West Nile fever--a reemerging mosquito-borne viral disease in Europe.

West Nile virus causes sporadic cases and outbreaks of human and equine disease in Europe (western Mediterranean and southern Russia in 1962-64, Belarus and Ukraine in the 1970s and 1980s, Romania in 1996-97, Czechland in 1997, and Italy in 1998). Environmental factors, including human activities, that enhance population densities of vector mosquitoes (heavy rains followed by floods, irrigation, higher than usual temperature, or formation of ecologic niches that enable mass breeding of mosquitoes) could increase the incidence of West Nile fever.

West Nile virus causes sporadic cases and outbreaks of human and equine disease in Europe (western Mediterranean and southern Russia in 1962-64, Belarus and Ukraine in the 1970s and 1980s, Romania in 1996-97, Czechland in 1997, and Italy in 1998).Environmental factors, including human activities, that enhance population densities of vector mosquitoes (heavy rains followed by floods, irrigation, higher than usual temperature, or formation of ecologic niches that enable mass breeding of mosquitoes) could increase the incidence of West Nile fever.

Synopses
virus seroreactions in Southeast Asia may, in fact, represent antibodies to Kunjin virus.

Arthropod Vectors
Mosquitoes, largely bird-feeding species, are the principal vectors of West Nile virus.The virus has been isolated from 43 mosquito species, predominantly of the genus Culex (Table 1).In Africa and the Middle East, the main vector is Cx.univittatus (although Cx. poicilipes, Cx. neavei, Cx. decens, Aedes albocephalus, or Mimomyia spp.play an important role in certain areas).In Europe, the principal vectors are Cx.pipiens, Cx. modestus, and Coquillettidia richiardii, and in Asia, Cx. quinquefasciatus, Cx. tritaeniorhynchus, and Cx.vishnui predominate.Successful experimental transmission of the virus has been described in Culiseta longiareolata, Cx. bitaeniorhynchus, and Ae.albopictus (8,13).Transovarial transmission of the virus has been demonstrated in Cx. tritaeniorhynchus, Ae. aegypti, and Ae.albopictus, though at low rates.

Vertebrate Hosts
Wild birds are the principal hosts of West Nile virus.The virus has been isolated from a number of wetland and terrestrial avian species in diverse areas (7)(8)(9)(10)(14)(15)(16). High, long-term viremia, sufficient to infect vector mosquitoes, has been observed in infected birds (7,17,18).The virus persists in the organs of inoculated ducks and pigeons for 20 to 100 days (18).Migratory birds are therefore instrumental in the introduction of the virus to temperate areas of Eurasia during spring migrations (12,(14)(15)(16)19).
Rarely, West Nile virus has been isolated from mammals (Arvicanthis niloticus, Apodemus flavicollis, Clethrionomys glareolus, sentinel mice and hamsters, Lepus europaeus, Rousettus leschenaulti, camels, cattle, horses, dogs, Galago senegalensis, humans) in enzootic foci (8)(9)(10).Mammals are less important than birds in maintaining transmission cycles of the virus in ecosystems.Only horses and lemurs (20) have moderate viremia and seem to support West Nile virus circulation locally.Frogs (Rana ridibunda) also can harbor the virus, and their donor ability for Cx.pipiens has been confirmed (21).

Transmission Cycles
Although Palearctic natural foci of West Nile virus infections are mainly situated in wetland ecosystems (river deltas or flood plains) and are characterized by the bird-mosquito cycle, argasid and amblyommine ticks may serve as substitute vectors and form a bird-tick cycle in certain dry and warm habitats lacking mosquitoes.Even a frog-mosquito cycle (21) may function under certain circumstances.
In Europe, West Nile virus circulation is confined to two basic types of cycles and ecosystems: rural (sylvatic) cycle (wild, usually wetland birds and ornithophilic mosquitoes) and urban cycle (synanthropic or domestic birds and mosquitoes feeding on both birds and humans, mainly Cx. pipiens/molestus).The principal cycle is rural, but the urban cycle predominated in Bucharest during the 1996-97 outbreak (2,3).Circulation of West Nile fever in Europe is similar to that of St. Louis encephalitis in North America, where the rural cycle of exoanthropic birdsCx.tarsalis alternates with the urban cycle of synanthropic birdsCx.pipiens/ quinquefasciatus.

Humans
West Nile fever in humans usually is a febrile, influenzalike illness, characterized by an abrupt onset (incubation period is 3 to 6 days) of moderate to high fever (3 to 5 days, infrequently biphasic, sometimes with chills), headache (often frontal), sore throat, backache, myalgia, arthralgia, fatigue, conjunctivitis, retrobulbar pain, maculopapular or roseolar rash (in approximately half the cases, spreading from the trunk to the extremities and head), lymphadenopathy, anorexia, nausea, abdominal pain, diarrhea, and respiratory symptoms (9).Occasionally (<15% of cases), acute aseptic meningitis or encephalitis (associated with neck stiffness, vomiting, confusion, disturbed consciousness, somnolence, tremor of extremities, abnormal reflexes,  23).An outbreak with approximately 50 patients, eight of whom died, was described in Algeria in 1994 (1).Other cases or outbreaks have been observed in Azerbaijan, Central African Republic, Democratic Republic of Congo (former Zaire), Egypt, Ethiopia, India, Madagascar, Nigeria, Pakistan, Senegal, Sudan, and in a few European countries.

Horses
Equine disease, called Near Eastern equine encephalitis in Egypt and lourdige in France, was observed and experimentally reproduced as fever and diffuse encephalomyelitis with a moderate to high fatality rate in Egypt (24), France (c.50 cases in 1962-65) (25), Italy (14 cases in 1998, six died or were euthanised) (R. Lelli, G. Ferrari, pers.comm.),Portugal (26) and Morocco (42 of 94 affected horses died) (27).In the 1960s, the biphasic, encephalomyelitic form, which causes staggering gait and weakness to paralysis of the hind legs, was apparent among infected semiferal horses in Camargue (25).

Other Mammals
Inoculation of sheep with West Nile virus results in fever, abortion in pregnant ewes, and rare encephalitis, in contrast to the asymptomatic infection seen in pigs and dogs (9,28).Rabbits, adult albino rats, and guinea pigs are resistant to West Nile virus infection, but laboratory mice and Syrian hamsters are markedly susceptible; they often become ill with fatal encephalitis, even when inoculated peripherally (8).Adult rodents stressed or immunosuppressed by cold, isolation, cyclophosphamide, corticosterone, or bacterial endotoxin contract fatal encephalitis, even when an attenuated viral strain is given (29).Inoculation of rhesus and bonnet monkeys (but not cynomolgus monkeys or chimpanzees) causes fever, ataxia, and prostration with occasional encephalitis, tremor of extremities, pareses, or paralysis.Infection may be fatal or cause long-term virus persistence in survivors (5,6,30).

Birds
Birds usually do not show any symptoms when infected with West Nile virus.However, natural disease due to the virus has been observed in a pigeon in Egypt (7), and inoculation of certain avian species (e.g., pigeons, chickens, ducks, gulls, and corvids) causes occasional encephalitis and death or long-term virus persistence (7,10,17,18).Chick embryos may be killed by the virus (8).

Synopses
The Future West Nile virus can cause sporadic human cases, clusters, or outbreaks of West Nile fever, even in temperate Europe.Environmental factors, including human activities that enhance vector population densities (irrigation, heavy rains followed by floods, higher than usual temperatures, and formation of ecologic niches enabling the mass breeding of mosquitoes) allow the reemergence of this mosquito-borne disease.For instance, global warming scenarios hypothesize warmer, more humid weather that may produce an increase in the distribution and abundance of mosquito vectors (71).Surveillance for West Nile fever (monitoring population densities and infection rates of principal vectors, serosurveys on vertebrates and exposed human groups, and routine diagnosis of human infections) should therefore be carried out in affected areas.
The mechanism of West Nile virus persistence in disease-endemic foci of temperate Europe presents a challenge for further research.General hypotheses of how an arbovirus could overwinter under adverse climatic conditions have already been postulated (72).The virus could persist in hibernating female Culex spp.; transovarially infected Culex spp.progeny; or chronically infected vertebrate hosts, perhaps birds or frogs.Alternatively, the virus may be reintroduced by chronically infected migratory birds from tropical or subtropical foci at irregular intervals.These issues have to be addressed, because present data substantiate all particular mechanisms and their combinations.For instance, the hibernating vector idea has been supported by a few field and experimental data on female Cx.univittatus (7,73).On the other hand, if the reintroduction scheme is correct, a greatly increased activity of West Nile virus in Africa should be followed by an epidemic occurrence of West Nile fever in Europe in the next few years.Zdenek Hubálek and Jirí Halouzka are scientists at the Academy of Sciences of the Czech Republic.They are interested in the ecology of arthropodborne human pathogenic viruses and bacteria.

Figure .
Figure.European distribution of West Nile virus, based on the virus isolation from mosquitoes or vertebrates, including humans (black dots), laboratory-confirmed human or equine cases of West Nile fever (black squares), and presence of antibodies in vertebrates (circles and hatched areas).