Detection of HSV-1 Encephalitis by Metagenomic Next-generation Sequencing After Negative Conventional Testing in a Toddler with Atypical Presentation
Su Jin Joo1, Anh Vo1, Elaine Cham2, Sudeb Dalai3, Steve Miller3
1Division of Infectious Diseases and Global Health, Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, 2Department of Pathology, UCSF Benioff Children’s Hospital Oakland, 3Delve Bio
Background:
HSV-1 encephalitis can present atypically and yield false-negative cerebrospinal fluid (CSF) results early in disease. Metagenomic next-generation sequencing (mNGS) enables comprehensive, sensitive pathogen detection in challenging CNS presentations.
Design/Methods:
CSF mNGS was performed using Delve Detect CSF (Delve Bio). One mL of CSF underwent whole-cell lysis, nucleic acid extraction, and DNA/RNA library preparation, sequenced to >10 million reads and analyzed against a curated microbial database. Clinical data were collected by chart review.
Results:
A previously healthy, fully vaccinated 21-month-old female presented to an outside hospital with acute bilateral facial twitching, tongue fasciculations, and confusion without fever. Initial CSF showed mild pleocytosis (WBC 17/uL; lymphocytes 94%; protein 33mg/dL; glucose 51mg/dL). MRI revealed bilateral periolandic diffusion restriction and thalamic T2/FLAIR hyperintensity, concerning for autoimmune encephalitis (AE), infection, or genetic/metabolic encephalopathy. Multiplex syndromic panel (BioFire) and CSF mNGS (Mayo) were both negative for HSV, without dedicated HSV PCR performed. Presumed AE was treated with IVIG and pulse steroids, and later plasma exchange. Empiric acyclovir was discontinued after negative CSF studies for HSV.
Following clinical and radiographic progression, the patient was transferred to UCSF on hospital day 14. mNGS (Delve Bio) on CSF collected 16 days after initial presentation identified HSV-1 (4,889 unique reads, 19M total reads, 88.1% genome coverage), subsequently confirmed by dedicated HSV PCR. Her clinical course was most consistent with primary HSV infection with possible secondary AE. She was treated with a 21-day course of acyclovir and plasma exchange, then transitioned to suppressive therapy after documented negative CSF HSV PCR, with gradual clinical improvement.
Conclusions:
CSF mNGS established HSV-1 encephalitis in a child with a nonclassic and non-diagnostic presentation. Initially negative HSV-1 results may reflect low viral titers early in disease, delayed reactivation, or assay sensitivity differences. Comprehensive pathogen detection enabled timely re-initiation of antivirals, underscoring its value in atypical CNS presentations.
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