West Nile Fever

CME learning objectives

• To learn about the epidemiology of West Nile virus
• To be able to recognize clinical manifestations of West Nile virus infection in humans
• To become familiar with the most effective measures for preventing infection with West Nile virus

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First in a series of articles on problem infections in primary care, coordinated by Larry J. Strausbaugh, MD, hospital epidemiologist and staff physician, Veterans Affairs Medical Center, Portland, Oregon, and professor of medicine, Oregon Health & Science University School of Medicine, Portland.

Preview: This summer and fall, primary care physicians may be seeing more cases of West Nile virus infection as circulation of the virus becomes more widespread across the United States. Although most cases are asymptomatic, the disease can cause fatal meningoencephalitis. Therefore, it is important to consider West Nile virus infection in differential diagnosis of certain illnesses. In this article, Dr Gelfand reviews the transmission cycle of the virus, appropriate clinical management, and the current strategies for disease prevention.
Gelfand MS. West Nile virus infection: What you need to know about this emerging threat. 2003;114(1):31-8

West Nile virus is a mosquito-borne flavivirus that is a neuropathogen in humans, horses, and birds (see section entitled "West Nile virus transmission cycle" at end of article) (1,2). Most infections are subclinical, but symptomatic infections can range in severity from an uncomplicated febrile illness (West Nile virus fever) to fatal meningoencephalitis (1). Severity of illness and mortality increase with age (1). West Nile virus is likely to persist in the Western Hemisphere as an endemic pathogen with periodic outbreaks, similar to another well-established arbovirus, St Louis encephalitis virus (1).

The purpose of this article is to familiarize practicing physicians with West Nile virus and to assist them in diagnosing and treating infections with this pathogen.

Epidemiologic factors

West Nile virus was first isolated in Uganda in 1937 and is indigenous to Africa, Asia, Europe, and Australia. Large epidemics of West Nile virus meningoencephalitis recently occurred in Russia, Israel, and Romania (3-5). The virus first appeared in the United States in 1999 with an outbreak of meningoencephalitis reported in New York City (6). The mode of introduction to North America is unknown. From 1999 to 2002, West Nile virus extended its range throughout most of the United States (figure 1) and has also been detected in Canada (7).

In 2002, the spread of West Nile virus in the United States resulted in the largest arboviral meningoencephalitis epidemic documented in the Western Hemisphere and the largest reported epidemic of West Nile virus encephalitis (7). As of December 20, 2002, a total of 3,389 cases of West Nile virus infection and 201 deaths were reported (7). Death occurred in 199 (9%) of 2,354 patients with West Nile virus encephalitis, compared with 2 (0.3%) of 704 patients with West Nile fever. The median age of all decedents was 78 years.

Mosquito-borne transmission of West Nile virus is the predominant mode. Animal-to-human transmission has not been documented. Although human-to-human transmission is rare, it has been reported to occur via transplacental passage to a fetus, breast-feeding, organ transplantation, and transfusion of blood and blood products (8-10). Several laboratory-acquired cases (percutaneous or inhalational mechanism) have also been reported (11). In the United States, most human infections occur between June and November (1) (figure 2). Persistence of West Nile virus between periods of ongoing transmission has been attributed to overwintering in hibernating adult Culex species mosquitoes, transovarial transmission in mosquitoes, and migration of viremic birds to temperate zones (1).

All ages and both sexes are equally susceptible to West Nile virus infection, but the incidence of encephalitis and mortality increase with age (1,2,4). Length of time spent outdoors, failure to apply mosquito repellent, and the presence of mosquitoes in the home are risk factors for West Nile virus infection in urban populations (1,2,12). Prevalence of background immunity and age structure of the population determine the severity of clinical syndromes. During the New York City outbreak, meningoencephalitis was estimated to occur at a rate of 1 case in 140 West Nile virus infections (12). The proportion is likely to be higher in populations that are predominantly elderly. In New York City, the estimated ratio of infection among persons older than 65 years was 1:50 (1,12). However, cases of West Nile virus fever may be more common than appreciated, because few patients who have a nonspecific fever without neurologic features are tested for West Nile virus infection and surveillance efforts are aimed at meningoencephalitis cases.

Clinical features

Most West Nile virus infections are asymptomatic. Fever develops in 20% of infected patients, and only half of them seek medical care for the illness (1,2). The incubation period of symptomatic infections is 2 to 14 days. Clinical manifestations of West Nile virus infection are nonspecific and cannot be distinguished from other infectious illnesses on clinical examination.

Uncomplicated West Nile virus infection is characterized by fever of sudden onset (usually >39°C [102.2°F]), headache, and myalgias, often with nausea and vomiting (table 1). The acute illness lasts 3 to 6 days, but prolonged malaise is common (1,2). A nonspecific maculopapular or roseolar rash and generalized lymphadenopathy often were reported in earlier epidemics but have been seen less frequently in US cases of the disease (13). West Nile virus meningitis is a typical aseptic viral meningitis with low mortality and accounts for 20% to 30% of the central nervous system (CNS) infections associated with the virus (1,2,13).

Two thirds of cases with CNS involvement manifest as encephalitis. West Nile virus encephalitis presents with fever, headache, mental status changes, muscle weakness, nausea, and vomiting. Seizures are uncommon. The disease progresses to coma in about 15% of patients (1,2,13). Depressed deep tendon reflexes, diffuse muscle weakness, flaccid paralysis, and respiratory failure may occur (1,2,13). Muscle weakness is a prominent part of the clinical presentation of West Nile virus encephalitis. In the New York City outbreak, paresis was documented in 50% of hospitalized patients, and 10% had flaccid paralysis (1,14). The latter was associated with the absence of deep tendon reflexes and a high incidence of respiratory failure (14). Results of electromyographic studies were usually consistent with those of a motor axonal polyneuropathy with a sparing of sensory fibers (unlike Guillain-Barré syndrome) (14).

Movement disorders, including tremors (often accentuated with movement), myoclonus, and parkinsonian features of cogwheel rigidity, hypokinesia, and postural instability, were seen during an investigation of the West Nile virus outbreak in Louisiana in the summer of 2002 (15). In that outbreak, several patients with encephalitis had hyperreflexia and bulbar findings, including cranial nerve abnormalities, dysphagia, and altered oculocephalic reflexes (15). Rare manifestations of West Nile virus infection include myocarditis, pancreatitis, fulminant hepatitis, and optic neuritis (1).

Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain do not show specific localization (unlike in herpes simplex virus encephalitis), even though West Nile virus encephalitis has a pathologic predilection for the brainstem, as demonstrated on postmortem examinations (1,2,13,14). In one third of affected patients, MRI showed diffuse meningeal enhancement (1,14).In the elderly population, preexisting focal abnormalities and atrophy (unrelated to West Nile virus infection) are common on CT and MRI (1-3). Findings in cerebrospinal fluid (CSF) include mild lymphocytic pleocytosis (30-100/microliter; range, 0-1,800/microliter), elevated protein concentration (80-105 mg/dL), and normal glucose level. Results of peripheral blood cell counts and chemistry analysis are not characteristically abnormal, but hyponatremia, anemia, and lymphocytopenia have been reported in some patients (1,2,13,14).

Acute, painless flaccid paralysis in the absence of meningitis or encephalitis is another recently described presentation of West Nile virus infection (16). Onset of paralysis during acute infection (within 48 hours of onset), asymmetrical weakness, absence of sensory changes, pleocytosis, and electromyographic changes suggestive of anterior horn cells or axonal injury, or both, are characteristic and help to distinguish this presentation of West Nile virus infection from Guillain-Barré syndrome and to avoid intravenous immunoglobulin therapy (16). Three principal neurologic syndromes of West Nile virus infection are described in table 2.

Overall case fatality rates in recent epidemics of West Nile virus encephalitis ranged from 4% to 14%; higher rates were noted in elderly patients, and virtually all deaths occurred in hospitalized patients (figure 3). In the outbreak in Israel (4), for example, the overall mortality rate in patients aged 70 years or older was 29%, and 32 of 33 deaths occurred in patients older than 68 years. In a recent outbreak in Volgograd, Russia (3), 40 (48%) of 84 patients with encephalitis died. Self-reports of residual physical, functional, and cognitive abnormalities are common in survivors of West Nile virus encephalitis (13).

Laboratory diagnosis

West Nile virus infection should be included in differential diagnosis of unexplained febrile illnesses seen in the summer and fall, aseptic meningitis, and encephalitis.

Serologic testing is the mainstay of diagnosis of West Nile virus infection. Antibody-capture enzyme-linked immunosorbent assay of immunoglobulin M (IgM) in serum or CSF is presumptive evidence of a recent infection, and its sensitivity is nearly 100% after the eighth day of illness (1,2,13). This assay is commercially available, and results often can be obtained in 24 to 48 hours. Confirmatory testing with a plaque-reduction neutralization assay eliminates the problem of cross-reactivity with other flaviviruses, especially St Louis encephalitis virus.

Serum IgM antibody can persist for up to 16 months in some patients with West Nile virus encephalitis, and the persistence may occasionally lead to diagnostic confusion in patients with an acute febrile illness or a neurologic illness, or both. No such prolonged IgM persistence should occur in the CSF (1,2,13).

The detection of a greater than fourfold rise in West Nile virus-specific neutralizing antibody serum titer between the acute and convalescent phases of illness is diagnostic after confirmation with a plaque-reduction neutralization assay (1). Isolation of the virus from CSF, serum, or tissues can be attempted but is not usually successful. Molecular amplification assays (eg, polymerase chain reaction) have been studied in West Nile virus encephalitis and have shown only moderate sensitivity in acute illness, possibly because of low magnitude and the transient nature of viremia. Polymerase chain reaction was useful in diagnosing West Nile virus encephalitis in an immunocompromised patient with lymphoma in whom serologic assays were persistently negative (17). In fatal cases of encephalitis, the virus can be readily demonstrated in the brain tissue by immunohistochemistry studies, molecular amplification techniques, and occasionally by culture (1,2).

Clinical management

There is no specific antiviral treatment for West Nile virus infection. Patients with West Nile virus encephalitis should be hospitalized to rule out a treatable illness, such as herpes simplex virus encephalitis, an early bacterial meningoencephalitis, or Guillain-Barré syndrome. The mortality of West Nile virus encephalitis is usually secondary to progressive neuronal dysfunction, cerebral edema, and respiratory failure (1,2). The efficacy and safety of corticosteroids in managing cerebral edema of West Nile virus encephalitis are unknown. Supportive care (ie, respiratory support, treatment of seizures, and prevention and treatment of bacterial superinfection, venous thromboembolism, gastric ulcerations, and decubitus ulcers) is the basis of clinical management.

Ribavirin and interferon-alfa have shown limited efficacy against West Nile virus in animal models and in vitro studies (1,2). In a retrospective analysis of ribavirin therapy in Israel, no effect on mortality was observed (1). The results of a therapeutic trial of interferon alfa-2b conducted during the 2002 epidemic in the United States are still unknown (18). Use of any specific antiviral therapy early enough in the clinical course to be effective would require a rapid and specific diagnosis.

Prevention

Possible and documented cases of West Nile virus infection should be promptly reported to the local health department. No human vaccine for West Nile virus is available, and because of the low incidence of West Nile virus disease in most areas, a vaccine is unlikely to be cost-effective. The only way to reduce infection rates, morbidity, and mortality due to West Nile virus is to reduce contact between humans and potentially infected mosquitoes (1,2). Avoiding activity in areas where infected mosquitoes may be present, eliminating peridomestic breeding sites (eg, standing water, clogged rain gutters), and maintaining window and door screens are important.

Arboviral surveillance and vector mosquito control programs are essential. States should maintain surveillance programs for avian, mosquito, equine, and human infection and implement vector control activities. Control of larval breeding sites (ie, through source reduction, water management, and chemical and biologic control methods) is essential. Chemical spraying to control adult vector mosquitoes should be reserved for emergency application after West Nile virus activity has been documented in the community.

Patients should be educated about how to avoid or decrease the risk of being bitten by mosquitoes. Outdoor activity during the peak mosquito-biting period (dusk to dawn) should be limited, and long-sleeved shirts and long trousers should be worn. Repellents containing deet as the active ingredient are recommended for application to clothing and exposed skin, whereas repellents containing permethrin can be applied to clothing (19). Deet should not be used on children younger than 2 years or on the hands of older children who may rub their eyes or mouth (2).

Summary

The most important aspects to remember about West Nile virus infection are summed up in the following points:

• West Nile virus is transmitted by bites from infected Culex species mosquitoes.
• Most infections do not result in serious illness.
• Encephalitis and serious morbidity and mortality are more likely to occur in elderly persons than in any other age-group.
• No effective antiviral treatment is available.
• Avoiding contact with mosquitoes is the key preventive measure.