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AS WEST NILE SPREADS WESTWARD, INTERFERON TRIAL GETS FDA APPROVAL

Summer 2002 has come to a close, and with it public health officials expect that cases of West Nile virus (WNV), the mosquito-borne virus that caused 98 deaths this year across the US, may likely spread to the Pacific coast before gradually tapering off in colder states.

Because the virus often has neurological effects – leading to encephalitis or meningitis in some but not all who contract it – Neurology Today interviewed experts to report on the most current understanding of the epidemic and its prognosis for the future.

Officials at the Centers for Disease Control and Prevention (CDC) in Atlanta believe the outbreak might have peaked in August, with a mortality rate of between 11 and 14 percent in those hospitalized with encephalitis and meningitis – about the same as the death rates in the previous three summers.

RAPID SPREAD OF EPIDEMIC

But this summer's epidemic struck earlier, spread faster, and affected younger people than it has before in the US, with the median age of hospitalized patients falling from 60 to 50 years of age. In parts of the globe where WNV has been endemic for years, older people carry antibodies to the virus; young children and adults with poor immune systems face the greatest risk.

In just three years, the virus has spread from a handful of cases in New York City throughout the Eastern US, and it shows every sign of becoming a viral mainstay of the summer months in hot and humid states where mosquitoes thrive.

ASYMPTOMATIC IN MOST PEOPLE

In a news conference, Lyle R. Petersen, MD, a medical epidemiologist with the CDC's Center for Infectious Diseases in Fort Collins, CO, said that, while the disease can be fatal, most infected people are asymptomatic or have mild symptoms.

“What we know from the serological surveys we have conducted is that about one in five persons develops West Nile fever, a mild febrile illness that usually last three to six days and then goes away on its own without any permanent sequelae,” he explained. “It's like a mild, flu-like illness. About one in 150 persons go on to develop encephalitis or meningitis. Most people infected with the virus have no symptoms at all.”

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Dr. James Sejvar

Infection results in a rapid onset of flu-like symptoms of varying degrees of severity, including severe headaches, fever, and body aches. More severe reactions include brain swelling, coma, paralysis, or death. Most US patients are admitted for encephalitis or meningitis, with viral infection confirmed by serum or spinal fluid assay within eight days of the onset of symptoms. (Clinical guidelines for detection and treatment of WNV are available on the CDC Web site at www.cdc.gov/ncidod/dvbid/westnile/clinical_guidance.htm.)

EMERGING EPIDEMIC

Addressing her first public health crisis since taking the helm at the CDC in early July, newly appointed Director Julie Gerberding, MD, MPH, called the virus an “emerging, infectious disease epidemic” that she predicted would likely spread to the Pacific Coast this year, following the natural migratory patterns of birds. Infected birds and mosquitoes have been identified in most Eastern states and in several Midwestern states, including Texas, Nebraska, and South Dakota, she told CBS's “Face the Nation.” Since then the virus has also been identified in horses and birds in Montana, Wyoming, Colorado, and New Mexico.

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Dr. Petersen and other epidemiologists point to St. Louis encephalitis – a very similar mosquito-borne viral illness – as a model one might use to forecast the eventual range of West Nile in the US.

“What we know about St. Louis encephalitis virus and West Nile virus is that they often share the same mosquito vectors,” Dr. Petersen said. “Because of that, we would expect that the virus would be able to thrive quite well on the West Coast, as well as it has elsewhere in the United States.”

FULL RECOVERY UNCERTAIN

Nonetheless, among patients with severe West Nile infection, the effects may linger, perhaps indefinitely, according to observational studies in 1999 and 2000, said Dr. Petersen.

“What we know – and there is not a lot of data out there – is that studies done in the Northeast among people with severe infection, meaning those who were hospitalized, is that a very large proportion of them at discharge have not returned to their baseline level of functioning. It appears to have very profound neurological sequelae such as the inability to walk.

“We do not collect detailed clinical data on all these people routinely, so I cannot comment about the details of all of these cases,” he continued. “What I can tell you is that the vast majority of them were hospitalized with meningitis and encephalitis.”

COMPLICATIONS

To date, the more serious disease complications have been limited to older patients with more severe illness, added James Sejvar, MD, a medical epidemiologist and neurologist with the CDC's Meningitis and Special Pathogens Branch at the Center for Infectious Diseases in Atlanta.

“We see full recovery in younger patients provided they don't have any underlying conditions such as immune system problems, cancer, or auto-immune disorders. In most younger patients recovery is very good – there's a robust antibody response.”

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Dr. Julie Gerberding

Physicians should be suspicious when younger patients come in with complaints of general fatigue and headaches, he advised, although most also have acute fever.

“All of these symptoms can be indicative of early meningitis,” Dr. Sejvar said. “For some patients, hospitalization times can be long, especially for older patients with other medical conditions who tend toward more severe encephalopathies. Some are comatose for days, then regain their senses and recover slowly. In the past, it has been a mixed bag in terms of severity of symptoms and length of recovery.”

INTERFERON STUDY APPROVED

James Rahal, MD, Director of the Infectious Disease Division of New York Hospital in Queens, was among the first physicians in the US to study West Nile when the first cases were confirmed in New York in 1999. Since then he has been studying possible drug treatments, including interferon alpha-2b (Intron A, manufactured by Schering-Plough).

In vitro studies show the drug is effective against the virus (Emerg Infect Dis 2002;8(1):107–8), and last year health officials in Louisiana invited Dr. Rahal to test interferon alpha-2b in a group of patients with suspected St. Louis encephalitis, a similar mosquito-borne virus that responds to the drug in the laboratory. Interferon has been approved for the treatment of viral hepatitis and certain cancers, and can be used by physicians treating other illnesses.

“These 15 patients were actually infected with West Nile,” said Dr. Rahal. “We compared treatment with a matched group of historic controls and found interferon showed potential efficacy and was well tolerated.”

Because the results of the study have been submitted for publication, he will not give any other details. In August, however, Dr. Rahal received approval from the Food and Drug Administration (FDA) to conduct the first human trial of Intron in hospitalized West Nile patients.

“The trials will involve 40 hospitalized persons, 50 years and over, chosen at random,” Dr. Rahal explained. “Half will receive the drug within the first four days of admission for West Nile encephalitis or meningeal encephalitis, while the others will be given a placebo. We feel the drug is more effective if given early. Younger patients will be enrolled only if they are diagnosed with encephalitis, and outpatients will not be eligible.”

PLANS FOR TRIALS

One week after receiving the FDA's approval – and at press time – one patient had already been enrolled, and Dr. Rahal said he is receiving many telephone calls and is confident he will soon have the necessary cohort called for in the study's protocol.

“Because of the St. Louis data, I consider this a phase 2 trial. It won't be a definitive study because it cannot be blinded due to the difficulty in coordinating placebo administration at different hospitals. Instead, it will be randomized. Hospitals anywhere around the country can participate, and we are hopeful enough patients will be willing to enroll in the study.”

He noted that in parts of the world where the virus is endemic, the normal blood supply already carries antibodies to West Nile. “Israeli doctors already treat infection using intravenous gamma globulin containing West Nile antibodies, and I know of one case at the National Institutes of Health where a patient with West Nile has been treated with IV gamma globulin from Israel.”

NATURAL IMMUNITY

Inasmuch as the virus has spread rapidly and widely, Dr. Rahal said it is clear that it is now entrenched in the US. But, he said, eventually, if enough people are exposed, a similar “herd” immunity will develop as it has in Israel and in parts of Asia and Africa, where the disease is endemic and antibodies are prevalent in the general population.

“It is hard to predict what the virus will do, but it is not going to happen this badly every year. Remember that for every case of West Nile reported, there are perhaps 100 or 200 people who are exposed and never develop symptoms, or whose symptoms are so mild they do not require medical treatment.”

Dr. Petersen noted that many questions remain about the virus and natural immunity, with the only clues coming from overseas and from similar viruses.

“What we don't know is whether being exposed to the virus will cause lifelong immunity,” he said. “What we do know from related viruses, like Japanese encephalitis, for example, or yellow fever, is that once you get infected with those viruses, you have immunity for life, and so we might expect the same thing to occur with the West Nile.”

Any pattern of natural immunity that might eventually evolve in this country will likely follow immunity in parts of the globe where the virus is highly endemic, Dr. Petersen said.

“In parts of Africa like the West Nile district, for example, what you see is this infection primarily in children. You don't see the infection so much in adults, and that would lead one to believe that people get infected at an early age and then become immune for life.”

Both Drs. Rahal and Petersen noted that there is no vaccine for West Nile, and while there are many researchers working on developing one, it may take years before a candidate is available. Nor is there any effective treatment for those infected with the virus. Instead, hospitals can provide supportive treatment against the symptoms of infection, including the respiratory assistance, rehydration with intravenous fluids, and prevention of secondary infections for patients with severe disease.

HELP FOR HARD-HIT STATES

The Department of Health and Human Services has responded to this summer's West Nile epidemic by offering $14 million to states, cities, and municipalities that have the greatest number of cases, and by providing ongoing technical and scientific help for detection and eradication efforts.

In late August, HHS Secretary Tommy Thompson announced an additional $6 million that will be available through the CDC. This brings to $31 million the total outlay for West Nile this year, and to $54 million the overall amount spent fighting the disease since it was first detected in New York in 1999.