Lack of Efficacy of High-Titered Immunoglobulin in Patients with West Nile Virus Central Nervous System Disease.

West Nile Virus (WNV) can result in clinically severe neurologic disease. There is no treatment for WNV infection, but administration of anti-WNV polyclonal human antibody has demonstrated efficacy in animal models. We compared Omr-IgG-am, an immunoglobulin product with high titers of anti-WNV antibody, with intravenous immunoglobulin (IVIG) and normal saline to assess safety and efficacy in patients with WNV neuroinvasive disease as part of a phase I/II, randomized, double-blind, multicenter study in North America. During 2003-2006, a total of 62 hospitalized patients were randomized to receive Omr-IgG-am, standard IVIG, or normal saline (3:1:1). The primary endpoint was medication safety. Secondary endpoints were morbidity and mortality, measured using 4 standardized assessments of cognitive and functional status. The death rate in the study population was 12.9%. No significant differences were found between groups receiving Omr-IgG-am compared with IVIG or saline for either the safety or efficacy endpoints.

West Nile virus neuroinvasive disease: neurological manifestations and prospective longitudinal outcomes.

BACKGROUND: West Nile Virus (WNV) is a mosquito-borne flavivirus that has caused ongoing seasonal epidemics in the United States since 1999. It is estimated that ≤1% of WNV-infected patients will develop neuroinvasive disease (West Nile encephalitis and/or myelitis) that can result in debilitating morbidities and long-term sequelae. It is essential to collect longitudinal information about the recovery process and to characterize predicative factors that may assist in therapeutic decision-making in the future. METHODS: We report a longitudinal study of the neurological outcomes (as measured by neurological examination, Glascow Coma Scale, and Modified Mini-Mental State Examination) for 55 subjects with WNV neuroinvasive disease (confirmed by positive CSF IgM) assessed on day 7, at discharge, and on days 14, 30, and 90. The neurological outcome measures were coma (presence and degree), global cognitive status, presence of cranial neuropathy, tremors and/or weakness. RESULTS: At initial clinical presentation 93% presented with a significant neurological deficit (49% with weakness, 35% with tremor, and 16% with cranial neuropathy). The number of patients with a cognitive deficit fell from 25 at initial evaluation to 9 at their last evaluation. Cranial neuropathy was present in 9 at onset and in only 4 patients at study conclusion. Of the 19 patients who had a tremor at enrollment, 11 continued to exhibit a tremor at follow-up. Seven patients died after initial enrollment in the study, with 5 of those having presented in a coma. The factors that predict either severity or long-term recovery of neurological function include age (older individuals were weaker at follow-up examination), gender (males recovered better from coma), and presentation in a coma with cranial nerve deficits (had a poorer recovery particularly with regard to cognition). CONCLUSIONS: This study represents one of the largest clinical investigations providing prospectively-acquired neurological outcomes data among American patients with WNV central nervous system disease. The findings show that the factors that influence prognosis from the initial presentation include age, gender, and specific neurological deficits at onset. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00138463 and NCT00069316.

West Nile virus: pathogenesis and therapeutic options.

West Nile virus, a member of the family Flaviviridae, has spread throughout the United States. With more than 9000 cases and 200 deaths in 2003, West Nile virus has become the most common cause of viral encephalitis in several states. West Nile virus encephalitis is a zoonosis. The life cycle of the virus includes mainly birds as hosts and mosquitoes as vectors. Humans are accidental hosts, insufficient to support the life cycle of the virus because of low-grade, transient viremia. However, human-tohuman transmission through blood, organ transplantation, and lactation has been documented. The frequency of severe neurologic disease in the current epidemic suggests a more neurovirulent strain of virus than the one classically associated with West Nile fever. Several neurologic manifestations have been described, but the most characteristic presentation is encephalitis with weakness. Magnetic resonance imaging scans may be normal initially, but a characteristic pattern of involvement of deep gray matter nuclei can be recognized. Although results of polymerase chain reaction may be positive in the cerebrospinal fluid early in the course of the disease, diagnosis is based on serologic tests. Possible cross-reactivity with other members of the genus flavivirus mandates caution when serologic testing results are interpreted. Thus far, no therapeutic intervention has shown consistent clinical efficacy in West Nile virus disease. Several approaches, including interferon-alpha2b and immunoglobulin with high titer against West Nile virus, offer promise based on animal models and limited clinical experience. New drugs with in vitro activity are being investigated, and a vaccine is being developed.