Assessment of a Cellular Host Response Test as a Sepsis Diagnostic for Patients Presenting to the Emergency Department Suspected of Respiratory Infections in the Setting of a Pandemic

ABSTRACT

Study Objectives: Emergency departments (EDs) serve as the front lines for diagnosing and treating patients with a variety of diseases encompassing the entire spectrum of severity. Patients with suspected respiratory tract infections, whether bacterial or viral, present to EDs with a range of unpredictable clinical courses, with a significant number at risk of progressing to critical illness caused by a dysregulated immune response that leads to organ dysfunction (sepsis) and death, as seen in severe COVID-19. In the setting of a pandemic or local outbreak caused by a novel pathogen or in situations where pathogen identification is limited, a pathogen-independent assessment of the host response could assist clinicians in the risk stratification of persons under investigation for infection by providing a patient-centered, objective assessment of the state of immune activity. The objective of this study was to assess the performance of IntelliSep test to stratify such a population for risk of sepsis and poor outcomes. Methods: The IntelliSep test is a novel in vitro diagnostic that quantifies the state of immune activation by measuring the biophysical properties of leukocytes from a routine blood draw sample in under 10 minutes. The test provides a single score, the IntelliSep Index (ISI), between 0.1-10.0 (inclusive), stratified into three discrete interpretation bands of risk for disease severity Green (0.1–4.9), Yellow (5.0–6.2), and Red (6.3–10.0), developed in prior sepsis-focused studies (O’Neal Jr., PLOS ONE, 2021). In a prospective study at a large academic medical center in Baton Rouge, LAA early in the COVID-19 pandemic (April 07 – April 28, 2020) and prior to widespread availability of rapid SARS-CoV-2 diagnostics, adult patients presenting to the ED with respiratory symptoms who had a CBC drawn within 4.5 hours of initial vital signs were enrolled. An aliquot from the CBC draw was tested, and patients were followed by retrospective chart review for outcome information. Sepsis disease status was determined by objective evaluation of infection (per modified CDC objective definitions), and organ dysfunction (defined as an increase in Sequential Organ Failure Assessment (SOFA) score of 2 or more points), and in select cases, physician clinical review. C-reactive protein (CRP) values were collected when ordered per standard care. Results: The 282 patients (34% SARS-CoV-2+) in the final analysis (observed sepsis incidence rate of 30.9%) were stratified by the ISI as 182 (64.5%) Green, 54 (19.1%) Yellow, and 46 (16.3 %) Red. The test achieved an area under the receiver operating curve of 0.85 (0.8 – 0.9, 95% CI). When comparing subjects in Green and Red Bands, negative predictive value and positive predictive value were 90% (78% – 96%, 95% CI) and 80% (68% – 90%, 95% CI), respectively, and a diagnostic odds ratio of 35.3 (22 – 48, 95% CI) was observed. Additionally, in the subpopulation of subjects with CRP ordered (N = 168), when compared to CRP with cutoff ≥ 75, the ISI showed superior negative predictive value (97.9% vs. 95.4%) in predicting all-cause 7-day mortality and positive predictive value is predicting the need for hospital stay of ≥ 2 days (94.4% vs. 87.3%). Conclusion: The ISI, a quantitative measure of immune activation, may offer a pathogen-independent means for rapid diagnosis and risk stratification for sepsis amongst ED patients presenting with respiratory symptoms, with the potential to aid physicians in improving outcomes and efficiency of care.