A novel cause of chronic viral meningoencephalitis: Cache Valley virus

Wilson, Michael R.; Suan, Dan; Duggins, Andrew; Schubert, Ryan D.; Khan, Lillian M.; Sample, Hannah A.; Zorn, Kelsey C.; Rodrigues Hoffman, Aline; Blick, Anna; Shingde, Meena; DeRisi, Joseph L.

Objective: Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients. Methods: We present the case of a 34-year-old man with X-linked agammaglobulinemia from Australia suffering from 3 years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen. Results: Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue. Interpretation: Cache Valley virus, a mosquito-borne orthobunyavirus, has only been identified in 3 immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self-limiting meningitis to a rapidly fatal meningoencephalitis with multiorgan failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Our research subject traveled to North and South Carolina and Michigan in the weeks prior to the onset of his illness. This report demonstrates that metagenomic next generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes. ANN NEUROL 2017; 82:105-114 O utbreaks of emerging and reemerging pathogens have stimulated international discussion about the most efficient means for improving early detection so that public and private resources can be mobilized quickly and efficiently to limit widespread transmission and treat affected patients. There is a growing consensus that an optimal surveillance regimen will (1) incorporate an unbiased approach to pathogen identification and (2) focus surveillance efforts on groups of people at high risk for unusual infections (eg, immunodeficient patients and people with relevant exposures). [1] [2] [3] An unbiased approach to pathogen identification is important because traditional candidate-based diagnostic tests essentially fail to identify novel and unusual pathogens, usually due to perceived rarity or exclusion from clinical consideration based on established geographical distribution. Global surveillance efforts need to be streamlined, because it is both time-consuming and costly for physicians to order many pathogen-specific tests for geographically and clinically novel organisms. Finally, in the modern era, when international travel has become so commonplace, the need for improved pathogen detection has become clear.