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Virus or bacterium? Gene expression may tell

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William Check, PhD

September 2014—At the 30th Annual Clinical Virology Symposium this spring, Gregory Storch, MD, related a typical case of a febrile child seen in the emergency department. Dr. Storch, a professor of pediatrics at Washington University School of Medicine, described a 20-month-old boy with a fever of 40°C, rash, cough, and nasal congestion but no gastrointestinal symptoms. White blood cell count was 7,800/µL. Blood culture was negative and a chest x-ray showed mild peribranchial thickening. Diagnosis, Dr. Storch says, was “viral syndrome.” The patient got a dose of ceftriaxone, which was “reasonable,” in Dr. Storch’s view, in light of the patient’s fever and the presence of bands on the peripheral blood smear.

To define viruses in children with fever without cause, Dr. Gregory Storch (right) and colleagues conducted the Febrile Children Study. Richard (Xinran) Hu, MD, MPH (left), played a key role in studies on human gene expression profiles.

To define viruses in children with fever without cause, Dr. Gregory Storch (right) and colleagues conducted the Febrile Children Study. Richard (Xinran) Hu, MD, MPH (left), played a key role in studies on human gene expression profiles.

This case typifies “fever without a source,” a common pediatric problem in physicians’ offices and in the ED, said Dr. Storch, who is also director of the Division of Pediatric Infectious Diseases and of the Division of Pediatric Laboratory Medicine at St. Louis Children’s Hospital. Many of these children receive antibiotics because “bacterial infection is always a serious concern,” he noted.

In his CVS talk, Dr. Storch spoke about his group’s efforts to improve the targeting of antibiotics. He posed the question: Can we do better using advanced molecular techniques? His work has foc-used on two newer techniques: next-generation sequencing—genomics, and gene expression profiles—transcriptomics. “This is where we have to think about moving in the future,” Dr. Storch tells CAP TODAY.

Of the possibility of translating the group’s results with transcriptomics into clinical utility, Dr. Storch says: “We can’t do that tomorrow, but it is not that far into the future. If we approached a specific clinical syndrome, we could go tomorrow and do a clinical study in that patient group using some of these markers. It would require more work to transfer [this technology] to samples other than blood or to other clinical syndromes, but the path is definitely open for people to do that.” Dr. Storch expects to see this method become part of routine clinical testing in perhaps five years.

He cites prior work with gene expression profiling in acute infections by a group led by Octavio Ramilo, MD, head of pediatric infectious diseases at Nationwide Children’s Hospital in Columbus, Ohio (Ramilo O, et al. Blood. 2007;109:2066–2077). Using what they call “discriminative transcriptional signatures,” Dr. Ramilo and his colleagues achieved 90 percent to 95 percent correct classification. They concluded that “[M]icroarray analyses of patient peripheral blood leukocytes might assist in the differential diagnosis of infectious diseases.”

A group at Duke University School of Medicine is working, too, with gene expression profiles as advanced diagnostics for distinguishing viral from bacterial infections. “The major driving issue is emergence of antimicrobial resistance,” says Christopher Woods, MD, MPH, who notes it’s a global problem owing to inappropriate antibiotic use.

“When someone presents with a possible res-piratory infection, it is the same in Nepal or Sri Lanka or Africa or downtown Durham. Our ability to determine whether a virus is causing their symptoms or a bacterium is extremely limited. One cannot usefully do it with clinical symptoms or current laboratory tests,” says Dr. Woods, a professor of medicine and of pathology at Duke and chief of the Infectious Diseases Division at the Durham VA Medical Center.

“What we have spent most of the last decade doing,” he tells CAP TODAY, “is working to develop a diagnostic test that provides a clinician with a robust result and an accurate result that distinguishes whether the patient has a bacterial or viral infection and that would drive therapeutic intervention.”
David R. Hillyard, MD, director of molecular infectious disease testing at ARUP Laboratories, is familiar with the work of both groups. He arranged for Dr. Storch to speak at the 2013 meeting of the Association for Molecular Pathology and for Dr. Woods to speak at this year’s AMP meeting in November.

Dr. Hillyard

Dr. Hillyard

“There is a tremendous potential and a need that has been longstanding and long discussed,” Dr. Hillyard says. Data presented so far from various groups suggest a good likelihood that gene expression profiling will become an important test. “We had seen in the general testing space a very rapid transition during the past several years from insensitive antigen detection or slow, relatively insensitive culture methods to monoplex molecular tests and now to multiplex molecular tests,” says Dr. Hillyard, who is also a professor of pathology at the University of Utah. “Some will be point-of-care or near-point-of-care tests very soon,” he adds.

But there is a big difference between detecting a pathogen with any of these methods and detecting the pathogen that is causing the disease process, Dr. Hillyard says. “Availability of very sensitive multiplex methods and methods detecting in some cases multiple pathogens really increases the pressure for rapid and rational clinical decisionmaking to define, maybe by host response, whether you have just the presence of a pathogen or have disease caused by that pathogen.

“These methods are gaining traction. With groups going full speed, they will likely be reduced to practical tests in the near future. We will see,” he says cautiously. “But this approach has a good chance of being very impactful.”

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