Clinical NGS IDs Pathogens in Brain and Spinal Fluid Missed by Other Tests

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Test tube containing liquid with computer monitor displaying results of automated DNA sequencing

Doctors were able to give critically ill patients with mysterious neurological symptoms life-saving treatment thanks to a new clinical application of next-generation sequencing (NGS). In a study published in 12 June 2019 in the New England Journal of Medicine, researchers report the use of metagenomic NGS to successfully identify potentially lethal pathogens in the brain and spinal fluid of 22 percent of patients that conventional testing missed.

“The infectious cause of half the cases of meningitis and encephalitis go undiagnosed in hospitals around the country,” said the study’s senior author, Charles Chiu, M.D., Ph.D., professor of laboratory medicine and medicine at the University of California, San Francisco in a press release. “This study was designed to evaluate the real-life clinical performance and effect of the metagenomic NGS assay in comparison with conventional microbiologic testing in patient-care scenarios in which the test is likely to be used,” Chiu and his colleagues wrote in the publication.

Doctors must often use their gut instincts when faced with critically ill patients with neurological symptoms that range from fever and headaches to seizures and confusion. Inflammation of the brain (encephalitis) and inflammation the lining surrounding the brain (meningitis) can lead to brain damage, stroke and death.

The challenge for front-line physicians is that fewer than half of encephalitis and meningitis cases are caused by pathogens (viruses, bacteria, fungi and parasites) and yet are clinically indistinguishable from cases caused by autoimmune disorders. And, giving immune suppressing drugs to someone with an infection could be could be harmful, while giving antibiotics to someone with an autoimmune disease is useless and could contribute to antibiotic resistance.

Metagenomic testing, the authors point out, offers an unbiased way of testing for the presence of pathogens in patients’ spinal fluid, allowing quick and decisive action if a pathogen is detected. “Having a broad-based test that either rules in infection or rules out infection can really aid these cases that are in gray areas between infection and not,” said Michael Wilson, MD, associate professor of neurology at UCSF and one of the study’s co-authors in the press release.

In the current study, researchers focused on difficult-to-diagnose patients because these are the ones that would most likely get tested using mNGS given current issues of cost, accessibility, and turnaround time. They followed 204 pediatric and adult critically ill patients at eight hospitals around the country who had not received a diagnosis for the cause of their symptoms at the time of mNGS testing. About half were admitted to the intensive care unit and the average length of hospitalization was 27 days.

Researchers were able to determine the cause of the neurologic inflammation in half of the patients. Using the mNGS assay, researchers identified more potential pathogens than conventional direct-detection testing of cerebrospinal fluid (32 vs. 27). A total of 13 infections were diagnosed solely by mNGS. Physicians adjusted treatment in seven cases.

“All conventional microbiology tests combined yield diagnoses in less than 50 percent of these patients. We’ve shown that a single test — mNGS — can make a significant dent in that number,” said Chiu, who is also director of the UCSF-Abbott Viral Diagnostics and Discovery Center, in the press release.

The researchers acknowledged in the study that NGS is not perfect and can result in false negatives. They were unable to diagnose 26 infections using mNGS. In most of these cases, there was not enough DNA in the cerebrospinal fluid sample — a problem that may be solved as they and others work to improve sensitivity. The timing and best population for the testing also requires further research, they said.

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