Candidemia, a common source of fungal infections, has become a key emerging nosocomial infection at hospitals. It can kill up to 15% of critically ill patients within the first day of infection. Left undetected for up to three days, the mortality rate rises to 30%. Diagnostics for this alarming pathogen are slow and inaccurate. In response, scientists from Duke University's Institute for Genome Sciences & Policy (Durham, North Carolina) have developed an early test for fungal infections that measures how a patient's genes are responding. It's a new and faster way to reveal an infection which occurs in very sick or immunocompromised patients, particularly critical care patients.

"What's novel is that we're taking advantage of the fact that we, as hosts of pathogens, have very specific responses to virus, fungi and bacteria," said Geoffrey Ginsburg, MD, director of Duke's Center for Genomic Medicine in the Institute for Genome Sciences & Policy, and the senior author of the study. "Different receptor signaling pathways recognize differing pathogens. Our premise is that we could capture that specificity by measuring gene expression signatures in blood."

With the study findings, which appear in Science Translational Medicine, "We are redefining the way that physicians identify infectious disease using a combination of host-based blood RNA tests with traditional microbiology methods," said co-lead author Aimee Zaas, MD, assistant professor of medicine in the Duke Division of Infectious Diseases and International Health, and the Duke Institute for Genome Sciences & Policy.

Ginsburg said these findings have broader implications beyond fungal infections. The study results provide a jumping-off point for producing gene-expression signatures to detect a number of infections. The candidemia test is being pursued first because of the high mortality rate in hospitalized patients with that hard-to-treat infection.

One of the problems in diagnosing candidemia is that it often appears to be similar in symptoms to other bloodstream infections. Finding out if an infection is fungal or bacterial can take up to 72 hours via blood culture tests. Even then, the results may only be positive half of the time.

Ginsburg and Zaas developed a gene-signature test that works to find candidemia in mice. They also found that the test can distinguish a fungal infection from a staph infection.

"RNA signatures are now somewhat routinely used as diagnostic platforms for other diseases such as cancer and HIV," Ginsburg said. "There is precedence for this type of technology to be used in a number of care settings. We want to migrate the microarray work to a PC platform."

In their study, Ginsburg and Zaas analyzed gene expression – which genes are turned on and active – in the blood samples of mice that were exposed to Candida albicans (C. albicans) and a group of healthy control mice. They looked at genes that are associated with immune response and found there were 20 sets of 60 to 80 genes being expressed together. One group of genes in particular distinguished the infected samples from the control samples. They were also able to combine data from the C. albicans group with data from a group of mice infected with Staphylococcus aureus. The team identified two groups of genes that could discriminate among the three groups of mice (healthy, those with candidemia and those with a staph infection).

They also developed distinct groups of genes that correlated with samples at different time points during the course of Candida infection. Using these groups of genes, the researchers could distinguish between an early and a late infection.

Armed with this information, Ginsburg said. "We don't know whether the signatures we've developed will pick up all fungal infections. The next step is to figure out if it's useful for all fungi. We're in the process of doing that."

Assuming all goes well with the next step, Ginsburg said his team would move the technology from the array-based platform to a device that's more appropriate for delivering rapid turnaround results at the point of care.

"If you can imagine it, critically ill patients might be routinely screened in an ICU," he said. "At the earliest sign that this signature was turning positive, they would get treated with appropriate antifungal agents. Today, treatment is often delayed because of current diagnostic platforms. We are working with three Duke engineering groups. Each is focused on point-of-care sensing devices. We're proceeding aggressively to develop prototypes."

Ginsburg said he is in early discussions with several medical technology firms, but that no deals have yet been signed to commercialize the genomics-based diagnostic.

Lynn Yoffee, 770-361-4789;
lynn.yoffee@ahcmedia.com