Virology, pathology, and clinical manifestations of West Nile Virus disease

Emerging Infectious Diseases, August, 2005 by Edward B. Hayes, James J. Sejvar, Sherif R. Zaki, Robert S. Lanciotti, Amy V. Bode, Grant L. Campbell

West Nile virus (WNV) causes epidemics of febrile illness, meningitis, encephalitis, and flaccid paralysis. Since it was first detected in New York City in 1999, and through 2004, >16,000 WNV disease cases have been reported in the United States. Over the past 5 years, research on WNV disease has expanded rapidly. This review highlights new information regarding the virology, clinical manifestations, and pathology of WNV disease, which will provide a new platform for further research into diagnosis, treatment, and possible prevention of WNV through vaccination.

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The impressive spread of West Nile virus (WNV) in the Western Hemisphere after its detection in 1999 during an outbreak of encephalitis in New York City has caused >16,000 human disease cases and >660 deaths in North America. Research on the signs, symptoms, and pathogenesis of WNV disease has greatly intensified in the past 5 years. The number of recognized cases of flaccid paralysis due to WNV infection has increased substantially, and research into prognosis and possible therapy has expanded. Genetic variation of the virus has been further characterized and continues to be explored. The pathology and pathogenesis of WNV disease have been described more completely than ever before. Several strategies are being pursued to develop effective vaccines to prevent WNV disease. This article highlights new information about the virology, clinical manifestations, laboratory diagnosis, pathology, and prognosis of WNV illness in humans. The expanded knowledge about WNV disease provides a new platform for future development of diagnostic tests, therapy, and vaccine development.

Characteristics of West Nile Virus

WNV is an arbovirus in the family Flaviridae. Its spherical, enveloped capsid has a diameter of [approximately equal to] 50 nm and contains single-stranded RNA that encodes the capsid (C), envelope (E), and premembrane (prM) proteins, as well as 7 nonstructural proteins that likely contribute to viral replication. The virus has 2 genetic lineages: lineage 1 strains are found in North America, Europe, Africa, Asia, and Australia; lineage 2 strains have been isolated only in subSaharan Africa and Madagascar. Lineage 1 strains have been further divided into 4 clades: Kunjin, Indian, A, and B (which includes an Indian isolate) (1). The isolates in clade B, which includes strains from the United States, are all virulent in mice; lineage 2 and other clades in lineage l comprise both virulent and attenuated strains (l). Differences in pathogenicity may be related to nucleotides that code for specific regions in the prM, E, or nonstructural proteins of the virus (1,2).

WNV strains from the United States are closely related to strains from Israel, with 99.7% homology in nucleotide sequences, indicating that the strains in the United States almost certainly originated from the Middle East (3). The strain isolated in New York in 1999 is more virulent in American crows (Corvus brachyrynchos) than strains from Kenya and Australia (Kunjin virus, a subtype of WNV), and both the New York strain and the Kenyan strain experimentally killed house sparrows whereas the Australian strain did not (4).

Two genetic variants of the North American WNV strain were isolated in Texas in 2002; the major variant differed from the New York 1999 isolate by 0.18% of nucleotides, and the minor variant by 0.35% (1). The 2 variants differed from each other by 0.5% of nucleotides, and their neuroinvasiveness in mice was similar to that of the New York 1999 isolate. In 2003, attenuated WNV strains were found in birds in Texas and Mexico, providing the first evidence of phenotypic variation of WNV strains in the Western Hemisphere (2,5). The reduced neuroinvasiveness and smaller plaque size of the Texas strains may be due to mutations in nonstructural proteins that result in lower levels of viremia; the attenuated strain from Mexico had a mutation in the E protein (2,5).

Pathogenesis

WNV is thought to replicate at the site of inoculation and then spread to lymph nodes and the bloodstream (6). Viral penetration of the central nervous system appears to follow stimulation of toll-like receptors and increased levels of tumor necrosis factor-[alpha], which increases permeability of the blood-brain barrier (7). WNV directly infects neurons, particularly in deep nuclei and gray matter of the brain, brainstem, and spinal cord (8-10). Collateral destruction of bystander nerve cells may contribute to paralysis (11). Immune-mediated tissue damage may also contribute to pathologic changes in some cases (12). Genetic susceptibility for severe disease in mice has been postulated to involve a deficiency in production of 2'-5'-oligoadenylate synthetase, but this genetic susceptibility has not been elucidated in humans (10). Although most nonfatal WNV infections appear to be cleared by the host immune response, the virus may persist in some vertebrate hosts (10,13).

Clinical Manifestations

The clinical spectrum of symptomatic WNV infection in humans has been further defined during the North American epidemics. About 80% of human infections are apparently asymptomatic (14). Of those persons in whom symptoms develop, most have self-limited West Nile fever (WNF), characterized by the acute onset of fever, headache, fatigue, malaise, muscle pain, and weakness; gastrointestinal symptoms and a transient macular rash on the trunk and extremities are sometimes reported (15,16). A recent follow-up study of WNF patients who sought medical attention found that difficulty concentrating and neck pain or stiffness were also prominent symptoms, and that fatigue and muscle weakness frequently lasted for [approximately equal to] 1 month after onset (16). Of the 98 patients interviewed, 31% were hospitalized, 79% missed school or work because of their illness, and the median time before patients felt fully recovered was 60 days. These patients probably represent the most severe WNF, but even without neurologic manifestations, WNV infection clearly can cause a notable public health problem, Additional nonneurologic clinical manifestations that may rarely occur during WNV infection include hepatitis, pancreatitis, myocarditis, rhabdomyolysis, orchitis, and ocular manifestations (17-24). Chorioretinitis may be more common than previously thought; a study in Tunisia found that 69% of 29 patients hospitalized with WNV disease had chorioretinitis (24). Cardiac dysrhythmias have been observed in some North American patients (Centers for Disease Control and Prevention [CDC], unpub, data) (22).