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Mass General Developing Test for Very Early Detection of Sepsis

NEW YORK (360Dx) – Researchers at Massachusetts General Hospital are developing a microfluidic device that monitors the movements of neutrophils as part of a test that could eventually detect sepsis before doctors even suspect their patients have the infection.

The researchers said in a paper published online this week in Nature Biomedical Engineering that the test is highly accurate in identifying patients that have the infection, and it could guide the development of new treatment regimens for sepsis that correct neutrophil activity.

Although the technique may still be many years away from being implemented in a commercial product, it has shown high sensitivity and specificity for identifying sepsis, Daniel Irimia, one of its developers and deputy director of the BioMEMS Resource Center at Mass General, said in an interview. In a double-blind observational study of 42 patients, the approach demonstrated 97 percent sensitivity and 98 percent specificity.

The assay is a microfluidic device that consists of an intricate arrangement of migration channels and mazes that enable measurement of the spontaneous motility of neutrophils in the presence of plasma. Measurements of neutrophil migration patterns "revealed significant differences" between patients who have sepsis and those who don't, the researchers said.

The Mass General researchers obtained a few milliliters of blood from patients suspected of sepsis. After separating the neutrophils from blood, they primed the microfluidic device with a chemical agent and introduced the neutrophils into a loading channel. They used time-lapse imaging to observe the behavior of the neutrophils at single-cell resolution as the cells moved through channels and mazes.

Using migratory parameters, the system calculated a neutrophil spontaneous motility score for each sample, and the researchers then tested correlations between their neutrophil scores and sepsis in patients. They noted that they developed the scoring system using machine learning and data from the patient cohort. When a drop of blood fills microscopic channels, the machine-learning algorithm correlates the movement of neutrophils with sepsis severity to calculate the score.

Irimia said that this type of test has the potential to determine within a few hours whether a patient has sepsis. Patients and clinicians wouldn't have to wait for a blood culture that can require days before enabling clinical action when it is used in combination with other diagnostic tests.

"It's very important to have a definitive and objective test for diagnosis of sepsis, as any delay…reduces the chances of survival for the patient," Janet Lord, a sepsis researcher and director of the University of Birmingham’s Institute of Inflammation and Ageing, said in an interview. "This test could improve on the current largely clinical criteria used for diagnosis," but it requires further technical development to make it easy to use and apply in a clinical setting, she added.

Irimia noted that he and his colleagues want to move the test "as far as we can go" along a commercial path. However, on average this type of device takes five to 10 years to develop, and it can cost more than $100 million to take a prototype to market, he said. When the timing is right, he noted, his team plans to turn over the test to people in a diagnostics company experienced in doing research and development of commercial tests.

The Mass General sepsis assay is different from others on the market because it evaluates one type of cell, the neutrophil, which produces an immediate immune system reaction to a sepsis infection, Irimia said. "The finding that the cells are completely altered during sepsis is rather new and unexpected," he said.

Neutrophils have a high sensitivity to infections, yet measurements of neutrophil surface markers, genomic changes, and phenotype alterations have in the past had only a marginal effect on sepsis diagnosis, the researchers noted in their paper. In the microfluidic assay, by contrast, they were able to measure the spontaneous motility of neutrophils in the presence of plasma using one drop of blood.

The researchers obtained blood samples for neutrophil testing from patients in the intensive care unit at Massachusetts General Hospital, which included patients with and without sepsis. Half of the patients without sepsis had systemic inflammatory response syndrome, or SIRS.

Biomarker options

The market for sepsis tests has become increasingly competitive as established companies and new entrants jostle for share in a clinical space that's of increasing concern for patients and clinicians.

Current tests, including FDA-cleared products, look for elevated markers indicative of the presence of sepsis, such as C-reactive protein, procalcitonin, and interleukin-6, or they leverage assays that look for specific pathogens that cause the infection.

Because some clinicians are dissatisfied with the performance of current tests, researchers are developing new solutions. The Mass General researchers noted that although sepsis is a life-threatening condition in which the body’s extreme response to severe infection damages tissues and organs, it is misdiagnosed in about 30 percent of patients.

The US Food and Drug Administration has cleared procalcitonin protein biomarker tests that are used by clinicians along with blood cultures and other tests in diagnosing sepsis. The tests include procalcitonin assays produced by Roche, BioMérieux, and Thermo Fisher Scientific among others. In February 2017, the FDA granted clearance for the expanded use of BioMérieux's Vidas Brahms PCT Assay to help healthcare providers determine if antibiotic treatment should be started or stopped in patients with lower respiratory tract infections and stopped in patients with sepsis.

One of the potentially beneficial outcomes of the Mass General assay, if commercialized, is that in addition to other applications, it has potential to enable clinicians to more quickly decide whether patients should take antibiotics or not, Irimia said.

Some researchers and clinicians are concerned about the utility of procalcitonin as a marker that guides antibiotic treatment.

Inflammatix, a spinout from Stanford University, is using gene expression markers to develop a sepsis test that could enable physicians to quickly decide whether to prescribe or withhold antibiotics. Inflammatix CEO and Cofounder Timothy Sweeney said he does not see procalcitonin as a perfect marker, and that there is room for alternatives.

Researchers have also explored changes in neutrophil biomarkers, such as the increased expression of the CD64 surface receptor, and found them to be sensitive not only to infections but also to major inflammatory states, such as SIRS.

Irimia noted that in evaluating a patient for sepsis, a clinician can implement both types of test, one to measure the host response and another to identify the pathogen.

A larger clinical trial involving 200 patients is among the next steps for his research group, he noted. In that study, the group expects to find how soon they can detect sepsis in the life cycle of the infection.

"There are many important questions that still need to be answered," Irimia said. For example, because most patients who become infected with sepsis are very sick and go to hospitals that have laboratories, a point-of-care version may not be necessary, he noted. However, if it's needed, the microfluidic device has all the characteristics of a point-of-care test.

The microfluidic device's high correlation between neutrophil motility and the onset of sepsis suggest that it could have a number of clinical applications, he said. For example, developing drugs that restore neutrophils to a phenotype seen in healthy individuals could be a clinical option. Here, the microfluidic chip could be developed as a screening assay used to test the effects of new therapies on neutrophils. It could be implemented in a 96-well format whereby a clinician, using a few milliliters of blood, could test the effects of several drugs as they target neutrophil function, Irimia said, adding the test could also be used to monitor patients over time — before, during, and after sepsis.