Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study
Rishi K Gupta, Joshua Rosenheim, Lucy Bell, Aneesh Chandran, José Afonso Guerra‐Assunção, Gabriele Pollara, Matthew V. X. Whelan, Jessica Artico, George Joy, Hibba Kurdi, Daniel M. Altmann, Rosemary J. Boyton, Mala K. Maini, Áine McKnight, Jonathan Lambourne, Teresa Cutiño‐Moguel, Charlotte Manisty, Thomas A. Treibel, James Moon, Benny 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 Luisa Baca, Sasha N. L. Bailey, Anish Bhuva, Alex Boulter, Ruth Bowles, Rosemary J. Boyton, Olivia V. Bracken, Benjamin O’Brien, Tim Brooks, Natalie Bullock, David K. Butler, Gabriella Captur, Nicola Champion, Carmen K. M. Chan, Aneesh Chandran, David Collier, Jorge Couto de Sousa, Xosé Couto‐Parada, Teresa Cutiño‐Moguel, Rhodri 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 W. Gilroy, Matt Hamblin, Gabrielle Harker, Jacqueline Hewson, Lauren M. Hickling, Aroon D. Hingorani, Lee Hamill Howes, Alun D. 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 Moon, Diana Mūnoz Sandoval, Sam M. Murray, Mahdad Noursadeghi, Ashley Otter, Corinna Pade, Susana Palma, Ruth Parker, Kush Patel
Abstract
BACKGROUND: We 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. METHODS: We 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. FINDINGS: (AUROCs 0·91-0·95). INTERPRETATION: 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. FUNDING: Barts Charity, Wellcome Trust, and National Institute of Health Research.