West Nile's lesson for pandemic influenza

We write so much here about influenza A virus that you might get the idea it is an especially clever virus, always changing genetically in ways that allow it to perform new and nastier tricks. But other viruses are capable of doing the same thing, and one of them West Nile Virus (WNV), is currently becoming a a more persistent and serious public health hazard, all because of a clever little genetic trick it learned in the last decade or so.

WNV has been around longer than that, although we didn't have a problem with it in North America until 1999, when this mosquito-borne disease showed up, in of all places, the Borough of Queens in New York City. Like influenza, WNV is primarily a disease of birds, infecting humans relatively rarely and then only as dead-emd hosts. And, like influenza, its genetic material is a single strand of positive sense RNA. WNV is classified as a flavivirus and belongs to a complex of viruses with similar immunologic reactivity (called the Japanese Encephalitis serocomplex) which includes other diseases of birds and mammals (including humans) spread by mosquitoes, namely Japanese Encephalitis and St. Louis Encephalitis virus. WNV infections in humans ranges from asymptomatic or slight flu-like illnesses with fever to a full blown potentially lethal encephalitis (brain inflammation) with paralysis. It was first found in 1937 in the blood of a woman in the West Nile district of Uganda, and has been responsible for relatively localized outbreaks (some quite large) in Asia, Eastern Europe, the Middle East and Africa. Female mosquitoes, seeking a blood meal prior to ovulation, suck the blood of an infected bird, amplify the virus in their bodies and then transfer it to another bird or a mammal such as a horse or a human, where it causes infection. Humans don't produce enough virus in their blood to allow msquitoes to pick it up from them and transfer it to another person, as happens with yellow fever, so humans are a dead end for the virus and not really part of its cycle in nature, which is primarily bird to bird. We are incidental hosts.

Which brings us to the clever genetic change WNV underwent sometime in the 1990s. WNV is capable of infecting a tremendous range of birds. So far over 300 species have been shown to be infected, although most of the WNV dead bird reports are in crows and jays. This may be because they are more susceptible or because they are large birds whose corpses are much more conspicuous. Whatever the reason, the lethality of WNV in crows increased suddenly after a specific genetic change which is only now being discovered and seems specific to North America -- for now:

Since its 1999 introduction into the U.S., the virus has cut crow populations almost in half in some regions, researchers said in May. [Aaron Brault's study, from the University of California, Davis, School of Veterinary Medicine], published in the journal Nature Genetics, suggests the culprit is a small mutation in a gene that makes a protein, called helicase, that unwinds RNA, or ribonucleic acid, a molecule that carries genetic messages.

The mutation was first seen in Israel in 1997, Brault said. Before that, most West Nile outbreaks caused fairly mild disease in people, and the virus grew so slowly in birds that it was difficult to recover from their bodies.

Today, crows infected by the North American strain of West Nile harbor so much virus that a single mosquito can take on a million copies in a single blood meal. Researchers are trying to determine how the mutation permits the virus to grow faster in crows, Brault said. (John Lauerman, Bloomberg)

Genetic success for a virus is to make as many copies of itself as it can. The mutation in the helicase gene allows it to make many more copies of itself in birds and this allows mosquitoes to transfer it more successfully to another bird or an unlucky human. This is the counterpart to a mutation in a bird flu virus that would make a more efficient bird to human or human to human transmission.

This season looks like it might be particularly nasty one for WNV in North America. So far there are 308 cases reported to CDC, compared to 192 at this point last year. A third of the cases have severe neurological involvement, with 11 deaths compared to 6 deaths at a comparable point in 2006.

So while we worry about preparing for an influenza pandemic, we should remember there are other pathogens out there that can do us in. Mosquito-borne disease once ravaged the United States, with yellow fever causing devastating epidemics in northern cities like Philadelphia. Malaria was endemic throughout the Mississippi Valley 19th century. If we are to make our communities more resilient to the shock of emerging and re-emerging infectious disease, we need to be careful not to take our eye off the main strategy: to harden and strengthen our public health and social service infrastructures so they can handle many different problems. A strategy that focuses on antivirals and vaccines for influenza will do little for WNV or whatever else there is out there. A robust public health system will helop us with all comers.

Not that you've heard me say this before, of course.

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This article fails to mention that a safe and effective treatment for WNV encephalitis was published three years ago. It should work for other viruses, including bird flu.

My company developed (and owns a pending patent for) the treatment, and has been using it in an ongoing free clinical trial for the past 5 summers.

Our initial results on 8 patients seen in Sept, 2003 were published in a peer-reviewed medical journal in July, 2004 (1). Publication in a peer-reviewed medical journal is all that's required for a treatment to officially exist.

Our approach lowers the host's response to the virus--the so-called "cytokine storm"--rather than targeting the virus itself. So it may work for most viruses as a kind of general viral antidote.

I was asked to describe our treatment to the White House Office of Science Technology and Policy (OSTP) in June, 2004. I volunteered to brief the Dept of Homeland Security later that summer. The UN is aware of our treatment in the context of avian influenza. It was included in the Project BioShield II Act of 2005, co-sponsored by Senators Lieberman, Hatch, and Brownback (2).

The FDA is happy for our trial to proceed, since we use already FDA-approved medications which are known to be safe for the general population.

I just described our treatment this past Friday, August 3rd, at the BARDA Industry Day hosted by the Dept of Health and Human Services (3).

The only agency not supportive of our efforts is the CDC, for reasons known only to them.

21 patients with WNV have responded so far, out of 25 (84%). We've also treated 4 horses (3 responded) and 12 birds (6 responded; birds present sicker than humans and horses). Our WNV trial is free from our end. The blood pressure meds we use are inexpensive (around $1/day) and are available by prescription from any drugstore in the country.

Anybody who wants to download our trial documents can do so at any time of day or night from our homepage at www.genomed.com.

Beginning treatment early--within the first 48 hrs of encephalitis symptoms--seems to be the only way to avoid long-term sequelae such as paralysis, chronic fatigue, cognitive problems, etc. WNV is notorious for still affecting half of WNV victims 18 months later.

If a family knows about our treatment ahead of time, they'll be in a much better position to get it prescribed for their relative who comes down with the disease.

Thanks to the inexplicable behavior of the CDC, which has redefined public health in the same way that FEMA redefined rescue, neither physicians nor patients have heard about our treatment for the fifth year in a row.

1. Moskowitz DW, Johnson FE. The central role of angiotensin I-converting enzyme in vertebrate pathophysiology. Curr Top Med Chem. 2004;4(13):1433-54. PMID: 15379656 (For PDF file, click on paper #6 at: http://www.genomed.com/index.cfm?action=investor&drill=publications)

2. Section 2151 of the Project BioShield II Act of April 28, 2005 (http://www.govtrack.us/congress/billtext.xpd?bill=s109-975)

3. http://www.hhs.gov/disasters/press/newsroom/spotlight/2007bardaday.html


Dave Moskowitz MD
Chairman, CEO & Chief Medical Officer
GenoMed, Inc.
"Our business is public health(TM)"

website: www.genomed.com
Ticker symbol: GMED.PK (on the OTC Pink Sheets)

Thanks Revere, interesting post. One small point
"And, like influenza, its genetic material is a single strand of positive sense RNA." Isn't Influenza -ssRNA ?

Well, as you know, I'm an advocate of keeping cool about this. 100 severe illnesses and 11 deaths in the USA is a barely noticeable public health problem. We talk about this a lot because it's novel but it's actually trivial. Remember that most people have mild or asymptomatic illness after which they have, as far as we know, lifelong immunity, which suggests that serious illnesses are going to peak at a low level.

The worst thing about this non-epidemic is that it has provoked innumerable jurisdictions to indiscriminately spray insecticide, including sending trucks down the streets of Jamaica Plain to fog the whole neighborhood three years ago. They generally use resmethrin or something like that which has little if any known direct impact on humans, but kills every invertebrate for a hundred feet or more up into the air column, plus amphibians. This is idiotic. I think we talk about WNV far too much.

There are plenty of other things to lose sleep over.

JJ: Oh, shit. That's what happens when you try to blog from the beach. I made the correction. Thanks.

cervantes: You are partially right but I think it is a mistake to minimize this. This is a nasty virus and it demands some kind of rational public health response. It could get considerably worse. To the extent it is preventable with proper mosquito control in the spring it is an important thing to do. Trivializing it will not lead to a better response than the baseless (at least given current evidence) use of broadcast spraying to kill adult mosquitoes.

You're right of course but that's exactly the problem. The press reports it every time somebody is diagnosed, it seems, which tends to greatly exaggerate the problem; but by then, as you say, it's the wrong time of year for effective and environmentally comparatively benign mosquito control, so we get this panicked and damaging overreaction.

What we need is a background piece in January, putting the problem in context; campaigns to get people to remove backyard standing water (old tires, containers, etc.); stocking of ponds with fish that eat larvae where feasible; and larvicidal approaches, which can be very selective for mosquitoes. What we don't need, by the way, is ditching salt marshes. This is all a long story but the bottom line is, there are vested interests in mosquito control in most parts of the country that keep their jobs and make their money from doing it the wrong way. The way WNV gets reported just feeds into this problem.

Another way in which West Nile is like pandemic flu is that interventions to reduce its impact need to occur well before you see many human cases--similar to implementing student dismissal from schools and preventing large public gatherings--when it is difficult to persuade elected officials to act.

For WNV, whether it's public education, larviciding, reducing standing water, or even adulticiding--which I understand you don't support--all need to be done well before significant numbers of human cases have occurred. If you wait till lots of people are sick, you've missed the opportunity to make a significant impact (although by then you'll have the political support.)

Human cases don't get reported for 2-3 weeks after illness onset, and 3-4 weeks after infection, on average. The 11 deaths and 100 serious illnesses could represent an order of magnitude more cases if you knew what was going on in real time. Adult mosquito control decisions need to be based on numbers of vector mosquitoes trapped and infection rates of mosquito pools, not human illness (excepting blood donors who test NAAT positive, and are the best human sentinels.)

Hijacking the blog for a moment. 7.9 and 7.5 quakes in Peru. Tsunami was generated and evaluations are underway to determine if a Pacific wide warning is warranted. Estimated time to Hawaii is about 8 hours from now.

Advisories on following: http://www.prh.noaa.gov/ptwc/

By M. Randolph Kruger (not verified) on 15 Aug 2007 #permalink

Another interesting aspect of the molecular biology of the -ssRNA West Nile virus:

1. within the U.S., there are regional sub-variations of the virus.

2. the West Nile virus originally identified in the U.S. in 1999 has mutated to the extent that may not occur naturally anywhere in the U.S. today

Crow song

What do crow sing when crow drop?
When the new people try to kill them, with silent love
trying to join the crow?

The joined crows sing, surviving, AAW
AAW, as it ever was, harsh in the throat
trying to rally the crow.

The new people sing in join crow, blood silent
as it ever was, maybe a hum of join.
You can't hear it, except join crow.

All join crow, gather in a tree, AAW
AAW, as it ever was, and trade round the call
of the joined, surviving, as it ever was, AAW, AAW --- AAW

What do crow sing when crow drop, surviving? AAW
AAW, maybe a hum of join in the blood, as it ever was, silent.


you make the crow call, not the word AAW