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 accuracy of combined WBC, ANC and CRP in adult emergency department patients suspected of acute appendicitis.

OBJECTIVES: To assess the sensitivity, specificity, and negative predictive value (NPV) of normal total white blood cell count (WBC) and normal absolute neutrophil count (ANC) combined with a normal proprietary C-reactive protein (pCRP) level in adult emergency department (ED) patients with abdominal pain suspected of possible acute appendicitis. METHODS: We prospectively enrolled patients ≥18 years of age at seven U.S. emergency departments with ≤72 h of abdominal pain and other signs and symptoms suggesting possible acute appendicitis. Sensitivity, specificity, and NPV for normal WBC and ANC combined with normal pCRP were correlated with the final diagnosis of acute appendicitis. RESULTS: We enrolled 422 patients with a prevalence of acute appendicitis of 19.1%. The combination of normal WBC and pCRP exhibited a sensitivity of 97.5% (95% CI, 91.3-99.3%), an NPV of 98.8% (95% CI, 95.9-99.7%) and a specificity of 50.0% (95% CI, 44.7-55.3%) for acute appendicitis. Normal ANC and pCRP resulted in a sensitivity of 100% (95% CI, 95.4-100%), a negative predictive value of 100% (95% CI, 97.5-100%) and a specificity of 44.4% (95% CI, 39.2-49.7%) for acute appendicitis. Normal WBC and pCRP correctly identified 171 of 342 (50.0%) patients who did not have appendicitis with 2 (2.5%) false negatives, while normal ANC and pCRP identified 150 of 338 (44.3%) of patients without appendicitis with no false negatives. CONCLUSION: The combination of normal WBC and ANC with normal pCRP levels exhibited high sensitivity and negative predictive value for acute appendicitis in this prospective adult patient cohort. Confirmation and validation of these findings with further study using commercially available CRP assays is needed.

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. RESULTS: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. CONCLUSIONS: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).

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.

Addition of a biomarker panel to a clinical score to identify patients at low risk for appendicitis.

BACKGROUND: The diagnosis of pediatric acute appendicitis can be difficult. Although scoring systems such as the Pediatric Appendicitis Score (PAS) are helpful, they lack adequate sensitivity and specificity as standalone diagnostics. When used for risk stratification, they often result in large percentages of moderate-risk patients requiring further diagnostic evaluation. METHODS: We applied a biomarker panel (the APPY1 Test) that has high sensitivity and negative predictive value (NPV) to patients with PAS in the moderate-risk range (3-7) and reclassified those patients with a negative result to the low-risk group. We compared the specificity, sensitivity, and NPV of the original and reclassified low-risk groups at several different PAS low-risk cutoffs. RESULTS: The application of a negative biomarker panel to a group of patients with a moderate risk for appendicitis (PAS, 3-7) resulted in 4 times more patients (586 vs 145) being safely classified as low risk. Reclassification increased the overall specificity or the proportion of patients without appendicitis who were correctly identified as low risk, from 10.3% to 42.0%. The high NPV (97.2%) in the original group was preserved (97.6%) in the reclassified low-risk group, as was the sensitivity (original 99.1% vs reclassified 96.9%). CONCLUSION: The addition of negative biomarker test results to patients with a moderate risk of appendicitis based on the PAS can safely reclassify many to a low-risk group. This may allow clinicians to provide more conservative management in children with suspected appendicitis and decrease unnecessary resource utilization.

Prospective validation of a biomarker panel to identify pediatric ED patients with abdominal pain who are at low risk for acute appendicitis.

OBJECTIVES: The objective of the study is to prospectively validate the diagnostic accuracy of a biomarker panel consisting of white blood cell, C-reactive protein, and myeloid-related protein 8/14 levels in identifying pediatric patients with abdominal pain who are at low risk for appendicitis. METHODS: This prospective observational study enrolled subjects aged 2 to 20 years presenting to 29 US emergency departments with abdominal pain suggesting possible acute appendicitis. Blood samples were analyzed for white blood cell, C-reactive protein, and myeloid-related protein 8/14 levels from which the composite biomarker panel results were calculated, then correlated with the final diagnosis either positive or negative for acute appendicitis. RESULTS: A total of 2201 patients were enrolled, with 1887 completing all aspects of the study. Prevalence of appendicitis in this cohort was 25.3%. The biomarker panel exhibited a sensitivity of 97.1% (95% confidence interval [CI], 95.1%-98.2%), negative predictive value of 97.4% (95% CI, 95.8%-98.5%), negative likelihood ratio of 0.08 (95% CI, 0.05-0.13), with a specificity of 37.9% (95% CI, 35.4%-40.4%) for appendicitis. The panel correctly identified 534 (37.8%) of 1410 patients who did not have appendicitis with 14 false negatives (2.9%). Overall, 23.7% (132/557) of computed tomographic (CT) scans were done for patients with negative biomarker panel results, including 31.2% (131/420) of patients who had CT but did not have appendicitis. CONCLUSION: This biomarker panel exhibited high sensitivity and negative predictive value for acute appendicitis in this large prospective cohort. This panel may be useful in identifying pediatric patients who are at low risk for appendicitis and might be followed clinically, potentially reducing the dependence on CT in the evaluation for acute appendicitis.

Generalizability of a simple approach for predicting hospital admission from an emergency department.

OBJECTIVES: The objective was to test the generalizability, across a range of hospital sizes and demographics, of a previously developed method for predicting and aggregating, in real time, the probabilities that emergency department (ED) patients will be admitted to a hospital inpatient unit. METHODS: Logistic regression models were developed that estimate inpatient admission probabilities of each patient upon entering an ED. The models were based on retrospective development (n = 4,000 to 5,000 ED visits) and validation (n = 1,000 to 2,000 ED visits) data sets from four heterogeneous hospitals. Model performance was evaluated using retrospective test data sets (n = 1,000 to 2,000 ED visits). For one hospital the developed model also was applied prospectively to a test data set (n = 910 ED visits) coded by triage nurses in real time, to compare results to those from the retrospective single investigator-coded test data set. RESULTS: The prediction models for each hospital performed reasonably well and typically involved just a few simple-to-collect variables, which differed for each hospital. Areas under receiver operating characteristic curves (AUC) ranged from 0.80 to 0.89, R(2) correlation coefficients between predicted and actual daily admissions ranged from 0.58 to 0.90, and Hosmer-Lemeshow goodness-of-fit statistics of model accuracy had p > 0.01 with one exception. Data coded prospectively by triage nurses produced comparable results. CONCLUSIONS: The accuracy of regression models to predict ED patient admission likelihood was shown to be generalizable across hospitals of different sizes, populations, and administrative structures. Each hospital used a unique combination of predictive factors that may reflect these differences. This approach performed equally well when hospital staff coded patient data in real time versus the research team retrospectively.

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.

Myocardial ischemia associated with clenbuterol abuse: report of two cases.

BACKGROUND: Clenbuterol is an orally administered long-acting beta-2 adrenergic agonist closely related to albuterol that, in recent years, has become a substance of abuse in the bodybuilding and athletic community. OBJECTIVES: We report two cases of acute myocardial ischemia associated with clenbuterol abuse in two healthy young male body builders. CASE REPORT: Two male bodybuilders, ages 18 and 22 years, presented to the Emergency Department with palpitations, nausea, vomiting, chest pain, diaphoresis, and tachycardia shortly after ingesting clenbuterol. Both patients experienced prolonged sinus tachycardia that, in one patient, was relatively resistant to both beta- and calcium channel blockade. Both patients were found to have elevated troponin levels, the first patient as high as 4.71 ng/mL (normal<0.04 ng/mL). Further investigation revealed normal coronary arteries at catheterization and normal cardiac magnetic resonance imaging in the first patient, and normal echocardiograms for both patients. The tachycardia gradually resolved and both patients recovered uneventfully. The etiology of cardiac ischemia in these patients is uncertain. CONCLUSIONS: Emergency physicians should be aware of the clinical presentation of clenbuterol abuse and overdose, and the possibility of related cardiac ischemia and rhythm disturbances. Suggested treatment includes intravenous fluids, oxygen, aspirin, beta-blockers, and benzodiazepines, although efficacy remains unproven.

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.

Occult splenic rupture presenting as acute scrotal swelling.

BACKGROUND: Scrotal pain and swelling is a common complaint encountered in emergency medicine. The differential diagnosis includes testicular, scrotal, and intra-abdominal pathology. CASE REPORT: We present a case of an 80-year-old man on warfarin therapy presenting with acute atraumatic scrotal pain and swelling initially diagnosed as a hydrocele. The diagnosis was subsequently determined to be a communicating hematocele secondary to occult splenic rupture. CONCLUSION: Intra-abdominal pathology can result in scrotal pain and swelling due to passage of intra-abdominal contents into the scrotum via a patent processus vaginalis. Therefore, any cause of hemoperitoneum may also cause hematocele and hematocele should be considered in the differential diagnosis of acute scrotal swelling in any patient with risk factors for bleeding. In these patients, both scrotal and abdominal imaging should be considered.

Utilization and yield of chest computed tomographic angiography associated with low positive D-dimer levels.

BACKGROUND: It is unclear to what degree broadly applied D-dimer testing combined with a low threshold for imaging with even minimally positive results may be contributing to the utilization of chest computed tomographic angiography (CTA). STUDY OBJECTIVES: To determine what proportion of chest CTAs for suspected pulmonary embolism (PE) were performed in the setting of minimally elevated D-dimer levels, and to determine the prevalence of PE in those patients when stratified by clinical risk. METHODS: Retrospective chart review of all patients who had chest CTA for the evaluation of suspected PE during the years 2002-2006 in a suburban community teaching hospital emergency department. RESULTS: There were 1136 eligible patient visits, of which 353 (31.1%) were found to have D-dimer levels in the low positive range (0.5-0.99 µg/mL). Of these 353 patients, 9 (2.6%; 95% confidence interval [CI] 0.9-4.2%) were diagnosed with PE. There were also 109 patients (9.6%) who had normal D-dimer levels (<0.5 µg/mL). Two of these 109 (1.8%; 95% CI 0-4.2%) were diagnosed with PE. When stratified by the Pulmonary Embolism Rule-out Criteria, 99 of 353 patients with low positive D-dimer levels (28.0%; 95% CI 23.4-32.7%), and 14 of 109 with normal D-dimer levels (12.8%; 95% CI 6.6-19.1%) were classified as low risk, none of whom had PE. CONCLUSIONS: Nearly one-third of all chest CTAs were done for patients with minimally elevated D-dimer levels, and another 9.6% for patients with normal D-dimer levels with very low yield. Further research to define clinical criteria identifying patients with minimal risk of PE despite low positive D-dimer levels represents an opportunity to improve both patient safety and utilization efficiency of chest CTA.