Long time readers may have noticed that the subject of West Nile Virus (WNV) pops up periodically here (and here, here, here, here, here). It's more than a passing fancy. I was professionally involved in public health measures around West Nile after its introduction to the US in 1999 and have maintained an interest, even though flu occupies much (too much) of my time.
WNV is a mosquito-borne flavivirus of birds that occasionally infects humans (in this sense it is like bird flu, although only in this sense; bird flu is not passed from birds to humans via mosquitoes). The resulting infection can range from asymptomatic to fatal, with a significant number of cases of meningoencephalitis (inflammation of the brain and its coverings). Since the first cluster of cases in a residential area of Queens, New York, WNV cases have appeared in all state of the continental US. It is a reportable disease and 25,000 cases have been so registered in the last 10 years, more than a thousand of them fatal. Most cases aren't so serious, but somewhere under 1% develop a neuroinvasive form that can lead to serious neurological symptoms, sometimes of long standing, or be fatal. The number of deaths and cases is undoubtedly under reported and we are still learning about the natural history of the disease. "Natural history" refers to the clinical course of the disease over time.
In order to study natural history you need to follow people who have been infected and see what happens to them over time. Early on it appeared that either you got sick and died or you got over your infection. Then some cases turned up that seemed to have prolonged effects. And now we are finding that some of those who are apparently recovered may harboring persistent infection. A new paper (available online here) in the Journal of Infectious Diseases has the first reports:
When WNV reached Houston in 2002, we established a longitudinal study to follow hospitalized WNVâinfected patients to determine risk factors for encephalitis and to understand longâterm clinical sequelae. Methods for WNV confirmation and study inclusion criteria have been described elsewhere. [snip] At 1 year after infection, 60% of patients remain symptomatic, particularly those who were encephalitic. Resolution of symptoms plateaued 2 years after infection, and after 5 years 60% of patients who presented with encephalitis continued to report clinical symptoms. Chronic symptoms were significantly associated with the persistence of detectable antiâWNV serum immunoglobulin M and also with a history of hypertension. Cytokine studies showed that many of the chronically symptomatic patients also had significantly elevated plasma levels of interferon γ-inducing protein, a marker of active viral infection (Murray et al., Persistent Infection with West Nile Virus Years after Initial Infection, The Journal of Infectious Diseases 2010;201:2-4).
Studies in monkeys and hamsters had already shown that WNV could persist in brain tissue and in the hamsters was also found in the kidney. The hamsters continued to shed virus in their urine up to 8 months. Now it appears the same is true of people. The Houston group has now followed 100 cases of severe WNV infection for 7 years, and while symptoms decreased over that time they seemed to level out at 2 years. As noted above, more than half were still having symptoms after 5 years. But five of them died of kidney failure, and putting that together with the hamster studies made the Texas researchers look at the urine of a sample of 25 from the cohort of 100. 5 of them, or 20%, seemed to be shedding virus in the urine. The evidence was in the form of entire viral genomic material. So far no virus has been isolated. But the length of time that genetic material is being shed indicates that virus is still being formed. So this is persistent infection.
WNV if now the most common arbovirus (arthropod borne virus) infection in the US. It may turn out to be a significant cause of kidney failure, although that is still unclear. What's intriguing (and worrying) is that we still don't have good fix on the epidemiology of this disease. We have assumed that significant levels of virus in the blood (viremia) of infected animals (birds) was required for a mosquito to have a large enough viral load to infect a human. That's why infected people didn't pass it on to others by having a mosquito bite both of them. But if the virus is present in other tissues there might be other modes of transmission. In an accompanying editorial by Ernest A. Gould of the Centre for Ecology and Hydrology, Oxford (UK) raised that issue:
Finally, one can ask, what is the significance of these findings to WNV transmission? Nonviremic transmission of WNV between mosquitoes cofeeding on mice and nonviremic transmission of Japanese encephalitis virus [3] from healthy nonviremic bats to feeding mosquitoes have both been reported. The findings of Murray and colleagues could therefore also raise important issues concerning the potential for WNV and other related flaviviruses to be transmitted to mosquitoes by apparently healthy humans or animals (assuming a similar pattern of WNV behavior in animals) and thus potentially initiate epidemics in new regions of the world. Could this be the method by which WNV arrived in North America in 1999?
This kind of science can be very worrying. But for a scientist it's also very, very interesting. Never a dull moment.
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Revere, I know you're tired of the flu but... any thoughts on whether this year's H1N1 might also have longer term effects than we might think? Limited anecdotal evidence leads me to think this might be an intriguing area to look at, but would be interested to know if a science expert thinks there might be anything there.
Trish: I have no information on that but "regular" flu bouts often hang on for very long periods, weeks and months, where you feel like you've been run over by a truck. We'll see at some point. But we can't see now.
People were infected with SV-40 from polio vaccines in the 50's and 60's since they were using kidneys from monkeys and the virus was not 100% inactivated. (This is a historical fact, a good history is in the book "The Virus and the Vaccine") Kidneys were continued to be used for polio vaccines until 2000, but supposedly are still being used in some other vaccines. Any virus has theoretically been inactivated and there should be no new viruses being transmitted, but who knows, do you really trust the FDA to ensure food and drugs are safe?. According to the above book the regulations do not require the manufacturers to use state of the art technology to rule out virus contamination, and older methods are used that may not be reliable.
So if you have an African virus that may infect monkeys and is also infecting humans in North America, and are unsure of the mode of infection, well......
pft: As I recall, it was a batch of Cutter vaccine that has SV40 in it intense follow-up revealed no sequelae (I don't remember anyone being infected with SV40 from the vaccine). But flu virus is grown in eggs for this vaccine, not monkey cells as is polio. And we've been doing it for half a century. So if you don't trust this year's vaccine, you don't trust any of the vaccine. Good luck to you.
I doubt that persistently infected humans will serve as a reservoir for mosquito transmission of WNV. If the investigators could not isolate infectious virus from urine, it's not likely to be present at high levels. Therefore mosquitoes will not take up sufficient virus to infect other humans when they have a blood meal. As far as I know mosquitoes don't drink urine.
Vincent: That was what I thought at first. But a moderator at ProMed thought there was indeed potential epidemiologic significance and it certainly has clinical importance.