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Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study.
Gupta, Rishi K; Rosenheim, Joshua; Bell, Lucy C; Chandran, Aneesh; Guerra-Assuncao, Jose A; Pollara, Gabriele; Whelan, Matthew; Artico, Jessica; Joy, George; Kurdi, Hibba; Altmann, Daniel M; Boyton, Rosemary J; Maini, Mala K; McKnight, Aine; Lambourne, Jonathan; Cutino-Moguel, Teresa; Manisty, Charlotte; Treibel, Thomas A; Moon, James C; Chain, Benjamin M; Noursadeghi, Mahdad.
  • Gupta RK; Institute of Global Health, University College London, London, UK.
  • Rosenheim J; Division of Infection and Immunity, University College London, London, UK.
  • Bell LC; Division of Infection and Immunity, University College London, London, UK.
  • Chandran A; Division of Infection and Immunity, University College London, London, UK.
  • Guerra-Assuncao JA; Division of Infection and Immunity, University College London, London, UK.
  • Pollara G; Division of Infection and Immunity, University College London, London, UK.
  • Whelan M; Division of Infection and Immunity, University College London, London, UK.
  • Artico J; Division of Infection and Immunity, University College London, London, UK.
  • Joy G; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • Kurdi H; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • Altmann DM; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • Boyton RJ; Department of Immunology and Inflammation, Imperial College London, London, UK.
  • Maini MK; Lung Division, Royal Brompton & Harefield NHS Foundation Trust, London, UK.
  • McKnight A; Division of Infection and Immunity, University College London, London, UK.
  • Lambourne J; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Cutino-Moguel T; Department of Infection, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • Manisty C; Department of Virology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • Treibel TA; Institute of Cardiovascular Sciences, University College London, London, UK.
  • Moon JC; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • Chain BM; Institute of Cardiovascular Sciences, University College London, London, UK.
  • Noursadeghi M; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
Lancet Microbe ; 2(10): e508-e517, 2021 10.
Article in English | MEDLINE | ID: covidwho-1475189
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:

We 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).

INTERPRETATION:

Our 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.

FUNDING:

Barts Charity, Wellcome Trust, and National Institute of Health Research.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Diagnostic study / Observational study / Prognostic study / Reviews / Risk factors Limits: Adolescent / Adult / Female / Humans / Male / Middle aged Language: English Journal: Lancet Microbe Year: 2021 Document Type: Article Affiliation country: S2666-5247(21)00146-4

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Diagnostic study / Observational study / Prognostic study / Reviews / Risk factors Limits: Adolescent / Adult / Female / Humans / Male / Middle aged Language: English Journal: Lancet Microbe Year: 2021 Document Type: Article Affiliation country: S2666-5247(21)00146-4