Powassan Virus Neuropathology and Genomic Diversity in Patients With Fatal Encephalitis

Abstract

Background Powassan virus (POWV) is an emerging cause of severe encephalitis; very little is known about human pathogenicity due to challenges in diagnosis and viral RNA recovery. We present three patients with fatal encephalitis due to POWV lineage II (deer tick virus). Methods We obtained 27 unique samples, including from brain biopsy and autopsy, and used metagenomic sequencing, RT-qPCR, and a newly developed CRISPR-based diagnostic assay to perform the first detailed characterization of POWV compartmentalization and genomics between and within human subjects. Results In all three patients, imaging and histopathology findings were notable for profound cerebellar involvement. All patients were initially diagnosed with POWV by metagenomic sequencing, and two of the three had negative clinical testing by serology. We detected POWV RNA in thirteen clinical samples; levels were highest in the cerebellum, and there was very little involvement of peripheral tissue. We assembled complete POWV genomes from eight samples, providing unique information about the strains of POWV lineage II (deer tick virus) that infect humans. Conclusions We demonstrate the utility of molecular assays for detecting POWV infection, including in seronegative patients, and nominate viral genomic features that may relate to human infection and neuropathogenicity. Cerebellum was identified as a key target POWV in fatal infection, by radiological and histopathological findings as well as molecular testing.

Fatal Powassan virus encephalitis in patients with chronic lymphocytic leukemia

“…Such was the case with one of our patients and has been reported in other clinic contexts [17]. Metagenomic next-generation sequencing, available from UCSF, and PCR testing, available at the CDC and some state public health labs, have emerged as useful tools for diagnosing Powassan virus, and clinicians may consider deploying if there is a high index of suspicion in the face of negative serologic assays [16,17].…”

“…There is a case report of a single patient with CLL, not on treatment, who contracted Powassan encephalitis and survived, although he experienced significant morbidity, including aphasia and spastic paraplegia [13]. Other reports of neuroinvasive Powassan virus among the immunocompromised include a 67-year-old female receiving adjuvant chemotherapy following hemicolectomy [14], a 61-year-old male receiving adalimumab for Crohn's disease [15], and a 63-year-old male with follicular lymphoma treated with rituximab [16].…”

Detect and destroy: CRISPR-based technologies for the response against viruses

“…When this technology was compared with gold-standard qPCR, DETECTR produced concordant results in all but two samples ( Chen et al., 2018 ). A growing number of CRISPR-based assays have since been developed and validated for human viruses: Japanese encephalitis virus (JEV), Epstein-Barr virus (EBV) ( Wu et al., 2019 ), Powassan virus ( Normandin et al., 2020 ), H7N9 influenza virus ( Liu et al., 2019 ), hantavirus ( Curti et al., 2020 ), Ebola virus (EBOV), and Lassa virus (LASV; causative agent of Lassa fever) ( Barnes et al., 2020 ). Due to the flexibility of these platforms, CRISPR-based assays could be developed for any viral pathogen with sufficient genomic information.…”

Powassan Encephalitis: A Case Report from New York, USA

“…Roughly, 50% of patients will have long term neurological sequelae of Powassan virus , such as recurrent headaches, cognitive disruption, and focal neurological deficits [ 5 , 9 ]. It is estimated that the 10% of patients with Powassan will expire from the disease [ 5 , 9 ].…”