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Table of Contents

Reviewed July 14, 2004

James Pile, MD

Department of General Internal
Medicine

Steven
Gordon, MD

Department of Infectious Disease

Print Chapter

Copyright 2003
The Cleveland Clinic Foundation

The West Nile virus (WNV) appeared unexpectedly in the Western Hemisphere in 1999, with an outbreak of encephalitis in the greater New York area. The geographic range of the virus spread progressively over the next 2 years (although with a limited number of severe human infections), and attracted considerable attention to WNV in both the medical and lay communities. For reasons not well understood, the incidence of West Nile infection increased exponentially in 2002, with the preponderance of cases occurring in areas that had seen little or no human disease previously. This chapter will review what is known about human WNV infection in late 2002, realizing that additional information will almost certainly emerge from analysis of this year's epidemic.

Definition

Prevalence/
Epidemiology

Pathogenesis

Signs and
Symptoms

Diagnosis

Therapy

Outcomes

Prevention

Conclusions

References

Infection with the West Nile virus was initially described in 1940, after isolation from the blood of a patient in Uganda with a mild febrile illness.¹ Over the following decades, the virus was established as the cause of a self-limited febrile syndrome, occurring year-round in tropical climates and during summer and early fall months in more temperate areas. The best-described disease outbreaks were reported from Israel, where military units sporadically experienced very high attack rates of symptomatic disease. "West Nile fever," as the illness became known, was reported to result in clinical attack rates in excess of 60% in some areas of Israel, and led to a 1974 epidemic in South Africa with many thousands of cases.^2,3 Notably, the reports of these clusters, involving numerous cases of disease, did not include patients with severe neurologic disease, and West Nile infection was thought to be a benign and rather transient phenomenon. Rare observations suggested that more serious neurologic disease could result from infection, but this was largely unappreciated until reports from Algeria and Romania in the mid-1990s linked the virus to severe neurologic illness.^4,5 The New York outbreak of 1999, consequently, was surprising not so much for the severity of disease but rather for its appearance in a geographically novel location.

Virology
West Nile is a single-stranded RNA virus belonging to the flavivirus family. Closely related viruses, phylogenetically, include the agents of Japanese encephalitis, St Louis encephalitis, Murray Valley encephalitis, and Kunjin. The West Nile strain circulating in North America is molecularly indistinguishable from a strain isolated from an Israeli goose in 1998, identifying the likely source of the virus.⁶ How the virus arrived in the Western Hemisphere remains an enigma, however. Possibilities include a viremic person, an infected mosquito or bird arriving in New York by airplane from an endemic area, or a stray migratory bird. The epidemiology and molecular typing of the strain militate against an intentional release or bioterrorism event.

Transmission Cycle
WNV is transmitted naturally in a mosquito-bird-mosquito cycle, with birds exhibiting a prolonged and high-level viremia that leads to persistence of circulating virus. A wide variety of birds have been found to be competent vectors. Crows and other corvids are not necessarily the most effective hosts, despite notoriety derived from large die-offs in the United States over the past several years. Bird-to-bird transmission has been demonstrated experimentally, but does not appear to play an important role in nature.

Many mosquito species likewise appear to be able to serve as competent vectors of infection, although members of the Culex genus seem primarily responsible for maintenance of circulating virus. C pipiens and C restuans are thought to represent the major vector species in most of the United States, whereas C quinquefasciatus plays an important role in the southern portion of this country. Although these culicine species maintain the virus naturally, the mosquito species responsible for most human infection is less clear. None of the aforementioned species regularly bites humans, leading to speculation that "bridge" species (ie, those with an affinity for blood meals from birds and humans) are necessary for widespread human disease. Aedes vexans and others have been suggested as likely candidates, but this has yet to be substantiated.

Although a variety of mammalian species may be symptomatically infected, they appear to play little if any role in maintenance of WNV. Viremia in humans and other mammals tends to be of low intensity and brief, resulting in "dead end" host status (Figure 1).

North American Epidemiology
In 1999, the presumed year of West Nile introduction, the virus was confined to several states in the mid-Atlantic region, and primarily involved the New York City area. The geographical range of the virus has since increased rapidly, and now includes 44 states, the District of Columbia, and a number of Canadian provinces (Figure 2). The three states reporting the highest number of cases in 2002 were Illinois, Michigan, and Ohio. A total of 149 cases of human meningoencephalitis were identified from 1999 to 2001, but at the time of this writing, nearly 4,000 cases and 200 deaths had been reported in 2002. Although drier-than-usual weather in much of the United States during the summer of 2002 has been suggested as a possible explanation for this dramatic increase, a definitive cause has yet to be elucidated.

Naturally occurring infection probably takes place after an incubation period lasting from 2 to 14 days, although some uncertainty surrounds the exact range. Likewise, the probability of viral transmission after the bite of an infected mosquito is unknown. After inoculation, virus may be disseminated to a variety of sites. Factors that lead to symptomatic infection of the central nervous system (CNS) are still poorly understood, although advanced age is clearly the major risk factor for encephalitis. Those over the age of 70 are at the greatest risk not only for CNS involvement but also for adverse outcomes, including death. Limited data suggest that diabetic and other immunosuppressed individuals may be at increased risk for neurologic disease and death as well.^7,8 The advent of multiple epidemics of neurologic disease during the last decade suggests a shift in the neurotropism of West Nile virus, although this remains speculative.

Results of postmortem examinations of four patients dying from West Nile meningoencephalitis were published recently.⁹ The pathologic findings demonstrate perivascular and leptomeningeal chronic inflammation, microglial nodules, and neuronophagia predominantly involving the temporal lobes and brainstem (Figure 3). These findings were also found in the spinal cord of a patient with poliolike paralysis (Kelley TW et al, in press).

Perhaps not surprisingly in view of the number of individuals infected in the United States in 2002, transmission of WNV via both organ transplantation and blood transfusion has recently been documented.^10,11 At least 33 cases of WNV infection in recipients of blood transfusions are under investigation by the Centers for Disease Control and Prevention (CDC). In addition, of four individuals receiving organs from a donor with unrecognized West Nile infection, three developed encephalitis, lending further support to immunosuppression as a possible risk factor for severe neurologic disease. Measures to safeguard the blood supply from WNV contamination are under discussion at the time of this writing.

West Nile Fever
Early reports of symptomatic West Nile infection, from Israel in particular, emphasized the benign, self-limited nature of illness. A classic report detailing disease in the Israeli military in the early 1950s described manifestations in a cohort of 70 young men. Fever was a prerequisite for diagnosis. Lymphadenopathy was reported in 90% of patients, headache in 80%, conjunctival injection in 60%, and rash in 50%. A significant number of patients manifested with ocular pain, severe myalgias, and gastrointestinal complaints. Splenomegaly was noted in 20%. Subsequent reports generally confirmed these manifestations, although substantial variability was noted between series.¹⁰ Recent reports of West Nile infection from New York in 1999 and Israel in 2000 have shown both similarities and differences when compared with older case series. Fever continues to be almost universally present, with most patients also demonstrating headache, malaise, myalgias, and arthralgias. Rash, on the other hand, has been described in only 20% of patients in the recent studies, with lymphadenopathy very unusual.⁷,¹¹ The focus of recent studies on patients with severe neurologic disease rather than on those with classic "West Nile fever," may conceivably have skewed findings somewhat. Serosurvey data from the New York outbreak of 1999 suggest that approximately 20% of individuals infected with WNV will develop a febrile illness.¹²

Neurologic Disease
Of individuals infected with West Nile infection, roughly one in 150, or 1 in 30 of those with symptomatic infection, will develop significant CNS disease, defined as encephalitis, meningitis, or a combination of these (meningoencephalitis). In the 1999 New York cluster of cases, 63% of patients presented with encephalitis, 29% with meningitis alone, and 8% with fever and headache without altered mental status or cerebrospinal fluid (CSF) abnormalities.⁷ A published review¹¹ of 233 Israeli patients hospitalized in 2000 revealed encephalitis in 58%, meningitis in 16%, and febrile illness only in 24%. Median ages in the two studies were 71 and 65, respectively.

Review of three large, recent studies^5,7,11 of WNV meningoencephalitis shows fever to be nearly universally present, ranging from 90% to 98%. Headache was noted by the majority of patients in these reports, gastrointestinal complaints were common, and meningismus ranged from 19% to 57%. Deterioration to coma was seen in 13% of patients in Romania⁵ and 17% of those in Israel.¹¹ The percentage of comatose patients was not specifically described in the New York experience.⁷

Weakness, while a concomitant of all recent outbreaks of severe WNV disease, has been best described in the United States. In the 1999 New York experience, 27% of individuals exhibited objective motor weakness, with 10% developing diffuse flaccid paralysis, in conjunction with an axonal polyneuropathy on electromyogram testing.⁷ Further information regarding acute flaccid paralysis has begun to emerge from the 2002 WNV epidemic, with weakness appearing to result from a poliomyelitis-like syndrome involving anterior horn cells and motor axons.¹³ The possibility of WNV meningoencephalitis should be entertained in the setting of suspected Guillain-Barré syndrome, as management of the two entities is markedly divergent.

Laboratory/Radiologic Studies
CSF will be abnormal in almost all patients with WNV meningitis or encephalitis. A lymphocytic pleocytosis has been noted in most cases, with CSF white blood cell count less than 500 in most cases but occasionally as high as several thousand. In the Cleveland Clinic experience, a substantial minority of 23 individuals hospitalized with meningoencephalitis presented with a predominance of neutrophils rather than lymphocytes. CSF protein is variably elevated, and glucose is virtually always normal. Total white blood cell count is typically either normal or modestly elevated, although a smaller percentage of patients demonstrate leukopenia. Lymphocytopenia is often noted. Notably, we have seen Mollaret-like cells (large monocytic-like cells with cerebriform nuclei) in the CSF of three of four patients with CSF available for cytologic examination.

Computed tomographic scans of the brain have not proved helpful in the diagnosis of WNV meningoencephalitis. Magnetic resonance imaging of the brain and spinal cord has been reported to show leptomeningeal and/or periventricular enhancement in one-third of patients,⁷ which has been approximated in our experience as well (Figures 4 and 5).

Differential Diagnosis
WNV encephalitis in many cases will not be distinguishable from other arthropod-borne (arboviral) encephalitides, although the presence of profound weakness should suggest the etiology, as should presentation during a period of known WNV activity (Table 1). Other encephalitic etiologies to be considered include herpes simplex virus, enteroviruses, rabies, rickettsial disease, Epstein-Barr virus, cytomegalovirus, and lymphocytic choriomeningitis virus (LCMV). Noninfectious entities including sarcoidosis, systemic lupus erythematosus, and CNS vasculitis may also need to be considered.

The differential diagnosis of WNV meningitis is that of aseptic meningitis, and most importantly includes the enteroviruses along with herpes simplex virus 2, human immunodeficiciency virus, LCMV, and drugs including sulfonamides and nonsteroidal anti-inflammatory agents.

Initial laboratory testing in cases of suspected WNV infection should consist of IgM antibody-capture enzyme immunoassay (EIA) of CSF, serum, or preferably both. This may be expected to be positive by the end of the first week of illness in the vast majority of cases, and in many patients has been found in CSF considerably earlier. Limitations of the serum IgM antibody-capture EIA include cross-reactivity with other flaviviral infections (particularly St Louis encephalitis), persistence for 6 months or more in many instances after infection, and false positivity after vaccination against Japanese encephalitis or yellow fever.¹⁴ Testing CSF for IgM antibody-capture overcomes all but the first of these confounders.

The CDC has outlined criteria for the definite diagnosis of West Nile infection in the appropriate clinical setting. These include fourfold or greater change in serum antibody by plaque reduction neutralization testing (PRNT), viral isolation or identification by molecular techniques, positive CSF IgM-capture antibody, or a positive serum IgM-capture EIA in conjunction with demonstration of IgG antibody by PRNT.¹⁵

Polymerase chain reaction (PCR) techniques employed on CSF may be of use in diagnosing WNV infection, although sensitivity thus far has been disappointing because the virus appears to be highly cell-associated. In the 1999 New York outbreak, 57% of CSF samples tested were positive for WNV by PCR, with only 14% of serum samples PCR-positive.⁷ PCR appears to be much more useful in the setting of brain and other tissues.

Treatment of WNV infection is primarily supportive. Measures such as analgesia and antipyretics may be useful in milder cases of illness. More severely ill patients, primarily those with encephalitis, will typically be hospitalized. Careful fluid and electrolyte management, nutritional support, skin care, and physical and occupational therapy are important. Mechanical ventilation may be required in those with severe illness.

A variety of specific therapeutic measures are under current consideration for the treatment of severe WNV disease. Ribavirin and interferon alfa-2b have demonstrated anti-WNV activity in vitro, but have not been studied in human disease in a controlled fashion.¹⁶ Ribavirin was employed in a subset of Israeli patients in 2000 without clear-cut benefit.¹¹ A randomized trial involving both agents is in the planning phase. Anecdotal evidence has suggested a possible role for Israeli intravenous immunoglobulin, containing high titers of antibodies to WNV, in the treatment of severe neurologic disease.¹⁷ A randomized, prospective treatment trial using high-titer anti-WNV intravenous immunoglobulin is being considered by the National Institutes of Health.

Uncomplicated West Nile fever has a self-limited course and a reliably favorable prognosis, with resolution of all symptoms generally occurring in 1 week or less. The outcome of neurologic disease is more varied. Meningitis patients appear to have an excellent outlook, with no documented long-term sequelae. Encephalitis, in contrast, has significant associated morbidity and mortality. Mortality in several of the already mentioned large outbreaks has ranged from 4.3% (Romania, 1996) to 12% (New York, 1999) to 8.4% (Israel, 2000).^5,7,18 At the time of this writing, mortality in the 2002 US outbreak is 5.4%.¹⁹

Advanced age has been the most powerful predictor not only of the development of CNS disease but also of mortality in each large series of WNV encephalitis. Nash et al⁷ reported the relative risk of death for those over the age of 75 to be 8.5 while estimating the risk of encephalitis to be 20-fold higher for those over age 50 compared with younger individuals. Chowers et al¹¹ found the mortality rate in those over age 70 to be almost 30%. Nash et al also noted a markedly higher mortality rate in patients with encephalitis and objective weakness.

Limited data suggest that survivors of WNV encephalitis experience a prolonged convalescence, with a variety of lingering difficulties. Follow-up of 1999 New York patients has documented high rates of ongoing fatigue, cognitive deficits, depression, and difficulty with ambulation.¹⁴

Optimal prevention of WNV infection requires a combination of mosquito control efforts and personal protective measures. Guidelines for WNV prevention and control have been published by the CDC, and are available online. The CDC recommendations stress the importance of integrated mosquito control programs at the local level. Mosquito control efforts are most effective when successful in achieving source reduction, including elimination of domestic breeding sites such as clogged gutters, discarded tires, open containers that collect rainwater, stagnant water in bird baths, and so forth. Public education is of obvious importance in this regard. The use of larvicides, or biological and chemical measures designed to reduce the numbers of larval mosquitoes, is also highly effective when properly employed. The focused nature of larviciding is also attractive, since smaller quantities of control agents can be utilized over limited areas. Adulticiding, or the use of ultra-low-volume aerosols to control adult mosquito populations, is in general the least effective strategy and needs to involve large areas. Typically, either organophosphate agents such as malathion and naled, or permethrins/pyrethroids are used. Although the safety profile of both classes of insecticides appears to be quite good, whether and when to employ adulticides has been the subject of much controversy since the initial US outbreak in 1999.

Personal protective measures, including wearing long sleeves and pants when outside after dusk, as well as use of a mosquito repellent containing N,N-diethyl-3-methylbenzamide (DEET) as the active ingredient, seem prudent in an attempt to minimize infection. Despite sporadic unfavorable media attention, DEET-containing repellents have proven to be extremely safe when used properly. Products for adult use should be limited to a DEET concentration of 30% to 35% or less and, per recommendations of the American Academy of Pediatrics, those preparations used on children should contain 10% DEET or less.²⁰ Although Culex mosquitoes bite only from dusk until dawn, the uncertainty over the role of "bridge" species makes the exact time of day individuals are at greatest risk somewhat unclear.

An experimental equine vaccine has been developed and appears effective, but no vaccine is currently available for human use. Efforts are under way in this regard, although neither the public interest in such a vaccine nor its cost effectiveness is clear.

With WNV now established over almost the entire continental United States and much of Canada, and in light of the dramatic rise in the incidence of human infection in 2002, the long-term public health ramifications of the virus are uncertain. The 2002 epidemic has been frequently compared to the outbreak of St Louis encephalitis in 1975, which has not been seen on a similar scale since. This has led to hope that establishment of background avian immunity to WNV in this country, along with other factors yet to be identified, will result in much lower rates of human infection in coming years. We believe that the incidence of human cases in the near future is likely to be substantially less than in 2002, but this remains to be seen. In the interim, mosquito control efforts will remain important, and development of an effective therapy for WNV meningoencephalitis is desirable.

Return to Medicine Index

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