Host Response Diagnostics: How It Works for Sepsis Detection

It is widely recognized that dysregulated immune response of the host is the primary driver of the multi-organ dysfunction, morbidity, and mortality associated with sepsis.¹ Yet, traditional diagnostics primarily focus on identifying pathogens, often overlooking the most crucial aspect of the condition. As a result, clinicians frequently face delays or uncertainties in diagnosing sepsis accurately, since pathogen detection alone may not adequately reflect the severity or the presence of sepsis. Host response diagnostics take a new, targeted approach by directly assessing the patient’s immune response to infection.

By shifting the diagnostic focus from pathogens to immune activation, clinicians can more rapidly and reliably detect sepsis, potentially improving patient outcomes.

What Is Host Response Diagnostics?

Host response diagnostics are tests that directly measure a patient’s immune response to infection. In response to an infection, cells of the innate immune system—such as neutrophils and monocytes—are activated at the site of infection to fight pathogens. A cascade of events follows, causing these immune cells to become highly active and behave differently from cells in a resting state.² These events include chemotaxis, phagocytosis, cytokine signaling, generation of reactive oxygen species (ROS), release of microbicidal granular contents, and in some cases, ultimately, the expulsion of neutrophil extracellular traps (NETs) into the extracellular space.^3,4

Normally, this immune activation remains localized and effective in fighting infection. In sepsis, however, it becomes systemic and uncontrolled, triggering a widespread proinflammatory cascade.⁵ This cascade can result in tissue injury and the multi-organ dysfunction associated with the syndrome.⁶

Host response diagnostics identify and quantify these changes in immune cell behavior, providing clinicians with actionable, real-time insights into a patient’s likelihood of having or developing sepsis.

How Can Host Response Diagnostics Help with Sepsis Detection?

Unlike traditional biomarkers which tend to be nonspecific and often measure inflammation or organ dysfunction, host response diagnostics aim to directly assess the state of immune activation in response to the infection. These advanced diagnostics provide distinct benefits, including:

• Speed—Results are often more rapidly available for quicker decision-making

• Accuracy—Direct measurement of the immune response for precise risk stratification

• Actionability—Clinically relevant outputs for appropriate patient management

Broadly, these new markers can be classified into three general groups: ⁷

• Biophysical measurement of white blood cells: These tests use a flow cytometry-like approach, with digital imaging and a pre-validated algorithm to assign a sepsis risk score. By directly measuring the changes in white blood cells, these technologies provide a rapid assessment of the complex host immune response and can easily be incorporated into ED workflows. Example: Cytovale’s IntelliSep test.

• Transcriptomic multi-analyte panels: These blood tests analyze immune cell activity by evaluating patterns in gene expression. RNA transcripts from multiple genetic markers are combined with mathematical algorithms and data sets from thousands of patients to form diagnostic tests that can distinguish sepsis from non-infectious SIRS (Systemic Inflammatory Response Syndrome), bacterial from viral infection, or determine the need for escalated care. Although RNA is the most dynamic cellular component and provides real-time insights of what is occurring in the cell, these approaches require time-consuming amplification and detection of molecular genetic signatures.7 They also may not easily integrate into existing ED workflows, depending on how the results are reported.

• Artificial intelligence-driven algorithms: These methods use preexisting medical record data to predict sepsis risk without requiring additional testing⁷ and may require little effort for integration into the electronic health record. However, as they rely on data and test results being entered into the patient’s chart, they are often retrospective rather than prognostic in an ED setting, and their performance varies widely.

How the IntelliSep Host Response Test Improves Sepsis Diagnosis

The IntelliSep test is an FDA-cleared early sepsis diagnostic for patients presenting to the ED with signs and symptoms of infection. It utilizes a microfluidic deformability cytometry technique to measure the properties of thousands of individual white blood cells in swift succession to assess the state of immune activation in less than 10 minutes. The result, a score between 0.1 and 10.0, is stratified into three interpretation bands of increasing sepsis probability. The test’s fast turnaround time, notable performance characteristics,⁸ and easy-to-interpret results, facilitate its integration into existing ED processes. A recent study highlighted that once integrated into an ED protocol, the test has the potential to significantly impact sepsis-associated patient outcomes.⁹

The field of host response diagnostics has the potential to revolutionize early sepsis diagnosis and vastly improve patient outcomes by addressing the heart of sepsis as it is known today, a dysregulated host response to infection.

Contact the Cytovale team to learn more.

References

1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016.

2. Crawford K, DeWitt A, Brierre S, et al. Rapid biophysical analysis of host immune cell variations associated with sepsis. Am J Respir Crit Care Med. 2018.

3. Mayadas T N, Cullere X, Lowell C A. The Multifaceted Functions of Neutrophils. Annu. Rev. Pathol. Mech. Dis. 2014.

4. Granger V, Faille D, Marani V, Noël B, Gallais Y, Szely N, Flament H, Pallardy M, Chollet-Martin S, de Chaisemartin L. Human blood monocytes are able to form extracellular traps. J Leukoc Biol. 2017.

5. Cinel I, Opal S M. Molecular biology of inflammation and sepsis: A primer. Crit Care Med. 2009.

6. O’Brien J M, Ali N A, Aberegg S K, Abraham E. Sepsis. Am J Med. 2007.

7. Chambliss AB, Devaraj S, Hinson JS, Katz SE, Kerbel RB, Ledeboer NA. New Sepsis Diagnostics and Their Impacts on Clinical Decision-Making and Treatment Protocols. Clin Chem. 2024.

8. O’Neal HR Jr, Sheybani R, Kraus CK, Self WH, Shah AM, Thomas CB, Tse HTK, Scoggins R. Cellular host response sepsis test for risk stratification of patients in the emergency department: A pooled analysis. Acad Emerg Med. 2024.

9. Thomas C B, Wyler B, D’ Antonio C M, et al. Improving Sepsis Outcomes: Insights from a Quality Improvement Initiative on Clinical and Operational Performance. Am J Respir Crit Care Med. Under Review.