Since the first cases of the West Nile virus (WNV) in the western hemisphere were identified in New York City in 1999, the virus has moved across the US (MMWR 2005;54:1253–1256). For the first 11 months of 2005, 2,744 cases were reported, 385 more from the same period in 2004, according to new data from the Centers for Disease Control and Prevention (CDC). And there is good cause for why neurologists should take notice: West Nile Neuroinvasive Disease (WNND) accounted for 1,165 (or 42 percent) of these cases, included meningitis, encephalitis, and acute flaccid paralysis.
“West Nile virus has not gone away,” said Ken Tyler, MD, a neuroinfectious disease expert and Reuler Lewin Family Professor of Neurology, at the University of Colorado Health Sciences Center in Denver. “It is virtually in every state in the US.” He added that the number of reported cases is artificially low because fever cases often go unreported if there are no neurological manifestations.
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Although California has had the most cases in the past few years, in 2005, the likelihood of getting the virus was highest in South Dakota, where there were 4.8 cases of WNND per 100,000 residents, followed by Nebraska (2.1 WNND cases per 100,000 residents) and North Dakota (1.9 cases per 100,000 residents). Other states with higher-than-average risk for serious disease were Illinois, Texas, and Louisiana.
The CDC report urges the “need for ongoing surveillance, mosquito control, promotion of personal protection from mosquito bites, and research into additional prevention strategies.” Right now, treatment is supportive.
GENE SUSCEPTIBILITY STUDIES
Researchers are homing in on potential drug targets, however. Phillip Murphy, MD, and co-investigators at the National Institute of Allergy and Infectious Diseases (NIAID) developed a mouse model to clarify how various immune system cells respond to WNV infection. Last fall, they reported in the Journal of Experimental Medicine (2005;202(8):1087–1098) that while most mice survive WNV infection, mice genetically engineered to lack the chemokine receptor called CCR5 did not survive infection by the virus. Further investigation showed that CCR5 promoted the movement of several classes of immune system cells into the brain and CNS, which appeared to protect normal mice from the encephalitis characteristic of WNV.
Dr. Murphy and his colleagues wanted to know if humans lacking CCR5 might be at greater risk of WNV-related complications. They examined human blood and CSF samples from 417 laboratory-confirmed cases of WNV that occurred in Colorado and Arizona in 2003 and 2004. In a study published online on Jan. 17 in the Journal of Experimental Medicine, they reported that the absence of normal CCR5 genes appeared to increase susceptibility for WNV infection.
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Most people inherit two normal copies of the gene that codes for CCR5 protein, according to the NIAID investigators. But about 1 percent of North American whites have a mutation in both copies and do not produce any CCR5.
“This is the first genetic risk factor to be identified for West Nile virus infection,” NIH Director Elias A. Zerhouni, MD, commented in a news release accompanying the paper. But, Dr. Zerhouni noted, the same mutation that raises the risk for WNV appears to protect again HIV infection.
Ten years ago, several groups of investigators, including another team of NIAID investigators led by Edgar A. Berger, MD, reported that CCR5 is the primary co-receptor used by HIV to infect cells (Science 1996;272:1955–1958).
Investigators reported that those lacking the CCR5 mutation were highly resistant to HIV infection, even when exposed to HIV repeatedly. These findings formed the cornerstone for research into new targets for anti-HIV therapies and approaches to developing better animal models of HIV infection. CCR5 inhibitors are in clinical trials for HIV.
“The findings may have important clinical implications for physicians who treat people with HIV,” Dr. Murphy noted. It might be prudent, he said, for HIV-positive individuals who are taking experimental CCR5-blockers to strictly limit mosquito exposure.
The National Institute of Allergy and Infectious Disease Collaborative Antiviral Study Group is sponsoring a phase 1/II safety and efficacy trial of Israeli anti-WNV intravenous immunoglobulin G antibodies (OMR-IG-Am) with a US preparation without WNV antibodies (NCT00068055). OMR-IG-Am is derived from antibodies to the virus from Israeli donors with high anti-West Nile virus antibody titers in patients with, or at risk for, progression to encephalitis or myelitis. The trial was launched in 2003.
Currently, 60 sites throughout the US and Canada are participating; the goal is to enroll 110 sites. Dr. Tyler estimated that the trial would require one more season before it is completed. Six additional clinical trials on WNV are listed on www.clinicaltrials.gov.
Despite ongoing research on novel therapies, “we do not have evidence-based treatment that will alter the natural history of WNV infection,” Arturo Leis, MD, Senior Scientist for Neuroscience and Neurologic Recovery at Methodist Rehabilitation Center in Jackson, MS, told Neurology Today.
He recommended incorporating WNV infection into the differential diagnosis for patients with encephalitis, viral meningitis, acute flaccid paralysis, or any unexplained neurological symptoms during the summer months or early fall, when viral infection is most prevalent.
“In areas with active West Nile Virus transmission, physicians need to be aware that infection can cause a polio-like syndrome and that the spectrum of neuromuscular signs and symptoms may range from acute flaccid paralysis in the absence of fever or meningoencephalitis to subjective weakness and disabling fatigue,” he wrote in Current Treatment Options in Neurology (2005;1:15–22). According to Dr. Leis, patients might also show focal neurological deficits, cerebellar syndromes, parkinsonism, or other movement disorders. Importantly, he stressed: “This awareness will help to avoid less tenable diagnoses and the morbidity associated with inappropriate treatment.”
“Ideally, you need an assay that can detect the virus in a patient's blood or CSF within a day,” Dr. Leis said, adding that diagnosis is often delayed. In part, the delays arise because clinicians do not suspect WNV.
ARTICLE IN BRIEF
✓ West Nile virus (WNV) incidence has increased over the past year, according to a report from the Centers for Disease Control and Prevention. But investigators are hopeful that recent findings on genetic risk factors for WNV could lead to potential new targets for therapy.