandan, ProfPhD
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Medicine (General) R5-920 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/73aa9043bc534c35a99d2626cfacd305
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spelling	oai:doaj.org-article:73aa9043bc534c35a99d2626cfacd3052021-11-04T04:40:47ZDiscovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study2666-524710.1016/S2666-5247(21)00145-2https://doaj.org/article/73aa9043bc534c35a99d2626cfacd3052021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2666524721001452https://doaj.org/toc/2666-5247Summary: Background: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We aimed to derive and validate a blood transcriptional signature to detect viral infections, including COVID-19, among adults with suspected infection who presented to the emergency department. Methods: Individuals (aged ≥18 years) presenting with suspected infection to an emergency department at a major teaching hospital in the UK were prospectively recruited as part of the Bioresource in Adult Infectious Diseases (BioAID) discovery cohort. Whole-blood RNA sequencing was done on samples from participants with subsequently confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes that met additional filtering criteria were subjected to feature selection to derive the most parsimonious discriminating signature. We validated the signature via RT-qPCR in a prospective validation cohort of participants who presented to an emergency department with undifferentiated fever, and a second case-control validation cohort of emergency department participants with PCR-positive COVID-19 or bacterial infection. We assessed signature performance by calculating the area under receiver operating characteristic curves (AUROCs), sensitivities, and specificities. Findings: A three-gene transcript signature, comprising HERC6, IGF1R, and NAGK, was derived from the discovery cohort of 56 participants with bacterial infections and 27 with viral infections. In the validation cohort of 200 participants, the signature differentiated bacterial from viral infections with an AUROC of 0·976 (95% CI 0·919−1·000), sensitivity of 97·3% (85·8−99·9), and specificity of 100% (63·1−100). The AUROC for C-reactive protein (CRP) was 0·833 (0·694−0·944) and for leukocyte count was 0·938 (0·840−0·986). The signature achieved higher net benefit in decision curve analysis than either CRP or leukocyte count for discriminating viral infections from all other infections. In the second validation analysis, which included SARS-CoV-2-positive participants, the signature discriminated 35 bacterial infections from 34 SARS-CoV-2-positive COVID-19 infections with AUROC of 0·953 (0·893−0·992), sensitivity 88·6%, and specificity of 94·1%. Interpretation: This novel three-gene signature discriminates viral infections, including COVID-19, from other emergency infection presentations in adults, outperforming both leukocyte count and CRP, thus potentially providing substantial clinical utility in managing acute presentations with infection. Funding: National Institute for Health Research, Medical Research Council, Wellcome Trust, and EU-FP7.Ho Kwong Li, MRCPMyrsini Kaforou, PhDJesus Rodriguez-Manzano, PhDSamuel Channon-Wells, MMathAhmad Moniri, MEngDominic Habgood-Coote, MScRishi K Gupta, MRCPEwurabena A Mills, BScDominique Arancon, BSNJessica Lin, MResYueh-Ho Chiu, PhDIvana Pennisi, MScLuca Miglietta, MScRavi Mehta, MRCPNelofar Obaray, PhDJethro A Herberg, PhDVictoria J Wright, PhDPantelis Georgiou, PhDLaura J Shallcross, PhDAlexander J Mentzer, DPhilMichael Levin, ProfPhDGraham S Cooke, ProfDPhilMahdad Noursadeghi, ProfPhDShiranee Sriskandan, ProfPhDElsevierarticleMedicine (General)R5-920MicrobiologyQR1-502ENThe Lancet Microbe, Vol 2, Iss 11, Pp e594-e603 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920 Microbiology QR1-502
spellingShingle	Medicine (General) R5-920 Microbiology QR1-502 Ho Kwong Li, MRCP Myrsini Kaforou, PhD Jesus Rodriguez-Manzano, PhD Samuel Channon-Wells, MMath Ahmad Moniri, MEng Dominic Habgood-Coote, MSc Rishi K Gupta, MRCP Ewurabena A Mills, BSc Dominique Arancon, BSN Jessica Lin, MRes Yueh-Ho Chiu, PhD Ivana Pennisi, MSc Luca Miglietta, MSc Ravi Mehta, MRCP Nelofar Obaray, PhD Jethro A Herberg, PhD Victoria J Wright, PhD Pantelis Georgiou, PhD Laura J Shallcross, PhD Alexander J Mentzer, DPhil Michael Levin, ProfPhD Graham S Cooke, ProfDPhil Mahdad Noursadeghi, ProfPhD Shiranee Sriskandan, ProfPhD Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study
description	Summary: Background: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We aimed to derive and validate a blood transcriptional signature to detect viral infections, including COVID-19, among adults with suspected infection who presented to the emergency department. Methods: Individuals (aged ≥18 years) presenting with suspected infection to an emergency department at a major teaching hospital in the UK were prospectively recruited as part of the Bioresource in Adult Infectious Diseases (BioAID) discovery cohort. Whole-blood RNA sequencing was done on samples from participants with subsequently confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes that met additional filtering criteria were subjected to feature selection to derive the most parsimonious discriminating signature. We validated the signature via RT-qPCR in a prospective validation cohort of participants who presented to an emergency department with undifferentiated fever, and a second case-control validation cohort of emergency department participants with PCR-positive COVID-19 or bacterial infection. We assessed signature performance by calculating the area under receiver operating characteristic curves (AUROCs), sensitivities, and specificities. Findings: A three-gene transcript signature, comprising HERC6, IGF1R, and NAGK, was derived from the discovery cohort of 56 participants with bacterial infections and 27 with viral infections. In the validation cohort of 200 participants, the signature differentiated bacterial from viral infections with an AUROC of 0·976 (95% CI 0·919−1·000), sensitivity of 97·3% (85·8−99·9), and specificity of 100% (63·1−100). The AUROC for C-reactive protein (CRP) was 0·833 (0·694−0·944) and for leukocyte count was 0·938 (0·840−0·986). The signature achieved higher net benefit in decision curve analysis than either CRP or leukocyte count for discriminating viral infections from all other infections. In the second validation analysis, which included SARS-CoV-2-positive participants, the signature discriminated 35 bacterial infections from 34 SARS-CoV-2-positive COVID-19 infections with AUROC of 0·953 (0·893−0·992), sensitivity 88·6%, and specificity of 94·1%. Interpretation: This novel three-gene signature discriminates viral infections, including COVID-19, from other emergency infection presentations in adults, outperforming both leukocyte count and CRP, thus potentially providing substantial clinical utility in managing acute presentations with infection. Funding: National Institute for Health Research, Medical Research Council, Wellcome Trust, and EU-FP7.
format	article
author	Ho Kwong Li, MRCP Myrsini Kaforou, PhD Jesus Rodriguez-Manzano, PhD Samuel Channon-Wells, MMath Ahmad Moniri, MEng Dominic Habgood-Coote, MSc Rishi K Gupta, MRCP Ewurabena A Mills, BSc Dominique Arancon, BSN Jessica Lin, MRes Yueh-Ho Chiu, PhD Ivana Pennisi, MSc Luca Miglietta, MSc Ravi Mehta, MRCP Nelofar Obaray, PhD Jethro A Herberg, PhD Victoria J Wright, PhD Pantelis Georgiou, PhD Laura J Shallcross, PhD Alexander J Mentzer, DPhil Michael Levin, ProfPhD Graham S Cooke, ProfDPhil Mahdad Noursadeghi, ProfPhD Shiranee Sriskandan, ProfPhD
author_facet	Ho Kwong Li, MRCP Myrsini Kaforou, PhD Jesus Rodriguez-Manzano, PhD Samuel Channon-Wells, MMath Ahmad Moniri, MEng Dominic Habgood-Coote, MSc Rishi K Gupta, MRCP Ewurabena A Mills, BSc Dominique Arancon, BSN Jessica Lin, MRes Yueh-Ho Chiu, PhD Ivana Pennisi, MSc Luca Miglietta, MSc Ravi Mehta, MRCP Nelofar Obaray, PhD Jethro A Herberg, PhD Victoria J Wright, PhD Pantelis Georgiou, PhD Laura J Shallcross, PhD Alexander J Mentzer, DPhil Michael Levin, ProfPhD Graham S Cooke, ProfDPhil Mahdad Noursadeghi, ProfPhD Shiranee Sriskandan, ProfPhD
author_sort	Ho Kwong Li, MRCP
title	Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study
title_short	Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study
title_full	Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study
title_fullStr	Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study
title_full_unstemmed	Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study
title_sort	discovery and validation of a three-gene signature to distinguish covid-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/73aa9043bc534c35a99d2626cfacd305
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Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study

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