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Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship.To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI.This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc.The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection.Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score0.73]) and compared with procalcitonin measurement.Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection.In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.

Background Difficulty discriminating bacterial from viral infections drives antibacterial misuse. Host gene expression tests discriminate bacterial and viral etiologies, but their clinical utility has not been evaluated. Methods Host gene expression and procalcitonin levels were measured in 582 emergency department participants with suspected infection. We also recorded clinician diagnosis and clinician-recommended treatment. These 4 diagnostic strategies were compared with clinical adjudication as the reference. To estimate the clinical impact of host gene expression, we calculated the change in overall Net Benefit (∆NB; the difference in Net Benefit comparing 1 diagnostic strategy with a reference) across a range of prevalence estimates while factoring in the clinical significance of false-positive and -negative errors. Results Gene expression correctly classified bacterial, viral, or noninfectious illness in 74.1% of subjects, similar to the other strategies. Clinical diagnosis and clinician-recommended treatment revealed a bias toward overdiagnosis of bacterial infection resulting in high sensitivity (92.6% and 94.5%, respectively) but poor specificity (67.2% and 58.8%, respectively), resulting in a 33.3% rate of inappropriate antibacterial use. Gene expression offered a more balanced sensitivity (79.0%) and specificity (80.7%), which corresponded to a statistically significant improvement in average weighted accuracy (79.9% vs 71.5% for procalcitonin and 76.3% for clinician-recommended treatment; P Conclusions Host gene expression–based tests to distinguish bacterial and viral infection can facilitate appropriate treatment, improving patient outcomes and mitigating the antibacterial resistance crisis.

Purpose of review The purpose of this study is to review the recent literature examining the clinical utility of markers of systemic oxygen extraction and perfusion in the diagnosis, treatment and prognosis of severe sepsis and septic shock. Recent findings When sepsis is accompanied by conditions in which systemic oxygen delivery does not meet tissue oxygen demands, tissue hypoperfusion begins. Tissue hypoperfusion leads to oxygen debt, cellular injury, organ dysfunction and death. Tissue hypoperfusion can be characterized using markers of tissue perfusion (central venous oxygen saturation and lactate), which reflect the interaction between systemic oxygen delivery and demands. For the last two decades, studies and quality initiatives incorporating the early detection and interruption of tissue hypoperfusion have been shown to improve mortality and altered sepsis care. Three recent trials, while confirming an all-time improvement in sepsis mortality, challenged the concept that rapid normalization of markers of perfusion confers outcome benefit. By defining and comparing haemodynamic phenotypes using markers of tissue perfusion, we may better understand which patients are more likely to benefit from early goal-directed haemodynamic optimization. Summary The phenotypic haemodynamic characterization of patients using perfusion markers has diagnostic, therapeutic and outcome implications in severe sepsis and septic shock. However, irrespective of haemodynamic phenotype, the outcome reflects the quality of care provided at the point of presentation. Utilizing these principles may allow more objective interpretation of resuscitation trials and translate these findings into current practice.