Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study
Authors: Rishi K Gupta, Joshua Rosenheim, Lucy C Bell, Aneesh Chandran, Jose A Guerra-Assuncao, Gabriele Pollara, Matthew Whelan, Jessica Artico, George Joy, Hibba Kurdi, Daniel M Altmann, Rosemary J Boyton, Mala K Maini, Aine McKnight, Jonathan Lambourne, Teresa Cutino-Moguel, Charlotte Manisty, Thomas A Treibel, James C Moon, Benjamin M Chain, Mahdad Noursadeghi, Hakam Abbass, Aderonke Abiodun, Mashael Alfarih, Zoe Alldis, Daniel M Altmann, Oliver E Amin, Mervyn Andiapen, Jessica Artico, João B Augusto, Georgiana L Baca, Sasha NL Bailey, Anish N Bhuva, Alex Boulter, Ruth Bowles, Rosemary J Boyton, Olivia V Bracken, Ben O'Brien, Tim Brooks, Natalie Bullock, David K Butler, Gabriella Captur, Nicola Champion, Carmen Chan, Aneesh Chandran, David Collier, Jorge Couto de Sousa, Xose Couto-Parada, Teresa Cutino-Moguel, Rhodri H Davies, Brooke Douglas, Cecilia Di Genova, Keenan Dieobi-Anene, Mariana O Diniz, Anaya Ellis, Karen Feehan, Malcolm Finlay, Marianna Fontana, Nasim Forooghi, Celia Gaier, Joseph M Gibbons, Derek Gilroy, Matt Hamblin, Gabrielle Harker, Jacqueline Hewson, Lauren M Hickling, Aroon D Hingorani, Lee Howes, Alun Hughes, Gemma Hughes, Rebecca Hughes, Ivie Itua, Victor Jardim, Wing-Yiu Jason Lee, Melaniepetra Jensen, Jessica Jones, Meleri Jones, George Joy, Vikas Kapil, Hibba Kurdi, Jonathan Lambourne, Kai-Min Lin, Sarah Louth, Mala K Maini, Vineela Mandadapu, Charlotte Manisty,, Áine McKnight, Katia Menacho, Celina Mfuko, Oliver Mitchelmore, Christopher Moon, James C Moon,, Diana Munoz Sandoval, Sam M Murray, Mahdad Noursadeghi, Ashley Otter, Corinna Pade, Susana Palma, Ruth Parker, Kush Patel, Babita Pawarova, Steffen E Petersen, Brian Piniera, Franziska P Pieper, Daniel Pope, Maria Prossora, Lisa Rannigan, Alicja Rapala, Catherine J Reynolds, Amy Richards, Matthew Robathan, Joshua Rosenheim, Genine Sambile, Nathalie M Schmidt, Amanda Semper, Andreas Seraphim, Mihaela Simion, Angelique Smit, Michelle Sugimoto, Leo Swadling, Stephen Taylor, Nigel Temperton, Stephen Thomas, George D Thornton, Thomas A Treibel, Art Tucker, Jessry Veerapen, Mohit Vijayakumar, Sophie Welch, Theresa Wodehouse, Lucinda Wynne, Dan Zahedi
Journal: The Lancet Microbe (2021)

BackgroundWe hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing.MethodsWe did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew's Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for "viral infection", "transcriptome", "biomarker", and "blood". We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive participants) during their first week of PCR positivity.FindingsWe identified 20 candidate blood transcriptomic signatures of viral infection from 18 studies and evaluated their accuracy among 169 blood RNA samples from 96 participants over 24 weeks. Participants were recruited between March 23 and March 31, 2020. 114 samples were from 41 participants with SARS-CoV-2 infection, and 55 samples were from 55 test-negative controls. The median age of participants was 36 years (IQR 27–47) and 69 (72%) of 96 were women. Signatures had little overlap of component genes, but were mostly correlated as components of type I interferon responses. A single blood transcript for IFI27 provided the highest accuracy for discriminating between test-negative controls and test-positive individuals at the time of their first positive SARS-CoV-2 PCR result, with AUROC of 0·95 (95% CI 0·91–0·99), sensitivity 0·84 (0·70–0·93), and specificity 0·95 (0·85–0·98) at a predefined threshold (Z score >2). The transcript performed equally well in individuals with and without symptoms. Three other candidate signatures (including two to 48 transcripts) had statistically equivalent discrimination to IFI27 (AUROCs 0·91–0·95).InterpretationOur findings support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection for screening individuals at high risk of infection, such as contacts of index cases, to facilitate early case isolation and early use of antiviral treatments as they emerge.FundingBarts Charity, Wellcome Trust, and National Institute of Health Research.