Challenges and Advances in Sepsis Detection

Sudden high fever, severe pain, and extreme exhaustion that escalates to loss of consciousness, facing amputation and ventilation to save your life, surgery and postpartum complications escalating to death—these are the stark yet all-too-common stories of people who have experienced sepsis.

Sepsis is defined as a “life-threatening organ dysfunction caused by a dysregulated host response to infection.” Each year, it accounts for 20 percent of all global deaths, resulting in 49 million cases and 11 million related deaths. In the United States alone, sepsis is the leading cause of hospital readmissions, with 1.7 million readmissions and 350,000 related deaths annually.

Despite these alarming statistics, many sepsis-related deaths are preventable through rapid diagnosis and treatment. By contributing to fast and accurate identification of sepsis, clinical labs and professionals can thus play a critical role in saving lives. 

Challenges of sepsis detection

Sepsis detection presents numerous challenges, especially in emergency and intensive care settings. Patients at high risk of sepsis, such as older adults or those with chronic conditions like kidney disease or cancer, often present to the emergency department (ED), where clinicians may have limited information regarding the patient’s medical history and corresponding risk factors. The situation is even more complicated in the intensive care unit (ICU), where many patients are already experiencing organ failure, making it difficult to identify sepsis.

These challenges underscore the need for a sepsis test that is specific, sensitive, and rapid, ideally with a turnaround time of less than 10 minutes like the troponin test for detecting ST-segment elevation myocardial infarction (STEMIs) and CT scans for strokes. In the absence of a definitive test, current sepsis diagnosis and management relies on a clinician’s judgment of infection and inflammation symptoms. This reliance can result in missed diagnoses, as well as overtreatment of non-septic patients. In fact, a recent study indicated that ruling out sepsis based on ICU-level care would have missed 57 percent of patients who were ultimately diagnosed with sepsis. 

Innovations in sepsis testing

Tests for sepsis currently used in healthcare settings have been reported to have low sensitivity and specificity, and they are often too slow to support clinical intervention in a timely manner. Current tests include complete blood count (CBC) tests to measure immune cell activation indicative of infection, positive blood culture for specific pathogens, blood tests for some sepsis biomarkers, and imaging tests such as X-rays, CT scans, and ultrasounds to identify the source of infection. 

Given the need for superior sepsis detection, there are “newer offerings in this space from broad-range sequencing and multiplex nucleic acid amplification tests to pathogen agnostic methods assessing multiple biological markers,” wrote Tyler Radke, MLS(ACSP)CM, in a Today's Clinical Lab article reporting from ADLM 2024. These methods are promising for early sepsis detection because of three main reasons: First, sepsis can be diagnosed more rapidly by measuring the host response to infection rather than detecting the causative pathogen. Second, EDs and clinical labs often implement these tests within their standard workflows, reducing time, cost, and labor for setting up new workflows. Third, many new tests are relatively cost-effective, which Radke highlighted as an important factor because “sepsis care is typically paid under a bundled payment, meaning labs are not being paid for each test performed.”

Increasingly, pathogen-specific and host-response biomarker measurements have been integrated into clinical care to improve sepsis diagnosis and treatment. More than 250 biomarkers for sepsis have been proposed as of 2020, with procalcitonin (PCT) and C-reactive protein (CRP) being the most frequently studied. High initial PCT levels are observed in response to bacterial infection, thus PCT measurements have been used for early identification of sepsis and are predictive of sepsis-associated mortality. Similarly, CRP is significantly elevated in sepsis non-survivors. However, neither PCT nor CRP are sufficiently sensitive or specific to sepsis.

Thus far, no one biomarker can reliably distinguish sepsis from similar conditions. Additionally, rather than single values, it’s the kinetics of biomarkers that are more useful in predicting and diagnosing sepsis, as well as in assessing response to antibiotic therapy. Therefore, multi-biomarker tests and integrated biomarker-guided algorithms hold great promise when it comes to sepsis treatment.

Sepsis tests that are FDA-approved or in development

In recent years, the U.S. Food and Drug Administration (FDA) has approved new biomarker-based diagnostic tools aimed at improving sepsis detection. In 2024, the (FDA) approved the first cellular host diagnostic for use in the ED, called Intellisep. In the ICU study mentioned earlier, the cellular response was measured by study sponsor Cytovale’s new IntelliSep Index (ISI). Using microfluidics and deformability cytometry on a small blood sample, followed by ultrahigh-resolution imaging and high-throughput image analysis with machine learning, the ISI examines deformability characteristics of white blood cells. By analyzing biophysical changes in immune cells that occur early in the immune response to systemic infection, Intellisep results in a score that reflects the probability level of sepsis. According to Cytovale’s economic evaluation, the ISI strategy will have an expected patient cost of less than $4,000 and expected survival of 95 percent.

At the beginning of this year, the FDA also approved Inflammatix’s TriVerity™ platform for sepsis, which adopts a transcriptomic-based approach alongside machine learning to help triage patients so that clinicians can narrow down the best treatment pathway for each patient. Specifically, TriVerity evaluates a blood sample for 29 genes to identify the presence of a viral versus bacterial infection alongside the risk of progressing to severe infection within seven days, i.e., progression to needing mechanical ventilation, vasopressors, or renal replacement therapy. Since the TriVerity test can be run on a compact instrument at room temperature near the patient with no-prep workflow, it can be easily implemented within routine ED workflows. “The test provides three scores to answer three questions: Is there an infection? If yes, is the pathogen a bacterium or a virus? And, how severe is the infection?” explained Inflammatix cofounder, Purvesh Khatri, PhD, in a recent StanfordReport article. “Within 30 minutes, an emergency department physician knows to treat for bacteria or for a virus, and whether to admit the patient or send them home.”

New biomarker tests offer promise for treating sepsis

Sepsis remains one of the most significant challenges in global health care, with its high mortality rate underscoring the urgency for rapid and accurate detection. Recent advancements in biomarker-based testing alongside machine learning approaches offer hope for more effective detection and treatment. The continued development of these tools, including FDA-approved tests like Intellisep and TriVerity, demonstrates the potential to significantly improve sepsis management. As these technologies become more integrated into clinical practice, they may offer the precision and speed needed for early detection and intervention, reducing the global burden of sepsis.