Diagnosing sepsis: Patients need precision

Vanessa Almendro is a Ph.D. scientist and MBA who has worked in healthcare for her entire career. She also takes care of her own health: When she contracted a mild bacterial infection eight years ago, she followed the standard treatment guidance at the time. But even with her education, experience, and access to high-quality medical care, she was still caught off-guard by a misunderstood condition with a nearly 30% mortality rate1: sepsis.

“Even for a person like me, there’s a lack of awareness,” she said. “I didn’t know the symptoms. I just thought I had back pain and a fever that I attributed to a cold or the flu, but I didn’t connect the two symptoms.” Instead, she landed in the hospital with an antibiotic-resistant blood infection – and doctors who weren’t sure they could successfully treat it.

Sepsis arises when the body’s response to an infection injures its own organs and tissues. It affects some 50 million people each year and is responsible for a shocking ~20% of deaths globally1. Like cancer, sepsis is not a single disease, but rather a broad clinical syndrome without a one-size-fits-all approach. The problem is that doctors lack the diagnostic capabilities to determine what type of sepsis a patient has or to guide their treatment decisions and post-sepsis care.

Almendro – who is now Vice President, Head of Science & Technology Innovation at Danaher – recognized that the severity of her symptoms was unusual for the flu and went to the ER. “At first, the doctors indicated that I was going to get antibiotics and be sent home. But then, after they got the results of the blood tests, that all changed,” she said. “I was admitted and immediately placed on IV antibiotics. The doctors told me I had sepsis, probably from an incompletely treated infection.”

Almendro’s doctors believed that her infection had moved into her kidneys and bloodstream. Additionally, it had developed resistance to at least one type of antibiotics. “It was really scary,” she said. “I said to the doctors, ‘you can treat it, right?’ and they said, ‘we will see.’”

In many ways, Almendro was lucky. After five days of intense treatment, the doctors were able to control her infection, which resolved the sepsis. However, since sepsis is related to an aberrant host immune response to an infection, this is not always the case. It is common for an infection to appear resolved using microbial culture assays, even while sepsis persists. “After the sepsis episode, I was sent home and told to monitor any additional symptoms, but I wasn’t sure what to expect,” said Almendro, “or what was the likelihood that it would happen again.”

“From the clinician perspective, treating septic patients is extremely challenging, as you are trying to manage both the infection and the patient’s immune response – both of which are highly dynamic,” said Ephraim Tsalik, M.D., Ph.D, Chief Scientific Officer of Infectious Disease at Danaher Diagnostics, who is leading the company’s effort to develop precision sepsis profiling tools. “We need better diagnostics that can rapidly inform treatment plans and support patient monitoring.”

Julian Knight, D.Phil – a Danaher collaborator and Professor of Genomic Medicine at Oxford University – leads the Genomic Advances in Sepsis study in the UK. The group’s goal is to better understand and define subtypes of sepsis using genomic approaches to provide clues as to how best to treat them. “What we want to move towards is evidence of groups of patients within the sepsis clinical syndrome – sub-phenotypes – that from a therapeutic point of view can be considered treatable traits,” said Knight. So far, the lab has applied machine learning to transcriptome-wide gene expression data to develop a Sepsis Response Signature (SRS). Critically, the data has helped identify patient groups who have specific immune response states and respond differently to certain sepsis treatments such as steroids.

To advance this work and ultimately develop a user-friendly profiling tool for clinicians, Knight and his lab are collaborating with Cepheid, a leading molecular diagnostics company and Danaher operating company, as part of the Danaher Beacons program, which funds product-driven scientific research with globally recognized academic investigators. “The goal here is to take this extremely novel SRS signature to drive clinical impact, and the GeneXpert is a great platform for this. We have scale, we have ease of use, we have speed and quantitation, and the capability to really enable patient impact,” said Jonathan Siegrist, Ph.D., CTO of Cepheid.

“With this Beacon program, what we’re going to do now is take the gene signature that we’ve identified, optimize it for its use within the GeneXpert cartridge, and test it on patient samples, all in a highly collaborative manner. We will then prospectively validate it through a new cohort of patients where we can also explore clinical use cases,” said Dr. Knight.

For Almendro, whose team oversees the Beacons Program, the work has a special meaning. “We need to bring precision medicine to sepsis,” she said. 

1. Rudd, K. E. et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 395, 200–211 (2020).