Predicting human West Nile virus infections with mosquito surveillance data.

West Nile virus (WNV) has become established across the Americas with recent heightened activity causing significant human illness. Surveillance methods to predict the risk of human infection are urgently needed to initiate timely preventative measures and justify the expense of implementing costly or unpopular control measures, such as aerial spraying or curfews. We quantified the links between mosquito surveillance data and the spatiotemporal patterns of 3,827 human WNV cases reported over 5 years in Colorado from 2003 to 2007. Mosquito data were strongly predictive of variation in the number of human WNV infections several weeks in advance in both a spatiotemporal statewide analysis and temporal variation within counties with substantial numbers of human cases. We outline several ways to further improve the predictive power of these data and we quantify the loss of information if no funds are available for testing mosquitoes for WNV. These results demonstrate that mosquito surveillance provides a valuable public health tool for assessing the risk of human arboviral infections, allocating limited public health resources, and justifying emergency control actions.

Delayed mortality in a cohort of persons hospitalized with West Nile virus disease in Colorado in 2003.

Most mortality associated with West Nile virus (WNV) disease occurs during the acute or early convalescent phases of illness. However, some reports suggest mortality may be elevated for months or longer after acute illness. The objective of this study was to assess the survival of a cohort of patients hospitalized with WNV disease in Colorado in 2003 up to 4 years after illness onset. We calculated age-adjusted standardized mortality ratios (SMRs) to evaluate excess mortality, evaluated reported causes of death in those who died, and analyzed potential covariates of delayed mortality. By 1 year after illness onset, 4% of the 201 patients had died (SMR, 2.7; 95% confidence interval [CI], 1.3-5.2), and 12% had died by 4 years after onset (SMR, 2.0; 95% CI, 1.3-3.0). Among those who had died, the most common immediate and contributory causes of death included pulmonary disease and cardiovascular disease; cancer, hepatic disease, and renal disease were mentioned less frequently. In multivariate analysis, age (hazard ratio [HR], 2.0 per 10-year increase; 95% CI, 1.4-2.7), autoimmune disease (HR, 3.0; 95% CI, 1.1-7.9), ever-use of tobacco (HR, 3.0; 95% CI, 1.3-7.0), encephalitis during acute WNV illness (HR, 2.6; 95% CI, 1.1-6.4), and endotracheal intubation during acute illness (HR 4.8; 95% CI, 1.9-12.1) were found to be independently associated with mortality. Our finding of an approximate twofold increase in mortality for up to 3 years after acute illness reinforces the need for prevention measures against WNV infection among at-risk groups to reduce acute as well as longer-term adverse outcomes.

Irrigated agriculture is an important risk factor for West Nile virus disease in the hyperendemic Larimer-Boulder-Weld area of north central Colorado.

This study focused on two West Nile virus (WNV) disease outbreak years, 2003 and 2007, and included a three-county area (Larimer, Boulder, and Weld) in North Central Colorado that is hyperendemic for WNV disease. We used epidemiological data for reported WNV disease cases at the census tract scale to: (1) elucidate whether WNV disease incidence differs between census tracts classified as having high versus lower human population density (based on a threshold value of 580 persons/km2) and (2) determine associations between WNV disease incidence and habitat types suitable as development sites for the larval stage of Culex mosquito vectors. WNV disease incidence was significantly elevated in census tracts with lower human population density, compared with those with high density of human population, in both 2003 (median per census tract of 223 and 143 cases per 100,000 population, respectively) and 2007 (median per census tract of 46 and 19 cases per 100,000 population). This is most likely related, in large part, to greater percentages of coverage in less densely populated census tracts by habitats suitable as development sites for Culex larvae (open water, developed open space, pasture/hay, cultivated crops, woody wetlands, and emergent herbaceous wetlands) and, especially, for the subset of these habitats made up by irrigated agricultural land (pasture/hay and cultivated crops) that presumably serve as major producers of the locally most important vector of WNV to humans: Culex tarsalis. A series of analyses produced significant positive associations between greater coverage of or shorter distance to irrigated agricultural land and elevated WNV disease incidence. As an exercise to produce data with potential to inform spatial implementation schemes for prevention and control measures within the study area, we mapped the spatial patterns, by census tract, of WNV disease incidence in 2003 and 2007 as well as the locations of census tracts that had either low (<25th percentile) or high (>75th percentile) WNV disease incidence in both outbreak years (relative to the incidence for each year). This revealed substantial changes from 2003 to 2007 in the spatial pattern for census tracts within the study area with high WNV disease incidence and suggests a dynamic and evolving scenario of WNV transmission to humans that needs to be taken into account for prevention and control measures to stay current and represent the most effective use of available resources.

Spatial risk assessments based on vector-borne disease epidemiologic data: importance of scale for West Nile virus disease in Colorado.

We used epidemiologic data for human West Nile virus (WNV) disease in Colorado from 2003 and 2007 to determine 1) the degree to which estimates of vector-borne disease occurrence is influenced by spatial scale of data aggregation (county versus census tract), and 2) the extent of concordance between spatial risk patterns based on case counts versus incidence. Statistical analyses showed that county, compared with census tract, accounted for approximately 50% of the overall variance in WNV disease incidence, and approximately 33% for the subset of cases classified as West Nile neuroinvasive disease. These findings indicate that sub-county scale presentation provides valuable risk information for stakeholders. There was high concordance between spatial patterns of WNV disease incidence and case counts for census tract (83%) but not for county (50%) or zip code (31%). We discuss how these findings impact on practices to develop spatial epidemiologic data for vector-borne diseases and present data to stakeholders.

Seasonal patterns for entomological measures of risk for exposure to Culex vectors and West Nile virus in relation to human disease cases in northeastern Colorado.

We examined seasonal patterns for entomological measures of risk for exposure to Culex vectors and West Nile virus (family Flaviviridae, genus Flavivirus, WNV) in relation to human WNV disease cases in a five-county area of northeastern Colorado during 2006-2007. Studies along habitat/elevation gradients in 2006 showed that the seasonal activity period is shortened and peak numbers occur later in the summer for Culex tarsalis Coquillett females in foothills-montane areas >1600 m compared with plains areas <1600 m in Colorado's Front Range. Studies in the plains of northeastern Colorado in 2007 showed that seasonal patterns of abundance for Cx. tarsalis and Culex pipiens L. females differed in that Cx. tarsalis reached peak abundance in early July (mean of 328.9 females per trap night for 18 plains sites), whereas the peak for Cx. pipiens did not occur until late August (mean of 16.4 females per trap night). During June-September in 2007, which was a year of intense WNV activity in Colorado with 578 reported WNV disease cases, we recorded WNV-infected Cx. tarsalis females from 16 of 18 sites in the plains. WNV infection rates in Cx. tarsalis females increased gradually from late June to peak in mid-August (overall maximum likelihood estimate for WNV infection rate of 8.29 per 1000 females for the plains sites in mid-August). No WNV-infected Culex mosquitoes were recorded from sites >1600 m. The vector index for abundance of WNV-infected Cx. tarsalis females for the plains sites combined exceeded 0.50 from mid-July to mid-August, with at least one site exceeding 1.00 from early July to late August. Finally, we found that abundance of Cx. tarsalis females and the vector index for infected females were strongly associated with weekly numbers of WNV disease cases with onset 4-7 wk later (female abundance) or 1-2 wk later (vector index).

Predictive spatial models for risk of West Nile virus exposure in eastern and western Colorado.

In the absence of a vaccine for use in humans against West Nile virus (WNV), mosquito control and personal protection against mosquito bites are the only measures available to prevent disease. Improved spatial targeting is desirable for costly mosquito and WNV surveillance and control schemes. We used a multivariate regression modeling approach to develop spatial models predicting high risk of exposure to WNV in western and eastern Colorado based on associations between Geographic Information System-derived environmental data and zip code of residence for 3,659 human WNV disease cases from 2002 to 2006. Models were robust, with user accuracies for correct classification of high risk areas of 67-80%. The importance of selecting a suitable model development area in an ecologically and climatically diverse environment was shown by models based on data from the eastern plains landscape performing poorly in the mountainous western part of Colorado and vice versa.

Combining mosquito vector and human disease data for improved assessment of spatial West Nile virus disease risk.

Assessments of spatial risk of exposure to vector-borne pathogens that combine vector and human disease data are needed for areas encompassing large tracts of public land with low population bases. We addressed this need for West Nile virus (WNV) disease in the northern Colorado Front Range by developing not only a spatial model for entomological risk of exposure to Culex tarsalis WNV vectors and an epidemiological risk map for WNV disease but also a novel risk-classification index combining data for these independently derived measures of entomological and epidemiological risk. Risk of vector exposure was high in the densely populated eastern plains portion of the Front Range but low in cooler montane areas to the west that are sparsely populated but used heavily for recreation in the summer. The entomological risk model performed well when applied to the western, mountainous part of Colorado and validated against epidemiologic data.

West Nile viremic blood donors and risk factors for subsequent West Nile fever.

BACKGROUND: While increasing age is a known risk factor for neuroinvasive West Nile virus (WNV) disease, little is known about risk factors for West Nile fever (WNF). In 2003, United States blood centers identified WN (West Nile) viremic donors using nucleic acid-amplification tests (NATs), making it possible to prospectively determine risk factors for WNF. We report the characteristics of WN viremia among donors at Colorado's largest blood center and risk factors for WNF in viremic donors. METHODS: Prospective public health surveillance was conducted in WN viremic donors. NAT-reactive donors who developed WNV-specific IgM antibody were considered viremic donors. Demographic data were abstracted from blood center records for all viremic donors aged>or=18 years. Standardized telephone questionnaires were administered a median of 39 days following donation. Donors reporting fever and headache within seven days following donation were considered West Nile fever (WNF) cases. RESULTS: Of 66,771 donations screened from July 1-October 31, 146 (0.22%) were from viremic donors (1:457 donations). Of 135 surveyed donors, 81 (60%) were male. The median age was 49 years (range: 18-78). Forty-one (30%) donors developed WNF; of these, 12 (29%) visited a physician. Other reported symptoms included body aches (98%), eye pain (63%), and skin rash (61%). The risk of WNF was inversely correlated with age (odds ratio: 0.95 for every 1-year increase in age; 95% CI 0.91, 0.99; p=0.008). CONCLUSIONS: WN viremia was frequently identified in Colorado blood donors during the 2003 WNV epidemic. The high frequency of WNF and subsequent physician visits among healthy blood donors suggest substantial morbidity from WNF in the general population. The inverse correlation between age and WNF is a new finding and its pathophysiology is unknown.

Outbreak of Q fever associated with a horse-boarding ranch, Colorado, 2005.

Coxiella burnetii is a bacterium located worldwide that can cause Q fever when inhaled. We describe an outbreak of Q fever associated with a horse-boarding ranch that had acquired two herds of goats. We conducted case finding and cohort studies among persons who boarded horses on the ranch and ranchers and among residents in the surrounding community, and conducted sampling of the goats and environment, to determine risk factors for infection and guide public health interventions. Sixty-six ranchers and persons who boarded horses on the ranch were interviewed; 62 (94%) were not professional ranchers. Twenty persons (53%) of 38 persons tested had evidence of infection with C. burnetii. Contact with goats was associated with seropositivity, including having helped birth goats (relative risk [RR] 2.4, 95% confidence interval [CI] 1.6-3.6), having had contact with newborn goats (RR 2.3, CI 1.2-4.3), having vaccinated goats (RR 2.1, CI 1.3-3.5), having had contact with stillbirths or newborns that died (RR 2.1, CI 1.2-3.7), and having fed goats (RR 2.1, CI 1.0-4.3). Among 138 tested persons living within 1 mile of the ranch, 11 (8%) demonstrated evidence of C. burnetii infection; eight seropositive persons (73%) had no direct contact with the ranch. Testing of the soil and goats with an IS1111 polymerase chain reaction (PCR) assay confirmed the presence of C. burnetii among the herd and in the environment. This outbreak of Q fever was caused by exposure to infected goats, but exposure to the environment likely played a secondary role. Laypersons should not participate in the birthing process of goats; professionals who come into contact with birthing goats should be educated on reducing their infection risk. This is the first time an IS1111 PCR assay has been used in an outbreak investigation in the United States.

Colorado surveillance program for chronic wasting disease transmission to humans: lessons from 2 highly suspicious but negative cases.

OBJECTIVE: To describe 2 patients with rapidly progressive dementia and risk factors for exposure to chronic wasting disease (CWD) in whom extensive testing negated the possible transmission of CWD. Design/ METHODS: We describe the evaluation of 2 young adults with initial exposure histories and clinical presentations that suggested the possibility of CWD transmission to humans. Patients A 52-year-old woman with possible laboratory exposure to CWD and a 25-year-old man who had consumed meat from a CWD endemic area. INTERVENTIONS: Clinical evaluation, neuropathological examination, and genetic testing. RESULTS: Neuropathological and genetic assessment in the 2 patients proved the diagnoses of early-onset Alzheimer disease and a rare genetic prion disease. CONCLUSION: No convincing cases of CWD transmission to humans have been detected in our surveillance program.

Human prion disease and relative risk associated with chronic wasting disease.

The transmission of the prion disease bovine spongiform encephalopathy (BSE) to humans raises concern about chronic wasting disease (CWD), a prion disease of deer and elk. In 7 Colorado counties with high CWD prevalence, 75% of state hunting licenses are issued locally, which suggests that residents consume most regionally harvested game. We used Colorado death certificate data from 1979 through 2001 to evaluate rates of death from the human prion disease Creutzfeldt-Jakob disease (CJD). The relative risk (RR) of CJD for CWD-endemic county residents was not significantly increased (RR 0.81, 95% confidence interval [CI] 0.40-1.63), and the rate of CJD did not increase over time (5-year RR 0.92, 95% CI 0.73-1.16). In Colorado, human prion disease resulting from CWD exposure is rare or nonexistent. However, given uncertainties about the incubation period, exposure, and clinical presentation, the possibility that the CWD agent might cause human disease cannot be eliminated.

West Nile virus disease: a descriptive study of 228 patients hospitalized in a 4-county region of Colorado in 2003.

BACKGROUND: Risk factors for complications of West Nile virus disease and prognosis in hospitalized patients are incompletely understood. METHODS: Demographic characteristics and data regarding potential risk factors, hospitalization, and dispositions were abstracted from medical records for residents of 4 Colorado counties who were hospitalized in 2003 with West Nile virus disease. Univariate and multivariate analyses were used to identify factors associated with West Nile encephalitis (WNE), limb weakness, or death by comparing factors among persons with the outcome of interest with factors among those without the outcome of interest. RESULTS: Medical records of 221 patients were reviewed; 103 had West Nile meningitis, 65 had WNE, and 53 had West Nile fever. Respiratory failure, limb weakness, and cardiac arrhythmia occurred in all groups, with significantly more cases of each in the WNE group. Age, alcohol abuse, and diabetes were associated with WNE. Age and WNE were associated with limb weakness. The mortality rate in the WNE group was 18%; age, immunosuppression, requirement of mechanical ventilation, and history of stroke were associated with death. Only 21% of patients with WNE who survived returned to a prehospitalization level of function. The estimated incidence of West Nile fever cases that required hospitalization was 6.0 cases per 100,000 persons; West Nile fever was associated with arrhythmia, limb weakness, and respiratory failure. CONCLUSIONS: Persons with diabetes and a reported history of alcohol abuse and older persons appear to be at increased risk of developing WNE. Patients with WNE who have a history of stroke, who require mechanical ventilation, or who are immunosuppressed appear to be more likely to die. Respiratory failure, limb weakness, and arrhythmia occurred in all 3 categories, but there were significantly more cases of all in the WNE group.

Birth outcomes following West Nile Virus infection of pregnant women in the United States: 2003-2004.

BACKGROUND: Congenital West Nile virus (WNV) infection was first described in a single case in 2002. The proportion of maternal WNV infections resulting in congenital infection and clinical consequences of such infections are unknown. METHODS: In 2003 and 2004, women in the United States who acquired WNV infection during pregnancy were reported to the Centers for Disease Control and Prevention by state health departments. Data on pregnancy outcomes were collected. One of the maternal WNV infections was identified retrospectively after the infant was born. Maternal sera, placenta, umbilical cord tissue, and cord serum were tested for WNV infection by using serologic assays and reverse-transcription polymerase chain reaction. Infant health was assessed at delivery and through 12 months of age. RESULTS: Seventy-seven women infected with WNV during pregnancy were clinically followed in 16 states. A total of 71 women delivered 72 live infants; 4 women had miscarriages, and 2 had elective abortions. Of the 72 live infants, 67 were born at term, and 4 were preterm; gestational age was unknown for 1. Of 55 live infants from whom cord serum was available, 54 tested negative for anti-WNV IgM. One infant born with umbilical hernia and skin tags had anti-WNV IgM in cord serum but not in peripheral serum at age 1 month. An infant who had no anti-WNV IgM in cord blood, but whose mother had WNV illness 6 days prepartum, developed WNV meningitis at age 10 days. Another infant, whose mother had acute WNV illness at delivery, was born with a rash and coarctation of the aorta and had anti-WNV IgM in serum at 1 month of age; cord serum was not available. A fourth infant, whose mother had onset of WNV illness 3 weeks prepartum that was not diagnosed until after delivery, had WNV encephalitis and underlying lissencephaly detected at age 17 days and subsequently died; cord serum was not available. The following major malformations were noted among live-born infants: aortic coarctation (n = 1); cleft palate (n = 1); Down syndrome (n = 1); lissencephaly (n = 1); microcephaly (n = 2); and polydactyly (n = 1). One infant had glycogen storage disease type 1. Abnormal growth was noted in 8 infants. CONCLUSIONS: Of 72 infants followed to date in 2003 and 2004, almost all seemed normal, and none had conclusive laboratory evidence of congenital WNV infection. Three infants had WNV infection that could have been congenitally acquired. Seven infants had major malformations, but only 3 of these had defects that could have been caused by maternal WNV infection based on the timing of the infections and the sensitive developmental period for the specific malformations, and none had any conclusive evidence of WNV etiology. However, the sensitivity and specificity of IgM testing of cord blood to detect congenital WNV infection are currently unknown, and congenital WNV infection among newborns with IgM-negative serology cannot be ruled out. Prospective studies comparing pregnancy outcomes of WNV-infected and -uninfected women are needed to better define the outcomes of WNV infection during pregnancy.

Genetic divergence of rabies viruses from bat species of Colorado, USA.

Molecular epidemiological studies have linked many cryptic human rabies cases in the United States with exposure to rabies virus (RV) variants associated with insectivorous bats. In Colorado, bats accounted for 98% of all reported animal rabies cases between 1977 and 1996. The genetic divergence of RV was investigated in bat and terrestrial animal specimens that were submitted for rabies diagnosis to the Colorado Department of Public Health and Environment (CDPHE), Colorado, USA. RV isolates from animal specimens across the United States were also included in the analysis. Phylogenetic analyses were performed on partial nucleoprotein (N) gene sequences, which revealed seven principal clades. RV associated with the colonial big brown bat, Eptesicus fuscus, an bats of the genus Myotis were found to segregate into two distinct clades (I and IV). Clade I was harbored by E. fuscus and Myotis species, but was also identified in terrestrial animals such as domestic cats and striped skunks (Mephitis mephitis). Clade IV was divided into subclades IVA, IVB, and IVC; IVA was identified in E. fuscus, and Myotis species bats, and also in a fox; subclades IVB and IVC circulated predominantly in E. fuscus. Clade II was formed by big free-tailed bat (Nyctinomops macrotis) and striped skunk (Mephitis mephitis) samples. Clade III included RVs that are maintained by generally solitary, migratory bats such as the silver-haired bat (Lasionycteris noctivagans) and bats of the genus Lasiurus. Big brown bats were found to harbor this RV variant. None of the Colorado specimens segregated with clades V and VII that harbor RVs associated with terrestrial animals. Different species of bats had the same RV variant, indicating active inter-species rabies transmission. In Colorado, animal rabies occurs principally in bats, and the identification of bat RVs in cat, gray fox Urocyon cinereoargenteus), and striped skunks demonstrated the importance of rabies spillover from bats to domestic and terrestrial wildlife species.