DENVER, Colorado — A test to detect pathogens related to meningitis, encephalitis, and other neurologic infections is more sensitive than are conventional diagnostics and could vastly improve diagnostic capabilities in the clinic, results of a real-world analysis show.
Metagenomic next-generation sequencing (mNGS) of RNA and DNA from cerebrospinal fluid (CSF) simultaneously tests for a wide range of infectious agents and identifies individual pathogens, including viruses, bacteria, fungi, and parasites.
About half of patients with a suspected central nervous system (CNS) infection may go undiagnosed due to a lack of tools that detect rare pathogens. Although mNGS is currently available only in specialized laboratories, expanding access to the diagnostic could address this problem, investigators noted.
"Our results justify incorporation of CSF mNGS testing as part of the routine diagnostic workup in hospitalized patients who present with potential central nervous system infections," study investigator Charles Chiu, MD, PhD, professor in the Department of Laboratory Medicine as well as Medicine and Department of Medicine - Infectious Diseases and director of the Clinical Microbiology Laboratory, University of California San Fransisco (UCSF), said at a press conference.
The findings were presented April 16 at the American Academy of Neurology (AAN) 2024 Annual Meeting.
'Real-World' Performance
Accurate diagnosis of CNS infections on the basis of CSF, imaging, patient history, and presentation is challenging, the researchers noted.
"Roughly 50% of patients who present with a presumed central nervous system infection actually end up without a diagnosis," Chiu said.
This is due to the lack of diagnostic tests for rare pathogens and because noninfectious conditions like cancer, autoantibody syndrome, or vasculitis can mimic an infection, he added.
CSF is "very limiting," Chiu noted. "We are unable, practically, from a volume perspective, as well as a cost and turnaround time perspective, to be able to send off every possible test for every possible organism."
The inability to rapidly pinpoint the cause of an infectious disease like meningitis or encephalitis can cause delays in appropriate treatment.
To assess the "real-world" performance of mNGS , researchers collected 4828 samples from mainly hospitalized patients across the United States and elsewhere from 2016 to 2023.
Overall, the test detected at least one pathogen in 16.6% of cases. More than 70% were DNA or RNA viruses, followed by bacteria, fungi, and parasites.
High Sensitivity
The technology was also able to detect novel or emerging neurotropic pathogens, including a yellow fever virus responsible for a transfusion-transmitted encephalitis outbreak and Fusarium solani, which caused a fungal meningitis outbreak.
Investigators also conducted a chart review on a subset of 1052 patients at UCSF to compare the performance of CSF nMGS testing with commonly used in-hospital diagnostic tests.
"We showed that as a single test, spinal fluid mNGS has an overall sensitivity of 63%, specificity of 99%, and accuracy of 90%," said Chiu.
The sensitivity of mNGS was significantly higher compared with direct-detection testing from CSF (46%); direct-detection testing performed on samples other than CSF, such as blood (15%); and indirect serologic testing looking for antibodies (29%) (P < .001 for all).
This suggests that mNGS could potentially "detect the hundreds of different pathogens that cause clinically indistinguishable infections," Chui said.
mNGS testing is currently confined to large specialized or reference laboratories. For greater access to the test, routine clinical labs or hospital labs would have to implement it, said Chiu.
"If you can bring the technology to the point of care, directly to the hospital lab that's running the test, we can produce results that would have a more rapid impact on patients," he said.
Guiding Therapy
Ultimately, he added, the purpose of a diagnostic test is to "generate actionable information that could potentially guide therapy."
Researchers are now evaluating medical charts of the same subcohort of patients to determine whether the test made a clinical difference.
"We want to know if it had a positive or negative or no clinical impact on the management and treatment of patients," said Chiu. "Producing data like this will help us define the role of this test in the future as part of the diagnostic paradigm."
The researchers are also working on a cost/benefit analysis, and Chiu said that US Food and Drug Administration approval of the test is needed "to establish a blueprint for reimbursement."
Commenting on the findings for Medscape Medical News, Jessica Robinson-Papp, MD, professor and vice chair of clinical research, Department of Neurology, Icahn School of Medicine, New York, said that the technology could be useful, especially in developing countries with higher rates of CNS infections.
"What's really exciting about it is you can take a very small CSF sample, like 1 mL, and in an unbiased way just screen for all different kinds of pathogens including both DNA and RNA viruses, parasites, bacteria, and fungi, and sort of come up with whether there's a pathogen there or whether there is no pathogen there," she said.
However, there's a chance that this sensitive technique will pick up contaminants, she added. "For example, if there's a little environmental bacterium either on the skin or in the water used for processing, it can get reads on that."
The study received support from Delve Bio and the Chan-Zuckerberg Biohub.
Chiu has received personal compensation for serving on a Scientific Advisory or Data Safety Monitoring Board for Biomeme and has stock in Delve Bio, Poppy Health, Mammoth Biosciences, and BiomeSense and has received intellectual property interests from a discovery or technology relating to healthcare. Robinson-Papp has no relevant conflicts of interest.