A novel cause of chronic viral meningoencephalitis: Cache Valley virus

Abstract

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 three 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 three immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self-limiting meningitis to a rapidly fatal meningoencephalitis with multi-organ 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. Indeed, 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.

Cache Valley virus: A scoping review of the global evidence

“…The first case was reported in 1995 in North Carolina (CDC, ; Sexton et al, ), followed by single cases occurring in Wisconsin in 2003 (Campbell et al, ), New York in 2011 (CDC, ; Nguyen et al, ) and Missouri 2015 (CDC, ). More recently, in 2016 two immune‐compromised men from New York and Australia, the latter with travel history to the USA, were diagnosed with CVV‐associated meningoencephalitis (Wilson et al, ; Yang, Qiu, et al, ). Researchers hypothesized that the Australian patient's exposure likely occurred in 2013, but the diagnosis of CVV infection did not occur until 2016 after several years of chronic neurological deficits, eventually diagnosed as chronic meningoencephalitis (Wilson et al, ).…”

“…Three patients experienced long‐term symptoms including persistent headaches (reported in 2/3 cases), difficulty in word finding (1/3), memory loss (1/3) and motor control deficits (1/3) (Campbell et al, ; Nguyen et al, ; Sexton et al, ). The Australian patient eventually diagnosed with CVV chronic meningoencephalitis displayed 6 months of progressive memory decline, slowing of speech and mood disturbance, predominantly anxiety; the diagnosis was made via metagenomic next‐generation sequencing of the patient's cerebrospinal fluid and brain biopsy tissue (Wilson et al, ). CVV illness was ultimately fatal, either directly or due to other complications, in three of five CVV cases for which outcome data were reported (Sexton et al, ; Wilson et al, ; Yang, Qiu, et al, ).…”

“…As with the CVV situation in animals, CVV exposure seems to occur much more frequently than clinical disease. However, there is insufficient evidence to identify the full spectrum of clinical signs during CVV‐associated illness, or the degree of under‐diagnosis of CVV occurring, or potentially at‐risk populations (e.g., 2/6 CVV cases occurred in immune‐compromised subjects) (Wilson et al, ; Yang, Qiu, et al, ).…”

“…Cache Valley virus circulates in mosquitoes and mammals throughout North America, Central America and parts of South America (Armstrong et al, ). However, there have only been a small number of cases of human illness attributed to CVV infection (Wilson et al, ). Most of the reports of mammalian pathology attributable to CVV infection in mammals describe infection in pregnant sheep and goats (McConnell, Livingston, Calisher, & Crandell, ; Rodrigues, ; Shapiro et al, ).…”

High-throughput sequencing for the aetiologic identification of viral encephalitis, meningoencephalitis, and meningitis. A narrative review and clinical appraisal

“…HTS was performed on CSF and brain specimens in five patients [26,29e32]. Positive results on both samples were obtained in a Cache Valley virus chronic meningoencephalitis case [30] and positive results on brain biopsies only were reported in two human astrovirus (HAstV)-VA1 and tick-borne encephalitis (TBEV) cases [29,33]. In one patient, HTS analysis did not identify a viral cause, but Balamuthia mandrillaris was identified in both CSF and brain biopsy [32].…”