Human West Nile Virus Infection Research Articles

Surveillance of West Nile Virus Disease, Tel Aviv District, Israel, 2005 to 2010

We present the findings of a six-year surveillance period (2005–2010) of human West Nile virus (WNV) infection in Tel Aviv district, Israel. Initial notifications of positively identified patients received from the Central Virology Laboratory were followed by epidemiological investigations of the local district health office. During 2005–2010, 104 patients, 79 with WNV neuroinvasive and 25 with WNV non-neuroinvasive disease were reported. The median age of the patients with a neuroinvasive disease was 74 years (range: 15 to 95 years) and 53 of such patients had encephalitis, 14 had acute flaccid paralysis, and 12 had meningitis. The case-fatality rate in these patients was 8%. The average annual incidence of neuroinvasive disease during 2005–2010 was 1.08 per 100,000 population. The incidence declined by 86% steadily between 2005 and 2009 (p for trend=0.005), but increased by more than six-fold in 2010. Elderly (≥65 years) men, comprising 25 patients of whom 24 were chronically-ill, had the highest incidence of WNV encephalitis <0.001). These findings are concordant with previous data, at the national level, published in Israel and the United States. Notably, the percentage of previously healthy patients, who developed a neuroinvasive disease was the highest (37%, p=0.001) in the surveillance period in 2010.

Retrospective screening of solid organ donors in Italy, 2009, reveals unpredicted circulation of West Nile virus

Since the occurrence of West Nile virus (WNV) infection in humans in 2008 in Italy, concerns have been raised about the potential risks associated with solid organ transplantation (SOT). A nationwide retrospective survey showed that 1.2% of SOT donors in 2009 were WNV-seropositive and demonstrated that human WNV infection is distributed throughout several Italian regions. Transmission of WNV or other arboviruses through SOT is a possibility and risk assessment should be carried out before SOT to avoid infection through transplantation.

Primary Causes of Death in Reported Cases of Fatal West Nile Fever, United States, 2002–2006

Morbidity and mortality associated with human West Nile virus (WNV) infection is generally attributable to severe neurologic disease; most illness with WNV, however, is characterized by febrile illness. Although generally considered to be a benign, self-limited syndrome, some cases of West Nile Fever (WNF) have been reported as resulting in fatal outcome. We reviewed cause-of-death information for 35 cases of WNF reported as fatal to the Centers for Disease Control and Prevention between 2002 and 2006, to determine underlying primary causes of death and identify groups at highest risk for fatal WNF. Fifteen were determined to be misclassified neuroinvasive disease cases; one death was medically unrelated to WNV infection. Among the remaining 23 cases, the median age was 78 years (range: 54-92), and 78% were >70 years old; the median age for all 13,482 reported cases of WNF during this time period was 47 years (range: 1 month-97 years). Cardiac (8 cases, 35%) and pulmonary complications (6 cases, 25%) were the most common primary causes of death. Underlying medical conditions among fatal WNF cases included cardiovascular disease (13; 76%), hypertension (8; 47%), and diabetes mellitus (6; 35%). Our study suggests that in some individuals, especially persons of advanced age and those with underlying medical conditions, WNF may precipitate death. The elderly are at increased risk of death from both West Nile neuroinvasive disease and WNF, which emphasizes the importance of primary prevention of WNV infection and close monitoring for cardiac and pulmonary complications in elderly patients hospitalized for WNV disease.

West Nile Virus Knowledge among Hispanics, San Diego County, California, USA, 2006

West Nile Virus Knowledge among Hispanics, San Diego County, California, USA, 2006

The Risk of West Nile Virus Infection Is Associated with Combined Sewer Overflow Streams in Urban Atlanta, Georgia, USA

BackgroundAt present, the factors favoring transmission and amplification of West Nile Virus (WNV) within urban environments are poorly understood. In urban Atlanta, Georgia, the highly polluted waters of streams affected by combined sewer overflow (CSO) represent significant habitats for the WNV mosquito vector Culex quinquefasciatus. However, their contribution to the risk of WNV infection in humans and birds remains unclear.ObjectivesOur goals were to describe and quantify the spatial distribution of WNV infection in mosquitoes, humans, and corvids, such as blue jays and American crows that are particularly susceptible to WNV infection, and to assess the relationship between WNV infection and proximity to CSO-affected streams in the city of Atlanta, Georgia.Materials and methodsWe applied spatial statistics to human, corvid, and mosquito WNV surveillance data from 2001 through 2007. Multimodel analysis was used to estimate associations of WNV infection in Cx. quinquefasciatus, humans, and dead corvids with selected risk factors including distance to CSO streams and catch basins, land cover, median household income, and housing characteristics.ResultsWe found that WNV infection in mosquitoes, corvids, and humans was spatially clustered and statistically associated with CSO-affected streams. WNV infection in Cx. quinquefasciatus was significantly higher in CSO compared with non-CSO streams, and WNV infection rates among humans and corvids were significantly associated with proximity to CSO-affected streams, the extent of tree cover, and median household income.ConclusionsOur study strongly suggests that CSO-affected streams are significant sources of Cx. quinquefasciatus mosquitoes that may facilitate WNV transmission to humans within urban environments. Our findings may have direct implications for the surveillance and control of WNV in other urban centers that continue to use CSO systems as a waste management practice.

Dry weather induces outbreaks of human West Nile virus infections

BackgroundSince 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.MethodsWe analyzed data on the human WNV incidences in the 82 counties of Mississippi in 2002, using standard morbidity ratio (SMR) and Bayesian hierarchical models, to determine relationships between precipitation and human WNV risks. We also entertained spatial autocorrelations of human WNV risks with conditional autocorrelative (CAR) models, implemented in WinBUGS 1.4.3.ResultsWe observed an inverse relationship between county-level human WNV incidence risk and total annual rainfall during the previous year. Parameters representing spatial heterogeneity in the risk of human exposure to WNV improved model fit. Annual precipitation of the previous year was a predictor of spatial variation of WNV risk.ConclusionsOur results have broad implications for risk assessment of WNV and forecasting WNV outbreaks. Assessing risk of vector-born infectious diseases will require understanding of complex ecological relationships. Based on the climatologically characteristic drought occurrence in the past and on climate model predictions for climate change and potentially greater drought occurrence in the future, we suggest that the frequency and relative risk of WNV outbreaks could increase.

CCR5 Deficiency Is a Risk Factor for Early Clinical Manifestations of West Nile Virus Infection but not for Viral Transmission

West Nile virus (WNV) is a neurotropic flavivirus transmitted to humans by mosquito vectors. Homozygosity for CCR5Delta32, a complete loss-of-function mutation in CC chemokine receptor 5 (CCR5), has been previously associated with severe symptomatic WNV infection in patients who present with clinical disease; however, whether it acts at the level of initial infection or in promoting clinical progression is unknown. Here, we address this gap in knowledge by comparing CCR5Delta32 distribution among US blood donors identified through a comprehensive blood supply screening program (34,766,863 donations from 2003 through 2008) as either WNV true positive (634 WNV-positive cases) or false positive (422 WNV-negative control participants). All subjects self-reported symptoms occurring during the 2 weeks following blood donation using a standardized questionnaire. No difference was observed in CCR5Delta32 homozygous frequency between the WNV-positive cases and WNV-negative control participants. However, CCR5Delta32 homozygosity was associated in cases but not controls with clinical symptoms consistent with WNV infection (P = .002). CCR5 deficiency is not a risk factor for WNV infection per se, but it is a risk factor for both early and late clinical manifestations after infection. Thus, CCR5 may function normally to limit disease due to WNV infection in humans.

RISK FACTORS ASSOCIATED WITH WEST NILE VIRUS MORTALITY IN AMERICAN CROW POPULATIONS IN SOUTHERN QUEBEC

Soon after the appearance of West Nile virus (WNV) in North America, a number of public health authorities designated the American Crow (Corvus brachyrhynchos) a sentinel for WNV detection. Although preliminary studies have suggested a positive association between American Crow mortality and increased risk of WNV infection in humans, we still know little about dynamic variation in American Crow mortality, both baseline levels and mortality associated with WNV. We hypothesized that the complex social behavior of American Crows, which is shaped by age and seasonal factors, influences both baseline mortality and WNV mortality in American Crow populations. We examined American Crow mortality data from Quebec for the 2005 WNV surveillance year, which lasted from 5 June to 17 September 2005. The variables of interest were age, gender, body condition index, time of year, and land cover. We used a log-linear model to examine baseline mortality. Logistic regression and general linear regression models were constructed to examine variables associated with mortality due to WNV. We found that both age and time of year were key variables in explaining baseline mortality. These two variables were also risk factors for WNV mortality. The probability that a carcass tested positive for WNV increased with the age of the dead bird and as summer progressed. WNV-positive carcasses also had a lower body condition index than WNV-negative carcasses. We believe that the first major wave of American Crow mortality observed in the early summer of 2005 was the result of natural mortality among young American Crows. Because this mortality was not linked to WNV, it appears that American Crow may not be a good species for early detection of WNV activity. Our data also suggest that second-year American Crows play a major role in propagating WNV during their movements to urban land covers during midsummer.

Risk factors for human infection with West Nile Virus in Connecticut: a multi-year analysis

BackgroundThe optimal method for early prediction of human West Nile virus (WNV) infection risk remains controversial. We analyzed the predictive utility of risk factor data for human WNV over a six-year period in Connecticut.Results and DiscussionUsing only environmental variables or animal sentinel data was less predictive than a model that considered all variables. In the final parsimonious model, population density, growing degree-days, temperature, WNV positive mosquitoes, dead birds and WNV positive birds were significant predictors of human infection risk, with an ROC value of 0.75.ConclusionA real-time model using climate, land use, and animal surveillance data to predict WNV risk appears feasible. The dynamic patterns of WNV infection suggest a need to periodically refine such prediction systems.MethodsUsing multiple logistic regression, the 30-day risk of human WNV infection by town was modeled using environmental variables as well as mosquito and wild bird surveillance.

Neuronal and glial cerebrospinal fluid protein biomarkers are elevated after West Nile Virus infection

Neurotrophic West Nile virus (WNV) disease is a severe arbovirus infection in which neuronal loss is the likely anatomical substrate for the high morbidity and mortality. We investigated whether cerebrospinal fluid (CSF) protein biomarkers were elevated in vivo and related to disease severity in patients with WNV infection. This exploratory study included 114 patients (24 acute WNV, 77 noninflammatory controls, six peripheral neuropathies, seven aseptic meningoencephalitis). CSF levels of neuronal (neurofilaments, NfH-SMI35) and glial (glial fibrillary acidic protein, GFAP, S100B) biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Immunocytochemistry was performed in two fatal WNV cases. A significant proportion of patients with WNV had pathological CSF levels for NfH-SMI35 (58%, median concentration 1.01 ng/mL), GFAP (58%, 10 pg/mL), and S100B (90%, 1.29 ng/mL). The results were consistent with postmortem evidence for neuronal death and astrogliosis. Surprisingly, CSF protein biomarker levels were also found to be pathological in a considerable proportion of patients who presented with WNV fever only (100% for GFAP and S100B and 43% for NfH-SMI35). Elevated CSF protein biomarker levels are suggestive of neuronal death and glial pathology in human WNV infection. The results indicate the presence of neuroinvasive disease across the spectrum of WNV disease, including WNV fever.

West Nile Virus in the New World: Trends in the Spread and Proliferation of West Nile Virus in the Western Hemisphere

The observed patterns and variations in the ecology, epidemiology, distribution and prevalence of the West Nile Virus (WNV) in different areas of the Western Hemisphere make this pathogen of particular importance as a model for understanding the potential risk factors associated with emerging pathogens worldwide, particularly those involving zoonotic pathogens whose epidemiology involves the potential for vertical transmission in arthropod vector species, and horizontal and vertical transmission within and among vertebrate host species. Record numbers of human WNV cases were recorded in Canada during 2007, with >50% more cases than documented in any previous year. Although overall numbers of human infections recorded in the United States were not exceptionally high during 2007 relative to epidemic levels reported in 2002 and 2003, the state of Oklahoma reported that the highest-ever number of human WNV cases and the numbers of human cases recorded in Canada were 50% higher than previous record levels recorded in 2003. The record and near-record numbers of human WNV infections recorded in several regions of North America during 2007 have important implications for the future management and surveillance of WNV vectors and reservoirs in North America. The spatiotemporal distribution of WNV infections in humans and animals recorded during 2007 in North America and South America have important implications for the surveillance and management of public health threats from WNV in the Western Hemisphere. Serological surveys conducted in areas of intense WNV transmission in the United States have reported low prevalence of antibodies to WNV in human s populations, indicating that additional epidemic outbreaks of human disease from WNV can be expected in the future.

Evaluation of an Epitope-Blocking Enzyme-Linked Immunosorbent Assay for the Diagnosis of West Nile Virus Infections in Humans

An epitope-blocking enzyme-linked immunosorbent assay (b-ELISA) was evaluated for the diagnosis of West Nile virus (WNV) infections in humans. Sera from patients diagnosed with WNV infections from an outbreak in 2003 in Colorado and from patients diagnosed with dengue virus infections from Mexico and Thailand were tested with the b-ELISA. The b-ELISAs were performed using the WNV-specific monoclonal antibody (MAb) 3.1112G and the flavivirus-specific MAb 6B6C-1. Although the WNV-specific b-ELISA was effective in diagnosing WNV infections in humans from Colorado, it was not efficacious for diagnosing WNV infections in serum specimens from Mexico and Thailand. In serum specimens from patients from Colorado, the WNV b-ELISA and the WNV plaque reduction neutralization test showed an overall agreement of 91%. The sensitivity and specificity of the WNV b-ELISA were 89% and 92%, respectively, with a false-positive rate of 5%, based on receiver operating characteristic analysis. In contrast, false-positive rate results in specimens from the countries of Mexico and Thailand, where flaviviruses are endemic, were 79% and 80%, presumably due to the presence of antibodies resulting from previous dengue virus infections in Mexico and/or Japanese encephalitis virus infections or vaccination in Thailand. Thus, in regions where people have experienced previous or multiple flavivirus infections, the use of the b-ELISA for WNV diagnosis is contraindicated.

Evidence of a humoral response to a novel protein WARF4 embedded in the West Nile virus NS4B gene encoded by an alternative open reading frame

West Nile virus (WNV) is a flavivirus that is maintained in a bird-mosquito transmission cycle. Humans, horses and other non-avian vertebrates are usually incidental hosts. However, WNV is a neurotropic virus, which requires an efficient humoral response for the control of a neuroinvasive infection. The WNV genome encodes three structural (capsid, premembrane/membrane and envelope) and seven non-structural proteins. Bioinformatic analysis performed on the WNV genomes detected a conserved alternative open reading frame restricted to the lineage I virus. To quickly verify the existence of this putative protein, entitled West Nile Alternative Reading Frame 4 (WARF4), we produced a prokaryotic recombinant source of WARF4 and verified its immunogenicity in vivo by analyzing 43 horse serum samples, of which 15 were positive for antibodies to WNV premembrane and envelope (prM-E) proteins. Specific antibodies to WARF4 were significantly detected in 5 out of the 15 serum samples testing positive for antibodies to prM-E WNV proteins. Our findings provide evidence of a significant antibody response to the WARF4 protein in the serum of the horse testing positive for antibodies to prM-E proteins, thus indicating that this antigen might be a potential tool for further characterization of the immune response of WNV infections in humans as well.

Infectious Disease in a Warming World: How Weather Influenced West Nile Virus in the United States (2001–2005)

BackgroundThe effects of weather on West Nile virus (WNV) mosquito populations in the United States have been widely reported, but few studies assess their overall impact on transmission to humans.ObjectivesWe investigated meteorologic conditions associated with reported human WNV cases in the United States.MethodsWe conducted a case–crossover study to assess 16,298 human WNV cases reported to the Centers for Disease Control and Prevention from 2001 to 2005. The primary outcome measures were the incidence rate ratio of disease occurrence associated with mean weekly maximum temperature, cumulative weekly temperature, mean weekly dew point temperature, cumulative weekly precipitation, and the presence of ≥ 1 day of heavy rainfall (≥ 50 mm) during the month prior to symptom onset.ResultsIncreasing weekly maximum temperature and weekly cumulative temperature were similarly and significantly associated with a 35–83% higher incidence of reported WNV infection over the next month. An increase in mean weekly dew point temperature was significantly associated with a 9–38% higher incidence over the subsequent 3 weeks. The presence of at least 1 day of heavy rainfall within a week was associated with a 29–66% higher incidence during the same week and over the subsequent 2 weeks. A 20-mm increase in cumulative weekly precipitation was significantly associated with a 4–8% increase in incidence of reported WNV infection over the subsequent 2 weeks.ConclusionsWarmer temperatures, elevated humidity, and heavy precipitation increased the rate of human WNV infection in the United States independent of season and each others’ effects.

Detection of West Nile Virus in Blood Donations—Puerto Rico, 2007

In the United States, West Nile virus (WNV) was first detected in humans in 1999; it subsequently spread to countries of Central and South America and the Caribbean. WNV is a mosquito-borne virus that produces potentially serious clinical disease, particularly among persons aged > or =50 years. Transmission by routes other than mosquito bites, including blood transfusion, transplacental infection, organ transplant, and possibly breast milk, also have been reported. On July 19, 2007, the American Red Cross in Puerto Rico notified the Puerto Rico Department of Health (PRDH) of three persons whose blood donations were positive for WNV by nucleic acid-amplification test (NAT) screening. These three donors had the first confirmed human WNV infections detected in Puerto Rico. In response, PRDH and CDC conducted in-depth interviews of the blood donors. This report describes these human infections and other recent surveillance for transmission of WNV in Puerto Rico. Detection of WNV infections in human blood donors indicates that heightened clinician awareness, ongoing surveillance, and educational activities are needed to monitor and assess the public health threat posed by WNV in Puerto Rico.

Increased Avian Diversity Is Associated with Lower Incidence of Human West Nile Infection: Observation of the Dilution Effect

Recent infectious disease models illustrate a suite of mechanisms that can result in lower incidence of disease in areas of higher disease host diversity–the ‘dilution effect’. These models are particularly applicable to human zoonoses, which are infectious diseases of wildlife that spill over into human populations. As many recent emerging infectious diseases are zoonoses, the mechanisms that underlie the ‘dilution effect’ are potentially widely applicable and could contribute greatly to our understanding of a suite of diseases. The dilution effect has largely been observed in the context of Lyme disease and the predictions of the underlying models have rarely been examined for other infectious diseases on a broad geographic scale. Here, we explored whether the dilution effect can be observed in the relationship between the incidence of human West Nile virus (WNV) infection and bird (host) diversity in the eastern US. We constructed a novel geospatial contrasts analysis that compares the small differences in avian diversity of neighboring US counties (where one county reported human cases of WNV and the other reported no cases) with associated between-county differences in human disease. We also controlled for confounding factors of climate, regional variation in mosquito vector type, urbanization, and human socioeconomic factors that are all likely to affect human disease incidence. We found there is lower incidence of human WNV in eastern US counties that have greater avian (viral host) diversity. This pattern exists when examining diversity-disease relationships both before WNV reached the US (in 1998) and once the epidemic was underway (in 2002). The robust disease-diversity relationships confirm that the dilution effect can be observed in another emerging infectious disease and illustrate an important ecosystem service provided by biodiversity, further supporting the growing view that protecting biodiversity should be considered in public health and safety plans.

Rapid GIS-based profiling of West Nile virus transmission: defining environmental factors associated with an urban-suburban outbreak in Northeast Ohio, USA.

Human West Nile virus (WNV) infection was first detected in Cuyahoga county, Ohio, USA, in 2002. During that year's extensive epidemic/epizootic among non-immune human and bird populations, the county experienced 155 cases of severe human West Nile neurological disease (WNND, incidence = 11.1 cases/100,000), with 11 fatalities. Structured serosurveys indicated that 1.9%, or approximately 26,000 of county residents (population = 1,372,303) were infected that year. In early 2003, in order to better focus monitoring and control efforts, we used a geographical information system (GIS) approach and spatial statistical analysis to identify the association of environmental factors and human population structure with the observed local risk for WNV transmission. Within the varied range of urban/suburban/ rural habitats across the 1186 km2 county, exploratory analysis indicated significant clustering of WNND risk in inner-ring suburbs. Subsequent discriminant factor analysis based on inputs of census and land-use/land cover data was found to effectively classify sub-areas of the county having low, medium and high WNV risk. On a 1036 ha quadrat scale of resolution, higher risk of human infection was significantly associated with higher-income areas, increased fractionation of habitat and older housing, while it was negatively associated with areas of agricultural land, wetland or forest. The areal classification of WNV transmission risk has been validated over time through detection of increased local Culex spp. mosquito density (2002-2006), and increased frequency of WNV positive mosquito pools within the medium- and high-risk quadrats. This timely working identification of the transmission scale effectively focused control interventions against newly invasive WNV in a complex North American habitat.

West nile virus attenuates activation of primary human macrophages.

West Nile virus (WNV) is a mosquito-borne flavivirus that has spread rapidly throughout the U.S. and there is currently no effective treatment. Understanding the pathogenesis of WNV infection in humans is critical for development of a potent therapy. In this study, we examined the activation of primary human macrophages in response to WNV infection, and showed that WNV interacts with human macrophages at multiple levels. While infection with WNV induced production of interleukin (IL)-8, production of IL-1beta, and type I interferon was inhibited. Infection with WNV interferes with the downstream JAK/STAT pathway, which is important for macrophage activation. In comparison to other related flaviviruses, the differential response of proinflammatory cytokines is distinct to WNV.

Flavivirus Serology by Western Blot Analysis

The spread of West Nile virus (WNV) across the United States into areas with endemic flavivirus activity has complicated serologic surveillance of seasonal virus activity and diagnosis of infected individuals. Here we describe preliminary results from a comparison of serologic assays for flaviviruses: the reference plaque reduction neutralization test (PRNT), enzyme immunoassay (EIA), and a Western blot (WB) in which crude viral lysates were electrophoresed and blotted onto nitrocellulose. Human and chicken sera were tested and compared by each method against WNV and St. Louis encephalitis virus (SLEV). Antibody binding to three viral proteins determined WB interpretation: non-structural protein 1 (NS1), envelope (E), and pre-membrane (prM). WB results for a group of serially collected human plasma samples from WNV seroconverting blood donors were also correlated with transcription mediated amplification (TMA) and polymerase chain reaction (RT-PCR) results. Reactivity with NS1 appeared to be the most useful differentiating marker of WNV and SLEV infection in humans and chickens. Envelope protein was highly cross-reactive and, as indicated by additional results from dengue virus (DENV)-positive human sera, is perhaps useful serologically as a flavivirus group antigen.

Seroprevalence of West Nile Virus and Tick-Borne Encephalitis Virus in Southeastern Turkey: First Evidence for Tick-Borne Encephalitis Virus Infections

West Nile virus (WNV) and tick-borne encephalitis virus (TBEV) are among the medically important Flaviviruses that cause significant morbidity and mortality in humans. In this study, seroprevalence of WNV and TBEV in sera from two state medical hospitals from the southeastern part of Turkey was investigated. One hundred eighty-one serum samples were evaluated for WNV immunoglobulin G (IgG) by an indirect immunofluorescence test (IIFT) and for IgG antibodies against TBEV by a commercial enzyme-linked immunosorbent assay (ELISA) kit with enhanced sensitivity and specificity. Sera positive for WNV IgG were further analyzed by plaque reduction neutralization assay (PRNA). TBEV IgM was also investigated by ELISA in all seroreactive samples. Of 181 sera, 29 (16%) were positive for WNV IgG by IIFT and 17 of 179 (9.5%) were confirmed by PRNA. Nineteen of 181 (10.5%) sera were detected to have TBEV IgG. Mean titer of TBEV IgG was 43.0 RU/mL (median, 33.9 RU/mL; cutoff: 20 RU/mL). Four samples with WNV IgG antibodies were also positive for TBEV IgG antibodies. TBEV IgM was detected in 9 of 39 (23%) of all seroreactive sera, where IgM positivity were accompanied by IgG for 6 samples. These results suggest the presence of possible human WNV and TBEV infections in southeastern Turkey where vector activity have previously been detected.