Sepsis is one of the most common and costly conditions encountered in hospitals and Emergency Departments (EDs) across the United States. Early recognition of sepsis is imperative to the initiation of aggressive therapy targeted at reversing physiologic derangements which, if left untreated, often lead to morbidity and mortality. Unfortunately, sepsis is a heterogeneous syndrome with highly variable manifestation and no “classic” presentation. While pathogen detection has often been the focus of advancements in infectious disease diagnostics, it is broadly recognized that dysregulated host response to the infection is the key cause of the downstream multi-organ dysfunction, morbidity, and mortality associated with sepsis (1). Currently, no rapid diagnostics exist with clinically actionable performance for early sepsis diagnosis in acute care environments; and ED clinicians, serving as the frontlines for diagnosing and treating patients with life-threatening conditions, must balance the benefits of early intervention against the risks of indiscriminate use of resource-intensive interventions.
As such, a rapid mechanism for the summative assessment of the complex host immune response could be invaluable in identifying those at highest risk of poor outcomes, while sparing others unnecessary interventions. The IntelliSep test attempts to fill this gap by quantifying the state of innate immune activity using the mechanical properties of white blood cells. These properties have been shown to differ in the septic patient when compared to those in the quiescent state, enabling rapid assessment of immune activation signatures and the diagnosis of sepsis (2). By leveraging microfluidic cell handling techniques in combination with the aid of the technological advances of high-speed imaging and machine learning, biophysical properties of thousands of cells can be analyzed in a few seconds and distilled into a score between 0.1-10.0, called the IntelliSep Index (ISI), providing a reflection of the state of activation of innate immunity from a routine blood draw sample in less than 10 minutes. To allow for easier clinical interpretation, the range is divided into three Interpretation Bands (Green, Yellow, Red) that correspond to increasing disease severity.
Multiple prospective development studies, carried out in patients presenting to the ED with signs or suspicion of infection, have demonstrated that the ISI is a reliable marker of sepsis and can provide clinically-actionable diagnostic performance. In a multi-site prospective study with a cohort of 290 adults presenting to the ED with signs or suspicion of infection, the test achieved a negative predictive value of 97% and a diagnostic odds ratio of 32.5, when comparing those stratified in the test Green and Red Bands to retrospective physician adjudication. In addition, the test has been shown to be capable of risk stratification based on severity of illness scores and hospital resource utilization, demonstrating its potential as a rapid sepsis assessment tool that is both diagnostic and prognostic (3).
Most recently, during the current COVID-19 pandemic, the ability of the ISI as a means for risk-stratifying those presenting to the ED with suspicion of SARS-CoV-2 infection was evaluated (4). The results of which concluded that the ISI rapidly identifies patients at high risk of adverse outcomes, including a 10-fold increase in mortality, increased severity of illness, and need for prolonged hospitalization, while also pinpointing those who may have self-limiting or more manageable infections and do not require the full scope of critical care interventions.
In summary, the ISI, a pathogen-agnostic direct assessment of white blood cell activation, allows for rapid quantification of host-immune response in an acute care setting, utilizing routine blood draw samples, requiring minimal operator input, and achieving a blood-to-answer turnaround time of <10 minutes. As such, it is anticipated to improve the identification, management, and treatment of sepsis.
- Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016.
- Crawford K, DeWitt A, et al. Rapid Biophysical Analysis of Host Immune Cell Variations Associated with Sepsis. Am J Respir Crit Care Med. 2018.
- Sheybani R, O’Neal HR Jr., et al. Rapidly assessing the host immune response for the diagnosis of sepsis, a prospective multi-site clinical study in the emergency department (ED) employing the leukocyte structural index (LSI), in American Association for Clinical Chemistry, 2020 Annual Scientific Meeting & Clinical Lab Expo, 2020, accepted.
- O’Neal HR Jr., Sheybani R, et al. Assessment of a cellular host response test to risk-stratify suspected COVID-19 patients in the Emergency Department setting. The American journal of emergency medicine, under review.