REVIEW ARTICLE |
West Nile Virus Infection: A Pediatric Perspective
* Arbovirus Disease Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado
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ABSTRACT |
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 TOP ABSTRACT EPIDEMIOLOGYTRANSMISSION FROM BLOOD...TRANSMISSION IN UTEROPROBABLE TRANSMISSION THROUGH...ETIOLOGIC AGENT AND PATHOGENESISECOLOGY OF TRANSMISSIONCLINICAL FEATURESDIAGNOSISTREATMENTPREVENTIONSUMMARYREFERENCES |
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West Nile virus (WNV) infection recently became a major public health concern in the western hemisphere. This article describes recent information regarding previously unrecognized mechanisms of WNV transmission and reviews clinical manifestations of WNV infection, diagnostic tests, and prevention strategies from a pediatric perspective. WNV is transmitted to humans primarily through the bite of infected mosquitoes, but during the epidemic that spread across North America in 2002, transmission of WNV through blood transfusions and organ transplantation was described for the first time. Individual case reports indicate that WNV can be transmitted also in utero and probably through breast milk. Although most WNV infections are asymptomatic, the virus causes a broad range of manifestations from uncomplicated febrile illness to meningitis, neuropathies, paralysis, and encephalitis. Severe manifestations of WNV infection are far more common in adults than in children, but 105 cases of neuroinvasive WNV disease were reported among children in the United States in 2002. The distribution of the virus in North America continues to spread. WNV infection can be diagnosed by detecting WNV-specific antibody in cerebrospinal fluid or serum, or by detecting the virus or viral nucleic acid in cerebrospinal fluid, blood, or tissues. Cornerstones of prevention include personal protection against mosquitoes, including wearing insect repellent, reducing populations of vector mosquitoes, and screening the blood supply for WNV-contaminated blood donations.
Key Words: West Nile virus • encephalitis • meningitis • congenital infection • breastfeeding
Abbreviations: WNV, West Nile virus • CDC, Centers for Disease Control and Prevention • WN, West Nile • Ig, immunoglobulin • CSF, cerebrospinal fluid • PCR, polymerase chain reaction • CMV, cytomegalovirus • DEET, N,N-diethyl-m-toluamide
In 1999, an outbreak of unexplained encephalitis in New York City marked the first recognition of West Nile virus (WNV) infection in the western hemisphere. Over the following 2 years, the distribution of this mosquito-borne virus in North America spread along the eastern seaboard and began to move westward as well as northward into Canada. By the end of 2002, WNV had spread dramatically across the continent and southward into Mexico and the Caribbean. Over 4000 cases of WNV illness were reported to the Centers for Disease Control and Prevention (CDC) in the United States during 2002. One hundred fifty cases were in persons <19 years old, and 105 of these children and adolescents had neuroinvasive WNV infections. Although the vast majority of WNV infections are acquired from the bite of infected mosquitoes, in 2002 three previously unrecognized mechanisms of transmission were described. First it was discovered that WNV could be transmitted through blood transfusion and organ transplantation. Shortly thereafter it was determined that WNV can be transmitted transplacentally and probably through breast milk, findings that are particularly relevant to pediatric practice.
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EPIDEMIOLOGY |
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TOPABSTRACTEPIDEMIOLOGYTRANSMISSION FROM BLOOD...TRANSMISSION IN UTEROPROBABLE TRANSMISSION THROUGH...ETIOLOGIC AGENT AND PATHOGENESISECOLOGY OF TRANSMISSIONCLINICAL FEATURESDIAGNOSISTREATMENTPREVENTIONSUMMARYREFERENCES |
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WNV is an arbovirus (transmitted to humans by arthropods) in the family Flaviviridae, a grouping of related viruses named for the most historically notable member, yellow fever virus. WNV is antigenically related to Japanese encephalitis virus and St Louis encephalitis virus. It is transmitted primarily through the bite of mosquitoes that acquire the virus after taking a blood meal from infected birds. WNV was first isolated from a febrile woman in the West Nile (WN) province of Uganda in 1937.1 In 1950, WNV was isolated from 3 apparently healthy children in Egypt and over the next few years from febrile Egyptian children as well.2 The first reported outbreak of WN encephalitis occurred among elderly patients at a nursing home in Israel in 1957.2,3 A study in 1959 of febrile children in Madras State, India, identified one 7-year-old girl with WN encephalitis.4 Adolescents with WN encephalitis in Israel were described in 1962 and 1981.2 WNV was isolated in the early 1980s in India from a 14-year-old boy, a 6-year-old boy, and a 4-year-old girl, all of whom suffered fatal encephalitis.5 Outbreaks of febrile WNV disease were identified in Israel during the 1950s, France in the early 1960s, and South Africa in 1974, 1983, and 1984.2 Outbreaks of WN meningitis and encephalitis affecting primarily adults struck Bucharest, Romania, in 1996, Volgograd, Russia, in 1999, and Israel in 2000.6–8
WNV was recognized first in the western hemisphere in 1999 when a cluster of patients with encephalitis was reported in New York City.9,10 Of 59 patients with WN encephalitis, 2 were <19 years old; the youngest was 5 years old. Over the next 3 years WNV spread across North America (Fig 1).
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In the United States, there were 21 cases of WNV disease reported in 2000 from 3 states and 66 cases in 2001 from 10 states. In 2002, the virus spread dramatically; 4156 cases of WNV disease were reported from 39 states.11 Demographic and clinical data were available for 4146 cases. Of these, 2942 were encephalitis or meningitis, 1157 were uncomplicated WN fever, and 47 were clinically unspecified; there were 284 fatalities. The incidence of neuroinvasive disease and death both increased with age. Of the 4146 cases with clinical and demographic information, 150 (3.6%) were <19 years old; 55 of them were <10 years old, and the youngest was a newborn who had been infected in utero (Table 1). Of the 150 children and adolescents, 87 (56%) were male. There were no fatalities caused by WNV disease in children or adolescents; the youngest fatality was in a 19-year-old person, and the median age among fatal cases was 78 years. Preliminary data indicate that at least 31 cases of WN encephalitis and 79 cases of WN meningitis occurred among children and adolescents in the United States during the 2003 epidemic (CDC, unpublished data, 2003).
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TRANSMISSION FROM BLOOD TRANSFUSION AND ORGAN TRANSPLANTATION |
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TOPABSTRACTEPIDEMIOLOGYTRANSMISSION FROM BLOOD...TRANSMISSION IN UTEROPROBABLE TRANSMISSION THROUGH...ETIOLOGIC AGENT AND PATHOGENESISECOLOGY OF TRANSMISSIONCLINICAL FEATURESDIAGNOSISTREATMENTPREVENTIONSUMMARYREFERENCES |
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During the North American epidemic in 2002 several novel routes of WNV transmission were described. In August 2002, WNV was transmitted to 4 recipients of organs that were transplanted from a common donor.12 The donor had received blood transfusions before her death. She had no evidence of WNV infection before her transfusions, but WNV was isolated from her serum and plasma 1 day after her last transfusion. Of the 4 organ recipients, 3 developed encephalitis and 1 had symptoms consistent with WN fever; all had laboratory evidence of WNV infection. The organ donor had received blood products from 63 donors, 1 of which had asymptomatic WNV viremia at the time of blood donation. Additional instances of transmission of WNV through blood transfusions were subsequently reported.13,14 The finding that WNV could be transmitted through blood and organ donations was followed shortly by discoveries of intrauterine transmission and probable transmission through breast milk.15,16
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TRANSMISSION IN UTERO |
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In August 2002, a 20-year-old woman in the 27th week of pregnancy was hospitalized in New York because of a febrile illness with headache, blurred vision, abdominal and back pain, and vomiting.15,17 The fetal heart rate was increased, but a fetal sonogram was normal. The woman's fever abated, but she had persistent pain and weakness of her legs and hyporeflexia in all extremities. She left the hospital against medical advice but was readmitted 2 days later after a fall and had persistent leg weakness. Fetal monitoring showed no abnormalities. WNV-specific immunoglobulin type M (IgM) antibodies were detected in maternal serum and cerebrospinal fluid (CSF). Polymerase chain reaction (PCR) tests of CSF were negative for WNV, enterovirus, and herpes simplex virus. At 38 weeks of gestation, the mother delivered a live infant with appropriate weight, head circumference at the 25th percentile, and normal physical appearance. However, the infant had bilateral chorioretinitis, severe bilateral loss of white matter in the temporal and occipital lobes of the brain, and cystic cerebral tissue destruction in 1 temporal lobe. WNV-specific IgM was detected in maternal serum at delivery, in cord blood, in infant serum obtained by heel-stick, and in a sample of the infant's CSF that contained red blood cells. The antibody reactivity to WNV in cord blood and infant heel-stick serum was confirmed by neutralization tests. PCR tests of CSF were negative for WNV, enterovirus, and herpes simplex virus. Infant serum was positive for cytomegalovirus (CMV)-reactive IgG but negative for CMV-reactive IgM, and a urine culture for CMV was negative. Serologic tests for toxoplasmosis and lymphocytic choriomeningitis were negative also. WNV nucleic acid was found in the placenta and umbilical cord tissue by PCR. Viral cultures of umbilical cord tissue, CSF, and placenta were negative for WNV.
After the report of this case, the CDC intensified national surveillance for WNV infections in pregnant women. Through collaboration with local and state health departments and health care providers, 3 additional pregnancies complicated by WNV infection in 2002 were detected and evaluated (Table 2). One additional report of WNV in pregnancy has been published.18 Of these 5 documented WNV infections during pregnancy, 1 clearly resulted in fetal infection (described above), in 1 it remains unknown whether the fetus was infected, and for 3 it seems that the fetus did not become infected. The 1 documented transplacental infection was associated with chorioretinitis and intracranial lesions in the infant, but it remains unclear whether WNV caused these lesions. To gather additional data on the outcomes of WNV infection in pregnancy, clinicians are encouraged to report WNV infections in pregnant women to their state health department.
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PROBABLE TRANSMISSION THROUGH BREAST MILK |
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In September 2002, a 40-year-old woman delivered a healthy infant but required blood transfusions to treat postpartum anemia.16 She was discharged from the hospital 2 days after delivery, but 8 days later she developed a persistent headache and subsequently a fever. On the 15th day after delivery, she was readmitted to the hospital, and WNV-specific IgM antibody was detected in her CSF. WNV nucleic acid was detected in a tubing segment of the blood donation from which her transfusions had originated. She had breastfed her infant from the day of delivery until 2 days after her readmission to the hospital. Both WNV nucleic acid and WNV-specific IgM and IgG antibody were detected in a sample of breast milk obtained 16 days after delivery. Viral culture of breast milk was negative for WNV. A second sample of breast milk taken 8 days after the first was negative for WNV nucleic acid but positive for WNV-specific IgM antibody. The infant remained healthy but had WNV-specific IgM antibody in serum taken at 25 days of age. The mother reported that the infant had mostly been indoors and had no obvious exposure to mosquitoes.
No other WNV infections of breastfeeding mothers have been documented in the medical literature to date. Of 6 infants with WNV illness reported to CDC in 2002, 1 was infected in utero as reported above, 1 had breastfed but the mother was not infected with WNV, and 4 others had not breastfed in the month before onset of their illness. Clinicians are encouraged to report to their state health departments any WNV infections in mothers who are breastfeeding their infants as well as WNV infections in infants who are breastfeeding.
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ETIOLOGIC AGENT AND PATHOGENESIS |
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WNV is a spherical, enveloped, single-stranded RNA virus with a diameter of
50 nm.19 Two distinct lineages of WNV have been described: lineage 1 viruses, which are found in Africa, the Middle East, Europe, India, Australia, and North America, and lineage 2 viruses, which are found only in Africa and do not seem to cause severe disease in humans.20 The original isolate of WNV obtained from a febrile woman in Uganda is in lineage 2; the strains of WNV currently circulating in North America are in lineage 1 and closely resemble strains isolated from Israel in 1998 and 1999.20,21 These recent isolates from North America and Israel seem to cause substantial mortality in birds, which apparently had not occurred during WNV outbreaks before 1997.22
The virus is thought to replicate in dendritic cells at the site of inoculation, then is carried to regional lymph nodes, and subsequently disseminated to other organs, probably through the bloodstream.23,24 WNV has been isolated from the blood of immunocompetent people from 2 days before onset of illness to 4 days after onset.25 In immunocompromised people, viremia may be detected up to 31 days after onset.12 Asymptomatic viremia has been found in blood donors.14 In cases of neuroinvasion, WNV particles are found within neurons, associated with neuronal degeneration and necrosis, and infiltrates of microglia, polymorphonuclear leukocytes, and mononuclear lymphocytes are seen in central nervous system tissues.26,27
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ECOLOGY OF TRANSMISSION |
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TOPABSTRACTEPIDEMIOLOGYTRANSMISSION FROM BLOOD...TRANSMISSION IN UTEROPROBABLE TRANSMISSION THROUGH...ETIOLOGIC AGENT AND PATHOGENESISECOLOGY OF TRANSMISSIONCLINICAL FEATURESDIAGNOSISTREATMENTPREVENTIONSUMMARYREFERENCES |
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WNV is transmitted in an enzootic cycle between birds and mosquitoes.22 Passerine birds such as sparrows and crows are important amplifying hosts that develop high levels of viremia. The virus can overwinter in infected mosquitoes that enter a hibernating state in colder months and can be transmitted transovarially from an infected mosquito to its offspring. Mosquitoes of the genus Culex have been implicated most frequently as important vectors. The relative contribution of any given mosquito species to WNV transmission in any given area depends on abundance of the species, susceptibility of the species to WNV infection and replication, and preference of the mosquito species for biting humans, birds, or other vertebrates.22
It seems that before 1997, WNV did not cause substantial avian mortality. However, as early as 1997, WNV began to kill birds in Israel, and the introduction of WNV into North America has resulted in substantial avian mortality, particularly of corvids (crows, blue jays, and magpies).22 Horses also have succumbed to WNV infection in North America. The viremias in both humans and horses are generally felt to be of insufficient magnitude and duration to infect feeding mosquitoes, although this issue deserves additional study.28 Although other mammals including squirrels, chipmunks, bats, cats, and dogs can be infected with WNV, and some of these species can develop disease, they are not currently believed to be important amplifying hosts.22 Some evidence suggests that frogs and alligators may be competent reservoirs for WNV.22
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CLINICAL FEATURES |
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TOPABSTRACTEPIDEMIOLOGYTRANSMISSION FROM BLOOD...TRANSMISSION IN UTEROPROBABLE TRANSMISSION THROUGH...ETIOLOGIC AGENT AND PATHOGENESISECOLOGY OF TRANSMISSIONCLINICAL FEATURESDIAGNOSISTREATMENTPREVENTIONSUMMARYREFERENCES |
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Most children who become infected with WNV are likely to be either asymptomatic or have a mild febrile illness. A serosurvey completed after the 1999 outbreak in New York City indicated that only
20% of people infected with WNV developed illness attributable to the infection.10 The incidence of severe disease increases with age.6,11 The incubation period from infection to onset of symptoms ranges from 2 to 14 days (usually 2–6 days).28 Prolonged incubation periods up to 21 days may be seen in immunocompromised people.12,14 Illness caused by WNV typically begins with the abrupt onset of fever (usually 38–40°C), headache, anorexia, myalgia, and often abdominal pain, nausea, vomiting, or diarrhea.2,8,28–31 A maculopapular rash, lymphadenopathy, sore throat, and cough have been described with varying frequency.2,8,28,30,32,33 The acute signs and symptoms of uncomplicated WN fever usually resolve in <1 week, but fatigue and malaise may linger for weeks.2,28 WNV infection may rarely cause myocarditis, pancreatitis, and fulminant hepatitis.28 Routine clinical laboratory findings do not distinguish WNV infection from many other viral infections. Less than 1% of people infected with WNV develop central nervous system disease such as meningitis or encephalitis, and severe neurologic disease is more common among adults than children.10,11,28 Patients with WN encephalitis develop mental status changes and often vomiting either with the onset of fever or a few days after a prodrome of fever and headache.28,31,34 Detailed clinical descriptions of WNV encephalitis in children are scarce, but the clinical course of a 7-year-old girl with WN encephalitis in India was described in some detail by Carey et al in 1968.4 The girl had been admitted to a hospital with a history of 4 days of fever and convulsions that progressed to coma. She gradually regained consciousness but developed a facial palsy by the time she left the hospital 3 weeks after admission. Among adults, motor neuronopathy associated with weakness and tremor have commonly been seen.34,35 Some patients may present with axonal neuropathy that resembles Guillain-Barre syndrome.29 Acute flaccid paralysis caused by WNV infection has been described both with and without encephalitis, and some patients may present with the acute onset of paralysis of a single limb without any apparent viral prodrome.34,36 Other neurologic manifestations of WNV infection in adults include myoclonus, parkinsonian dyskinesias, seizures, polyradiculitis, optic neuritis, and other cranial neuropathies.28,35 The CSF generally reveals a mild-to-moderate leukocytosis; brain imaging and electroencephalography do not yield any findings that are specific for WN encephalitis.31,37 Electromyographs and nerve-conduction studies may show evidence of anterior horn cell injury with axonal degeneration and/or demyelination.31,37
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DIAGNOSIS |
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TOPABSTRACTEPIDEMIOLOGYTRANSMISSION FROM BLOOD...TRANSMISSION IN UTEROPROBABLE TRANSMISSION THROUGH...ETIOLOGIC AGENT AND PATHOGENESISECOLOGY OF TRANSMISSIONCLINICAL FEATURESDIAGNOSISTREATMENTPREVENTIONSUMMARYREFERENCES |
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WNV infection should be considered in the differential diagnosis of any child who presents with a febrile or acute neurologic illness and has had recent exposure to mosquitoes, a blood transfusion, or organ transplantation. Infants born to mothers who may have had WNV infection during pregnancy should be evaluated carefully for congenital neurologic abnormalities and any signs of viral infection. Although WNV-infected breast milk has not been shown to cause illness in infants, data on the risk of WNV infection that might be associated with breastfeeding are limited. Until additional data are available, mothers who have been infected with WNV and are breastfeeding should be advised to consult their physician if any illness develops in the infant within 1 month of the mother's onset of WNV illness.
The first step in laboratory diagnosis of WNV infection is to test serum and CSF (if there are signs of central nervous system involvement) for the presence of WNV-reactive IgM antibody by using an enzyme-linked immunoassay. If the IgM enzyme-linked immunoassay is positive in either CSF or serum, then it may be necessary to evaluate cross-reactivity with other flaviviruses by performing a viral neutralization assay. A second serum sample obtained 2 to 3 weeks after the first is helpful in confirming WNV infection through the demonstration of a fourfold rise in specific antibody titer. IgM antibody to WNV may persist for >1 year in some patients.38
Many laboratories can test CSF for the presence of WNV nucleic acid, and although the sensitivity is low, a positive result would provide strong evidence that the patient had WNV infection of the central nervous system. WNV, on occasion, can be cultured from CSF and blood, but the sensitivity of viral culture is also low. A few reference laboratories can detect WNV in tissue specimens by immunohistochemical staining, nucleic acid testing, or viral culture.
The incidence of viral meningitis in temperate climates is highest in the summer and fall. An estimated 80% of viral meningitis cases in children are caused by enteroviruses.39 Although the relative prominence of WNV as a cause of viral meningitis and encephalitis in North America is evolving, WNV should now be considered, along with enteroviruses and other neurotropic viruses, in the differential diagnosis of children in North America who develop aseptic meningitis or encephalitis in the summer and fall.
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TREATMENT |
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Patients with WNV should receive supportive care. There is no specific treatment for WNV infection that has been proven effective. Both ribavirin and interferon seem to inhibit WNV replication and cytopathogenicity in vitro, but no controlled clinical trials have been completed.40,41 During the WNV outbreak in Israel in 2000, ribavirin was administered to a 4-year-old child with Hodgkin's lymphoma and WNV infection with successful outcome, but an observational report of the outbreak did not provide any indication that patients treated with ribavirin fared better than those who did not receive ribavirin.8,42
WNV-infected mice were treated successfully with Ig or pooled plasma derived from Israeli donors with antibody to WNV.43 Ig from US donors with low prevalence of antibody to WNV was of no benefit. A 70-year-old woman with a history of chronic lymphocytic leukemia who became comatose after WNV infection and a 42-year-old male lung transplant recipient who subsequently developed WN encephalitis both improved clinically after treatment with Ig from Israeli donors.44,45 Of 6 other patients who were treated similarly, 2 improved, 2 had no improvement, and 2 eventually expired.46 As with ribavirin, clinical trials are needed to assess the efficacy of Ig in treating WNV infection.
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PREVENTION |
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WNV infection can be prevented by avoiding exposure to infected mosquitoes. In many areas, this is facilitated by coordinated mosquito control programs.47 Pregnant women and children who live in areas with WNV-infected mosquitoes should apply insect repellent to skin and clothes when exposed to mosquitoes and avoid being outdoors during peak mosquito-feeding times (usually dawn and dusk). The most effective repellent for use on the skin against mosquitoes is N,N-diethyl-m-toluamide (DEET).48–50 DEET or permethrin also can be applied directly to clothing to repel mosquitoes. The American Academy of Pediatrics recommends using formulations of no more than 30% DEET on infants and children and that DEET not be used on infants <2 months old.51 The Canadian Pediatric Society advises using formulations of no more than 10% DEET on children <12 years old and recommends against using DEET in infants <6 months old.52 Although DEET is absorbed systemically from the skin and has been shown to cross the placenta, studies in both animals and humans indicate that DEET can be used during pregnancy without adverse effects on the fetus.49
To prevent additional transmission of WNV through blood transfusions and organ donations, blood donations in the United States are currently undergoing screening for WNV with nucleic acid amplification tests.53 Although this process is investigational, it is expected to substantially reduce the risk of WNV infection from blood transfusion.
Although WNV seems to be transmitted through breast milk, to date no adverse effects of such transmission on breastfeeding infants have been documented. Because the benefits of breastfeeding seem to outweigh the risk of any WNV illness contracted through breastfeeding, mothers should be encouraged to breastfeed even in areas of ongoing WNV transmission. Currently, there are no available data to indicate when, during the course of WNV infection, the virus might appear in breast milk or how long infectious virus might be found in breast milk. Additional data is needed to determine whether there is any risk of WNV illness in breastfeeding infants.
A killed WNV vaccine has been produced for the vaccination of horses. Development of human vaccines against WNV is underway, but to date no results of clinical trials in humans have been published. A chimeric virus vaccine that incorporates WNV antigens into a backbone of the 17-D yellow fever vaccine has been shown to be efficacious in hamsters.54 Another chimeric vaccine that incorporates WNV antigens into a backbone of dengue virus (serotype 4) has induced protective immunity to WNV in rhesus monkeys.55 A DNA vaccine that elicits expression of WNV proteins has been evaluated in mice and horses.56 Finally, a DNA vaccine that elicits expression of attenuated Kunjin virus, which is related closely to WNV, elicited protective immunity to WNV in mice.57
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SUMMARY |
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TOPABSTRACTEPIDEMIOLOGYTRANSMISSION FROM BLOOD...TRANSMISSION IN UTEROPROBABLE TRANSMISSION THROUGH...ETIOLOGIC AGENT AND PATHOGENESISECOLOGY OF TRANSMISSIONCLINICAL FEATURESDIAGNOSISTREATMENTPREVENTIONSUMMARYREFERENCES |
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Beginning in the late 1990s, WNV transmission seems to have increased in Europe and the Middle East, and after the introduction of the virus into North America, WNV infection has become a major public health concern in the western hemisphere. The discoveries that WNV could be transmitted to the fetus during pregnancy and probably in breast milk, as well as through blood and organ donations, are of particular relevance to pediatric practice. The vast majority of WNV infections continue to be transmitted by mosquitoes. Most WNV infections are asymptomatic, but the virus can cause uncomplicated febrile illness, meningitis, encephalitis, neuropathies, and paralysis. Although disease caused by WNV tends to be more severe with increasing age, severe neurologic disease in children and pregnant women has been described. Although enteroviruses remain the most common cause of aseptic meningitis in children, WNV infection should be considered in the differential diagnoses of children with aseptic meningitis or viral encephalitis in North America. Diagnosis depends on detection of WNV-specific antibody in CSF or serum or detection of WNV or its components in CSF, blood, or tissues. Cornerstones of prevention include personal protection against mosquitoes, including wearing insect repellent, reducing populations of vector mosquitoes, and screening the blood supply for WNV nucleic acid.
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ACKNOWLEDGMENTS |
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We thank Grant L. Campbell and John T. Roehrig for helpful comments on this manuscript and Stephanie Kuhn and Krista Kniss for help in preparation of the figure and tables.
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FOOTNOTES |
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Received for publication Oct 17, 2003; Accepted Jan 8, 2004.
Reprint requests to (E.B.H.) Arbovirus Disease Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, PO Box 2087, Fort Collins, CO 80522. E-mail: ebh2{at}cdc.gov
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