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.

Estimated global incidence of Japanese encephalitis: a systematic review.

OBJECTIVE: To update the estimated global incidence of Japanese encephalitis (JE) using recent data for the purpose of guiding prevention and control efforts. METHODS: Thirty-two areas endemic for JE in 24 Asian and Western Pacific countries were sorted into 10 incidence groups on the basis of published data and expert opinion. Population-based surveillance studies using laboratory-confirmed cases were sought for each incidence group by a computerized search of the scientific literature. When no eligible studies existed for a particular incidence group, incidence data were extrapolated from related groups. FINDINGS: A total of 12 eligible studies representing 7 of 10 incidence groups in 24 JE-endemic countries were identified. Approximately 67,900 JE cases typically occur annually (overall incidence: 1.8 per 100,000), of which only about 10% are reported to the World Health Organization. Approximately 33,900 (50%) of these cases occur in China (excluding Taiwan) and approximately 51,000 (75%) occur in children aged 0-14 years (incidence: 5.4 per 100,000). Approximately 55,000 (81%) cases occur in areas with well established or developing JE vaccination programmes, while approximately 12,900 (19%) occur in areas with minimal or no JE vaccination programmes. CONCLUSION: Recent data allowed us to refine the estimate of the global incidence of JE, which remains substantial despite improvements in vaccination coverage. More and better incidence studies in selected countries, particularly China and India, are needed to further refine these estimates.

Novel arenavirus infection in humans, United States.

Immunoglobulin G against Whitewater Arroyo virus or lymphocytic choriomeningitis virus was found in 41 (3.5%) of 1,185 persons in the United States who had acute central nervous system disease or undifferentiated febrile illnesses. The results of analyses of antibody titers in paired serum samples suggest that a North American Tacaribe serocomplex virus was the causative agent of the illnesses in 2 persons and that lymphocytic choriomeningitis virus was the causative agent of the illnesses in 3 other antibody-positive persons in this study. The results of this study suggest that Tacaribe serocomplex viruses native to North America, as well as lymphocytic choriomeningitis virus, are causative agents of human disease in the United States.

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.

Epidemiology of Colorado tick fever in Montana, Utah, and Wyoming, 1995-2003.

Colorado tick fever (CTF) is a biphasic, febrile illness caused by a Coltivirus and transmitted by the Rocky Mountain wood tick, Dermacentor andersoni, in the western United States and Canada. Symptoms generally include acute onset of fever, headache, chills, and myalgias; illness often lasts for 3 weeks or more. Laboratory-confirmed cases of CTF were identified from public health department records in Montana, Utah, and Wyoming, and from the Centers for Disease Control and Prevention diagnostic laboratory records. Additional descriptive epidemiologic data were obtained by medical record abstraction. Ninety-one cases were identified from 1995 to 2003, resulting in an overall annual incidence of 2.7 per 1,000,000 population. The annual incidence decreased over the 9-year study period. Cases were 2.5 times more frequent in males than females. The highest incidence of cases occurred in persons aged 51-70. Tick exposure prior to illness onset was reported in 90% of the cases in which a more detailed history was available. The most common symptoms were fever, headache, and myalgia; 18% of the case patients were hospitalized. While there has been an overall decline in the recognized incidence of CTF cases, the reasons for the decline are unknown. Possibilities include a reduced intensity of surveillance and a true decrease in incidence. As more people continue to visit, move to and work in endemic areas, CTF should be considered in anyone presenting with a febrile illness following tick exposure in an endemic area. Heightened awareness for the disease and tick prevention messages should be part of public health measures to further decrease the incidence of disease.

Epidemiology of neuroinvasive arboviral disease in the United States, 1999-2007.

From 1999-2007, the most common causes of neuroinvasive arboviral disease in the United States, after West Nile virus (WNV), were California (CAL) serogroup viruses, St. Louis encephalitis virus (SLEV), and eastern equine encephalitis virus (EEEV). The CAL serogroup virus disease was primarily reported from Appalachia and the upper Midwest, SLEV disease from southern states, and EEEV disease from areas along the Atlantic and Gulf coasts. Children accounted for 88% of CAL serogroup virus disease, whereas 75% of SLEV disease occurred among older adults. The EEEV disease had the highest case-fatality rate (42%). The incidence of CAL serogroup virus and EEEV disease remained stable before and after the detection of WNV in the United States in 1999. The SLEV disease declined 3-fold after 1999; however, SLEV disease has occurred in sporadic epidemics that make trends difficult to interpret. The CAL serogroup virus, SLEV, and EEEV disease are persistent public health concerns in the United States warranting ongoing prevention efforts.

Increased recognition of Powassan encephalitis in the United States, 1999-2005.

Powassan virus (POWV) disease is a rare human disease caused by a tick-borne encephalitis group flavivirus maintained in a transmission cycle between Ixodes cookei and other ixodid ticks and small and medium-sized mammals. During 1958-1998, only 27 POWV disease cases (mostly Powassan encephalitis) were reported from eastern Canada and the northeastern United States (average, 0.7 cases per year). During 1999-2005, nine cases (described herein) of serologically confirmed POWV disease were reported in the United States (average, 1.3 cases per year): four from Maine, two from New York, and one each from Michigan, Vermont, and Wisconsin. The Michigan and Wisconsin cases are the first ever reported from the north-central United States. Of these nine patients, 5 (56%) were men, the median age was 69 years (range: 25-91 years), and 6 (67%) had onset during May-July. All but one patient developed encephalitis with acute onset of profound muscle weakness, confusion, and other severe neurologic signs. In one case, no neurologic symptoms were present but the presence of pleocytosis, an elevated cerebrospinal fluid (CSF) protein concentration, and POWV-specific immunoglobulin M in CSF suggested neuroinvasion. All patients recovered from their acute disease, but most had long-term neurologic sequelae. Periresidential ecologic investigations were performed in three cases, including tests of local mammals and ticks for evidence of POWV infection. Woodchucks (Marmota monax), striped skunks (Mephitis mephitis), and a raccoon (Procyon lotor) collected at two of the Maine case-patients' residences had neutralizing antibody titers to POWV. I. cookei were found on woodchucks and skunks and questing in grassy areas of one of these residences; all were negative for POWV. Although POWV disease is rare, it is probably under-recognized, and it causes significant morbidity, and thus is an additional tick-borne emerging infectious disease entity. Because no vaccine or specific therapy is available, the basis of prevention is personal protection from ticks (or "tick hygiene") and reduced exposure to peridomestic wild mammals.

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.

Chikungunya virus in US travelers returning from India, 2006.

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, is endemic in Africa and Asia. In 2005-2006, CHIKV epidemics were reported in islands in the Indian Ocean and in southern India. We present data on laboratory-confirmed CHIKV infections among travelers returning from India to the United States during 2006.

Detection of West Nile virus in formalin-fixed, paraffin-embedded human tissues by RT-PCR: a useful adjunct to conventional tissue-based diagnostic methods.

BACKGROUND: West Nile virus (WNV), a member of genus Flavivirus, causes febrile illness, encephalitis, meningitis, myelitis, and occasional deaths in humans. Although several reverse transcription-polymerase chain reaction (RT-PCR) assays have been developed for detection of WNV in serum, cerebrospinal fluid, and fresh tissues, the usefulness of WNV RT-PCR assays for RNA extracted from formalin-fixed human tissues has not previously been demonstrated. OBJECTIVE: The objective of this study was to evaluate the application of a RT-PCR technique for the detection of WNV in routinely processed, formalin-fixed, paraffin-embedded (FFPE) human tissues, and to compare it with conventional serology and immunohistochemistry (IHC). STUDY DESIGN: We performed two WNV-specific nested RT-PCR assays targeting the viral capsid, premembrane, and envelope genes in FFPE central nervous system tissue samples from 27 patients with fatal WNV encephalitis, as confirmed by serology or IHC, and compared the results. The presence of WNV in RT-PCR-positive samples was confirmed by amplicon sequencing. RESULTS: Twenty (74%) patients were WNV RT-PCR positive while 24 (89%) were seropositive. WNV IHC staining of neurons and neuronal processes was positive in fourteen (52%) patients. The concordance between IHC and serology was 41% (11/27) and between RT-PCR and serology was 63% (17/27). All 11 seropositive/IHC-positive patients and 6 (46%) of 13 seropositive/IHC-negative patients were RT-PCR positive while all 3 seronegatives were positive by both IHC and RT-PCR. CONCLUSIONS: In this study, RT-PCR was significantly more sensitive than IHC in detecting WNV infections and provided specific sequence information about the infecting virus. RT-PCR on FFPE tissues may be a particularly useful diagnostic tool in patients who die relatively soon after disease onset and for whom serology may be negative. Combined use of serology, IHC, and RT-PCR would be expected to have the best overall sensitivity and improve detection of fatal WNV infection.

West Nile Virus-associated flaccid paralysis outcome.

We report 1-year follow-up data from a longitudinal prospective cohort study of patients with West Nile virus-associated paralysis. As in the 4-month follow-up, a variety of recovery patterns were observed, but persistent weakness was frequent. Respiratory involvement was associated with considerable illness and death.

Second human case of Cache Valley virus disease.

We document the second known case of Cache Valley virus disease in a human. Cache Valley virus disease is rarely diagnosed in North America, in part because laboratories rarely test for it. Its true incidence, effect on public health, and full clinical spectrum remain to be determined.

Fatal hemorrhagic fever caused by West Nile virus in the United States.

BACKGROUND: Most West Nile virus (WNV) infections in humans are asymptomatic; severe disease occurs in relatively few patients and typically manifests as encephalitis, meningitis, or acute flaccid paralysis. A few cases of life-threatening disease with diffuse hemorrhagic manifestations have been reported in Africa; however, this clinical presentation has not been documented for any of the >16,700 cases of WNV disease reported in the United States during 1999-2004. We describe a case of fulminant WNV infection in a 59-year-old Florida man who died following a brief illness that resembled hemorrhagic disease caused by Rickettsia reckettsii, dengue virus or yellow fever virus. METHODS: Traditional and contemporary diagnostic assays, including culture isolation, electron microscopic examination, reverse-transcriptase polymerase chain reaction amplification, and immunohistochemical stains, were used to confirm systemic WNV infection in the patient. RESULTS: WNV was isolated in a cell culture from a skin biopsy specimen obtained from the patient shortly prior to death. Electron microscopic examination identified the isolate as a flavivirus, and reverse-transcriptase polymerase chain reaction amplified specific WNV sequences from the isolate and patient tissue. Quantitative polymerase chain reaction identified approximately 1x10(7) viral copies/mL in the patient's serum. WNV antigens were detected by immunohistochemical stains in intravascular mononuclear cells and endothelium in skin, lung, liver, kidney, spleen, bone marrow, and central nervous system; no viral antigens were identified in neurons or glial cells of the central nervous system. CONCLUSIONS: Although hemorrhagic disease is a rare manifestation of WNV infection, the findings provided by this report may offer new insights regarding the clinical spectrum and pathogenesis of WNV disease in humans.

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.

West Nile virus infection among pregnant women in a northern Colorado community, 2003 to 2004.

OBJECTIVE: Since West Nile virus (WNV) was first detected in New York in 1999, it has spread across North America and become a major public health concern. In 2002, the first documented case of intrauterine WNV infection was reported, involving an infant with severe brain abnormalities. To determine the frequencies of WNV infections during pregnancy and of intrauterine WNV infections, we measured WNV-specific antibodies in cord blood from infant deliveries after a community-wide epidemic of WNV disease. METHODS: Five hundred sixty-six pregnant women who presented to Poudre Valley Hospital (Fort Collins, CO) for delivery between September 2003 and May 2004 provided demographic and health history data through self-administered questionnaires and hospital admission records. Umbilical cord blood was collected from 549 infants and screened for WNV-specific IgM and IgG antibodies with enzyme-linked immunosorbent assays, with confirmation by plaque-reduction neutralization tests. Newborn growth parameters, Apgar scores, and hearing test results were recorded. RESULTS: Four percent (95% confidence interval: 2.4-5.7%) of cord blood samples tested positive for WNV-specific IgG antibodies. No cord blood samples were positive for WNV-specific IgM antibodies. There were no significant differences between infants of seropositive and seronegative mothers with respect to any of the growth parameters or outcomes measured. CONCLUSIONS: Intrauterine WNV infections seemed to be infrequent. In our study, WNV infection during pregnancy did not seem to affect adversely infant health at birth. Larger prospective studies are necessary to measure more completely the effects of maternal WNV infection on pregnancy and infant health outcomes.

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.

Epidemiology and transmission dynamics of West Nile virus disease.

From 1937 until 1999, West Nile virus (WNV) garnered scant medical attention as the cause of febrile illness and sporadic encephalitis in parts of Africa, Asia, and Europe. After the surprising detection of WNV in New York City in 1999, the virus has spread dramatically westward across the United States, southward into Central America and the Caribbean, and northward into Canada, resulting in the largest epidemics of neuroinvasive WNV disease ever reported. From 1999 to 2004, >7,000 neuroinvasive WNV disease cases were reported in the United States. In 2002, WNV transmission through blood transfusion and organ transplantation was described for the first time, intrauterine transmission was first documented, and possible transmission through breastfeeding was reported. This review highlights new information regarding the epidemiology and dynamics of WNV transmission, providing a new platform for further research into preventing and controlling WNV disease.