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

Abstract

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.

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

“…Additionally, there are no accepted cut off values for procalcitonin in the diagnosis of sepsis in the ED, which makes a direct comparison of positive and negative percent agreement with the adjudicated standard difficult. Despite the small sample size of our study, our assessment of the performance of procalcitonin is similar to other studies evaluating its performance for similar application ( 36 , 37 ), and the performance of the ISI is also similar to our previous findings ( 16 ).…”

“…The median ISI for all patients was 5.2. Using the prespecified cut offs ( 16 ), 143 (53.8%) were in the green band, 66 (24.8%) in the yellow, and 55 (20.7%) in the red. There were no significant differences in baseline demographics (age, sex, and race) or comorbidities across interpretation bands, except for hypertension, which was more common in the red band patients (40 [72.7%]) than in green band patients (72 [50.3%]; p < 0.01).…”

“…The ISI ranges from 0.1 to 10.0 (inclusive) and is stratified into three discrete interpretation bands of risk for sepsis: green (low risk, 0.1–5.4), yellow (intermediate risk, 5.5–6.7), and red (high risk, 6.8–10.0). The algorithm for calculating the ISI and limits for interpretation bands were derived from prior investigation ( 16 ).…”

“…Our early work demonstrated that deformability cytometry that quantifies innate immune activation may be used to distinguish septic from nonseptic patients ( 15 ). More recently, we have expanded this work to develop the IntelliSep Index (ISI), a quantitative measure of the changes in cellular structure exhibited during the activation of the host immunity, which distinguishes sepsis from nonsepsis with an area under the curve of greater than or equal to 0.9 ( 16 ).…”

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

“…By assessing the biophysical properties of thousands of leukocytes [ 15 , 16 ], we are able to quantify the state of innate immune activation in the Intellisep Index (ISI) [ 17 ], which we have shown to have the potential to be a rapid, reliable diagnostic for sepsis in patients presenting to the emergency department with signs or suspicion of infection [ 18 ]. To explore the utility of the ISI in the setting of a pandemic caused by a novel pathogen, we conducted a prospective, observational study of patients presenting to the ED of a large academic medical center with respiratory symptoms early in the COVID-19.…”