Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection.

Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Interventions: The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection. Main Outcomes and Measures: 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 score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement. Results: 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. Conclusions and Relevance: 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.

Diagnostic performance of a biomarker panel as a negative predictor for acute appendicitis in adult ED patients with abdominal pain.

OBJECTIVES: Evaluate the diagnostic accuracy of the APPY1TM biomarker panel, previously described for use in pediatric patients, for identifying adult ED patients with abdominal pain who are at low risk of acute appendicitis. METHODS: This study prospectively enrolled subjects >18years of age presenting to seven U.S. emergency departments with <72hours of abdominal pain suggesting possible acute appendicitis. The APPY1 panel was performed on blood samples drawn from each patient at the time of initial evaluation and results were correlated with the final diagnosis either positive or negative for acute appendicitis. RESULTS: 431 patients were enrolled with 422 completing all aspects of the study. The APPY1 biomarker panel exhibited a sensitivity of 97.5% (95% CI, 91.3-99.3%), a negative predictive value of 98.4% (95% CI, 94.4-99.6%), a negative likelihood ratio of 0.07 (95% CI, 0.02-0.27), with a specificity of 36.5% (95% CI, 31.6-41.8%) for acute appendicitis. The panel correctly identified 125 of 342 (36.6%) patients who did not have appendicitis with 2 (2.5%) false negatives. The CT utilization rate in this population was 72.7% (307/422). Of 307 CT scans, 232 were done for patients who did not have appendicitis and 79 (34%) of these patients were correctly identified as negative with "low risk" biomarker panel results, representing 26% (79/307) of all CT scans performed. CONCLUSION: This biomarker panel exhibited high sensitivity and negative predictive value for acute appendicitis in this prospective adult cohort, thereby potentially reducing the dependence on CT for the evaluation of possible acute appendicitis.

A novel biomarker panel to rule out acute appendicitis in pediatric patients with abdominal pain.

OBJECTIVES: To identify a biomarker panel with sufficient sensitivity and negative predictive value to identify children with abdominal pain at low risk for acute appendicitis in order to avoid unnecessary imaging. METHODS: We prospectively enrolled 503 subjects aged two to 20 years with <72 hours of abdominal pain consistent with appendicitis. Blood samples from each patient were analyzed for CBC, differential, and 5 candidate proteins. Biomarker values were evaluated using principal component, recursive partitioning and logistic regression to select the combination that best discriminated between those subjects with and without disease. RESULTS: The prevalence of acute appendicitis was 28.6%. A mathematical combination of three inflammation-related markers in a panel comprised of white blood cell count (WBC), C-reactive protein (CRP), and myeloid-related protein 8/14 complex (MRP 8/14) provided the best discrimination. This panel exhibited a sensitivity of 96.5% (95% CI, 92-99%), a negative predictive value of 96.9% (95% CI, 93-99%), a negative likelihood ratio of 0.08 (95% CI, 0.03- 0.19), and a specificity of 43.2% (95% CI, 38-48%) for acute appendicitis. Sixty of 185 CT scans (32.4%) were done for patients with negative biomarker panel results which, if deferred, would have reduced CT utilization at initial presentation by one third at the cost of missing five of 144 (3.5%) patients with appendicitis. CONCLUSION: This panel may be useful in identifying pediatric patients with signs and symptoms suggestive of acute appendicitis who are at low risk and can be followed clinically, potentially sparing them exposure to the ionizing radiation of CT.

Diagnostic characteristics of S100A8/A9 in a multicenter study of patients with acute right lower quadrant abdominal pain.

OBJECTIVES: Over the past decade, clinicians have become increasingly reliant on computed tomography (CT) for the evaluation of patients with suspected acute appendicitis. To limit the radiation risks and costs of CT, investigators have searched for biomarkers to aid in diagnostic decision-making. We evaluated one such biomarker, calprotectin or S100A8/A9, and determined the diagnostic performance characteristics of a developmental biomarker assay in a multicenter investigation of patients presenting with acute right lower quadrant abdominal pain. METHODS: This was a prospective, double-blinded, single-arm, multicenter investigation performed in 13 emergency departments (EDs) from August 2009 to April 2010 of patients presenting with acute right lower quadrant abdominal pain. Plasma samples were tested using the investigational S100A8/A9 assay. The primary outcome of acute appendicitis was determined by histopathology for patients undergoing appendectomy or 2-week telephone follow-up for patients discharged without surgery. The sensitivity, specificity, negative likelihood ratio (LR-), and positive likelihood ratio (LR+) of the biomarker assay were calculated using the prespecified cutoff value of 14 units. A post hoc stability study was performed to investigate the potential effect of time and courier transport on the measured value of the S100A8/A9 assay test results. RESULTS: Of 1,052 enrolled patients, 848 met criteria for analysis. The median age was 24.5 years (interquartile range [IQR] = 16-38 years), 57% were female, and 50% were white. There was a 27.5% prevalence of acute appendicitis. The sensitivity and specificity for the investigational S100A8/A9 assay in diagnosing acute appendicitis were estimated to be 96% (95% confidence interval [CI] = 93% to 98%) and 16% (95% CI = 13% to 19%), respectively. The LR- ratio was 0.24 (95% CI = 0.12 to 0.47), and the LR+ was 1.14 (95% CI = 1.10 to 1.19). The post hoc stability study demonstrated that in the samples that were shipped, the estimated time coefficient was 7.6 × 10(-3) ± 2.0 × 10(-3) log units/hour, representing an average increase of 43% in the measured value over 48 hours; in the samples that were not shipped, the estimated time coefficient was 2.5 × 10(-3) ± 0.4 × 10(-3) log units/hour, representing a 13% increase on average in the measured value over 48 hours, which was the maximum delay allowed by the study protocol. Thus, adjusting the cutoff value of 14 units by the magnitude of systematic inflation observed in the stability study at 48 hours would result in a new cutoff value of 20 units and a "corrected" sensitivity and specificity of 91 and 28%, respectively. CONCLUSIONS: In patients presenting with acute right lower quadrant abdominal pain, we found the investigational enzyme-linked immunosorbent assay (ELISA) test for S100A8/A9 to perform with high sensitivity but very limited specificity. We found that shipping effect and delay in analysis resulted in a subsequent rise in test values, thereby increasing the sensitivity and decreasing the specificity of the test. Further investigation with hospital-based laboratory analyzers is the next critical step for determining the ultimate clinical utility of the ELISA test for S100A8/A9 in ED patients presenting with acute right lower quadrant abdominal pain.

Emergency department crowding and risk of preventable medical errors.

The objective of the study is to determine the association between emergency department (ED) crowding and preventable medical errors (PME). This was a retrospective cohort study of 533 ED patients enrolled in the National ED Safety Study (NEDSS) in four Massachusetts EDs. Individual patients' average exposure to ED crowding during their ED visit was compared with the occurrence of a PME (yes/no) for the three diagnostic categories in NEDSS: acute myocardial infarction, asthma exacerbation, and dislocation requiring procedural sedation. To accommodate site-to-site differences in available administrative data, ED crowding was measured using one of three previously validated crowding metrics (ED Work Index, ED Workscore, and ED Occupancy). At each site, the continuous measure was placed into site-specific quartiles, and these quartiles then were combined across sites. We found that 46 (8.6%; 95% confidence interval, 6.4-11.3%) of the 533 patients experienced a PME. For those seen during higher levels of ED crowding (quartile 4 vs. quartile 1), the occurrence of PMEs was more than twofold higher, both on unadjusted analysis and adjusting for two potential confounders (diagnosis, site). The association appeared non-linear, with most PMEs occurring at the highest crowding level. We identified a direct association between high levels of ED crowding and risk of preventable medical errors. Further study is needed to determine the generalizability of these results. Should such research confirm our findings, we would suggest that mitigating ED crowding may reduce the occurrence of preventable medical errors.