Sepsis is the overwhelming response of the body’s immune system to infection, leading to life-threatening tissue and organ damage. The condition is poorly understood, hard to diagnose, and currently kills 30-50% of those with a confirmed diagnosis in the developed world and 60-80% of those diagnosed in developing countries. Sepsis is estimated to be the most common cause of death of hospitalized patients, and typically kills more people in Europe and North America annually than bowel, breast, and prostate cancers combined.
Seattle-based in vitro diagnostic company Immunexpress has developed the first FDA-approved sepsis diagnostic test, SeptiCyte, which is capable of diagnosing sepsis directly from a sample of blood in a matter of hours.
Medgadget editor Tom Peach sat down with Rolland “Rollie” Carlson from Immunexpress to hear more about the company’s SeptiCyte platform and what the future of sepsis diagnosis and treatment may look like.
Tom Peach, Medgadget: It’s a pleasure to meet you Rollie. Could you please tell me a little more about your role at Immunexpress and the journey that led you there?
Rollie Carlson: I am the CEO of Immunexpress, having joined the company about four months ago. Before joining the team, I was aware of Immunexpress for a good four or five years because my former company, Asuragen, had collaborated with Immunexpress to develop reagents and a testing platform for the FDA registration trial of Immunexpress’ SeptiCyte™ product.
I was brought into Immunexpress to extend the work of the scientific founders and to both finalize the development of the product and start commercialization. Immunexpress has a fantastic technology that is addressing a huge unmet need—and in a clinical area where we really need to make a difference.
I’ve been in Biotech for a number of years, originally with Abbott laboratories, where I was hired out of Post-Doctoral research in Marine Biochemistry. Since then, I’ve had pharmaceutical and diagnostic business responsibilities in similar companies over the last 30 years or so with a particular focus on oncology and infectious disease. My role has been to take products into new markets by building on excellent science and clinical groundwork.
Medgadget: What is the history of Immunexpress and the science that underpins the company’s in-vitro diagnostic products?
Carlson: The company was founded in 2006 by a brother-sister veterinary team based in Australia, each with a research background in molecular biology and biochemistry. They observed something very interesting in the veterinary world, which is that horses are the only other organisms to have a sepsis-like response that is similar to humans. This led to research in horses that had become septic. After gene profiling, the founding team of Immunexpress found a link to a number of genes in which upregulation could distinguish between true pathogen-induced sepsis and the less severe SIRS (Systemic Inflammatory Response Syndrome).
This work led to collaborations in the U.S. and Europe, especially the Netherlands, on human samples. From there, next generation sequencing of the human genes showed similar effects as observed in the equine model. These findings were combined with bioinformatics and machine learning to isolate the specific set of genes that are capable of identifying sepsis in humans. We can now distinguish between the sepsis cascade initiating in a patient, whose life is at risk if not rushed to the ICU, and a patient with SIRS, who should be treated with watchful waiting.
Medgadget: How is a sepsis diagnosis currently made and why is it so important to distinguish between sepsis and SIRS (Systemic Inflammatory Response Syndrome)?
Carlson: Currently sepsis diagnosis is rather inconsistent, depending on the hospital or institution; there’s no definitive “Gold Standard” to distinguish between sepsis and SIRS. A clinician will have a suspicion of sepsis from multiple clinical signs, ranging from fever or chills to elevated white blood cell count, and from that they will make a diagnosis. Even when a patient has gone through the full sepsis cascade, the diagnosis is still made through a combination of blood chemistry and clinical observations, with the ultimate option being blood culture—which takes 24-48 hours. If a blood culture is done, a septic patient only shows a positive blood culture result around 20% of the time. As such, the default position of most clinicians is to place all patients suspected of sepsis on antibiotic therapy, regardless of the presence of a septic infection. Major research across a number of populations has indicated almost half of those patients don’t need to go on antibiotics—but hesitancy of clinicians who really don’t want to miss a sepsis case commonly leads to overtreatment. The problem of balancing the risk of sepsis with overtreatment has led to clinicians being retrained with a series of “if this, then that” decision guidelines, known as “sepsis bundles,” in an attempt to try to refine the diagnosis process.
Our test sits at the top of the diagnostic decision tree, in which a clinician takes a patient presenting with two or more signs of sepsis, and then determines if that patient is could begin to experience the sepsis cascade or is suffering from SIRS. It is an important distinction to make, as it will probably determine which patients a hospital is able to admit to the limited number of ICU beds.
Medgadget: Immunexpress’ SeptiCyte received FDA clearance last year (2017). How is the system going to be integrated into the diagnostic pathway, and when can we expect to see the test in clinical use?
Carlson: The proof in principle of our technology was a prospective clinical trialthat we conducted across seven sites and 447 patients. One thing that became very clear in the trial was the fundamental dilemma in sepsis diagnostics: there is no Gold Standard diagnosis for being septic to compare our test to. Even when blood culture is taken, only around 20% of septic patients will show a positive blood culture result. Additionally, there is discrepancy amongst clinicians in diagnosing sepsis when the blood culture is not positive.
In the trial, our test correctly diagnosed every single one of those 20% of patients with a positive blood culture, but for the other patients we had to rely on a three-person expert committee who determined the diagnosis as to whether a patient had sepsis or SIRS. Only 65% of the time all of the experts agreed on the diagnosis, and only 25% of the time did two agree—so in 10% of cases none of these three experts in the field agreed on the diagnosis. This is especially concerning as the opinion of three experts is probably the best Gold Standard currently available.
Knowing that we have an effective diagnostic product, our next goal is to improve the time for the assay to give a result. The first iteration of our assay typically took six to eleven hours to give a result, which was too long in an environment in which a sepsis patient’s risk of mortality increases at around 8% per hour. An effective test also needs a very fast turnaround. We plan to apply our previously FDA-cleared technology to a sample-to-result platform that can produce a report in under 90 minutes. We’re currently working with a Belgian company, Biocartis, on realizing that goal using their Idylla™ platform in a very easy to use setup that is essentially a “sample to answer” system.
We expect to have a Research Use Only (RUO) product coming out of that collaboration by the end of the year, which we hope to then rapidly move through the CE-IVD process by mid-2019. We’ll then use that product for investigative use only—so not making clinical calls—in a number of ICU environments to begin familiarizing users with how to integrate the test into their diagnostic decisions after we get device approval.
Medgadget: What are the benefits of Immunexpress’ technology for both patients and clinicians?
Carlson: The benefits are really two-fold for patients: both a more accurate diagnosis and a faster triaging of that septic event following a positive result. Overall, this leads to better clinical outcomes for patients. We are no longer waiting for a blood culture to be completed while a patient is proceeding down the sepsis cascade, which is increasing the mortality risk to the patient with each passing hour.
Better treatment of patients is clearly important for clinicians and hospitals, but our test also allows for a patient to be put in the right place at the right time. With an accurate diagnostic tool, a hospital no longer filling its ICU with patients who are not in a critical care situation. Now if our test says a patient does not have sepsis, that patient won’t just be discharged—a patient would instead be placed on a ward for monitoring, and they may take a precautionary oral antibiotic. But that is far more preferable to placing a mainline catheter, admitting the patient to the ICU for three days, and administering a level of antibiotics that they really don’t need.
Medgadget: Finally, what do you think the future will hold for Immunexpress and in-vitro diagnostic (IVD) field more generally?
Rollie Carlson: I sincerely believe that Immunexpress’ technology has the ability to become the Gold Standard of sepsis diagnosis that we currently do not have and desperately need. That leads to some great commercial opportunities for Immunexpress, both domestically and more globally. In most European and North American areas, sepsis in adults is associated with bacteria, but when you move into paediatrics, there are many more cases of virus-induced sepsis. The prevalence of virus-induced sepsis is also generally much higher across both adults and children in areas like Asia. In the future, we plan to have a diagnostic pipeline that is capable of distinguishing the precise cause of sepsis in each case.
In the IVD field more generally, we are experiencing rapid advances in technology, leading to increasingly sensitive gene-detection tools, faster turnaround times, and dramatically lowered costs. I think the industry is going to see a number of opportunities related to more specific management of sick patients—currently the broad-spectrum antibiotic therapy given to patients is the nuclear option, but the resistance we’re seeing to antibiotics in hospitals is very troubling. Clinicians are looking to IVDs to provide patient-specific indications of the right treatment for a specific organism—be that an antibiotic, antiviral or antifungal.
Link: Immunexpress homepage…