Meningitis and encephalitis are leading global causes of central nervous system (CNS) disability and mortality. Current diagnostic workflows remain inefficient, requiring costly pathogen-specific assays and sometimes invasive surgical procedures.

Mutations in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that confer escape from neutralizing antibodies can arise in immunocompromised patients with prolonged infection.^1,2 Such viral evasion is hypothesized to contribute to the emergence of global variants of concern.³ In the absence of effective immune responses, selective pressures such as those from monoclonal antibody treatment may lead to the emergence of immunologically important mutations.

Domestic arthropod-borne viruses (arboviruses) are single-stranded RNA viruses, the most common of which include the mosquito-borne West Nile virus, St. Louis encephalitis virus, La Crosse virus, Jamestown Canyon virus, and eastern equine encephalitis virus, as well as the tick-borne Powassan virus. Previously considered rare infections, they have been detected with increasing frequency over the past 2 decades. Here, we present an overview of the domestic arboviruses listed above and describe the modalities employed to diagnose infection.

Reports of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection have raised important questions about the strength and durability of the immune response to primary infection, which are key factors in predicting the course of the pandemic. Identifying reinfection requires detecting the virus at two different time points and using viral genomic data to distinguish reinfection from persistent viral carriage.

We describe a patient with severe and progressive encephalitis of unknown etiology. We performed rapid metagenomic sequencing from cerebrospinal fluid and identified Powassan virus, an emerging tick-borne flavivirus that has been increasingly detected in the United States.