Cellular host response sepsis test for risk stratification of patients in the emergency department: A pooled analysis.

OBJECTIVES: Sepsis is one of the most common, costly, and misdiagnosed conditions in U.S. emergency departments (EDs). ED providers often treat on nonspecific signs, subjective suspicion, or presumption of infection, resulting in over- and undertreatment. An increased understanding of host response has opened a new direction for sepsis diagnostics. The IntelliSep test is a U.S. Food and Drug Administration-cleared cellular host response diagnostic that could help distinguish sepsis in ED settings. Our objective was to evaluate the potential of the cellular host response test to expedite appropriate care for patients who present with signs of infection. METHODS: We performed a pooled analysis of five adult (≥18 years) cohorts enrolled at seven geographically diverse U.S. sites in separate studies. Structured blinded adjudication was used to classify presence or absence of sepsis, and only patients with high confidence in the adjudicated label were included (n = 1002), defined as patients for whom there was consensus in the determination of sepsis per the Sepsis-3 and severe sepsis per the Sepsis-2 definitions between both the independent adjudication panel and the site-level physician. RESULTS: Among patients with signs or suspicion of infection, the test achieved similar or better performance compared to other indicators in identifying patients at high risk for sepsis (specificity > 83%) and significantly superior performance in identifying those at low risk (sensitivity > 92%; 0% sepsis-associated mortality). The test also stratified severity of illness, as shown by 30-day in-hospital mortality (p < 0.001), hospital length of stay (p < 0.01), and use of hospital resources (p < 0.001). CONCLUSIONS: Our data suggest that the cellular host response test provides clinically actionable results for patients at both high and low risk for sepsis and provides a rapid, objective means for risk stratification of patients with signs of infection. If integrated into standard of care, the test may help improve outcomes and reduce unnecessary antibiotic use.

Validation of a Novel, Rapid Sepsis Diagnostic for Emergency Department Use.

OBJECTIVES: To assess the in vitro IntelliSep test, a microfluidic assay that quantifies the state of immune activation by evaluating the biophysical properties of leukocytes, as a rapid diagnostic for sepsis. DESIGN: Prospective cohort study. SETTING: Five emergency departments (EDs) in Louisiana, Missouri, North Carolina, and Washington. PATIENTS: Adult patients presenting to the ED with signs (two of four Systemic Inflammatory Response Syndrome criteria, where one must be temperature or WBC count) or suspicion (provider-ordered culture) of infection. INTERVENTIONS: All patients underwent testing with the IntelliSep using ethylene diamine tetraacetic acid-anticoagulated whole blood followed by retrospective adjudication for sepsis by sepsis-3 criteria by a blinded panel of physicians. MEASUREMENTS AND MAIN RESULTS: Of 599 patients enrolled, 572 patients were included in the final analysis. The result of the IntelliSep test is reported as the IntelliSep Index (ISI), ranging from 0.1 to 10.0, divided into three interpretation bands for the risk of sepsis: band 1 (low) to band 3 (high). The median turnaround time for ISI results was 7.2 minutes. The ISI resulted band 1 in 252 (44.1%), band 2 in 160 (28.0%), and band 3 in 160 (28.0%). Sepsis occurred in 26.6% (152 of 572 patients). Sepsis prevalence was 11.1% (95% CI, 7.5-15.7%) in band 1, 28.1% (95% CI, 21.3-35.8%) in band 2, and 49.4% (95% CI, 41.4-57.4%) in band 3. The Positive Percent Agreement of band 1 was 81.6% and the Negative Percent Agreement of band 3 was 80.7%, with an area under the receiver operating characteristic curve of 0.74. Compared with band 1, band 3 correlated with adverse clinical outcomes, including mortality, and resource utilization. CONCLUSIONS: Increasing ISI interpretation band is associated with increasing probability of sepsis in patients presenting to the ED with suspected infection.

Costs and Consequences of a Novel Emergency Department Sepsis Diagnostic Test: The IntelliSep Index.

Sepsis causes 270,000 deaths and costs $38 billion annually in the United States. Most cases of sepsis present in the emergency department (ED), where rapid diagnosis remains challenging. The IntelliSep Index (ISI) is a novel diagnostic test that analyzes characteristics of WBC structure and provides a reliable early signal for sepsis. This study performs a cost-consequence analysis of the ISI relative to procalcitonin for early sepsis diagnosis in the ED. PERSPECTIVE: U.S. healthcare system. SETTING: Community hospital ED. METHODS: A decision tree analysis was performed comparing ISI with procalcitonin. Model parameters included prevalence of sepsis, sensitivity and specificity of diagnostic tests (both ISI and procalcitonin), costs of hospitalization, and mortality rate stratified by diagnostic test result. Mortality and prevalence of sepsis were estimated from best available literature. Costs were estimated based on an analysis of a large, national discharge dataset, and adjusted to 2018 U.S. dollars. Outcomes included expected costs and survival. RESULTS: Assuming a confirmed sepsis prevalence of 16.9% (adjudicated to Sepsis-3), the ISI strategy had an expected cost per patient of $3,849 and expected survival rate of 95.08%, whereas the procalcitonin strategy had an expected cost of $4,656 per patient and an expected survival of 94.98%. ISI was both less costly and more effective than procalcitonin, primarily because of fewer false-negative results. These results were robust in sensitivity analyses. CONCLUSIONS: ISI was both less costly and more effective in preventing mortality than procalcitonin, primarily because of fewer false-negative results. The ISI may provide health systems with a higher-value diagnostic test in ED sepsis evaluation. Additional work is needed to validate these results in clinical practice.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). INTERPRETATION: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04362176; URL: www. CLINICALTRIALS: gov.

Assessment of a cellular host response test to risk-stratify suspected COVID-19 patients in the Emergency Department setting.

OBJECTIVE: Assess the IntelliSep Index (ISI) for risk stratification of patients presenting to the Emergency Department (ED) with respiratory symptoms suspected of COVID-19 during the pandemic. METHODS: An observational single-center study of prospective cohort of patients presenting to the ED during the early COVID-19 pandemic with respiratory symptoms and a CBC drawn within 4.5 hours of initial vital signs. A sample of this blood was aliquoted for performance of the ISI, and patients were followed for clinical outcomes. The study required no patient-centered activity beyond standard of care and treating clinicians were unaware of study enrollment and ISI test results. MAIN FINDINGS: 282 patients were included. The ISI ranges 0.1 to 10.0, with three interpretation bands indicating risk of adverse outcome: low (green), 0.1-4.9; intermediate (yellow), 5.0-6.2; and high (red), 6.3-10.0. Of 193 (68.4%) tested for SARS-CoV-2, 96 (49.7%) were positive. The ISI resulted in 182 (64.5%) green, 54 (18.1%) yellow, and 46 (15.6%) red band patients. Green band patients had a 1.1% (n = 2) 3-day mortality, while yellow and red band had 3.7% (n = 2, p > .05) and 10.9% (n = 5, p < .05) 3-day mortalities, respectively. Fewer green band patients required admission (96 [52.7%]) vs yellow (44 [81.5%]) and red (43 [93.5%]). Green band patients had more hospital free days (median 23 (Q1-Q3 20-25) than yellow (median 22 [Q1-Q3 0-23], p < 0.05) and red (median 21 [Q1-Q3 0-24], p < 0.01). SOFA increased with interpretation band: green (2, [Q1-Q3 0-4]) vs yellow (4, [Q1-Q3 2-5], p < 0.001) and red (5, [Q1-Q3 3-6]) p < 0.001). CONCLUSIONS: The ISI rapidly risk-stratifies patients presenting to the ED during the early COVID-19 pandemic with signs or suspicion of respiratory infection.

Retrospective identification of infection in the emergency department: A significant challenge in sepsis clinical trials.

BACKGROUND: This study examined three methods for retrospectively identifying infection in emergency department (ED) patients: modified objective definitions of infection (MODI) from the CDC/NHSN, physician adjudication determination of infection, and ED treating physician behavior. METHODS: This study used a subset of data from a prospective sepsis trial. We used Fleiss's Kappa to compare agreement between two physicians retrospectively adjudicating infection based on the patient's medical record, modified infection definition from the CDC/NHSN, and ED treating physician behavior. RESULTS: Overall, there was similar agreement between physician adjudication of infection and MODI criteria (Kappa=0.59) compared to having two physicians independently identify infection through retrospective chart review (Kappa=0.58). ED treating physician behavior was a poorer proxy for infection when compared to the MODI criteria (0.41) and physician adjudication (Kappa = 0.50). CONCLUSIONS: Retrospective identification of infection poses a significant challenge in sepsis clinical trials. Using modified definitions of infection provides a standardized, less time consuming, and equally effective means of identifying infection compared to having multiple physicians adjudicate a patient's chart.

Assessment of a Cellular Host Response Test as a Sepsis Diagnostic for Those With Suspected Infection in the Emergency Department.

OBJECTIVES: Sepsis is a common cause of morbidity and mortality. A reliable, rapid, and early indicator can help improve efficiency of care and outcomes. To assess the IntelliSep test, a novel in vitro diagnostic that quantifies the state of immune activation by measuring the biophysical properties of leukocytes, as a rapid diagnostic for sepsis and a measure of severity of illness, as defined by Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation-II scores and the need for hospitalization. DESIGN SETTING SUBJECTS: Adult patients presenting to two emergency departments in Baton Rouge, LA, with signs of infection (two of four systemic inflammatory response syndrome criteria, with at least one being aberration of temperature or WBC count) or suspicion of infection (a clinician order for culture of a body fluid), were prospectively enrolled. Sepsis status, per Sepsis-3 criteria, was determined through a 3-tiered retrospective and blinded adjudication process consisting of objective review, site-level clinician review, and final determination by independent physician adjudicators. MEASUREMENTS AND MAIN RESULTS: Of 266 patients in the final analysis, those with sepsis had higher IntelliSep Index (median = 6.9; interquartile range, 6.1-7.6) than those adjudicated as not septic (median = 4.7; interquartile range, 3.7-5.9; p < 0.001), with an area under the receiver operating characteristic curve of 0.89 and 0.83 when compared with unanimous and forced adjudication standards, respectively. Patients with higher IntelliSep Index had higher Sequential Organ Failure Assessment (3 [interquartile range, 1-5] vs 1 [interquartile range, 0-2]; p < 0.001) and Acute Physiology and Chronic Health Evaluation-II (7 [interquartile range, 3.5-11.5] vs 5 [interquartile range, 2-9]; p < 0.05) and were more likely to be admitted to the hospital (83.6% vs 48.3%; p < 0.001) compared with those with lower IntelliSep Index. CONCLUSIONS: In patients presenting to the emergency department with signs or suspicion of infection, the IntelliSep Index is a promising tool for the rapid diagnosis and risk stratification for sepsis.

Development and validation of a cellular host response test as an early diagnostic for sepsis.

Sepsis must be diagnosed quickly to avoid morbidity and mortality. However, the clinical manifestations of sepsis are highly variable and emergency department (ED) clinicians often must make rapid, impactful decisions before laboratory results are known. We previously developed a technique that allows the measurement of the biophysical properties of white blood cells as they are stretched through a microfluidic channel. In this study we describe and validate the resultant output as a model and score-the IntelliSep Index (ISI)-that aids in the diagnosis of sepsis in patients with suspected or confirmed infection from a single blood draw performed at the time of ED presentation. By applying this technique to a high acuity cohort with a 23.5% sepsis incidence (n = 307), we defined specific metrics-the aspect ratio and visco-elastic inertial response-that are more sensitive than cell size or cell count in predicting disease severity. The final model was trained and cross-validated on the high acuity cohort, and the performance and generalizability of the model was evaluated on a separate low acuity cohort with a 6.4% sepsis incidence (n = 94) and healthy donors (n = 72). For easier clinical interpretation, the ISI is divided into three interpretation bands of Green, Yellow, and Red that correspond to increasing disease severity. The ISI agreed with the diagnosis established by retrospective physician adjudication, and accurately identified subjects with severe illness as measured by SOFA, APACHE-II, hospital-free days, and intensive care unit admission. Measured using routinely collected blood samples, with a short run-time and no requirement for patient or laboratory information, the ISI is well suited to aid ED clinicians in rapidly diagnosing sepsis.

Do aspirin and statins prevent severe sepsis?

PURPOSE OF REVIEW: Sepsis is an inflammatory condition associated with significant morbidity and mortality. Given the lack of specific therapies for the condition, prevention has garnered significant interest and increased importance. The article reviews the current literature regarding the use of aspirin and statins for the prevention of sepsis. RECENT FINDINGS: Aspirin and statins have been integral in the prevention of atherosclerotic disease. Additionally, statins have proven beneficial in the prevention of nonatherosclerotic conditions secondary to their pleiotropic effects. In animal models, this pleiotropism modulates many inflammatory pathways of sepsis. The platelet also plays an integral role in this inflammatory cascade of sepsis. Scientific data indicates that antiplatelet therapy, including aspirin, may attenuate these undesirable effects of platelets. Finally, observational studies have shown that patients taking statins have a decreased incidence of sepsis and septic shock, and aspirin may potentiate these benefits. SUMMARY: Sepsis is a deadly and costly condition with no available, specific treatment options. The statins and aspirin are well tolerated and widely used for prevention of cardiovascular disease. Because of their effects on the immune system and inflammatory pathways, they may present viable medical options for the prevention of sepsis.

Functional conservation of Dhh1p, a cytoplasmic DExD/H-box protein present in large complexes.

The DHH1 gene in the yeast Saccharomyces cerevisiae encodes a putative RNA helicase of remarkable sequence similarity to several other DExD/H-box proteins, including Xp54 in Xenopus laevis and Ste13p in Schizosaccharomyces pombe. We show here that over-expression of Xp54, an integral component of the stored messenger ribonucleoprotein (mRNP) particles, can rescue the loss of Dhh1p in yeast. Localization and sedimentation studies showed that Dhh1p exists predominantly in the cytoplasm and is present in large complexes whose sizes appear to vary according to the growth stage of the cell culture. In addition, deletion of dhh1, when placed in conjunction with the mutant dbp5 and ded1 alleles, resulted in a synergistically lethal effect, suggesting that Dhh1p may have a role in mRNA export and translation. Finally, similar to Ste13p, Dhh1p is required for sporulation in the budding yeast. Taken together, our data provide evidence that the functions of Dhh1p are conserved through evolution.