Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis
Open accessAbstract
BACKGROUND: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).
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Metagenomic next-generation sequencing to detect microbial cell-free DNA in plasma is a promising approach that potentially allows earlier detection and diagnosis of fungal infections when other blood biomarkers or tests are still negative.
“Metagenomic next-generation sequencing (mNGS) to detect microbial cell-free DNA (mcfDNA) in plasma is a promising approach, potentially allowing earlier detection and diagnosis of fungal infections when other blood biomarkers/tests are still negative.23”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [23]
The Abstract describes mNGS as promising for detecting infectious causes, including fungi, and the Discussion reports diagnoses from CSF mNGS when conventional tests were negative. The study tested cerebrospinal fluid, not plasma microbial cell-free DNA, and does not establish earlier detection of fungal infections while blood biomarkers remain negative. (LLM, conf=0.88)
Experimental — accuracy not yet measuredmNGS was able to identify 16 pathogens that could not otherwise be detected by routine methods.
“In fact, mNGS was able to identify 16 pathogens that could not otherwise be detected by routine methods (35), attesting to its robustness and sensitivity.”
From Viruses Causing Aseptic Meningitis: A Tertiary Medical Center Experience With a Multiplex PCR Assay (2020) · cites this paper as [35]
The Results section (Performance of Metagenomic NGS Relative to Conventional Testing; page not available) reports that mNGS alone diagnosed infections missed by conventional testing, but the number was 13 infections, not 16 pathogens. The paper also reports 19 infections detected by both methods, so those cannot be counted as missed by routine testing. (LLM, conf=0.89)
Experimental — accuracy not yet measuredmNGS has been shown to detect more neuroinvasive viruses accurately.
“A new emerging technique that might be very broad yet highly accurate at detection is the mNGS, which has been shown to detect more neuroinvasive viruses accurately (32, 35).”
From Viruses Causing Aseptic Meningitis: A Tertiary Medical Center Experience With a Multiplex PCR Assay (2020) · cites this paper as [35]
The Results (Performance of Metagenomic NGS Relative to Conventional Testing; page unavailable) report that mNGS identified viral infections, including St. Louis encephalitis and hepatitis E, and detected more infections overall than conventional direct-detection testing of CSF (32 versus 27). The paper does not establish that it detected more neuroinvasive viruses specifically, and its Methods (Study Design; page unavailable) say unbiased estimates of sensitivity and specificity were not possible. Thus, the claim’s virus-specific comparison and implication of established accuracy go beyond the reported findings. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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- Authors
- Wilson, M. R., Sample, H. A., Zorn, K. C., Arevalo, S., Yu, G., Neuhaus, J., Federman, S., Stryke, D., Briggs, B., Langelier, C., Berger, A., Douglas, V., Josephson, S. A., Chow, F. C., Fulton, B. D., DeRisi, J. L., Gelfand, J. M., Naccache, S. N., Bender, J., Dien Bard, J., Murkey, J., Carlson, M., Vespa, P. M., Vijayan, T., Allyn, P. R., Campeau, S., Humphries, R. M., Klausner, J. D., Ganzon, C. D., Memar, F., Ocampo, N. A., Zimmermann, L. L., Cohen, S. H., Polage, C. R., DeBiasi, R. L., Haller, B., Dallas, R., Maron, G., Hayden, R., Messacar, K., Dominguez, S. R., Miller, S., & Chiu, C. Y.
- Affiliations
- University of California, San Francisco (US)
- Children's Hospital Los Angeles (US)
- From the Departments of Neurology (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), Biochemistry and Biophysics (H.A.S., K.C.Z., J.L.D.), Laboratory Medicine (S.A., G.Y., S.F., D.S., B.B., B.H., S.M., C.Y.C.), and Epidemiology and Biostatistics (J.N.), the Department of Medicine, Division of Infectious Diseases (C.L., C.Y.C.), the Department of Medicine, Division of Hospital Medicine (A.B.), and Weill Institute for Neurosciences (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), University of California, San Francisco ...
- University of California, Los Angeles (US)
- Children's National (US)
- San Francisco General Hospital (US)
- St. Jude Children's Research Hospital (US)
- ORCID
- Wilson, Michael R.
- Sample, Hannah A.
- Zorn, Kelsey C.
- Yu, Guixia
- Neuhaus, John
- Federman, Scot
- Briggs, Benjamin
- Langelier, Charles
- Douglas, Vanja
- Josephson, S. Andrew
- Chow, Felicia C.
- Fulton, Brent D.
- DeRisi, Joseph L.
- Gelfand, Jeffrey M.
- Naccache, Samia N.
- Bender, Jeffrey
- Murkey, Jamie
- Vijayan, Tara
- Allyn, Paul R.
- Humphries, Romney M.
- Klausner, Jeffrey D.
- Cohen, Stuart H.
- Polage, Christopher R.
- DeBiasi, Roberta L.
- Dallas, Ronald
- Hayden, Randall
- Messacar, Kevin
- Dominguez, Samuel R.
- Miller, Steve
- Chiu, Charles Y.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2019-06-13
- Volume
- 380
- Issue
- 24
- Pages
- 2327-2340
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC6764751
- OpenAlex
- W2953017819
- Cited by
- 1,067
- References
- 27
- Citations by year
- 2026: 148 · 2025: 152 · 2024: 149 · 2023: 151 · 2022: 164 · 2021: 146 · 2020: 116 · 2019: 39
- FWCI
- 83.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (K08NS096117)
- National Heart, Lung, and Blood Institute (HL105704, U54HL119893)
- California Initiative to Advance Precision Medicine
- National Center for Advancing Translational Sciences (UL1TR000004)
- Bowes Foundation
- Charles and Helen Schwab Foundation
- Sandler Foundation
- Rachleff Family Endowment
- Chan Zuckerberg Biohub
- George and Judy Marcus Innovation Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Bacterial Identification and Susceptibility Testing
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
- Keywords
- metagenomic sequencing, cerebrospinal fluid, infectious meningitis, encephalitis, neuroinvasive infection, pathogen detection, clinical microbiology, telemedicine, physician feedback, pediatric patients, intensive care unit admission
- MeSH terms
- Adolescent, Adult, Cerebrospinal Fluid, Child, Child, Preschool, Encephalitis, Female, Humans, Infant, Infections, Length of Stay, Male, Meningitis, Meningoencephalitis, Middle Aged, Myelitis, Prospective Studies, Sequence Analysis, DNA, Sequence Analysis, RNA, Young Adult, Metagenomics, High-Throughput Nucleotide Sequencing, Genome, Microbial
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