west nile viral encephalitis

Rev. sci. tech. Off. int. Epiz., 2000, 19 (1), 166-176

West Nile viral encephalitis N. Komar Centers for Disease Control and Prevention/National Center for Infectious Diseases/Division of Vector-Borne Infectious Diseases, P.O. Box 2087, Fort Collins, Colorado 80522, United States of America

Summary West Nile virus (WNV) has emerged in recent years in temperate regions of Europe and North America, presenting a threat to both public and animal health. The most serious manifestation of infection is fatal encephalitis in humans and horses, as well as mortality in certain domestic and wild birds. A recent development in the epizootiology of this mosquito-borne flavivirus was the occurrence of a severe outbreak in N e w York City and surrounding areas. During this outbreak, mortality was observed in humans, horses, a cat and numerous species of wild birds, particularly members of the family Corvidae (crows). The author reviews basic information and summarises recent developments in the epidemiology and epizootiology of WNV.

Keywords Arboviruses - Epidemiology - Equine encephalitis - Equines - Flaviviruses - North America - Public health - Reviews - West Nile virus - Zoonoses.

Introduction West Nile virus (WNV) has emerged in recent years in temperate regions of Europe and North America, presenting a threat to public health, equine heal th, and since 1998, the health of bi rd populations. The mos t serious manifestation of infection is fatal encephalitis in humans and horses , as well as mortality in certain domest ic and wild birds. A comprehens ive review of the eco logy and ep idemiology of WNV has b e e n prepared previously (28) . This chapter reviews basic information and summarises recent deve lopments in the ep idemio logy and epizoot io logy of WNV.

History West Nile virus was first isolated from a febrile adult w o m a n in the West Nile District of Uganda in 1937 (78) . T h e eco logy as a mosqui to-borne virus was characterised in Egypt in the 1950s (83). T h e virus b e c a m e recognised as a cause of severe h u m a n meningoencephali t is in elderly patients during an outbreak in Israel in 1957 (80) . Equine disease was first no ted in Egypt and France in the early 1960s (27, 75) . T h e appearance of WNV in North America in 1999, with encephalitis reported in humans (14) and horses (62) , may b e an important milestone in the evolving history of this virus.

Geographic distribution West Nile virus has b e e n descr ibed in Africa, Europe, south Asia, Oceania (sub-type Kunjin), and mos t recently, North America. T h e list of countries affected b y W N V has b e e n summarised (31). Recent outbreaks of WNV encephalitis in humans have occurred in Algeria in 1994 (44) , Romania in 1996-1997 (31 , 67, 86 ) , the C z e c h Republic in 1997 (32) , the Democratic Republic of the Congo in 1998 (59) , Russia in 1999 (A. Platonov, personal communicat ion) and the United States of America (USA) in 1999 (14) . Epizootics of disease in horses occurred in Morocco in 1996 (84) , Italy in 1998 (12) and the USA in 1999 (62). In the USA, WNV has b e e n recovered in the north-eastern States of N e w York, Connecticut, N e w Jersey and Maryland (Fig. 1). In humans, disease has only b e e n reported in south-east N e w York State, including N e w York City. Equine disease was clustered on Long Island, east of N e w York City.

Molecular biology West Nile virus is a positive-stranded ribonucleic acid (RNA) virus belonging to the Japanese encephalitis s e rocomplex of the family Flaviviridae (38). Structurally, the virus forms a 40 nm-diameter particle c o m p o s e d of an 11 .3-kb genomic RNA associated with a core protein (nucleocapsid), surrounded b y a host-derived m e m b r a n e with viral m e m b r a n e and envelope proteins (71). T w o genetic lineages

Rev. sci. tech. Off. int. Epiz., 19 (1) 167

Cases in humans or horses, and multiple bird Isolates

Mult iple bird Isolates only

Mosquito isolates

• Single bird isolates

Fig. 1 Geographic distribution of West Nile virus in the United States of America in 1999

of WNV have b e e n descr ibed b y Berthet et al. (7). Lineage 1 includes isolates from Europe, the Middle East, Africa, India, Australia (Kunjin) and the recent isolates from North America (42). Lineage 2 includes tropical African isolates that are not associated with disease outbreaks.

Transmission cycles West Nile virus is amplified during per iods of adult mosqui to blood-feeding b y continuous transmission b e t w e e n mosqui to vectors and avian reservoir hosts (Fig. 2) . Infectious mosqui toes carry virus particles in the salivary glands and infect susceptible bird species during b l o o d - m e a l acquisition. Competent bi rd reservoirs will sustain an infectious viraemia for 1 to 4 days subsequent to exposure , after wh ich these hosts deve lop life-long immunity. A sufficient number of vectors must feed o n an infectious host to ensure that s o m e survive the extrinsic incubation per iod (approximately two

w e e k s depending o n temperature) (17) to feed again, o n a susceptible reservoir host . People , ho r se s a n d most other mammals rarely deve lop the infectious-level of viraemia, and thus are cons idered 'dead-end ' bos t s (28) . T h e transmission cycle m a y amplify w h e n complex ecological and climatological criteria are met , bu t usually endures only a f ew months , after w h i c h eco log ica l parameters h inder transmission.

Primary vector spec ies a n d vertebrate reservoir hos t spec ies vary with geographic locat ion (Table I ) . Determining the species c o m p o n e n t s of transmission cycles generally requires experimental data for vector a n d vertebrale hos t c o m p e t e n c e , multiple virus isolations f rom mosqu i toes and vertebrates, and serological data. Serological surveys alone w h i c h indicate exposure to WNV, are insufficient to incriminate a particular vertebrate hos t as an amplification reservoir. In general, Culex species mosqui toes serve as vectors and passerine b i rds are vertebrate reservoirs in enzootic WNV transmission cycles.

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Fig. 2 Basic transmission cycle of West Nile virus in birds and Culex mosquitoes Alternative transmission cycles may exist

Alternative vector-borne transmission cycles for WNV have b e e n p roposed . Natural infections in ticks have b e e n observed o n multiple occasions in Ornithodoros maritimus and Argas hermanni (soft ticks), and Hyalomma marginatum (hard ticks), as well as single isolations from five other species of hard ticks in Africa, Europe and Asia (31) . Swallow bugs (Oeciacus hirundinis) have b e e n implicated as vectors in Austria (77). Infections of non-culicine ar thropods are considered incidental o r of secondary importance and not essential for virus perpetuation. However , inter-epizootic maintenance of WNV has not b e e n well characterised, and may depend on alternative hosts.

Experimental transmission of WNV in the absence of arthropod vectors has b e e n descr ibed for hamsters (70) and mice (56, 60) . A preliminary finding of experimental low-level transmission b e t w e e n birds using the N e w York strain of WNV requires further documentat ion (N. Komar, unpubl ished findings).

Mechanisms for WNV maintenance b e t w e e n per iods of continuous transmission are u n k n o w n but may also d e p e n d on alternative vectors and reservoir hosts . Shuttling of WNV b e t w e e n temperate transmission foci and sub-tropical/tropical foci b y means of viraemic migrating birds has b e e n p r o p o s e d (45, 52 , 55). Mechanisms for overwintering in temperate zones m a y include pro longed infection in hibernating adult Culex species mosqui toes that undergo diapause during

Table I Candidate vertebrate reservoir hosts and vector mosquitoes considered important in the transmission cycles of West Nile virus, by region (4, 10, 18, 23, 26, 29, 31, 32, 35, 42, 49, 54, 57, 58, 64, 74, 85, 88)

Location Vertebrate hosts Vector mosquitoes

Europe House sparrow Culex pipiens

{Passer domesticus) Cx. modestus

Coquillettidia richardii

Africa House sparrow Cx. univittatus

Hooded crow Cx. poicilipes [Corvus corone sardonius)

Other birds Cx. antennatus

Cx. decens

Aedes albocephalus

Mimomyia species

Middle East Turtle dove (Streptopelia turtur)

Other birds

Cx. univittatus

South Asia Birds Cx. vishnui

Cx. quinquefasciatus

Cq. richardii

Oceania Herons [Ardeidae]

Other birds

Cx. annulirostris

North America Passerine birds Cx. pipiens

winter mon ths (83) or low-level transovarial transmission in certain species of mosqui toes (28, 55) .

Experimental infections Most classes of vertebrate hosts are susceptible to WNV infection, including birds, mammals , amphibians and reptiles (28). Experimental infections of birds have b e e n descr ibed for crows, falcons, ch ickens (63, 83) , doves (48, 91) , p igeons (48, 76, 83) , ducks (48, 76) , herons (9, 48 , 91) , sparrows (48, 91) and other birds (48). Experimental infection studies of other vertebrates are descr ibed for pigs (34) , d o n k e y s (75), mules, sheep , a water buffalo (83), cattle (81), dogs (8), lemurs (72) and other primates (30, 53 , 63 , 68, 78) , African wild rodents (46), laboratory mice (21 , 22 , 24 , 4 3 , 56, 60, 63 , 78 , 87) , rats (21 , 22) , hamsters (65, 70) , guinea-pigs (36, 78) , hedgehogs and rabbits (78), frogs (40) and humans (79). These studies confirm that high-titred viraemia is rare in species other than birds. Additional studies employing the N e w York strain of WNV are in progress with a variety of species .

At least sixteen species of mosqui toes are competen t vectors in experimental transmission studies of WNV (28, 33 , 35, 65) , including five species, namely: Culex pipiens, Aedes japonicus, Ae. sollicitans, Ae. taeniorhynchus and Ae. vexans, wh ich were tested with a N e w York strain of WNV (M.J. Turell, personal communicat ion) . Interestingly, C. pipiens comp lex mosqui toes , although implicated as vectors in urban


outbreaks, are consistently poor vectors in competence studies (2, 37, 39). Some non-culicine arthropods, including the soft ticks O. maritimus and 0. erraticus (28) and A. arborais, A. hermanni and A. persicus (1) have been evaluated experimentally and were found to be competent hosts for viral replication and, in some cases, for transmission to vertebrates.

Disease associations In humans, WNV infection is usually asymptomatic, but WNV-attributed morbidity occurred in 11% of a population of cancer patients experimentally infected with the EG101 strain (79). The apparent-to-inapparent ratio of infections during the WNV epidemic in Romania was estimated between 1:140 and 1:320 (86). Disease attributed to WNV (and Kunjin virus) is typically associated with fever and in rare cases, a more severe syndrome that includes meningitis and encephalitis (28, 66). In recent outbreaks, the case fatality rate was 4% of 393 cases in Romania (86), approximately 6% of 500 encephalitis and meningitis cases in Russia (A. Platonov, personal communication), and 11% of 61 cases in New York (15).

In horses, WNV disease is detected rarely. Serological studies in horses suggest that neurological infections represented approximately 20% of all infections in Tuscany, Italy, in 1998 (R. Lelli, personal communication), and less than 40% in Long Island, New York, in 1999 (S. Trock, personal communication). These studies indicated that infection rates in horses residing in close proximity to case premises were approximately 40% in Tuscany and approximately 20% in Long Island. Neurological disease in horses is characterised principally by posterior ataxia, proprioception deficits (Fig. 3) and altered behaviour. The most severe cases evolve to paralysis of the hind legs, recumbency, terminal convulsion and death (84; J. Lubroth, personal communication). The case fatality rate in Morocco in 1996 was 44% of 94 cases (84), 43% of 14 cases in Italy in 1998 (12), and 45% of 20 cases in the USA in 1999 (62). In other mammals, naturally acquired WNV encephalitis is unknown, with the exception of a single case which occurred during the outbreak in North America in a domestic cat (euthanised after the onset of seizures), which was confirmed by virus isolation from the brain (N. Komar, unpublished findings).

Avian morbidity and mortality resulting from natural WNV infection is a novel characteristic of WNV emergence. Prior to 1998, the only evidence for virulence in naturally infected birds was the isolation of WNV from a sick fledgling pigeon (Columba livia) in Egypt (90). Experimental evidence of avian mortality is limited to the observation of severe mortality in hooded crows (Corvus corone sardonius) (100%) and house sparrows (Passer domesticus) (79%), but not doves (Streptopelia senegalensis), falcons (Falco tinnunculus) or herons (Bubulcus ibis), as a result of mosquito-borne infection

Fig. 3 Proprioception deficits in a horse infected with West Nile virus a) Braced stance of the hind quarters This an imal seemed unwi l l i ng to move f rom th is pos i t ion b) Cross-legged stance The an imal rema ined in th is pos i t ion fo r p ro t rac ted per iods of t ime Photographs: courtesy of J. Lubroth, United States Department of Agriculture

with the Ar-248 strain of WNV (91). In 1998, WNV was isolated in Israel from the brains of four dead white storks (Ciconia ciconia), a lappet-faced vulture (Torgos traceliotus) and domestic geese (Anser spp.) (52). An isolate from a goose was 100% homologous, based on limited nucleotide sequence data, to the WNV isolates from North America that also caused severe mortality in certain avian populations (42). An outbreak of WNV among eight- to ten-week-old domestic geese in Israel in November 1999 resulted in 400 cases with a mortality rate of 40% (61).

The impact of WNV on North American bird populations during the 1999 epiornitic has not yet been evaluated fully. Nonetheless, it is clear that corvids (crows and jays) in particular, as well as members of thirteen other families of


Treatment and control Currently, there are n o p roven treatments for clinical WNV infection in humans , horses or any other animal. Experimentally infected animals (usually mice) have b e e n treated with pentoxyphyll ine (3), gentamicin (5), melatonin (6), tilorone hydrochlor ide (87) or steroids (25). Encephalitis in humans should b e treated with supportive therapy. Partial recovery was obse rved in a patient after treatment with an appetite stimulant (66) . Intravenous administration of nutritional fluids for horses and other encephalit ic animals may alleviate emaciat ion that results f rom the inability to eat during the neurological phase of disease.

No WNV vaccine is available commercial ly. As is the case with other arboviral encephali t ides, h u m a n W N V encephalitis is so rare that vaccine deve lopment m a y not b e feasible economically. Vaccination of horses m a y have benefits in protecting valuable animals from a potentially fatal disease, but trade and compet i t ion practices may m a k e this undesirable as s o m e countries m a y use positive ant ibody tests, which wou ld result f rom either vaccination or natural infection, as justification for importat ion restrictions, albeit unwarranted o n scientific grounds. In 1999, commerc ia l goose f locks in Israel were vaccinated against Israel turkey meningoencephalit is (ITM) virus, a flavivirus wh ich is distantly related to WNV, with the intent to cross-protect against W N V infection (61). Further studies are required to determine the efficacy of flavivirus vaccines, such as those against ITM and J E viruses for protect ion against WNV infection.

Control of WNV infection is bes t achieved by reducing vector populations. Methods of mosqui to control have b e e n described (19, 41 ) .

Surveillance Surveillance for W N V outbreaks generally relies o n passive case reporting of h u m a n and equine cases of encephalitis. Historically, mosqu i to -based surveillance for WNV and use of sentinel birds (chickens and pigeons) have b e e n used successfully to moni tor WNV transmission in enzootic regions such as South Africa (47, 50) and Australia (20, 73). Recent p rogrammes of active surveillance for WNV in bird and mosqui to populat ions were instituted in Romania (74), the Czech Republic (32) and Italy (G. Ferrari, personal communication). Active surveillance in the USA began in September 1999 as a result of the ep idemic in N e w York, and relied o n laboratory confirmation of W N V in tissues of dead crows. The monitoring of dead birds appeared to b e the mos t sensitive surveillance tool to determine the geographic range of WNV activity during the North American outbreak, as indicated in Figure 1, and should b e the preferred m e t h o d of surveillance for WNV in regions of North America where virus activity has not yet b e e n detected.

Mosquito- and b i rd-based surveillance p rogrammes are mos t useful for monitoring arbovirus activity in k n o w n transmission foci. The WNV infection rate of C. pipiens mosqui toes col lected during the ou tbreak investigation in Romania was less than 0 . 1 % (74) . Seroprevalence in resident birds, o n the other hand, is generally h igh in enzoot ic transmission foci (83) and in epizoot ic foci (74). Investigation of avian infection in Romania in 1996 revealed that m o r e than 30% of fowl h a d d e v e l o p e d neutralising antibodies to WNV. Preliminary studies in 1999 have confi rmed this observat ion among resident birds in N e w York City, but not among migrating birds (N. Komar , unpubl i shed findings).

Active surveillance in the USA in 2 0 0 0 will rely o n surveillance systems already in p lace for SLE, w h i c h include virus isolation and antigen detect ion in Culex mosqu i toes , and serological detect ion of specific IgM and haemagglutination-inhibiting (HI) antibodies in sentinel ch ickens . In s o m e States, house sparrows are sampled as wild bird sentinels (51). In such instances, detect ion of SLE antibodies may serve as a screen for flavivirus infection. Positive samples should b e retested using the plaque-reduct ion neutralisation test to differentiate b e t w e e n SLE virus and W N V infections. Guidelines have b e e n publ ished to assist States in developing n e w arbovirus surveillance programmes in preparation for the possible spread of WNV activity in North America (15).

Economic impact T h e e c o n o m i c impact of W N V infection has not b e e n evaluated thoroughly. However, other cost studies of arboviral encephalitis may apply to WNV. The finding that a single case of residual eastern equine encephalitis (EEE) in a h u m a n infant may e x c e e d a cost of US$3 million is considered a strong justification for active surveillance programmes for EEE in the USA (89). One estimate of public expenditure attributed to the W N V outbreak in N e w York State in 1999 exceeds US$15 mill ion (D.J. White , personal communicat ion) . Additional costs in the USA outbreak resulted f rom embargoes on s o m e international shipments of horses , including the exit of horses through N e w York City ports (N. Faizi, personal communicat ion) .

Perspectives West Nile virus encephalitis appears to b e an emerging concern for public heal th in European and North American cities, and for equine heal th in horse-fanning communit ies . Several outbreaks of h u m a n and equine encephalitis have occurred since 1996, whereas prior to that year, outbreaks were recorded on rare occasions. Global climate change has b e e n speculated as contributing to the increase in W N V disease outbreaks in temperate regions (31) . A novel deve lopment with WNV in the USA and Israel is the observation of avian mortality, especially among wild crows.

172 Rev. sci. tech. Off. int. Epiz., 19(1)

Presumably, the possible spread of WNV in North America could b e t racked b y mapping WNV-confi rmed crow deaths. Crow mortality may b e c o m e an important surveillance tool and consequently he lp prevent encephalitis in h u m a n and horse populations. T h e long-term impact of decimated c row populat ions is u n k n o w n at present. Determining the impact o n public, veterinary and wildlife health as a consequence of WNV introduction in North America will undoubtedly provide many valuable lessons for the preparation against other emerging zoonot ic diseases yet to b e recognised.

Acknowledgements T h e author wou ld l ike to thank the following p e o p l e for their

valuable contributions to this work : J. Behrens, R.S. Lanciotti,

B.R. Miller, C.G. Moore, R.S. Nasci, Centers for Disease

Control and Prevention; R. Crom, N. Faizi and J. Lubroth,

United States Department of Agriculture; M.J. Turell, United

States Army Medical Research Institute of Infectious Diseases;

D.J. Whi te , N e w York State Department of Health;

W.B . Stone, N e w York State Department of Environmental

Conservation; T.S. McNamara, Wildlife Conservation Society;

S. Trock , Cornell University; R. Lelli, Istituto Zooprofilattico

Sperimentale Abruzzo e Molise 'G. Caporale ' (Teramo, Italy);

G. Ferrarli, Istituto Zooprofìlattico Sperimentale delle Regioni

Lazio e Toscana (Rome, Italy); M. Maikinson, Kimron

Veterinary Institute (Israel); A.E. Platonov, Central Research

Institute of Epidemiology (Moscow); P.G. J u p p , National

Institute for Virology (South Africa). Special thanks are

ex tended to J. Lubroth for his critical review of the

manuscript.

Encéphalite due au virus West Nile N. Komar

Résumé

Le virus W e s t Nile est apparu ces dernières années dans les régions tempérées d'Europe et d 'Amér ique du Nord , fa isant peser une lourde menace sur la santé des animaux et de l 'homme. La mani festat ion la plus grave de l ' infect ion est une encéphal i te mortel le pour l 'homme comme pour le cheval , ainsi qu 'une infect ion mortel le a f fectant plusieurs espèces d 'o iseaux domest iques et sauvages. Le f lav iv i rus causal , t ransmis par des moust iques, a récemment connu une nouvelle progress ion avec l 'appari t ion d'une grave épidémie à N e w York et dans la région. Celle-ci a entraîné plusieurs décès chez l 'homme ainsi que la mor t de chevaux, de plusieurs espèces d'oiseaux sauvages (notamment des corvidés) et d'un chat. L'auteur fa i t le point sur l'état actuel des connaissances ainsi que sur les récentes découver tes en matière d 'épidémiologie et d'épizoot iologie de l ' infect ion par le v i rus Wes t Ni le.

Mots-clés Amérique du Nord - Arbovirus - Encéphalite équine - Épidémiologie - Équidés -Flavivirus - Santé publique - Synthèses - Virus West Nile - Zoonoses.

Encefalitis causada por el virus West Nile N. Komar

Resumen

El v i rus Wes t Ni le, surgido en los últ imos años en regiones templadas de Europa y Nor teamér ica , const i tuye una notable amenaza en té rminos tan to de salud públ ica como de sanidad animal. Tanto en el hombre como en el cabal lo , la mani festac ión más grave de la infección es una encefal i t is de consecuenc ias


fa ta les. La in fecc ión también afecta a var ias especies de aves domést icas y s i lvestres, ocas ionando morta l idad entre estos animales. La rec iente apar ic ión de un brote de considerable gravedad en la c iudad de Nueva York y áreas c i rcundantes const i tuye un hecho inédito en la epizootiología de este f laviv i rus t ransmi t ido por mosqui tos. Dicho brote provocó casos morta les en seres humanos, cabal los, un gato y var ias especies de aves s i lvestres, per tenec ientes sobre todo a la fami l ia de los córv idos. El autor repasa los datos fundamenta les y sintetiza la evolución rec iente de la epidemiología y la epizootiología del v i rus Wes t Ni le.

Palabras clave Arbovirus - Encefalitis equina - Epidemiología - Equinos - Flavivirus - Norteamérica -Salud pública - Síntesis - Virus West Nile - Zoonosis.

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