CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
William Check, PhD
April 2014—In what may be a first for the burgeoning field of next-generation sequencing, this powerful new technology was used to identify the cause of encephalitis in a teenage boy who had been critically ill in the intensive care unit for several weeks. Diagnosis suggested a specific treatment. Within two weeks of initiating therapy, the boy had recovered and was discharged.
It is becoming common practice to use NGS to detect mutations that can help select drug therapy in cancer cases and to find genetic variations responsible for inherited diseases. However, NGS has not previously been considered a useful tool in critical care situations, where a short turnaround time is crucial. “Next-generation sequencing can have great utility in these types of cases,” Joe DeRisi, PhD, professor of biochemistry and biophysics and Howard Hughes investigator at the University of California, San Francisco, School of Medicine, said in a presentation at the Advances in Genome Biology and Technology (AGBT) conference in February. In the case Dr. DeRisi described, the 48-hour turnaround time from extraction of nucleic acid to identification of the cause of disease provides a new perspective on the utility of this rapidly expanding molecular technology.
Encephalitis could be a particularly fruitful field in which to exploit NGS’ newly demonstrated ability. In a seven-year study, California Encephalitis Project investigators found that, after extensive workup with existing methods, 63 percent of cases went undiagnosed (Glaser CA, et al. Clin Infect Dis. 2006;43:1565–1577). The problem, says Charles Chiu, MD, PhD, professor of laboratory medicine and infectious diseases at UCSF and a senior investigator in the study, is that “the causes of encephalitis are broad in scope,” ranging from infectious agents, especially in immunosuppressed individuals, to non-infectious autoimmune disease and vasculitis.
Michael Wilson, MD, professor of neurology at UCSF, was working in Dr. DeRisi’s laboratory to learn NGS technology at the time of this case. “From the neurologist’s standpoint,” he tells CAP TODAY, “when a patient with encephalitis comes into the hospital, you expect that more often than not you won’t come up with a diagnosis, no matter how many tests you run. Infectious disease doctors share that frustration. This kind of case is exactly why I wanted to learn next-generation sequencing.
“What still kind of amazes me is that not only do we fail to identify a pathogen many times, but often we fail to differentiate between an autoimmune or an infectious cause. That’s what happened in this case, too,” he says. “Any technology that might increase that otherwise very poor yield is exciting.”
Dr. DeRisi and his colleagues are seeking to exploit this newly discovered potential of NGS by setting up a protocol for investigating cases of encephalitis and meningitis. Prospectively obtained samples will be divided between brain slices to search for evidence of autoimmune disease and next-gen sequencing to find infectious agents.