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2563. Clinical Metagenomic Next-Generation Sequencing for Diagnosis of Meningitis and Encephalitis

ABSTRACT: Abstract Background Metagenomic next-generation sequencing (mNGS) of CSF can identify nearly all pathogens in a single test. We previously validated a CSF mNGS assay in a licensed clinical laboratory. To date, the utility of mNGS for infectious disease diagnosis has been described in case reports and small case series, but not in a large-scale clinical trial. Methods The PDAID (“Precision Diagnosis of Acute Infectious Diseases”) study was a 1-year nationwide prospective study across 8 tertiary care hospitals to evaluate the performance and utility of a clinical metagenomic sequencing assay for diagnosis of meningitis, encephalitis, or myelitis from cerebrospinal fluid (CSF) (ClinicalTrials.gov number NCT02910037). We recruited acutely ill hospitalized inpatients lacking a diagnosis at the time of enrollment. CSF samples were processed and analyzed by mNGS testing within 1 week of receipt in the clinical microbiology laboratory, with sequencing results reported in the patient medical record and used to make contemporaneous treatment decisions. Weekly clinical microbial sequencing boards were convened to discuss mNGS results with treating physicians, and clinical impact evaluated by surveys, chart review, and direct clinician feedback. Results A total of 204 patients were enrolled. Patients were severely ill (ICU 48%, average length of stay 26 days, overall 30-day mortality 7.4%). Fifty-nine neurologic infections were diagnosed in 57 patients (27.9%). mNGS identified 15 (25.4%) infections that were missed by all conventional microbiological tests, including emerging and/or uncommon pathogens such as St. Louis encephalitis virus, hepatitis E virus acquired by lung transplant, and Nocardia farcinica. Twelve of the 15 mNGS-only diagnoses (80%) had clinical impact, with 9 of 15 (60%) guiding appropriate treatment. For diagnosis of infections by direct detection CSF testing, mNGS had 79.1% sensitivity and 98.8% specificity, versus 65.1% sensitivity and 99.4% specificity by conventional testing. Conclusion A significant proportion of neurologic infections are missed despite extensive diagnostic testing performed in tertiary care hospitals. Clinical metagenomic CSF testing was found to be useful in increasing the number of diagnosed neurologic infections and providing actionable information for physicians. Disclosures All authors: No reported disclosures.

SUBMITTER: Wilson M

PROVIDER: S-EPMC6252609 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:Importance:Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective:To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. Design, Setting, and Participants:In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based on z scores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weighted z score was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes and Measures:Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. Results:The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weighted z score-based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. Conclusions and Relevance:Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of C dubliniensis meningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies.

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2563. Clinical Metagenomic Next-Generation Sequencing for Diagnosis of Meningitis and Encephalitis

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