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West Nile encephalitisVaccination News Home Page subscribe Vaccination NewsLetter http://bmj.com/cgi/content/full/326/7394/865 BMJ 2003;326:865-869 ( 19 April ) Clinical reviewWest Nile encephalitisTom Solomon a Departments of Neurological Science and Medical Microbiology, University of Liverpool, Liverpool L9 7LJ, b Universiti Malaysia Sarawak, 94300 Kota Samarahan, Sarawak, Malaysia, c WHO Collaborating Center for Tropical Diseases, Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0609, USA, d Department of Neurological Science, University of Liverpool, Malawi-Liverpool-Wellcome Trust Programme for Tropical Medicine Research Correspondence to: Tom Solomon tsolomon@liv.ac.uk Although West Nile encephalitis is yet to spread to the United Kingdom, it is becoming more prevalent in the rest of the world. This article reviews the recent outbreaks and examines the current methods of diagnosis, treatment, and prevention In the summer of 1999, crows dropping from the New York sky, sick birds at the Bronx zoo, and an unusual cluster of cases of human encephalitis heralded the arrival of West Nile virus in North America.1 Although there were only 62 cases and seven deaths in 1999, the virus has since moved across the continent, and during 2002 there were more than 3500 cases and 200 deaths (see fig A on bmj.com). West Nile virus also occurs in Africa, parts of Asia, and southern Europe, with recent outbreaks in Romania, Russia, and Israel (fig 1).2-4 Unpublished evidence is reported to show that birds in the British Isles may also have antibody to the virus.5 The recent outbreaks of West Nile virus have drawn attention to the devastating potential of mosquito-borne neurogenic flaviviruses to spread (see box 1 for details).6
We reviewed the epidemiology and clinical features of infection with West
Nile virus, highlighting the many unanswered questions about how and
why such viruses spread and focusing on how to recognise, diagnose,
and treat patients with the infection.
We examined new information from recent outbreaks in America, Israel, and Southern Europe cited on PubMed and the internet to 11 December 2002. We also examined literature on West Nile virus from before 1966.
In 1937 British virologists first isolated West Nile virus from the blood of a febrile woman in the West Nile region of northern Uganda. It was soon shown to be transmitted between vertebrate hosts (especially birds) by mosquitoes, thus conforming to the ecological description "arthropod-borne virus" or arbovirus. Although not associated with neurological disease at that time, it was shown by serological cross reactivity to be closely related to two recently identified neurotropic viruses: Japanese encephalitis virus and St Louis encephalitis virus. Sporadic cases and larger outbreaks of febrile disease (West Nile fever) were reported in Africa, the Middle East, and Asia (table).11 Although meningeal irritation was noted, the first cases of encephalitis due to West Nile virus were, ironically, in New York in the early 1950s when the virus was given as an experimental (and unsuccessful) treatment for advanced cancer. The first naturally occurring cases of West Nile encephalitis were in the elderly residents of a nursing home in Israel.12 Outbreaks of equine and human meningoencephalitis occurred in southern France during the 1960s, and a subtype of West Nile virus (Kunjin virus) was isolated in Australasia. Since the 1990s the clinical epidemiology of West Nile virus seems to have changed, with increasing frequency and severity of outbreaks, including urban disease (table). 2-4 13
The virus is a member of the Japanese encephalitis serogroup of the genus Flavivirus, family Flaviviridae. The flaviviruses are thought to have evolved from a common ancestor as recently as 10 000 years ago and are rapidly evolving to fill new ecological niches.14 Like other flaviviruses, West Nile virus is a small, single stranded, positive sense RNA virus comprising about 11 000 nucleotides wrapped in a nucleocapsid and surrounded by a lipid membrane. An envelope glycoprotein on the surface is thought to be responsible for mediating viral entry into cells, tissue tropism, and host range. Molecular phylogenetic studies have shown that isolates of the virus can be
divided into two lineages. Linage II strains have mostly been found
in Africa, whereas lineage I strains are more widely distributed and
have been responsible for all the recent large outbreaks. This has
led to the suggestion that they may be more virulent, though
neuroinvasive strains have been shown in both lineages in animal
models.15
In nature West Nile virus is transmitted between birds by mosquitoes. Recent studies in the United States have found infection in 146 species of bird and 29 species of mosquito. Members of the order Passeriformes (jays, blackbirds, finches, warblers, sparrows, crows) seem to be important in maintaining the virus in nature (because of their high viraemias). Members of the Corvidae family (crows, blue jays) are particularly susceptible. Because of their low and brief viraemias, humans and horses do not normally transmit the virus to biting mosquitoes and are thus considered dead end hosts. Of the many mosquito species from which West Nile virus has been isolated, Culex species, particularly C pipiens, seem to be important in the enzootic cycle, though different species may act as "bridging vectors," transmitting the virus to humans (fig 2).
How the virus is introduced to new areas is not completely understood.
Migratory birds are thought to be important for the movement of the
virus from Africa into southern Europe. They may have been involved
in the virus's introduction into North America, though imported
exotic birds, a viraemic human, or inadvertently transported
mosquitoes seem more likely.16 Evidence from
studies in molecular genetics suggests there was a single
introduction into the United States of a strain closely related to
one isolated from a goose in Israel.17
A complex interplay of viral, avian, mosquito, human, and climatic
factors may contribute to the large outbreaks that have characterised
the disease in recent years. During the 2002 outbreak in the United
States it became clear that transmission can also occur via
transplanted organs, infected blood products, and possibly breast
milk.18
Most human infections with West Nile virus are asymptomatic. Epidemiological
surveys after the 1999 outbreak in New York showed that about one in
five people infected with the virus develops West Nile fever, and
only about one in 150 develops central nervous system disease.13 These are similar to the rates seen in the
outbreak in Romania in 19973 but are much
higher than those reported in Egypt and South Africa.
11 19 In New York, Romania,
and Israel the risk of febrile disease and neurological disease
increased with age, which may in part explain the differences
compared with parts of Africa. In Egypt most people are infected
during childhood, and neurological disease is rare.19
But in South Africa a large outbreak affected an estimated 18 000
people of all ages, yet only one case of encephalitis was reported.11
After an incubation period, which is typically 2-6 days but may extend to 14 days, patients with West Nile fever develop a sudden onset of an acute non-specific flu-like illness, characterised by high fever with chills, malaise, headache, backache, arthralgia, myalgia, and retro-orbital pain.20 Other non-specific features include anorexia, nausea, vomiting, diarrhoea, cough, and sore throat. In epidemics fever, a flushed face, conjunctival injection, and generalised lymphadenopathy were common. A maculopapula or pale roseolar rash was reported in about half the patients and was more common in children. In one outbreak, a fifth of patients had hepatomegaly, and 10% had splenomegaly.21 Myocarditis, pancreatitis, and hepatitis have also been described occasionally in severe infections. Figure 3 shows the clinical course of West Nile encephalitis. Patients with neurological disease typically have a febrile prodrome of 1-7 days, which may be biphasic, before they develop neurological symptoms. Although in most cases the prodrome is non-specific, 15-20% of patients may have features suggestive of West Nile fever, including eye pain, facial congestion, or a rash, though less than 5% have lymphadenopathy.22 Neurological manifestations of infection are similar to those of other
flaviviruses and depend on which part of the nervous system is
damaged Although convulsions occurred in about 30% of patients in the early
descriptions of West Nile encephalitis, they did not seem to be an
important feature in the outbreaks in Romania or New York.23 Other neurological features include cranial
neuropathies, optic neuritis, and ataxia. Stiffness, rigidity spasms,
and tremors associated with basal ganglia damage, similar to that
seen in Japanese encephalitis,25 have
also recently been recognised in West Nile encephalitis.26
Overall death rates for patients admitted to hospital during recent outbreaks ranged from 4-14% but were higher in older patients. 2 23 Other risk factors were the presence of profound weakness, deep coma, failure to produce IgM antibody, immunosuppressive treatment, and coexisting illness such as hypertension and diabetes mellitus. 23 27 Neurological sequelae are common among survivors. In one study, half of patients admitted to hospital still had a functional deficit at discharge,28 and only one third had recovered fully after one year.
About half of patients have peripheral leukocytosis, and 15% have leucopenia.
23 28 Hyponatraemia
sometimes occurs in those with encephalitis. Examination of the
cerebrospinal fluid typically shows a moderate lymphocytic
pleocytosis, though sometimes there may be no cells or neutrophils
may predominate. Protein concentrations are moderately increased, and
the glucose ratio is typically normal. Computed tomography of the
brain usually yields normal results. Initial magnetic resonance
imaging reports were of non-specific enhancement of the meninges or
periventricular areas. 23 29
More recent studies suggest that high signal intensities on T2
weighted images in the thalamus and other basal ganglia may be an
early indicator that a patient has West Nile encephalitis.26
Nerve conduction studies typically show the reduced motor axonal
amplitudes consistent with anterior horn cell damage, though there
may also be some slowing of conduction velocities and some changes
to sensory nerves.20
Infection with West Nile virus is confirmed by detecting the virus or
antibodies against the virus. Attempts at virus isolation from serum
or cerebrospinal fluid are usually unsuccessful because viraemias are
low and the virus has cleared by the time most patients present (fig
3). Newer techniques include detection of viral antigen
by enzyme linked immunosorbant assay (ELISA) or of viral nucleic
acid with reverse transcriptase polymerase chain reaction (PCR)
or kinetic quantitative ("real time") PCR. Real time PCR, the most
sensitive of these techniques, detects infection in only 55% of
patients.30 The accepted standard for rapidly
diagnosing infection is therefore the detection of IgM antibodies
against the virus in cerebrospinal fluid or serum, or both, by using
IgM ELISAs.31 Whereas antibody is
detected in the serum of those with West Nile fever, or even
asymptomatic infection, IgM in the cerebrospinal fluid is specific
for infection in the nervous system. About half of patients have
antibody on admission, and almost all have antibody by the seventh
day of admission. A few patients, particularly those who are
immunocompromised, may never make antibody, but such patients are
more likely to have virus detected by isolation or PCR.
There is no established antiviral treatment for West Nile encephalitis, or indeed any flavivirus infection. Various compounds have shown promise in vitro or in animal models. Interferon alpha has antiviral activity against West Nile virus and other flaviviruses in vitro,32 and open clinical trials in patients with St Louis encephalitis and Japanese encephalitis have produced promising results.33 This prompted many physicians to give the drug on a presumptive basis during the US outbreak in 2002. An open randomised trial of interferon versus placebo has been set up in the United States, though a double blind trial showed it was not effective in Japanese encephalitis.34 High dose ribavirin is also effective in vitro and was given to patients during the Israeli outbreak in 2000, thought with no obvious benefit.2 Immunoglobulin from patients previously infected with West Nile virus has also been given to a small number of patients with apparently promising results and is being considered for further clinical trials. Supportive treatment for patients with West Nile encephalitis includes attention to the complications of infection such as respiratory paralysis, pneumonia, pressure sores, and seizures, usually in an intensive care setting.
In areas where the virus is circulating, individuals are encouraged to
protect themselves from mosquito bites by wearing appropriate
clothing, applying mosquito repellent containing 10-30% DEET
(N,N-diethyl-3-methlybenzamide) to clothes and exposed skin, and
minimising time spent outdoors during the early morning and evening,
when Culex mosquitoes bite. This is particularly important for
those in "at risk" groups, such as elderly and immunocompromised
people. Measures to reduce the number of circulating mosquitoes
include removing mosquito breeding sites from around the house (for
example, collections of stagnant water), draining swampy areas, and
applying larvicide to potential breeding sites. During outbreaks,
public health authorities have sprayed with pyrethroid formulations
to kill adult mosquitoes. In the United States prompt reporting of
suspected cases is encouraged, and there has been intensive
surveillance of mosquitoes, dead birds, horses, and sentinel chickens
(chickens deliberately exposed and tested regularly for evidence of
infection). There is no human vaccine for West Nile virus yet, though
a crude formalin inactivated vaccine has been developed for horses,
and vaccines for humans are being developed. Ultimately these may be
used to protect humans at risk during epidemics, but because of its
natural bird-mosquito cycle, West Nile virus will never be
eradicated. Active surveillance and early mosquito control measures
may offer the best hope for disease control in the future.
We thank Alan Barrett and Jane Cardosa for helpful discussions. MJM is a Wellcome Trust Training Fellow and TS is a Wellcome Trust Career Development Fellow.
Contributors: TS was invited to put the article together and planned the initial draft. MHO focused on the Asian flaviviruses, Japanese encephalitis, and Murray Valley encephalitis. DWBC provided expertise on the spread of West Nile virus across America and the newer diagnostic methods. MM concentrated on the epidemiology of West Nile virus in Africa and the clinical features. All authors approved the final version. TS is the guarantor.
Competing interests: None declared.
(Accepted 6 March 2003) © 2003 BMJ
Publishing Group Ltd
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