Powassan Virus

Etiology

Taxonomically POW virus is an arbovirus classified into the family Flaviviridae and subclassified into the genus Flavivirus. The flaviviruses are transmitted by tick or mosquito vectors and include several clinically significant viruses that cause human infection. Other notable viruses among this family are those known to cause Yellow fever, Japanese encephalitis, West Nile, Dengue, and Zika.[10]

POW virus is a single-stranded RNA virus, and genomic sequencing has identified two distinct lineages or genotypes.[2][11] Though distinguishing these lineages may have epidemiologic importance, cross-neutralization and natural history studies have demonstrated that they are serologically and clinically indistinguishable.[1][12] 

Transmission to humans occurs primarily through the bite of an infected tick. Three main species of ticks have been identified as vectors for the transmission of the POW virus, but Ixodes scapularis (deer tick) is the primary vector.[9][2] Ixodes scapularis also serves as a vector for other common pathogens that cause human infection, including Borrelia burgdorferi, Babesia microti, and Anaplasma phagocytophilum. Ixodes cookei (groundhog tick) and Ixodes marxi (squirrel tick) can also transmit the POW virus but rarely bite humans.[8]

The primary ecologic reservoir for the POW virus is rodents and small mammals. It has been most commonly isolated in mice, groundhogs, voles, and squirrels. However, larger animals such as skunks, foxes, deer, and horses likely play a role in transmission as well.[13][14] 

Once infected, animals develop high viremia and onward transmission to ticks that feed on these infected hosts. Ticks then become vectors for the POW virus, enabling subsequent transmission of the virus to humans or other animals. Infection in humans is not thought to result in high enough viremia levels to result in onward transmission, and thus humans are considered dead-end hosts.[4]

Epidemiology

Although POW virus infection is rare compared to other flavivirus infections, globally, cases have been steadily on the rise in endemic areas. Human infections have been primarily identified in Canada, Russia, and the United States. Within the US, most cases have occurred in New England and the Great Lakes regions, with the highest number of cases reported annually in Minnesota, Wisconsin, Massachusetts, and New York.[15][16] In Canada, cases have been documented in British Columbia, Alberta, and the Maritime provinces. However, the majority have occurred in Eastern Canada, with Ontario and Quebec leading in overall case numbers.[13] Russia has also reported cases, which have predominated in the far eastern province of Primorsky Krai, though seropositive rodents have been identified in other regions, including Siberia.[3] In each region, case incidence peaks between April to November, coinciding with seasonal tick activity, although infections have been reported year-round when milder conditions predominate. 

Seroprevalence studies support a much wider POW distribution across Europe and North America than previously identified by clinical case reports. In Canada and the United States, serologic surveys have shown POW from coast to coast, even extending into parts of northern Mexico.[17] However, cross-reactivity due to the homology of POW virus antigens and those expressed by other flaviviruses may confound some of these studies.[18] 

Few contemporary epidemiologic studies have examined the seroprevalence of POW in endemic areas, but older studies suggest prevalence rates range between 1% to 6%.[19][20] Although it remains unclear if POW virus immunoglobulins wane seasonally or can remain positive lifelong after infection. Comparing seroprevalence data with the low yearly incidence of clinical cases in endemic regions underscores the hypothesis that most infections are mild or sub-clinical and result in neuroinvasive disease.

Over the past decade, there have been several outbreaks of the POW virus. In 2001, a cluster of neuroinvasive cases occurred in Maine and Vermont after years of inactivity, and similar outbreaks have occurred across New England and the midwestern United States.[6][21][22] Between 2010 and 2019, the CDC reported 347 cases of POW virus infection in the United States, of which 166 were neuro-invasive.[23] In 2019 the CDC reported its highest yearly case count of neuroinvasive disease to date with a total of 39 cases, representing a 5-fold increase from 2015.[23] Though it is evident cases are rising, it remains unclear what ecologic or epidemiologic factors may be driving the resurgence of the POW virus.

Pathophysiology

The initial stages of the POW virus disease result from viremia that develops in the setting of an infected tick bite. Animal models have shown that infection can occur in as short as 15 minutes after tick attachment.[24][6] Human studies have validated these observations and have established that infection can occur within three hours of tick attachment.[9] This contrasts the much longer attachment times needed to transmit other common tick-borne infections like Babesia microti, Anaplasma phagocytophilum, and Borrelia burgdorferi. After primary infection occurs, patients can develop non-specific flu-like symptoms that are typically self-limited. Subsequently, days to weeks later, a subset of patients will develop neurologic manifestations that most commonly present as encephalitis or meningoencephalitis.[4][13] The risk factors and molecular mechanisms underlying the progression from mild symptoms to neuroinvasion remain unclear.

History and Physical

The most common clinical presentation of POW virus infection is encephalitis or meningoencephalitis though seroprevalence studies suggest that most infections are sub-clinical. The incubation period ranges from 1 to 5 weeks and can result in a non-specific prodromal illness.[7] This is typified by fever, myalgias, malaise, weakness, headache, and sore throat. Symptoms can also include nausea, vomiting, or a morbilliform rash. The prodromal phase can last 1 to 3 days and always precedes neurologic symptoms.[1] If neurologic manifestations develop, they occur weeks to months after the initial prodromal illness. It remains unknown what percentage of cases will progress to develop neuroinvasive disease or what risk factors might predict worse outcomes among those with neurologic symptoms.

In those who present with severe disease that includes CNS symptoms, it is common to see prolonged fever, confusion, decreased level of consciousness, and seizures. Ocular symptoms can also be seen, such as ophthalmoplegia and nystagmus. Spastic and flaccid paralysis have also been associated with human POW virus infection, but these features are less frequent.[6][14] Although many of these symptoms are common, none are specific to the POW virus, and thus they cannot be used to distinguish it clinically from the syndromes caused by other arboviruses such as West Nile, Eastern Equine, La Crosse, or Saint Louis encephalitis virus.

Evaluation

The evaluation of a patient with suspected POW virus infection should focus on the presence or absence of neurologic symptoms. Those who present with non-specific flu-like symptoms are unlikely to benefit from disease-specific testing. However, in patients with geographic exposure presenting with encephalitis or meningoencephalitis, POW virus testing should be considered. Those with a high clinical suspicion for infection, brain imaging, serology, and lumbar puncture are key aspects of the diagnostic approach. Cerebrospinal fluid (CSF) analysis typically shows a lymphocytic pleocytosis, elevated protein, and normal glucose, though CSF findings can also be unremarkable. Other general laboratory findings may be seen in the peripheral blood, including thrombocytopenia, lymphopenia, and elevated inflammatory markers.  

A confirmatory diagnosis can be made by several methods, direct virus amplification (PCR), detection of IgM antibodies in serum by enzyme immunoassay (EIA), or detection of IgM antibodies in the CSF by EIA are all acceptable.[9][14] However, positive serum IgM tests should be confirmed by a plaque neutralization assay to improve their specificity.[9][4] Serologic tests on the CSF remain the gold standard for confirming neuroinvasive disease through the role of PCR, and metagenomic sequencing may expand in the future.[25] 

Given the overlapping geographic distribution of the POW virus with other arthropod diseases, it is also critical to assess patients for co-infection. Concurrent infections can lead to increased morbidity and mortality when not identified and are often treatable. Observational studies have shown that in those with confirmed POW virus encephalitis, a co-infection with Anaplasma phagocytophilum or Borrelia burgdorferi can be found in 10% to 30% of patients.[26][1]

Treatment / Management

Currently, there is no approved chemoprophylaxis, vaccine, or disease-specific treatment for POW virus infection. Management of patients is supportive and should involve the expertise of an infectious disease specialist. General supportive treatment with intravenous fluids, antipyretics, and critical care, as required, have been effective, but the overall case mortality remains high. Several case reports have proposed the potential use of high-dose corticosteroids or intravenous immunoglobulin (IVIG).[27][25] However, there are no clinical studies supporting improved clinical outcomes with either agent, and caution should be used if considering their use. Data on specific antivirals with activity against POW is also scant, and there are currently no antiviral agents with known efficacy against the POW virus.

Differential Diagnosis

The differential for POW virus infection is broad and will vary depending on a patient’s geographic exposures, host immune status, and other epidemiologic risk factors. However, the differential should encompass the common causes of viral and tick-borne encephalitis.

• West Nile virus (WNV)
• Herpes simplex virus (HSV-1 and HSV-2)
• Varicella-zoster virus (VZV)
• Cytomegalovirus (CMV)
• Epstein-Barr virus (EBV)
• Human Herpesvirus 6 (HHV-6)
• Neuroborreliosis (Lyme)
• Anaplasmosis
• Ehrlichiosis
• Tick-borne relapsing fever
• Saint Louis encephalitis virus (SLEV) 
• Eastern Equine Virus
• Tick-borne encephalitis virus (TBEV)
• Adenovirus
• Influenza A
• Enterovirus
• La Crosse virus
• Dengue
• Murray Valley encephalitis
• Japanese encephalitis
• Bacterial meningitis
• HIV
• Neurosyphilis
• Rabies

Prognosis

The prognosis in most patients infected with the POW virus, who have asymptomatic or mildly symptomatic disease, is thought to be excellent, and asymptomatic infection often goes completely unrecognized. However, a subset of patients progress and will go on to develop neuroinvasive disease, which typically presents as encephalitis or meningoencephalitis. Among these neuroinvasive cases, the mortality rate is high and estimated at 10% to 15%.[6][7]

Complications

In patients who develop severe infections involving the CNS, most of the expected complications result in neurologic disability. In those who develop the neuroinvasive disease but survive, about 50% will have some form of long-lasting neurologic disability.[6]

Retrospective studies have highlighted a wide spectrum of deficits, but the most common include persistent headaches, memory impairment, ataxia, tremor, weakness, encephalopathy, hemiplegia, or persistent ophthalmoplegia.[1][28]