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West Nile virus (WNV) is the most common cause of human arboviral disease in the contiguous United States, where only lineage 1 (L1) WNV had been found. In 2023, an immunocompetent patient was hospitalized in Nebraska with West Nile neuroinvasive disease and multisystem organ failure. Testing at the Centers for Disease Control and Prevention indicated an unusually high viral load and acute antibody response. Upon sequencing of serum and cerebrospinal fluid, we detected lineage 3 (L3) and L1 WNV genomes. L3 WNV had previously only been found in Central Europe in mosquitoes. The identification of L3 WNV in the United States and the observed clinical and laboratory features raise questions about the potential effect of L3 WNV on the transmission dynamics and pathogenicity of WNV infections. Determining the distribution and prevalence of L3 WNV in the United States and any public health and clinical implications is critical.

West Nile virus (WNV) is a public health concern in Europe. Rising temperatures and the migration of potential vectors promote the spread of viruses to previously unaffected areas. In 2023, the Apulia region of Southern Italy experienced an unexpected increase in West Nile neuroinvasive disease (WNND); no such cases had been reported in the previous 10 years. Overall, eight autochthonous cases of WNV infection were identified between July and October 2023, six of which were WNND. All cases were male (median age, 73 years). Two of the cases were blood donors. All WNND cases were hospitalized and all recovered within a few weeks. Surveillance data showed that, in the Apulia region, WNV Lineage 2 was detected in humans, mosquitoes, and horses. Based on the number of WNND cases reported, we can assume that a high number of infections occurred during the summer period. Changes in the climate in the region over recent years could be considered among the main drivers of the rapid increase in WNV infections. Therefore, integrated surveillance should be strengthened to avoid the potential massive spread of WNV in Southern Italy. Moreover, the implementation of whole-genome sequencing of WNV strains, as well as seroepidemiological studies in the area, will facilitate a better understanding of circulation dynamics., Competing Interests: The authors declare no conflicts of interest.

Short and low-level viremia and virorachia, antibody cross-reactivity, IgM persistence, and inaccessibility of neutralization test, make laboratory diagnosis of West Nile virus (WNV) infection difficult. Recent investigations imply that WNV is excreted in urine longer and at higher concentrations compared to blood. The detection of WNV nucleic acid in cerebrospinal fluid (CSF), serum, and urine samples collected from 41 patients with suspected WNV neuroinvasive disease, was done by real-time RT-PCR assay. CSF and serum samples were also serologically tested using anti-WNV IgM/IgG ELISA kits. WNV infection was confirmed in 46.3% of patients by positive WNV RNA results in serum and/or CSF samples. The WNV RNA testing of urine allowed confirmation of 31.7% more cases. No association between WNV RNA urine positivity and age, gender, or the day of sample collection was found. The urine qRT-PCR can be a valuable diagnostic test for confirmation of probable cases of WNV neuroinvasive disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: West Nile virus (WNV) is the leading cause of mosquito-borne illness in the continental USA. WNV occurrence has high spatiotemporal variation, and current approaches to targeted control of the virus are limited, making forecasting a public health priority. However, little research has been done to compare strengths and weaknesses of WNV disease forecasting approaches on the national scale. We used forecasts submitted to the 2020 WNV Forecasting Challenge, an open challenge organized by the Centers for Disease Control and Prevention, to assess the status of WNV neuroinvasive disease (WNND) prediction and identify avenues for improvement., Methods: We performed a multi-model comparative assessment of probabilistic forecasts submitted by 15 teams for annual WNND cases in US counties for 2020 and assessed forecast accuracy, calibration, and discriminatory power. In the evaluation, we included forecasts produced by comparison models of varying complexity as benchmarks of forecast performance. We also used regression analysis to identify modeling approaches and contextual factors that were associated with forecast skill., Results: Simple models based on historical WNND cases generally scored better than more complex models and combined higher discriminatory power with better calibration of uncertainty. Forecast skill improved across updated forecast submissions submitted during the 2020 season. Among models using additional data, inclusion of climate or human demographic data was associated with higher skill, while inclusion of mosquito or land use data was associated with lower skill. We also identified population size, extreme minimum winter temperature, and interannual variation in WNND cases as county-level characteristics associated with variation in forecast skill., Conclusions: Historical WNND cases were strong predictors of future cases with minimal increase in skill achieved by models that included other factors. Although opportunities might exist to specifically improve predictions for areas with large populations and low or high winter temperatures, areas with high case-count variability are intrinsically more difficult to predict. Also, the prediction of outbreaks, which are outliers relative to typical case numbers, remains difficult. Further improvements to prediction could be obtained with improved calibration of forecast uncertainty and access to real-time data streams (e.g. current weather and preliminary human cases)., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

West Nile viral infection causes severe neuroinvasive disease in less than 1% of infected humans. There are no targeted therapeutics for this serious and potentially fatal disease, and to date no vaccine has been approved for humans. With climate change expected to result in rising incidence of West Nile and other related vector-borne viral infections, there is an increasing need to identify those at risk for serious disease and potential leads for therapeutic and vaccine development. Genetic variation, particularly in genes whose products are either directly or indirectly connected to immune response to infections, is a critical avenue of investigation to identify those at higher risk of clinically apparent West Nile infection. Given the small percent of infections that progress to severe disease and the relatively low numbers of reported infections, it is challenging to conduct well-powered studies to identify genetic factors associated with more severe outcomes. In this chapter, we outline several approaches with the objective to take full advantage of all available data in order to identify genetic factors which lead to increased risk of severe West Nile neuroinvasive disease. These methods are generalizable to other conditions with limited cohort size and rare outcomes., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

West Nile virus (WNV) is an emerging pathogen in Hungary, causing severe outbreaks in equines and humans since 2007. The aim of our study was to provide a comprehensive report on the clinical signs of West Nile neuroinvasive disease (WNND) in horses in Hungary. Clinical details of 124 confirmed equine WNND cases were collected between 2007 and 2019. Data about the seasonal and geographical presentation, demographic data, clinical signs, treatment protocols, and disease progression were evaluated. Starting from an initial case originating from the area of possible virus introduction by migratory birds, the whole country became endemic with WNV over the subsequent 12 years. The transmission season did not expand significantly during the data collection period, but vaccination protocols should be always reviewed according to the recent observations. There was not any considerable relationship between the occurrence of WNND and age, breed, or gender. Ataxia was by far the most common neurologic sign related to the disease, but weakness, behavioral changes, and muscle fasciculation appeared frequently. Apart from recumbency combined with inappetence, no other clinical sign or treatment regime correlated with survival. The survival rate showed a moderate increase throughout the years, possibly due to the increased awareness of practitioners.

West Nile virus (WNV) can cause asymptomatic infection in humans, result in self-limiting febrile illness, or lead to severe West Nile Neuroinvasive disease (WNND). We conducted a pilot study to compare selected biomarkers of oxidative stress in sera of viremic West Nile virus patients and asymptomatic infected blood donors to investigate their potential as predictors of disease severity. We found that total oxidant status was elevated in WNND and in uncomplicated WNV infections (median 9.05 (IQR 8.37 to 9.74) and 7.14 (7.03 to 7.25) µmol H 2 O 2 equiv./L, respectively) compared to asymptomatic infections (0.11 (0.07 to 0.19) µmol H 2 O 2 equiv./L) ( p = 0.048). MDA levels showed a similar trend to TOS, but differences were not significant at α = 0.05. Total antioxidant status did not differ significantly between different disease severity groups. Oxidative stress appears to be associated with more severe disease in WNV-infected patients. Our preliminary findings warrant prospective studies to investigate the correlation of oxidative stress with clinical outcomes and severity of WNV infection.

West Nile neuroinvasive disease (WNND) is a severe neurological illness that can result from West Nile virus (WNV) infection, with long-term disability and death being common outcomes. Although WNV arrived in North America over two decades ago, risk factors for WNND are still being explored. The objective of this study was to identify WNND comorbid risk factors in the Ontario population using a retrospective, population-based cohort design. Incident WNV infections from laboratory records between 1 January 2002 - 31 December 2012 were individually-linked to health administrative databases to ascertain WNND outcomes and comorbid risk factors. WNND incidence was compared among individuals with and without comorbidities using risk ratios (RR) calculated with log binomial regression.Three hundred and forty-five individuals developed WNND (18.3%) out of 1884 WNV infections. West Nile encephalitis was driving most associations with comorbidities. Immunocompromised (aRR 2.61 [95% CI 1.23-4.53]) and male sex (aRR 1.32 [95% CI 1.00-1.76]) were risk factors for encephalitis, in addition to age, for which each 1-year increase was associated with a 2% (aRR 1.02 [95% CI 1.02-1.03]) relative increase in risk. Our results suggest that individuals living with comorbidities are at higher risk for WNND, in particular encephalitis, following WNV infection.

Background: West Nile virus (WNV) is the most commonly reported mosquito-borne disease in the USA. California reports more WNV disease than any other state., Methods: We identified WNV-associated hospitalizations from 2004 through 2017 in California and estimated hospitalization incidence using Patient Discharge Data. We described demographic, geographic, and clinical characteristics of WNV hospitalizations; identified risk factors for in-hospital death; and tabulated hospitalization charges., Results: From 2004 through 2017, 3109 Californians were hospitalized with WNV (median, 214 patients/year; range, 72-449). The majority were male (1983; 63.8%) and aged ≥60 years (1766; 56.8%). The highest median annual hospitalization rate (0.88 hospitalizations/100 000 persons) was in the Central Valley, followed by southern California (0.59 hospitalizations/100 000 persons). Most patients (2469; 79.4%) had ≥1 underlying condition, including hypertension, cardiovascular disease, diabetes, chronic kidney disease, or immunosuppression due to medications or disease. Median hospitalization length of stay was 12 days (interquartile range, 6-23 days). During hospitalization, 1317 (42%) patients had acute respiratory failure and/or sepsis/septic shock, 772 (24.8%) experienced acute kidney failure, and 470 (15.1%) had paralysis; 272 (8.8%) patients died. Nearly 47% (1444) of patients were discharged for additional care. During these 14 years, $838 680 664 (mean $59.9 million/year) was charged for WNV hospitalizations, 73.9% through government payers at a median charge of $142 321/patient., Conclusions: WNV-associated hospitalizations were substantial and costly in California. Hospitalization incidence was higher in males, elderly persons, and patients with underlying conditions. WNV persists as a costly and severe public health threat in California., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: West Nile virus (WNV) infections have become increasingly prevalent in certain European countries, including Hungary. Although most human infections do not cause severe symptoms, in approximately 1% of cases WNV infections can lead to severe WNV neuroinvasive disease (WNND) and death. The goal of our study was to assess the neurological status changes of WNV -infected patients admitted to inpatient care and to identify potential risk factors as underlying reasons for severe neurological outcome., Methods: We conducted a retrospective chart review of 66 WNV-infected patients from four Hungarian medical centers. Patients' neurological status at hospital admission and at two follow-up intervals (1st follow-up, within 60-90 days and 2nd follow-up, within 150-180 days, after hospital discharge) were assessed. All of the 66 patients in the initial sample had some type of neurological symptoms and 56 patients were diagnosed with WNND. The modified Rankin Scale (mRS) and the West Nile Virus Neurological Index (WNV-N Index), a scoring system designed for the purpose of this study, were used for neurological status assessment. Patients were dichotomized into two categories, "moderately severe" and "severe" based on their neurological status. Descriptive analysis for sample description, stratified analysis for calculation of odds ratio (OR) and logistic regression for continuous input variables, were performed., Results: The average number of days between the onset of neurological symptoms and hospital admission (the neurological symptom interval) was 6.01 days. Complications during the hospital stay arose in almost a fifth of the patients (18.2%) and 5 patients died. Each day's increase in the neurological symptom interval significantly increased the risk for developing a severe neurological status following hospital admission (0.799-fold and 0.688-fold, based on the WNV-N Index and mRS, respectively). Patients' age, comorbidity, presence of complications and symptoms of malaise, and gait uncertainty were shown to be independent risk factors for severe neurological status., Conclusions: Timely hospital admission of patients with neurological symptoms as well as risk assessment by clinicians - possibly with an optimal assessment tool for estimating neurological status- could improve the neurological outcome of WNV-infected patients.

West Nile virus (WNV) is a mosquito-borne virus which causes symptomatic disease in a minority of infected humans. To identify novel genetic variants associated with severe disease, we utilized data from an existing case-control study of WNV and included population controls for an expanded analysis. We conducted imputation and gene-gene interaction analysis in the largest and most comprehensive genetic study conducted to date for West Nile neuroinvasive disease (WNND). Within the imputed West Nile virus dataset (severe cases n = 381 and asymptomatic/mild controls = 441), we found novel loci within the MCF.2 Cell Line Derived Transforming Sequence Like ( MCF2L ) gene (rs9549655 and rs2297192) through the individual loci analyses, although none reached statistical significance. Incorporating population controls from the Wisconsin Longitudinal Study on Aging (n = 9012) did not identify additional novel variants, a possible reflection of the cohort's inclusion of individuals who could develop mild or severe WNV disease upon infection. Many of the top gene-gene interaction results were intergenic, with currently undefined biological roles, highlighting the need for further investigation into these regions and other identified gene targets in severe WNND. Further studies including larger sample sizes and more diverse populations reflective of those at risk are needed to fully understand the genetic architecture of severe WNDD and provide guidance on viable targets for therapeutic and vaccine development.

Following a distinct summer heat wave, nine autochthonous cases of West Nile fever and West Nile neuroinvasive disease, including one fatality, were observed in Leipzig, Germany, in August and September 2020. Phylogenetic analysis demonstrated close relationships in viruses from humans, animals and mosquitos in eastern Germany, obtained during the preceding 2 years. The described large cluster of autochthonous West Nile virus infections in Germany indicates endemic seasonal circulation of lineage 2 viruses in the area.

We report details of the first seven equine cases of confirmed West Nile neuroinvasive disease in Austria. The cases presented during summer and autumn of 2016 (n = 2), 2017 (n = 3) and 2018 (n = 2). All horses showed gait abnormalities and 6 of 7 horses exhibited fasciculations and/or tremors, and we provide video recordings of these. Three horses also showed cranial nerve involvement. Following rapid improvement, three horses were discharged. Four horses were euthanized due to the severity of clinical signs and subjected to neuropathological examination. West Nile virus (WNV) lineage 2 nucleic acid was detected in 5 of 7 horses, and WNV-specific neutralizing antibodies in all 7 horses. In addition, serologic evidence of WNV infection was found in two out of fourteen in-contact horses. Horses may be considered a sentinel species for human WNV infections, integrating human and veterinary medicine and thus contributing to the one health concept., (© 2019 The Authors. Transboundary and Emerging Diseases published by Blackwell Verlag GmbH.)

West Nile Virus (WNV) is a mosquito-transmitted flavivirus which causes encephalitis especially in elderly and immunocompromised individuals. Previous studies have suggested the protective role of the Toll-like receptor 3 (TLR3) pathway against WNV entry into the brain, while the WNV non-structural protein 1 (NS1) interferes with the TLR3 signaling pathway, besides being a component of viral genome replication machinery. In this study, we investigated whether immunization with NS1 could protect against WNV neuroinvasion in the context of TLR3 deficiency. We immunized mice with either an intact or deleted TLR3 system (TLR3KO) with WNV envelope glycoprotein (gE) protein, NS1, or a combination of gE and NS1. Immunization with gE or gE/NS1, but not with NS1 alone, induced WNV neutralizing antibodies and protected against WNV brain invasion and inflammation. The presence of intact TLR3 signaling had no apparent effect on WNV brain invasion. However, mock-immunized TLR3KO mice had higher inflammatory cell invasion upon WNV brain infection than NS1-immunized TLR3KO mice and wild type mice. Thus, immunization against NS1 may reduce brain inflammation in a context of TLR3 signaling deficiency.

Using reported case data from ArboNET and previous seroprevalence data stratified by age and sex, we conservatively estimate that ≈7 million persons in the United States have been infected with West Nile virus since its introduction in 1999. Our data support the need for public health interventions and improved surveillance.

Infection with West Nile virus (WNV) has a well-characterized acute disease process. However, long-term consequences are less understood. We searched death records for 4,142 residents of Texas, USA, infected with WNV during 2002-2012 and identified 557 (13%) deaths. We analyzed all-cause and cause-specific deaths after WNV infection by calculating standardized mortality ratios and using statewide mortality data. Acute-phase deaths (<90 days after symptom onset) occurred in 289 (7%) of case-patients; of those deaths, 289 (92%) were cases of West Nile neuroinvasive disease (WNND). Convalescent-phase deaths (>90 days after symptom onset) occurred in 268 (7%) of the remaining 3,853 case-patients; 210 (78%) of these deaths occurred in patients with WNND. Convalescent-phase WNND case-patients showed excess deaths from infectious and renal causes; case-patients <60 years of age had increased risk for all-cause death, specifically from renal, infectious, digestive, and circulatory causes. We provide population-level evidence of increased risk for death after WNV infection resulting in WNND.

Between 28 June and 17 September 2018, 27 cases of human West Nile virus infections were recorded in Austria; four cases of West Nile neuroinvasive disease, 11 cases of West Nile fever, six infections detected by blood donation screening and six imported cases. In addition, 18 cases of human Usutu virus infections (all blood donors) were recorded. This is the highest number of annual infections recorded in Austria since the introduction of both viruses.

Objectives: West Nile Virus (WNV) is endemic in Israel and was responsible for several outbreaks in the past 16 years. The aim of the present study was to investigate the spatial distribution of WNV acute infections from an outbreak that occurred in 2015 in Israel and report the molecular and geographic characterization of WNV isolates from human cases and mosquito pools obtained during this outbreak., Methods: Using a geographical layer comprising 51 continuous areas of Israel, the number of WNV infection cases per 100 000 people in each area and the locations of WNV-infected mosquitoes in 2015 were analysed. Sequencing and phylogenetic analyses followed by geographic localization were performed on 13 WNV human isolates and 19 WNV-infected mosquito pools., Results: Substantial geographical variation in the prevalence of acute WNV in patients in Israel was found and an overall correlation with WNV-infected mosquitoes. All human patients sequenced were infected only with the Mediterranean subtype of WNV Lineage 1 and resided primarily in the coastal regions in central Israel. In contrast, mosquitoes were infected with both the Mediterranean and Eastern European subtypes of WNV lineage 1; however, only the Mediterranean subtype was found in mosquitoes from the coastal region in central Israel., Conclusion: These results demonstrate differential geographic dispersion in Israel of the two WNV subtypes and may also point to a differential pattern of human infections. As a geographical bridge between Europe, Asia and Africa, analysis of WNV circulation in humans and mosquitoes in Israel provides information relevant to WNV infections in Eurasia., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

During the 2012 outbreak of West Nile virus in the United States, approximately one third of the cases were in Texas. Of those, about half occurred in northern Texas. Models based on infected blood donors and persons with neuroinvasive disease showed, respectively, that ≈0.72% and 1.98% of persons in northern Texas became infected.

West Nile virus (WNV) is an emerging flavivirus responsible for an increasing number of outbreaks of neuroinvasive disease in North America, Europe, and neighboring countries. Almost all WNV infections in humans are transmitted through the bite of infected mosquitoes. Transmission during pregnancy and through breastfeeding has been reported, but the risk seems to be very low. West Nile disease in children is less common (1-5% of all WNV cases) and associated with milder symptoms and better outcome than in elderly individuals, even though severe neuroinvasive disease and death have been reported also among children. However, the incidence of WNV infection and disease in children is probably underestimated and the disease spectrum is not fully understood because of lack of reporting and underdiagnosis in children. Infection is diagnosed by detection of WNV-specific antibodies in serum and WNV RNA in plasma and urine. Since no effective WNV-specific drugs are available, therapy is mainly supportive.

This is the second subsequent year of West Nile neuroinvasive disease (WNND) outbreak in Croatia. Between July and October 2013, 22 patients presented with symptoms of WNND: all with meningitis and 18 additionally with encephalitis. In contrast to 2012, where six autochthonous infections were confirmed in eastern Croatia, the majority of this year's cases occurred in and around the city of Zagreb, where no West Nile virus infections have been observed before. Viral RNA was recovered from two patients and phylogenetic analyses revealed West Nile virus lineage 2. This represents the first molecular characterization and phylogenetic analysis of the circulating West Nile virus strain in Croatia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Detection of West Nile virus (WNV) RNA in urine has been anecdotally described and proposed for the diagnosis of WNV infection. This study reports the routine use of real-time reverse-transcription polymerase chain reaction for the detection of WNV RNA in urine to support diagnosis of WNV infection during the large outbreak that occurred in northeastern Italy in 2012. Fourteen of 32 patients (43.8%) with symptomatic WNV infection, defined as neuroinvasive disease and fever, had detectable WNV RNA in urine at the time of diagnosis, at a higher rate and load and for a longer time than detection of WNV RNA in blood. Detection of WNV RNA in urine was less frequent (2 of 14 patients [14.2%]) in blood donors in whom WNV infection was identified by WNV nucleic acid amplification testing. Infectious virus was isolated from the urine of a patient with neuroinvasive disease and a high WNV RNA load in urine.