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Discovery and Validation of a 3-Gene Transcriptional Signature to Distinguish COVID-19 and Other Viral Infections from Bacterial Sepsis in Adults; A Case-Control then Observational Cohort Study

38 Pages Posted: 2 Feb 2021

See all articles by Ho Kwong Li

Ho Kwong Li

Imperial College London

Myrsini Kaforou

Imperial College London

Jesus Rodriguez-Manzano

Imperial College London

Samuel Channon-Wells

Imperial College London

Ahmad Moniri

Imperial College London

Dominic Habgood-Coote

Imperial College London

Rishi K. Gupta

University College London

Ewurabena A. Mills

Imperial College London

Dominique Arancon

Imperial College Healthcare NHS Trust

Jessica Lin

Department of Infectious Disease, Imperial College London

Yueh-Ho Chiu

Imperial College London - Institute of Reproductive and Developmental Biology

Ivana Pennisi

Imperial College London

Luca Miglietta

Imperial College London

Nelofar Obaray

Imperial College London

Ravi Mehta

Department of Infectious Disease, Imperial College London

Jethro A. Herberg

Imperial College London

Victoria J. Wright

Imperial College London

Pantelis Georgiou

Imperial College London

Laura Shallcross

University College London - Institute for Health Informatics

Alexander J. Mentzer

University of Oxford - Wellcome Trust Centre for Human Genetics; University of Oxford - Li Ka Shing Centre for Health Information and Discovery

Michael Levin

Department of Infectious Disease, Imperial College London

Graham S. Cooke

Imperial College London - Department of Infectious Disease

Mahdad Noursadeghi

University College London - Division of Infection and Immunity

Shiranee Sriskandan

Imperial College London - Department of Medicine; Imperial College London - MRC Centre for Molecular Bacteriology & Infection; Imperial College London - NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance

More...

Abstract

Background: Emergency hospital admissions for infection often lack microbiological diagnostic certainty. Novel approaches to discriminate likelihood of bacterial and viral infections are required to support antimicrobial prescribing decisions and infection control practice. We sought to derive and validate a blood transcriptional signature to differentiate bacterial infections from viral infections including COVID-19.

Methods: Blood RNA sequencing was performed on a discovery cohort of adults attending the Emergency Department with confirmed bacteraemia or viral infection. Differentially expressed host genes were subjected to feature selection to derive the most parsimonious discriminating signature. RT-qPCR validation of the signature was then performed in a prospective cohort of patients presenting with undifferentiated fever and a second case-control cohort of patients with bacteraemia or COVID-19.

Findings: A 3-gene transcript signature was derived from the discovery cohort of 56 definite bacterial and 27 viral infection cases. In the validation cohort, the signature differentiated bacterial and viral infections with an area under receiver operating characteristic curve (AUC) of 0.976 (95% CI: 0.919-1.000), sensitivity 97.3% and specificity of 100%. The AUC for C-reactive protein and leucocyte count was 0.833 (95% CI: 0.694-0.944) and 0.938 (95% CI: 0.840-0.986) respectively. In the second validation analysis the signature discriminated 34 SARS-CoV-2 positive COVID-19 from 35 bacterial infections with AUC of 0.953 (95% CI: 0.893-0.992), sensitivity 88.6% and specificity of 94.1%.

Interpretation: This novel 3-gene signature discriminates viral infections including COVID-19 from bacterial sepsis in adults, outperforming both leucocyte count and CRP, thus potentially providing significant clinical utility in managing acute presentations with infection.

Funding Statement: Work in this study was funded by the NIHR Imperial Biomedical Research Centre, the Medical Research Council, the Wellcome Trust and the European Union FP7 (EC-GA 279185) (EUCLIDS).

Declaration of Interests: None of the authors have any relevant interest to declare.

Ethics Approval Statement: Ethical approval was obtained to take deferred consent from patients from whom an RNA specimen had been collected (or from next of kin or nominated consultee) (REC references 14/SC/0008 and 19/SC/0116).

Suggested Citation

Li, Ho Kwong and Kaforou, Myrsini and Rodriguez-Manzano, Jesus and Channon-Wells, Samuel and Moniri, Ahmad and Habgood-Coote, Dominic and Gupta, Rishi K. and Mills, Ewurabena A. and Arancon, Dominique and Lin, Jessica and Chiu, Yueh-Ho and Pennisi, Ivana and Miglietta, Luca and Obaray, Nelofar and Mehta, Ravi and Herberg, Jethro A. and Wright, Victoria J. and Georgiou, Pantelis and Shallcross, Laura and Mentzer, Alexander J. and Levin, Michael and Cooke, Graham S. and Noursadeghi, Mahdad and Sriskandan, Shiranee, Discovery and Validation of a 3-Gene Transcriptional Signature to Distinguish COVID-19 and Other Viral Infections from Bacterial Sepsis in Adults; A Case-Control then Observational Cohort Study. Available at SSRN: https://ssrn.com/abstract=3766286 or http://dx.doi.org/10.2139/ssrn.3766286

Ho Kwong Li

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Myrsini Kaforou

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Jesus Rodriguez-Manzano

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Samuel Channon-Wells

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Ahmad Moniri

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Dominic Habgood-Coote

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Rishi K. Gupta

University College London

Gower Street
London, WC1E 6BT
United Kingdom

Ewurabena A. Mills

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Dominique Arancon

Imperial College Healthcare NHS Trust

Praed St
London
United Kingdom

Jessica Lin

Department of Infectious Disease, Imperial College London

Yueh-Ho Chiu

Imperial College London - Institute of Reproductive and Developmental Biology

London
United Kingdom

Ivana Pennisi

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Luca Miglietta

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Nelofar Obaray

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Ravi Mehta

Department of Infectious Disease, Imperial College London

Jethro A. Herberg

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Victoria J. Wright

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Pantelis Georgiou

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Laura Shallcross

University College London - Institute for Health Informatics ( email )

Gower Street
London, WC1E 6BT
United Kingdom

Alexander J. Mentzer

University of Oxford - Wellcome Trust Centre for Human Genetics

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

University of Oxford - Li Ka Shing Centre for Health Information and Discovery ( email )

Oxford, OX3 7FZ
United Kingdom

Michael Levin

Department of Infectious Disease, Imperial College London

Graham S. Cooke

Imperial College London - Department of Infectious Disease ( email )

Exhibition Road
London, SW7 2AZ
United Kingdom

Mahdad Noursadeghi

University College London - Division of Infection and Immunity

Gower Street
London, WC1E 6BT
United Kingdom

Shiranee Sriskandan (Contact Author)

Imperial College London - Department of Medicine ( email )

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Imperial College London - MRC Centre for Molecular Bacteriology & Infection ( email )

London
United Kingdom

Imperial College London - NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance ( email )

London
United Kingdom

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