NEW YORK ─ As it prepares a submission to the US Food and Drug Administration for clearance of a 10-minute, direct-from-blood test for sepsis, Cytovale is simultaneously evaluating the potential of its technology to predict the risk for adverse health outcomes for individuals presenting to an emergency department with symptoms of COVID-19.
The San Francisco-based firm is wrapping up a multisite clinical study it believes will lead to a regulatory clearance for marketing its test in the US. Called the IntelliSep Index (ISI), the test is for use by emergency department physicians who are seeking to rapidly diagnose and risk-stratify individuals suspected of having sepsis, said Hollis O'Neal, a critical care physician at the Louisiana State University Health Sciences Center and a principal investigator of the study.
At the same time, following a study recently published in PLOS One, Cytovale is exploring the potential for the use of ISI to evaluate the risk of patients infected with SARS-CoV-2 of having either a severe or mild illness, said O'Neal, who is also an author and principal investigator of the recently published study.
In the PLOS One study, O'Neal and his colleagues evaluated the clinical utility of ISI using samples from 282 patients presenting with respiratory complaints at the emergency department of Our Lady of the Lake Regional Medical Center in Baton Rouge, Louisiana.
Enrollment began early in the pandemic when SARS-CoV-2 was an emerging infection and physicians struggled to assess and treat patients, O'Neal said, adding that he and his colleagues tried out multiple biomarkers, including C-reactive protein, procalcitonin, and ferritin, "looking for a clue about how sick patients could be."
With none of the markers panning out, O'Neal decided to test the correlation between the ISI platform's results and near-term health outcomes for patients entering the emergency department.
O'Neal, an adviser to Cytovale and a pulmonology critical care physician at Our Lady of the Lake Regional Medical Center, said about two-thirds of the patients enrolled in the study were tested for SARS-CoV-2 and about one-half were positive for the infection based on PCR test results.
The investigators also found that the IntelliSep Index was "a very good predictor of adverse outcomes in those patients who tested positive for SARS-CoV-2," with a sensitivity level greater than 90 percent, O'Neal said.
The test system evaluates whether the immune system has become active and dysregulated in response to an infection by combining high-speed imaging and artificial intelligence to examine structural changes in neutrophils and monocytes, the cells of innate immunity.
The system first lyses red blood cells from the sample and then suspends the white blood cells in a solution that is fed into the IntelliSep analyzer.
Pressurized air pushes the random assortment of white blood cells in fluid into microfluidic channels. The cells become aligned and move in one direction, colliding with fluid moving in the opposite direction. A camera capturing 500,000 to 600,000 frames per second records the collision, and the system uses artificial intelligence to identify cells that reflect an activated immune system by their shape.
Based on this evaluation of shapes, the test compiles a score on a scale of 0.1 to 10.0, with 10.0 representing an immune system that is most active.
In the study, individuals with a score of 0.1 to 4.9, a range represented by a green band on the ISI test's display, were assigned a low level of risk for an adverse health outcome. Individuals with a score of 5.0 to 6.2, represented by a yellow band, were deemed to be at intermediate risk, and individuals with a score of 6.3 to 10.0, represented by a red band, were deemed to be at high risk.
The ISI score told us "who will develop severe hypoxia, who is at risk of dying, and who is at risk for being admitted to the hospital intensive care unit within three and seven days of testing," O'Neal said. "Ultimately, we saw that the test could be used to risk stratify patients in a pandemic caused by a novel pathogen that we didn't understand."
If it can be made broadly available, such a test "would help emergency departments understand who they need to admit and who they can send home," O'Neal added.
According to Tim Sweeney, cofounder and CEO of Burlingame, California-based Inflammatix, the PLOS One study is "one more piece of evidence that profiling the innate immune response can be informative for prognosis in patients in the emergency department."
In January, Inflammatix demonstrated similar findings using a 6-mRNA host response classifier as part of a study published in Scientific Reports, said Sweeney, who is not affiliated with Cytovale.
"That said, the challenge of any new test is to provide physicians with actionable information," Sweeney said. "Physicians are pretty good at conducting risk stratification at baseline, and so a test for decompensation risk must provide additional power beyond a physician’s inherent judgement. It is critical to measure new risk parameters in conjunction with the standard of care, not just on their own."
While it explores the potential of its technology for risk stratification during a pandemic, Cytovale is also analyzing the information it has gathered during a study to evaluate and validate ISI as a test for sepsis. The study enrolled about 600 patients at Louisiana State University, the University of Washington, the University of Missouri, and Wake Forest University.
Though the results of the current study are not pubic, ISI in past studies has demonstrated a negative predictive value of 90 percent or more, said O'Neal, adding, "Just as important for sepsis diagnostics, the index is a strong predictor for those patients whose conditions will worsen and will need admission to the ICU."
Similar to Cytovale, a few companies including Inflammatix are developing rapid diagnostic tests for sepsis and seeking to provide actionable results without requiring a time-consuming blood culture.
For example, Wiltshire, UK-based startup Presymptom Health is developing an RNA-expression test that would run on PCR platforms in hospital laboratories connected with emergency departments.
T2 Biosystems, with two direct-from-blood testing panels in the market, continues to see revenue growth from its FDA-cleared T2Bacteria and T2Candida panels for sepsis which provide test results within a few hours.
With the aim of achieving better penetration in the market for sepsis and bloodstream pathogen identification and antimicrobial susceptibility testing, Tucson, Arizona-based Accelerate Diagnostics is launching two new products this year and is developing a third that operate from a positive blood culture.
In February, Cytovale announced it had received additional funding from the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority to ramp up manufacturing of its IntelliSep sepsis risk stratification test, bringing its total BARDA funding to $9 million.
If the firm can obtain FDA clearance for ISI as a sepsis diagnostic test, it will pursue reimbursement and seek to show that the tool can save costs by enabling a focus on patients who most need treatment, according to O'Neal.
Longer term, the firm may seek FDA authorization or clearance for ISI to stratify patients at risk of severe disease due to a viral infection, he said.
Sweeney noted that risk assessment is part of the equation for evaluating health outcomes for patients presenting to emergency departments, but physicians also need to quickly make other critical decisions such as whether to treat with antibiotics and order additional diagnostic tests.
"Effecting a practice change in early emergency department triage will probably require more comprehensive data about both risk and infection status," Sweeney said.