Abstract
SummaryBackgroundEmergency 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.MethodsIndividuals (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.FindingsA 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%.InterpretationThis 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.FundingNational Institute for Health Research, Medical Research Council, Wellcome Trust, and EU-FP7.
Highlights
There has been extensive interest in biomarkers that discriminate between bacterial and viral infections in emergency medicine, primarily fuelled by the aspiration to reduce inappropriate prescribing of antibacterial agents.[1]
Our search returned more than 70 papers, and five gene expression signatures that distinguish between bacterial and viral infections, none were derived and validated in adult emergency settings, and none have been validated in patients with COVID-19
We evaluated the clinical utility of each of leukocyte count, C-reactive protein (CRP), and the three-gene signature to identify definite and probable viral or bacterial infections among all participants in the entire pre-COVID-19 prospective validation cohort where all three measurements were available, including the indeterm inate groups, thereby avoiding over optimistic estimates of test performance derived from case-control analyses
Summary
There has been extensive interest in biomarkers that discriminate between bacterial and viral infections in emergency medicine, primarily fuelled by the aspiration to reduce inappropriate prescribing of antibacterial agents.[1] The COVID-19 pandemic has highlighted a further need for tests that can trigger infection control and antiviral interventions before a specific diagnosis is available. Evidence before this study Differentiation of infections is a major challenge in emergency settings, where decisions to prescribe antibiotics to potentially save life must be weighed against the risk of aiding antimicrobial resistance or of complications through over-use. Several molecular diagnostic biomarkers to distinguish between viral and bacterial infection have been proposed but none are in routine use. Our search returned more than 70 papers, and five gene expression signatures that distinguish between bacterial and viral infections, none were derived and validated in adult emergency settings, and none have been validated in patients with COVID-19
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