REVIEW ARTICLE
West Nile Virus Infection: A Pediatric Perspective
Edward B. Hayes, MD; and Daniel R. O’Leary, DVM
ABSTRACT. West Nile virus (WNV) infection recently became a major public health concern in the western hemisphere. This article describes recent information re-garding previously unrecognized mechanisms of WNV transmission and reviews clinical manifestations of WNV infection, diagnostic tests, and prevention strate-gies from a pediatric perspective. WNV is transmitted to humans primarily through the bite of infected mosqui-toes, 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 asymp-tomatic, the virus causes a broad range of manifestations from uncomplicated febrile illness to meningitis, neu-ropathies, paralysis, and encephalitis. Severe manifesta-tions 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 di-agnosed by detecting WNV-specific antibody in cerebro-spinal 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 screen-ing the blood supply for WNV-contaminated blood donations.Pediatrics2004;113:1375–1381;West Nile virus, encephalitis, meningitis, congenital infection, breastfeed-ing.
ABBREVIATIONS. WNV, West Nile virus; CDC, Centers for Dis-ease Control and Prevention; WN, West Nile; Ig, immunoglobulin; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; CMV, cytomegalovirus; DEET,N,N-diethyl-m-toluamide.
I
n 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 distribu-tion 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 andthe Caribbean. Over 4000 cases of WNV illness were reported to the Centers for Disease Control and Pre-vention (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 neu-roinvasive WNV infections. Although the vast ma-jority of WNV infections are acquired from the bite of infected mosquitoes, in 2002 three previously unrec-ognized mechanisms of transmission were de-scribed. 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 par-ticularly relevant to pediatric practice.
EPIDEMIOLOGY
WNV is an arbovirus (transmitted to humans by arthropods) in the family Flaviviridae, a grouping of related viruses named for the most historically nota-ble member, yellow fever virus. WNV is antigeni-cally 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 chil-dren in Egypt and over the next few years from febrile Egyptian children as well.2The 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 en-cephalitis.4Adolescents with WN encephalitis in
Is-rael 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.5Outbreaks of
fe-brile WNV disease were identified in Israel during the 1950s, France in the early 1960s, and South Africa in 1974, 1983, and 1984.2Outbreaks of WN
meningi-tis and encephalimeningi-tis 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 hemi-sphere in 1999 when a cluster of patients with en-cephalitis was reported in New York City.9,10Of 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).
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
dra-From the Arbovirus Disease Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Con-trol and Prevention, Fort Collins, Colorado.
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: [email protected]
matically; 4156 cases of WNV disease were reported from 39 states.11Demographic and clinical data were
available for 4146 cases. Of these, 2942 were enceph-alitis 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 ad-olescents; 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, un-published data, 2003).
TRANSMISSION FROM BLOOD TRANSFUSION AND ORGAN TRANSPLANTATION
During the North American epidemic in 2002 sev-eral novel routes of WNV transmission were de-scribed. 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 consis-tent with WN fever; all had laboratory evidence of WNV infection. The organ donor had received blood products from 63 donors, 1 of which had
asymptom-Fig 1. Counties reporting the presence of WNV: United States, 1999 –2002.
TABLE 1. Cases of WNV Illness in Children: United States, 2002
Age, y
Encephalitis Meningitis Unspecified
Neuroinvasive*
West Nile Fever
Other/ Unknown
⬍1 0 2 3 0 1
1–4 5 3 2 7 1
5–9 9 6 12 4 0
10–14 7 12 5 9 1
15–18 8 17 14 21 1
atic WNV viremia at the time of blood donation. Additional instances of transmission of WNV through blood transfusions were subsequently re-ported.13,14The finding that WNV could be
transmit-ted through blood and organ donations was
fol-lowed shortly by discoveries of intrauterine
transmission and probable transmission through breast milk.15,16
TRANSMISSION IN UTERO
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 sono-gram 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 bilat-eral chorioretinitis, severe bilatbilat-eral loss of white mat-ter 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 nega-tive for CMV-reacnega-tive 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 nega-tive 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 ad-ditional pregnancies complicated by WNV infection in 2002 were detected and evaluated (Table 2). One additional report of WNV in pregnancy has been published.18Of 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 chori-oretinitis and intracranial lesions in the infant, but it remains unclear whether WNV caused these lesions.
To gather additional data on the outcomes of WNV TABLE
2. Outcomes of Pregnancies Complicated by West Nile Virus (WNV) Infection: United States, 2002 Mother ’s Age
Gestation atInfection
infection in pregnancy, clinicians are encouraged to report WNV infections in pregnant women to their state health department.
PROBABLE TRANSMISSION THROUGH BREAST MILK
In September 2002, a 40-year-old woman delivered a healthy infant but required blood transfusions to treat postpartum anemia.16She 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 read-mitted to the hospital, and WNV-specific IgM anti-body was detected in her CSF. WNV nucleic acid was detected in a tubing segment of the blood dona-tion 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 nega-tive for WNV nucleic acid but posinega-tive 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 expo-sure 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 encour-aged 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.
ETIOLOGIC AGENT AND PATHOGENESIS
WNV is a spherical, enveloped, single-stranded RNA virus with a diameter of ⬃50 nm.19 Two
dis-tinct 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.20The
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 1999.20,21These recent isolates from North
America and Israel seem to cause substantial mortal-ity in birds, which apparently had not occurred dur-ing 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 immuno-competent people from ⬃2 days before onset of ill-ness to ⬃4 days after onset.25 In
immunocompro-mised people, viremia may be detected up to 31 days after onset.12Asymptomatic viremia has been found
in blood donors.14In 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 ner-vous system tissues.26,27
ECOLOGY OF TRANSMISSION
WNV is transmitted in an enzootic cycle between birds and mosquitoes.22Passerine birds such as
spar-rows and cspar-rows are important amplifying hosts that develop high levels of viremia. The virus can over-winter in infected mosquitoes that enter a hibernat-ing state in colder months and can be transmitted transovarially from an infected mosquito to its off-spring. 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 re-sulted 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 cur-rently believed to be important amplifying hosts.22
Some evidence suggests that frogs and alligators may be competent reservoirs for WNV.22
CLINICAL FEATURES
Most children who become infected with WNV are likely to be either asymptomatic or have a mild fe-brile illness. A serosurvey completed after the 1999 outbreak in New York City indicated that only⬃20% of people infected with WNV developed illness at-tributable to the infection.10The incidence of severe
disease increases with age.6,11The 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 immunocom-promised people.12,14 Illness caused by WNV
typi-cally begins with the abrupt onset of fever (usually 38 – 40°C), headache, anorexia, myalgia, and often
abdominal pain, nausea, vomiting, or
diar-rhea.2,8,28–31A maculopapular rash,
lymphadenopa-thy, sore throat, and cough have been described with varying frequency.2,8,28,30,32,33 The acute signs and
myo-carditis, pancreatitis, and fulminant hepatitis.28
Rou-tine clinical laboratory findings do not distinguish WNV infection from many other viral infections.
Less than 1% of people infected with WNV de-velop central nervous system disease such as men-ingitis 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 enceph-alitis in India was described in some detail by Carey et al in 1968.4The girl had been admitted to a
hos-pital with a history of 4 days of fever and convul-sions that progressed to coma. She gradually re-gained 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, parkin-sonian dyskinesias, seizures, polyradiculitis, optic neuritis, and other cranial neuropathies.28,35The CSF
generally reveals a mild-to-moderate leukocytosis; brain imaging and electroencephalography do not yield any findings that are specific for WN enceph-alitis.31,37 Electromyographs and nerve-conduction
studies may show evidence of anterior horn cell in-jury with axonal degeneration and/or demyelina-tion.31,37
DIAGNOSIS
WNV infection should be considered in the differ-ential diagnosis of any child who presents with a febrile or acute neurologic illness and has had recent exposure to mosquitoes, a blood transfusion, or or-gan transplantation. Infants born to mothers who may have had WNV infection during pregnancy should be evaluated carefully for congenital neuro-logic 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 breast-feeding are limited. Until additional data are avail-able, 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 in-fection is to test serum and CSF (if there are signs of central nervous system involvement) for the pres-ence of WNV-reactive IgM antibody by using an linked immunoassay. If the IgM enzyme-linked immunoassay is positive in either CSF or se-rum, 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 demonstra-tion 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 cul-ture is also low. A few reference laboratories can detect WNV in tissue specimens by immunohisto-chemical staining, nucleic acid testing, or viral cul-ture.
The incidence of viral meningitis in temperate cli-mates is highest in the summer and fall. An esti-mated 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 di-agnosis of children in North America who develop aseptic meningitis or encephalitis in the summer and fall.
TREATMENT
Patients with WNV should receive supportive care. There is no specific treatment for WNV infec-tion 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 adminis-tered to a 4-year-old child with Hodgkin’s lym-phoma 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 lym-phocytic leukemia who became comatose after WNV infection and a 42-year-old male lung transplant re-cipient who subsequently developed WN encephali-tis both improved clinically after treatment with Ig from Israeli donors.44,45Of 6 other patients who were
treated similarly, 2 improved, 2 had no improve-ment, and 2 eventually expired.46As with ribavirin,
clinical trials are needed to assess the efficacy of Ig in treating WNV infection.
PREVENTION
WNV infection can be prevented by avoiding ex-posure to infected mosquitoes. In many areas, this is facilitated by coordinated mosquito control pro-grams.47Pregnant women and children who live in
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).48–50DEET or permethrin also can be applied
directly to clothing to repel mosquitoes. The Ameri-can Academy of Pediatrics recommends using for-mulations 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
ad-vises 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.53Although this process is
inves-tigational, 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 trans-mission on breastfeeding infants have been docu-mented. Because the benefits of breastfeeding seem to outweigh the risk of any WNV illness contracted through breastfeeding, mothers should be encour-aged to breastfeed even in areas of ongoing WNV transmission. Currently, there are no available data to indicate when, during the course of WNV infec-tion, 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 vac-cines against WNV is underway, but to date no re-sults of clinical trials in humans have been pub-lished. 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
incorpo-rates 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 evalu-ated 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
SUMMARY
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 trans-mitted by mosquitoes. Most WNV infections are asymptomatic, but the virus can cause uncompli-cated febrile illness, meningitis, encephalitis, neurop-athies, 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 an-tibody 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, re-ducing populations of vector mosquitoes, and screening the blood supply for WNV nucleic acid.
ACKNOWLEDGMENTS
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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DOI: 10.1542/peds.113.5.1375
2004;113;1375
Pediatrics
Edward B. Hayes and Daniel R. O'Leary
West Nile Virus Infection: A Pediatric Perspective
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2004;113;1375
Pediatrics
Edward B. Hayes and Daniel R. O'Leary
West Nile Virus Infection: A Pediatric Perspective
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