At Last: First Breakthrough FDA-Approved Test for Sepsis Unveiled

Every hour of delay in diagnosing sepsis is associated with 4 to 9% increased mortality

The mere mention of sepsis sends a shudder down my spine. It takes me back to that fateful day a few years ago when my father was rushed to Apollo Hospitals in Chennai, India for a gall bladder surgery, due to a looming infection. While the surgery was messy, he appeared to be on the mend. Then, an unexpected infection struck, swiftly landing him in the emergency ward. Within days, his once hopeful recovery took a harrowing turn as his body faltered, organs failing in succession. The attending doctors delivered the devastating news too late: sepsis had taken hold. My dear father was on life support and I couldn't do a damn thing! It was one of the worst days of my life and the memory is still raw.

Fueled by frustration towards the doctors, I delved into researching sepsis. Sepsis (or septicemia) is an overwhelming and dangerous whole-body immune response to an infection or an injury to the human body. Instead of the immune response being localized to fight the infection, it becomes widespread and dysregulated, releasing large amounts of inflammatory cytokines that start to damage the body's own tissues and organs. This dangerous overreaction by the immune system to the original bacterial trigger is what defines the life-threatening condition of sepsis, which occurs unpredictably and can progress rapidly. In the worst cases, blood pressure drops, the heart weakens, and the patient spirals toward septic shock - when multiple organs quickly fail, and the patient inevitably dies. Once, the cascade of events begins, even the strongest antibiotics are often powerless to stop the progression of this dysregulated inflammatory response.

A key factor that leads to such a dysregulated and excessive immune response is gut dysbiosis -- an imbalance in the gut microbiome. A healthy gut microbiome helps regulate the immune system, so disruptions can lead to an excessive inflammatory response. Other factors include environmental toxin exposures, genetic defects impacting immune regulation, and the aging process.

Each year, according to the Centers for Disease Control and Prevention (CDC), sepsis is the leading cause of death in hospitals with at least 1.7 million adults in the U.S. developing sepsis, and nearly 270,000 dying as a result. It is also the most expensive condition, costing an estimated $62 billion annually in hospitalizations and skilled nursing care. As shown in the figure, there is clear evidence that delays in diagnosing and initiating treatment for sepsis are associated with substantial increases in mortality risk, ranging from around 4-9% higher mortality for every hour of delay. Furthermore, failure to consider sepsis as a potential diagnosis early on contributes to deadly delays in a significant proportion of cases. Prompt recognition and timely treatment emerge as critical factors in reducing sepsis mortality.

Procalcitonin (PCT), a protein produced by cells in response to bacterial infections, is used as a biomarker to help diagnose and manage sepsis and other bacterial infections. Higher PCT levels are associated with greater risk of severe sepsis, septic shock, and mortality. However, PCT as a diagnostic tool could lead to some cases being missed (false negatives) or incorrectly identified as septic (false positives), given that it has a sensitivity of only 75% and specificity of 79% for detecting sepsis in the emergency department setting. In fact, the aforementioned study found 4 patients with positive blood cultures had PCT levels ≤0.1 ng/mL, suggesting PCT may miss some true sepsis cases very early on. Furthermore, PCT can be elevated in some non-infectious inflammatory conditions such as adrenal failure, after stem cell transplants. It is clear that a rapid, targeted and highly predictive test for diagnosing sepsis is desperately needed.

First and Only Rapid FDA-approved Test for Diagnosing Sepsis

Cytovale, a medical diagnostics company focused on developing early detection technologies, recently received FDA 510(k) clearance in December 2022 for IntelliSep test, which aids in the rapid diagnosis of sepsis for adult patients with signs and symptoms of infection in emergency departments. It provides results in under 10 minutes by analyzing biophysical properties of white blood cells from a standard blood sample to assess the body's immune response. IntelliSep applies a technique called "deformability cytometry" which measures how the white blood cells deform or change shape under certain pressures. White blood cells from septic patients exhibit distinct biophysical changes and deformation patterns compared to healthy cells when analyzed by the IntelliSep system. Using proprietary algorithms, IntelliSep is able to detect these cellular deformation "signatures" indicative of dysregulated immune activation seen in sepsis. Based on this cellular analysis, the test generates an "IntelliSep Index" value that categorizes patients into one of three bands indicating low (Band 1), moderate (Band 2) or high (Band 3) probability of sepsis within 3 days.

The IntelliSep test was evaluated in a blinded, prospective, observational, multicenter cohort study (CV-SQuISH-ED; ClinicalTrials.gov Identifier: NCT04933760); the primary analysis included 572 patients who ranged in age from 18 years to 103 years and presented to the emergency department.  These patients had infections affecting or originating from all major organ systems. Of the total cohort, 152 patients were ultimately diagnosed with sepsis. Researchers examined the test's performance across three interpretation bands, each representing different probabilities for sepsis. They discovered that among the 160 patients categorized in Band 3 (high probability), 79 had sepsis, resulting in a positive predictive value of 49.4%. Similarly, 45 out of 160 patients in Band 2 were diagnosed with sepsis, yielding a positive predictive value of 28.12%. In contrast, emergency department (ED) providers identified only 52 (34.2%) out of the 152 patients with sepsis, as stated in the abstract. According to Dr. Hollis R. O’Neal, medical director of research at Our Lady of the Lake Regional Medical Center and critical care physician at LSU Health Sciences Center, the findings show the potential of the IntelliSep test as a groundbreaking diagnostic tool to help clinicians quickly make critical, time-sensitive decisions and focus their resources where they are most needed. He also observed that the bands trended strongly with both hospital care metrics and sepsis-based mortality. 97% of those who were categorized as low sepsis probability (Band 1) did not have sepsis upon adjudication. At the same time, about 50% of those who received a high probability score (Band 3) were adjudicated as having sepsis.

SEP-1 refers to the "Severe Sepsis and Septic Shock: Management Bundle" guidelines issued by the Centers for Medicare & Medicaid Services (CMS) for treating sepsis in hospitals. SEP-1 was first implemented by CMS in October 2015 as a quality measure for hospitals to follow in managing severe sepsis and septic shock cases. It is a lengthy and complex bundle of care requirements that clinicians must provide to all patients with possible sepsis within 3 hours, including drawing blood cultures, administering broad-spectrum antibiotics, and other interventions. The guidelines are quite prescriptive in terms of the diagnostic criteria, time frames, and interventions required to comply with SEP-1 for appropriate sepsis management. IntelliSep can support hospital needs to meet these SEP-1 guidelines and report to CMS for Medicare/Medicaid reimbursement purposes.

Independent research from Penn State University, found that IntelliSep test demonstrated superior diagnostic accuracy and predictive ability for early sepsis detection compared to the more established PCT biomarker, especially among emergency department patients with suspected infections. While PCT is still considered valuable, the evidence suggests IntelliSep's rapid cellular analysis approach provides a new level of diagnostic performance and actionable risk information to clinicians for enabling more accurate and expedited sepsis identification in acute care settings, compared to soluble biomarkers such as PCT.

Takeaway: If you or a loved one find yourselves in a situation where the emergency room physician suspects sepsis, ask them about the IntelliSep test. If the hospital doesn't have the IntelliSep test yet, make sure they measure PCT.