Clinical Manifestations and Outcomes of West Nile Virus Infection

Since the emergence of West Nile virus (WNV) in North America in 1999, understanding of the clinical features, spectrum of illness and eventual functional outcomes of human illness has increased tremendously. Most human infections with WNV remain clinically silent. Among those persons developing symptomatic illness, most develop a self-limited febrile illness. More severe illness with WNV (West Nile neuroinvasive disease, WNND) is manifested as meningitis, encephalitis or an acute anterior (polio) myelitis. These manifestations are generally more prevalent in older persons or those with immunosuppression. In the future, a more thorough understanding of the long-term physical, cognitive and functional outcomes of persons recovering from WNV illness will be important in understanding the overall illness burden.     

B Cell Response and Mechanisms of Antibody Protection to West Nile Virus

West Nile virus (WNV) has become the principal cause of viral encephalitis in North America since its introduction in New York in 1999. This emerging virus is transmitted to humans via the bite of an infected mosquito. While there have been several candidates in clinical trials, there are no approved vaccines or WNV-specific therapies for the treatment of WNV disease in humans. From studies with small animal models and convalescent human patients, a great deal has been learned concerning the immune response to infection with WNV. Here, we provide an overview of a subset of that information regarding the humoral and antibody response generated during WNV infection.     

Measles vaccine expressing the secreted form of West Nile virus envelope glycoprotein induces protective immunity in squirrel monkeys, a new model of West Nile virus infection

West Nile virus (WNV) is a mosquito-borne flavivirus that emerged in North America and caused numerous cases of human encephalitis, thus urging the development of a vaccine. We previously demonstrated the efficacy of a recombinant measles vaccine (MV) expressing the secreted form of the envelope glycoprotein from WNV to prevent WNV encephalitis in mice. In the present study, we investigated the capacity of this vaccine candidate to control WNV infection in a primate model. We first established experimental WNV infection of squirrel monkeys (Saimiri sciureus). A high titer of virus was detected in plasma on day 2 after infection, and viremia persisted for 5 days. A single immunization of recombinant MV-WNV vaccine elicited anti-WNV neutralizing antibodies that strongly reduced WNV viremia at challenge. This study demonstrates for the first time the capacity of a recombinant live attenuated measles vector to protect nonhuman primates from a heterologous infectious challenge.     

Dry weather induces outbreaks of human West Nile virus infections

Background  

Since its first occurrence in the New York City area during 1999, West Nile virus (WNV) has spread rapidly across North America and has become a major public health concern in North America. By 2002, WNV was reported in 40 states and the District of Columbia with 4,156 human and 14,539 equine cases of infection. Mississippi had the highest human incidence rate of WNV during the 2002 epidemic in the United States. Epidemics of WNV can impose enormous impacts on local economies. Therefore, it is advantageous to predict human WNV risks for cost-effective controls of the disease and optimal allocations of limited resources. Understanding relationships between precipitation and WNV transmission is crucial for predicting the risk of the human WNV disease outbreaks under predicted global climate change scenarios.     

Live measles vaccine expressing the secreted form of the West Nile virus envelope glycoprotein protects against West Nile virus encephalitis

The Schwarz strain of measles virus (MV), a live attenuated RNA virus, is one of the safest and most effective human vaccines available. Immunization with MV vaccine expressing heterologous antigen is an attractive strategy to prevent emerging viral diseases. West Nile virus (WNV), which recently emerged in North America, is an important mosquito-borne flavivirus that causes numerous cases of human encephalitis, thus urging the development of a vaccine. To evaluate the efficacy of recombinant MV for the prevention of WNV encephalitis, we constructed a live attenuated Schwarz MV (MVSchw-sE(WNV)) expressing the secreted form of the envelope glycoprotein from the virulent IS-98-ST1 strain of WNV. Inoculation of MV-susceptible mice with MVSchw-sE(WNV) induced both high levels of specific anti-WNV neutralizing antibodies and protection from a lethal challenge with WNV. Passive administration with antisera to MVSchw-sE(WNV) prevented WNV encephalitis in BALB/c mice challenged with a high dose of WNV. The present study is the first to report that a recombinant live attenuated vector based on an approved and widely used MV vaccine can protect against a heterologous, medically important pathogen.     

West Nile virus: where are we now?

Since the publication of a comprehensive review on West Nile virus (WNV) in 2002, there has been substantial progress in understanding of transmission, epidemiology, and geographic distribution of the virus and manifestations of disease produced by the infection. There have also been advances in development of diagnostic and therapeutic agents and vaccines. Nevertheless, many questions about the epidemic remain unanswered, and several new issues have arisen--for example: whether the epidemic will increase as the virus spreads to the Pacific coast of North America; whether arthropods other than mosquitoes will act as vectors for the infection; whether WNV will spread to South America and cause an epidemic there; whether the distribution of WNV in Asia and Europe will increase; and whether adaptation of WNV to new ecosystems will produce viruses with altered genetic and phenotypic properties. This review aims to provide an update on knowledge of WNV biology that can be used to highlight the advances in the field during the past 2 years and help to define the questions that academic, industrial, and public-health communities must address in development of measures to control WNV disease.     

Rhabdomyolysis in patients with west nile encephalitis and meningitis

Since 1999, more than 6,500 cases of West Nile virus neuroinvasive disease (WNND) have been reported in the United States. Patients with WNND can present with muscle weakness that is often assumed to be of neurological origin. During 2002, nearly 3,000 persons with WNV meningitis or encephalitis (or both) were reported in the United States; in suburban Cook County, Illinois, with 244 persons were hospitalized for WNV illnesses. The objective of this investigation was to describe the clinical and epidemiological features of identified cases of WNV neuroinvasive disease and rhabdomyolysis. Public health officials investigated patients hospitalized in Cook County, and identified a subset of WNV neuroinvasive disease patients with elevated creatine kinase levels. Cases were defined as hospitalized persons with a WNV infection, encephalitis or meningitis, and rhabdomyolysis. Retrospective medical record reviews were conducted and data was abstracted with a standardized data collection instrument. Eight patients with West Nile encephalitis and one with West Nile meningitis were identified with rhabdomyolysis. Median age of the nine patients was 70 years (range, 45-85 years), and eight were men. For all nine patients, the peak CK level was documented a median of 2 days after hospitalization (range, 1-24 days). Median CK level during hospitalization for all case-patients was 3,037 IU (range, 1,153-42,113 IU). Six patients had history of recent falls prior to admission. Although the temporal relationship of rhabdomyolysis and neurological WNV illness suggested a common etiology, these patients presented with complex clinical conditions which may have led to development of rhabdomyolysis from other causes. The spectrum of WNV disease requires further investigation to describe this and other clinical conditions associated with WNV infection.     

West Nile encephalitis: an emerging disease in the United States.

In 1999, an epidemic of West Nile virus (WNV) encephalitis occurred in New York City (NYC) and 2 surrounding New York counties. Simultaneously, an epizootic among American crows and other bird species occurred in 4 states. Indigenous transmission of WNV had never been documented in the western hemisphere until this epidemic. In 2000, the epizootic expanded to 12 states and the District of Columbia, and the epidemic continued in NYC, 5 New Jersey counties, and 1 Connecticut county. In addition to these outbreaks, several large epidemics of WNV have occurred in other regions of the world where this disease was absent or rare >5 years ago. Many of the WNV strains isolated during recent outbreaks demonstrate an extremely high degree of homology that strongly suggests widespread circulation of potentially epidemic strains of WNV. The high rates of severe neurologic illness and death among humans, horses, and birds in these outbreaks are unprecedented and unexplained. We review the current status of WNV in the United States.     

Role of Natural Killer and Gamma-Delta T cells in West Nile Virus Infection

Natural Killer (NK) cells and Gamma-delta T cells are both innate lymphocytes that respond rapidly and non-specifically to viral infection and other pathogens. They are also known to form a unique link between innate and adaptive immunity. Although they have similar immune features and effector functions, accumulating evidence in mice and humans suggest these two cell types have distinct roles in the control of infection by West Nile virus (WNV), a re-emerging pathogen that has caused fatal encephalitis in North America over the past decade. This review will discuss recent studies on these two cell types in protective immunity and viral pathogenesis during WNV infection.     

West Nile virus: a primer for infection control professionals

In 1999, an outbreak of human West Nile encephalitis occurred in New York City. During the outbreak, 62 cases of human West Nile virus (WNV) infection were diagnosed, with 7 deaths. This was the first time that human WNV infections were detected in the Western Hemisphere. By 2002, the total number of human cases of WNV that year alone reached 4156, with 284 fatalities. In addition, investigations have shown that WNV can be acquired through organ transplantation, blood transfusion, breast milk, transplacental transmission, and occupational exposure. This article provides an overview of the 2002 WNV epidemic in the United States and reviews the epidemiology of WNV, the clinical presentation of human WNV infection, and the prevention and control of this emerging pathogen.     

Vector Surveillance,Host Species Richness,and Demographic Factors as West Nile Disease Risk Indicators

West Nile virus (WNV) is the most common arthropod-borne virus (arbovirus) in the United States (US) and is the leading cause of viral encephalitis in the country. The virus has affected tens of thousands of US persons total since its 1999 North America introduction, with thousands of new infections reported annually. Approximately 1% of humans infected with WNV acquire neuroinvasive West Nile Disease (WND) with severe encephalitis and risk of death. Research describing WNV ecology is needed to improve public health surveillance, monitoring, and risk assessment. We applied Bayesian joint-spatiotemporal modeling to assess the association of vector surveillance data, host species richness, and a variety of other environmental and socioeconomic disease risk factors with neuroinvasive WND throughout the conterminous US. Our research revealed that an aging human population was the strongest disease indicator, but climatic and vector-host biotic interactions were also significant in determining risk of neuroinvasive WND. Our analysis also identified a geographic region of disproportionately high neuroinvasive WND disease risk that parallels the Continental Divide, and extends southward from the US–Canada border in the states of Montana, North Dakota, and Wisconsin to the US–Mexico border in western Texas. Our results aid in unraveling complex WNV ecology and can be applied to prioritize disease surveillance locations and risk assessment.     

West Nile virus neuroinvasive disease incidence in the United States, 2002-2006

As the geographic range of reported human West Nile virus (WNV) disease has expanded across the United States, seasonal transmission and outbreaks have persisted over several years in many areas of the country. West Nile virus neuroinvasive disease (WNND) case reports from 2002 to 2006 were reviewed to determine which areas of the country have the highest reported cumulative incidence and whether those areas have had consistently high annual incidence. During the 5-year period examined, 9632 cases of WNND were reported nationwide. The cumulative incidence of WNND ranged from 0.2 to 32.2 per 100,000 population by state and from 0.1 to 241.2 per 100,000 population by county. States and counties with the highest cumulative incidence were primarily located in the northern Great Plains. States with consistently high annual incidence included South Dakota, North Dakota, Wyoming, New Mexico, Mississippi, Nebraska, Louisiana, and Colorado. All of these states, with the exception of New Mexico, were also among the states with the highest cumulative incidence. Counties with repeatedly high annual incidence were also primarily in the Great Plains and mid-South. The risk of WNND appears to be highest in areas where the primary WNV vectors are Culex tarsalis and Cx. quinquefasciatus mosquitoes.     

Genome Sequencing of West Nile Virus from Human Cases in Greece, 2012

A West Nile Virus (WNV) lineage 2 strain, named Nea Santa-Greece-2010, has been demonstrated to be responsible for the large outbreaks of neuroinvasive disease (WNND) that have been occurring in Greece since 2010, based on sequence similarities of viral isolates identified between 2010–2012. However, knowledge on the evolution of this strain is scarce because only partial WNV genome sequences are available from Greece. The aim of this study was to get the complete genome sequence of WNV from patients with infection. To this aim, plasma and urine samples collected during the 2012 Greek outbreak were retrospectively investigated. Full WNV genome sequence was obtained from a patient with WNND. The genome had 99.7% sequence identity to Nea Santa, higher than to other related WNV lineage 2 strains, and five amino acid changes apparently not relevant for viral pathogenicity or fitness. In addition, infection by WNV lineage 2 was confirmed in additional nine patients with WNND; in three of them the infection with WNV Nea Santa was demonstrated by sequencing. In conclusion, this study characterized for the first time a WNV full genome from a patient with WNND from Greece, demonstrated the persistence of the Nea Santa strain, and suggested that the virus might have locally evolved.     

Vaccines and immunotherapeutics for the prevention and treatment of infections with West Nile virus

The emergence of West Nile virus (WNV) in North America in 1999 as a cause of severe neurological disease in humans, horses and birds stimulated development of vaccines for human and veterinary use, as well as polyclonal/monoclonal antibodies and other immunomodulating compounds for use as therapeutics. Although disease incidence in North America has declined since the peak epidemics in 2002-2003, the virus has continued to be annually transmitted in the Americas and to cause periodic epidemics in Europe and the Middle East. Continued transmission of the virus with human and animal disease suggests that vaccines and therapeutics for the prevention and treatment of WNV disease could be of great benefit. This article focuses on progress in development and evaluation of vaccines and immunotherapeutics for the prevention and treatment of WNV disease in humans and animals.     

Vaccines in Development against West Nile Virus

West Nile encephalitis emerged in 1999 in the United States, then rapidly spread through the North American continent causing severe disease in human and horses. Since then, outbreaks appeared in Europe, and in 2012, the United States experienced a new severe outbreak reporting a total of 5,387 cases of West Nile virus (WNV) disease in humans, including 243 deaths. So far, no human vaccine is available to control new WNV outbreaks and to avoid worldwide spreading. In this review, we discuss the state-of-the-art of West Nile vaccine development and the potential of a novel safe and effective approach based on recombinant live attenuated measles virus (MV) vaccine. MV vaccine is a live attenuated negative-stranded RNA virus proven as one of the safest, most stable and effective human vaccines. We previously described a vector derived from the Schwarz MV vaccine strain that stably expresses antigens from emerging arboviruses, such as dengue, West Nile or chikungunya viruses, and is strongly immunogenic in animal models, even in the presence of MV pre-existing immunity. A single administration of a recombinant MV vaccine expressing the secreted form of WNV envelope glycoprotein elicited protective immunity in mice and non-human primates as early as two weeks after immunization, indicating its potential as a human vaccine.     

West Nile virus: immunity and pathogenesis

West Nile virus (WNV) is a neurotropic, arthropod-borne flavivirus that is maintained in an enzootic cycle between mosquitoes and birds, but can also infect and cause disease in horses and humans. WNV is endemic in parts of Africa, Europe, the Middle East, and Asia, and since 1999 has spread to North America, Mexico, South America, and the Caribbean. WNV infects the central nervous system (CNS) and can cause severe disease in a small minority of infected humans, mostly immunocompromised or the elderly. This review discusses some of the mechanisms by which the immune system can limit dissemination of WNV infection and elaborates on the mechanisms involved in pathogenesis. Reasons for susceptibility to WNV-associated neuroinvasive disease in less than 1% of cases remain unexplained, but one favored hypothesis is that the involvement of the CNS is associated with a weak immune response allowing robust WNV replication in the periphery and spread of the virus to the CNS.     

West Nile virus surveillance and diagnostics: A Canadian perspective

A surveillance program has been in place since 2000 to detect the presence of West Nile virus (WNV) in Canada. Serological assays are most appropriate when monitoring for human disease and undertaking case investigations. Genomic amplification procedures are more commonly used for testing animal and mosquito specimens collected as part of ongoing surveillance efforts. The incursion of WNV into this country was documented for the first time in 2001 when WNV was demonstrated in 12 Ontario health units during the late summer and fall. In 2002 WNV activity was documented by avian surveillance in Ontario by mid-May with subsequent expansion of the virus throughout Ontario and into Quebec, Manitoba, Saskatchewan and Nova Scotia. Human cases were recorded in both Ontario and Quebec in 2002 with approximately 800 to 1000 probable, confirmed and suspect cases detected. The possible recurrence and further spread of WNV to other parts of Canada in 2003 must be anticipated with potential risk to public health. The continued surveillance and monitoring for WNV-associated human illness is necessary and appropriate disease prevention measures need to be in place in 2003.Key Words: Corvids, Diagnostics, Humans, Mosquitoes, Surveillance, West Nile virusThe unexpected incursion of West Nile virus (WNV) into North America occurred during the summer of 1999 when an outbreak of neurological illness among humans, birds and horses was identified in the metropolitan area of New York City (1,2). This outbreak (62 human cases, including a visiting Canadian) was the first time that laboratory-confirmed cases of WNV disease had been observed in the Western hemisphere. By the end of 2002, the geographic range of WNV had expanded to 44 states, the District of Columbia and five Canadian provinces (3). In 2002, approximately 3000 cases of meningoencephalitis (ME) and over 1000 cases of WNV fever had been documented in the United States and Canada, making this epidemic the largest arboviral ME outbreak ever recorded in the ''New World'' and the largest WNV ME outbreak ever seen worldwide. This review describes the ecology and epidemiology of WNV and focuses on the diagnostic tests used to detect infection in birds, mosquitoes and people, and on the surveillance programs used to detect virus activity in Canada.     

Nonviremic transmission of West Nile virus

West Nile virus (WNV) is now the predominant circulating arthropod-borne virus in the United States with >15,000 human cases and >600 fatalities since 1999. Conventionally, mosquitoes become infected when feeding on viremic birds and subsequently transmit the virus to susceptible hosts. Here, we demonstrate nonviremic transmission of WNV between cofeeding mosquitoes. Donor, Culex pipiens quinquefasciatus mosquitoes infected with WNV were fed simultaneously with uninfected "recipient" mosquitoes on na?ve mice. At all times, donor and recipient mosquitoes were housed in separate sealed containers, precluding the possibility of mixing. Recipients became infected in all five trials, with infection rates as high as 5.8% and no detectable viremia in the hosts. Remarkably, a 2.3% infection rate was observed when 87 uninfected mosquitoes fed adjacent to a single infected mosquito. This phenomenon could potentially enhance virus survival, transmission, and dispersion and obviate the requirement for viremia. All vertebrates, including immune and insusceptible animals, might therefore facilitate mosquito infection. Our findings question the status of dead-end hosts in the WNV transmission cycle and may partly explain the success with which WNV established and rapidly dispersed throughout North America.