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Study Validates Single-Gene Biomarker That Discriminates Between Influenza and Bacterial Infections

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NEW YORK (GenomeWeb) – A single-gene biomarker that has shown clinical performance on the level of multi-gene panels could be what clinicians need in measuring the immune response while diagnosing people at risk of serious illness from influenza, according to its developers.

Clinicians demonstrated that the biomarker, IFI27, was expressed in patients with influenza infection, but not in bacterial infection in a study that involved the collaboration of several hospitals in countries spanning multiple continents. They found that they could apply the biomarker not just to diagnose influenza infection, but also predict the risk of it leading to serious illness.

In published papers, researchers have reported results from studies that used 20 to more than 100 biomarkers at a time to achieve the same level of performance, said Benjamin Tang, a doctor in the Department of Intensive Care Medicine at Nepean Hospital, who is among the study's investigators. "These tests would give similar diagnostic information to ours," he said, "but the number of genes required in the panels makes it challenging to use them in a clinical setting."

The new study, supported by the Nepean Institute of Critical Care Education and Research in Kingswood, Australia, and published earlier this month in the European Respiratory Journal, involved collaboration from clinicians and hospitals in Australia, Canada, the US, and Germany.

The work done to validate the IFI27 biomarker used an integrated genomic analysis of 1071 people and in vitro experiments using "well-established infection models," the researchers said.

Its discovery was initiated during the 2009 influenza pandemic when the researchers at Nepean Hospital began collecting samples from severely ill patients with influenza infections, with the goal of identifying genes that were highly expressed in the samples and that reflected a breakdown of the immune system.

"We show in our study that the performance of a single biomarker, in terms of conducting a diagnosis, is as good as that of multigene biomarker panels previously published in several journals," Tang said, and added "That, by itself, is a game changer."

The researchers noted that in their study, the IFI27 biomarker showed 88 percent diagnostic accuracy and 90 percent specificity in discriminating between influenza and bacterial infections.

"IFI27 represents a significant step forward in overcoming a translational barrier in applying [a] genomic assay in [a] clinical setting," the researchers wrote. "Its implementation may improve the diagnosis and management of respiratory infection."

According to the World Health Organization, about 5 to 10 percent of adults and 20 to 30 percent of children come down with influenza each year, resulting in around 3 million to 5 million cases of severe illness, and about 250,000 to 500,000 deaths.

In most cases, symptoms can last a week or more, and then the patient's immune system tends to recover. However, "it's more serious than that for some people," Tang said, as the flu infection can progress to pneumonia and severe respiratory infections.

"We know that every time we tell a patient to go home and get rest, there's a small chance that the condition can deteriorate, and that was reflected in our experience in 2009 when many patients with nearly identical flu-like symptoms presented at the emergency department," he said. "Doctors sent many home but some of them came back with severe respiratory failure caused by pneumonia from influenza. By the time they came back to us, we realized that it was too late and we should have intervened earlier."

The experience provided the inspiration to find a biomarker that would look at a person's immune system and evaluate its response to influenza, he said. "We wanted an early warning that the immune system was falling apart," he noted, "and that would consequently allow us to identify those high-risk patients and intervene early."

The researchers are working with the Australian Ministry of Health's commercialization office toward integrating the biomarker into the development of a commercial diagnostic test. They have received Australian and Japanese patents for use of the IFI27 biomarker in a diagnostic test, and they are awaiting patents in the US, China, and Europe.

The researchers hope to engage with a commercial partner, possibly "a biotech company that's interested in commercializing the assay on a viable platform," Tang said, adding he believes the test could be on the market within two to five years.

The test platform would be a very simple PCR system that enables easy integration of the biomarker-based assay, and that has the advantage of being available in most hospitals, he said. The researchers expect that early commercial adoption is likely in such a setting, with test labs near the point of care.  

Influenza test options

Many types of influenza tests require laboratory use. In general, clinicians take samples from the back of the throat or from the nose and send them out for testing. They receive results after a length of time that varies depending, in part, on the type of test.  

Companies such as Quidel, BioMérieux, Cepheid, Alere, Luminex, and Roche have received US Food and Drug Administration clearances, as well as CLIA waivers, for tests that diagnose flu and respiratory infections, as they seek to capitalizing on a need for molecular and rapid immunoassays that enhance clinical value.   

Healthcare and lab workers have a wide swath of testing options for influenza, including rapid immunoassays, viral culture tests, and serology tests. But while demand for immunoassays remains high, molecular assays for flu and respiratory conditions are gaining ground, fueled, in part at least, by a consensus that combining such technologies with rapid immunoassays may be the best approach to diagnosing influenza.

The single-gene biomarker test "detects a signal from the immune system, so it gives you another side to the story," to what's provided by existing tests, Tang said.

If commercialization is achieved, clinicians would ideally use the biomarker test along with another existing flu test, he said, adding that both types are important. "The existing influenza tests allow you to detect the presence of a virus, and the biomarker test gives complementary information about how the body is reacting to that virus," he said.

Ideally, the single-gene biomarker would eventually be integrated with a point-of-care system, he noted, but the researchers would need to engage with experts to integrate the assay and validate it with a platform that's portable, cheap, fast, and reliable, "so that hopefully one day the test will be used not just in laboratories, but also in clinics and out in the field," he said.

Proponents of point-of-care testing believe that there are benefits to applying them in the treatment and diagnosis of influenza.

Researchers at Stanford University department of emergency medicine recently published a study in the Journal of Molecular Diagnostics that described a study of the impact of using molecular point-of-care tests on managing pediatric acute respiratory illnesses. They found that these kinds of tests have the potential to decrease emergency department length of stay, reduce the number of diagnostic tests and patient charges, and increase appropriate use of antibiotics and antiviral agents.

In a separate study published in Lancet Respiratory Medicine, a team of UK researchers used BioFire Diagnostics' FilmArray respiratory panel to test patients who presented with an acute respiratory illness at University Hospital Southampton. According to the study, patients who underwent point-of-care diagnostic testing received the right treatment for their respiratory illness faster than those who received the standard of care.

With memories of the 2009 influenza pandemic still fresh, Tang said that an ideal application for point-of-care influenza tests, including potentially the single-gene biomarker test, could be to provide for rapid triage in towns, cities, and elsewhere "when the next flu pandemic hits us."

He noted that his team plans to publish a couple of additional papers within the next 12 months that reflect work they've done to identify a second, as-yet-undisclosed gene that could be used as a complementary biomarker to IF127 and strengthen the overall test's prediction capability.

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