Could Measuring Host Immune Activation Hold the Key to Early Sepsis Detection?

Ajay Shah, MSME, PhD, is co-founder and CEO of Cytovale, a medical diagnostics company focused on providing rapid and insightful tools to improve early detection of fast-moving and immune-mediated diseases. An expert in cell-based diagnostic technologies, Ajay received his PhD from the Harvard-MIT Division of Health Sciences and Technology, where he developed a novel platform for circulating tumor cell isolation.

Sepsis is a leading cause of death in hospitals, taking the lives of about 270,000 people every year in the US—which is more than opioid overdoses, prostate cancer, and breast cancer combined. Sepsis also costs the US health system more than $38 billion each year. The mortality from sepsis increases as much as 8 percent for every hour of delayed treatment, and as many as 80 percent of sepsis deaths could be prevented with rapid diagnosis and treatment, making early detection essential. However, sepsis is often difficult to diagnose quickly and accurately, as it presents with undifferentiated signs and symptoms.

In February 2016, a task force assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine published new definition of sepsis (Sepsis-3), defining it as “life-threatening organ dysfunction caused by a dysregulated host response to infection.” The challenge with this definition is that dysregulated host immune response has not been directly measurable, requiring providers to piece together multiple tests and biomarkers, such as C-reactive protein (CRP), procalcitonin (PCT), and lactate. Unfortunately, elevation in these biomarkers is non-specific to sepsis and offers only moderate guidance about host activation. As such, the timely detection of sepsis represents an ongoing challenge.

Emerging host response technologies may offer new hope. One approach currently being developed attempts to evaluate the level of systemic immune activation by measuring biomechanical properties of tens of thousands of white blood cells (leukocytes), in a process similar to cytometry. It relies on the fundamental principle that cell structure follows cell function. As leukocytes become activated, their internal structure may undergo changes in a process known as NETosis. These structural changes alter how the cell responds to external stimuli. Since compared to quiescent cells, highly activated leukocytes have different responses to stimuli, measuring structural changes can reveal the level of activation of a group of cells.

White blood cell deformation in a septic patient (top) and a non-septic patient (bottom).

Cytovale

Based on that knowledge, a new type of test has been designed to quantify the state of immune activation by measuring the biophysical properties of leukocytes from a routine blood sample in less than 10 minutes. Designed for clinical laboratory use, the approach uses microfluidic cell-handling techniques (Figure 2) to apply pressure to leukocytes, then views their deformation using high-speed imaging. By applying machine learning, the test analyzes tens of thousands of leukocytes, yielding a score that provides a potential window into a patient’s immune activation state.

Early clinical evaluations of the technology appear to correlate with retrospective physician adjudication of sepsis. As such, the test may provide laboratorians with a much needed way to assess immune dysregulation, allowing them to better inform clinical decision-making, including rapid sepsis diagnosis and more confident triage of suspected sepsis patients.