A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations

Journal article

Background: Early and accurate diagnosis of acute infection has important consequences for antibiotic stewardship, resource allocation, and clinical outcomes. However, limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics have the potential to address these challenges, but accuracy varies widely across heterogeneous global patient populations.

Methods: We performed a multi-cohort analysis of 4,200 unique samples across 69 retrospective blood transcriptome datasets from 20 countries. These samples were collected from patients with acute bacterial or viral infections representing a broad spectrum of biological (age, sex, race, ethnicity, pathogen, host genetics), clinical (severity, day of presentation), and technical (Affymetrix, Agilent, Illumina) heterogeneity. We also enrolled patients with infectious diseases in two cohorts from Laos and Nepal.

Findings: Current host-response-based gene signatures distinguished intracellular bacterial infection from viral infections with substantially lower accuracy. Using 69 datasets, divided into training and validation datasets, we identified an 8-gene signature that distinguished intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC) >0.91 (85.9% specificity, 90.2% sensitivity). In two prospective cohorts from Nepal and Laos, profiled using Fluidigm RT-PCR, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity, 91% sensitivity).

Interpretation: The 8-gene signature met the target product profile (90% sensitivity, 80% specificity) proposed by the WHO and others for distinguishing bacterial and viral infections. The 8-gene signature should be considered for further validation and implementation.

Authors: Rao, AM; Popper, SJ; Gupta, S; Davong, V; Vaidya, K

• Publication status: Submitted
• Peer review status: Not peer reviewed
• Publisher: SSRN
• Journal: Preprints with the Lancet
• Publication date: 2021-11-12
• DOI: 10.2139/ssrn.3962154
• EISSN: 1556-5068
• Language: English