Pandemic News/Awareness - Thread 3

Russia - H5N1 Confirmed

Getting too close for comfort. See the map, 2d link.

http://www.flutrackers.com/forum/showpost.php?p=148734&postcount=32

http://tinyurl.com/3qvvy4

"Migrant birds are coming to us from Southeast Asia, Indonstan and Africa, which have the bird flu problem. We are vigilant," Onishchenko said.

In his words, bird flu outbreaks are possible in Primorye, Siberia, the Urals and European areas of Russia.

Specialists say bird flu outbreaks are not ruled out in autumn in Korea, Japan, Canada, the United States and Mexico.

Three links on South Korea, and Bird Flu:

http://afludiary.blogspot.com/2008/04/south-korean-outbreak-continues-to.html

South Korea's bird flu problems continue to escalate with outbreaks either suspected or confirmed now in 32 locations.

So far there is no explanation as to how this virus found its way into that nation's poultry farms, nor why it has spread so rapidly.

http://crofsblogs.typepad.com/h5n1/2008/04/korean-entrepre.html

Park bought 600 ducks from the farm between April 4 and 6, and sold some 40 of them to a duck seller, identified only by his surname Kim, who then sold them to a restaurant attached to the farm in Gimje.

The farm in question was located within the alert zone, about 1.7 kilometers away from another farm where the highly pathogenic H5N1 strain of bird flu was detected for the first time. Movements of poultry have been under strict control in the area.

http://afludiary.blogspot.com/2008/04/south-korea-new-bird-flu-pattern.html

Previous outbreaks have occurred in colder months, and, according to scientists, this latest outbreak is spreading faster than before.

Whether these observed changes in the behavior of the virus indicate some mutation, or are a harbinger of greater infectivity for humans, is impossible to say at this point. It has captured the attention of scientists, however.

In the past Korea has quickly contained bird flu outbreaks, mostly through the use of aggressive culling. In November of 2006, they admitted that they were killing cats and dogs within the culling zone, which caused some public outcry.

Cameroon

http://www.flutrackers.com/forum/showpost.php?p=148979&postcount=1

Abstract on H5N1 found in this Western Africa, bordering the Bight of Biafra,

between Equatorial Guinea and Nigeria. Makes you wonder about what is

going on in the other countries in the area...

Central Russia

http://www.flutrackers.com/forum/showpost.php?p=149018&postcount=36

http://www.flutrackers.com/forum/showthread.php?t=63974&page=2

Scientists in Russia's Perm region are investigating the death of around

40,000 birds at a poultry farm. It's still unclear whether it was caused by

bird flu.

South Korea

Three duck vendors have been arrested

http://afludiary.blogspot.com/2008/04/south-korea-arrests-made-as-bird-flu.html

Three duck vendors have been arrested, and will be imprisoned or fined for

selling ducks in the infected zone. Yes, some people think nothing of smuggling

poultry across boarders or selling to restaurants in a hot zone area. Amazingly,

other people are willing to buy from them.

South Korea Sends In Troops, Raises Alert Level

http://afludiary.blogspot.com/2008/04/south-korea-sends-in-troops-raises.html

South Korea today raised their alert level to `Orange' and extended it to

cover their entire nation. `Orange' is the 2nd highest alert level, and

officials concede that they may have to raise the alert level to `Red' if the

virus is not contained.

Soldiers have been dispatched to infected farms to help with the culling and

burying of chickens and ducks. Reportedly, 2.2 million birds have been culled,

thus far, in these recent outbreaks.

http://crofsblogs.typepad.com/h5n1/2008/04/south-korea-cul.html

As awful as this sounds, it also looks as if the Koreans have launched a serious blitzkrieg against H5N1. If it succeeds (and it may not), other hot-zone countries will have no excuse for their own half-hearted culling attempts.

Another H5N1 Positive Case in Egypt

http://afludiary.blogspot.com/2008/04/egypt-2-year-old-infected-with-bird-flu.html

A 2-year-old Egyptian boy has been infected with the deadly H5N1 bird flu virus, bringing the number of cases in the most populous Arab country to 50, state news agency MENA said on Wednesday.

MENA identified the child as Mahmoud Ibrahim Ramadan from the Nile Delta province of Sharkia, quoting Egypt's health ministry. It said he had been infected after exposure to household birds.

The Ukraine

Given that the number of dead poultry is in the thousands, this is a highly

pathogenic virus. The second link is a commentary on a news translation,

revealing that this is an H5 virus. Put the two observations together, and

it is most likely H5N1.

It is interesting to note that they are admitting that those pelicans

died of bird flu, not hunger, back in 2006.

http://www.flutrackers.com/forum/showpost.php?p=150016&postcount=1

http://www.recombinomics.com/News/04190801/H5N1_Shpol_Confirmed.html

Health inspectors discovered thousands of dead chickens at a Ukrainian poultry farm, with bird flu suspected as the cause, the Interfax news agency reported Thursday. The die-off took place at a poultry-processing plant near the city Shpol, in the northern Cherkassy province.

The last incident of bird flu in Ukraine prior to 2008 was registered in July 2006, when health inspectors detected the disease in domestic poultry in the eastern Sumy region, resulting in the destruction of more than 12,000 chickens, ducks and geese.

Bird flu in 2006 also was found in pelicans living in the marshy Sivash wetland of the Crimean peninsula, but that outbreak did not make the jump to domestic birds, the Health Ministry said at the time.

Still Spreading in South Korea with 25 Confirmed Outbreaks

http://afludiary.blogspot.com/2008/04/south-korea-25-confirmed-outbreaks-of.html

It is rather alarming to think that the South Koreans are having this much

difficulty stopping the spread of H5N1. Of course, no word from North

Korea yet so maybe their birds are uniquely immune to bird flu...

Quarantine officials said they have culled 3.71 million birds so far since confirmation of this year's first bird flu case in early April.

The ministry estimated that the bird flu outbreak has caused around 30 billion won (30.1 million U.S. dollars) worth of losses.

UPDATE

5 Million Birds Now Culled

http://afludiary.blogspot.com/2008/04/s-korea-culls-5-million-birds-in-bid-to.html

http://www.recombinomics.com/News/04200801/H5N1_Korea_Record.html

...this outbreak will almost certainly be the largest outbreak reported to date in South Korea (almost 5 million birds have already been culled), and would also highlight significant surveillance detection / reporting failures in neighboring countries, including Japan which has announce plans to implement a pre-pandemic vaccine program targeting 10-20 million citizens, beginning with first responders.

Transparency Issues in South Korea Regarding Their First Human Case of Bird Flu

http://www.recombinomics.com/News/04220805/H5N1_Korea_Transparency.html

Transparency issues occur in almost any country dealing with outbreaks of

bird flu. Remember, there are economic consequences, and authorities seem

to have the ever present fear that the people will panic if told the truth. They

admit that this is an H5 flu virus. Many, many birds have died, so we can see

that this is a highly pathogenic H5 avian flu virus (HPAI).

Does anyone doubt that it is HPAI H5N1?

This soldier had on PPE and was receiving Tamiflu. So, what happened?

www.recombinomics.com

...the government is using the same hair splitting approach to delay confirming that the soldier is H5N1 positive with the same H5N1 detected in the birds being culled. The number of infected farms is approximately 50, indicating the H5N1 is easily passed from farm to farm, and these connections are likely linked to migratory birds (see satellite map). The infection of a soldier/culler, who had PPE's and prophylactic Tamiflu would once again suggest that transmission to humans was efficient.

With permission from Effect Measure:

Important new flu paper in Cell: part I

The cells of your body don't just sit there, unmindful of what is going on around them. They have to respond to things, even cooperate with other cells to get things done for the common good. Humans do the same thing. We've developed a system of signaling to each other using an intricate vocal system, a complex grammar, ears, eyes and smell detecting systems. It's a very complicated package with a lot of moving parts. It's not so surprising, then, that cells also have complex signaling systems with a lot of parts that they use to respond to their environment. Just as we sometimes make a coordinated response to something in our lives (I touch a hot stove or I have a fight or flight response to a threatening situation), so do cells respond to their environment (there is a virus touching my cell surface). Communication in cells is tied up with almost everything, including tissue repair, development, cancer and a lot more. Now a new paper in the journal Cell describes how a particular cell signaling pathway might be involved in the catastrophic response of lungs when infected by certain viruses or bacterial toxins. Because of the potential importance of this paper we are going to take some time to explain it.

The central actor in the paper by Imai et al. ("Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury", Cell, Vol 133, 235-249, 18 April 2008 is a cell signaling receptor called TLR4, which stands for Toll-Like Receptor 4. The Toll-like receptors are a family of molecules, some, like TLR4, found on the surface of certain cells that are part of the innate immune system. The adaptive immune system produces antibodies and requires some previous exposure but the innate immune system sounds a non-specific alarm. It says, "Danger here, mobilize defenses." The TLRs get their name because they bear similarity to a gene on fruitflies that had the name Toll. Toll means "weird" in German:

Christiane Nüsslein-Volhard of the Max Planck Institute in Tübingen analyzed mutations in fruit flies. In 1985, she saw a weird-looking fly larva in which the ventral portion of the body was underdeveloped. Her spontaneous comment was "Das war ja toll!" meaning "That was weird!" and she coined the name Toll for the mutated gene. (Hansson GK, Edfeldt K, Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1085)

Not so weird that it prevented Nüsslein-Volhard from receiving the 1995 Nobel Prize for her work. But the story did get weirder. In 1995 it was found that this gene was not only associated with differentiating back to front in the developing fruitfly but also was somehow involved in its resistance to fungal infection. By the early 1990s other genes similar to the toll gene in fruitflies had been found in humans. While the initial thought was the gene was probably related to development as in the fruitfly, there was soon evidence that one of them, now called TLR4, was the button pushed by lipopolysaccharide (LPS), a component of the cell wall of gram negative bacteria and the endotoxin involved in "gram negative sepsis," the devastating multi-organ system collapse seen in some bacterial infections. Gram-negative sepsis in turn was also similar to the cytokine storm of Acute Lung Injury (ALI) seen in SARS, H5N1, 1918 H1N1, inhalation anthrax and some cases of Monkeypox. TLR4 is now part of a whole family (13 at last count) of Toll-like genes that produce generalized pattern recognition receptors for broad classes of pathogen components. As such they are part of the innate immune system that begins to act before there is any antibody selection or response. Our knowledge of the TLR system is very recent since their discovery is barely ten years old. But already the original TLR gene, TLR4, is becoming part of the bird flu story.

Unfortunately the story is still hazy and it isn't possible to draw any straight line conclusions from Imai et al.'s very interesting paper. But it feels like we're getting somewhere. This is only a piece of the puzzle but I'm guessing it will later be seen as a major piece. We'll have to see. Meanwhile, what did they show? We'll pick this up in the next post.

The Editors of Effect Measure are senior public health scientists and practitioners. Paul Revere was a member of the first local Board of Health in the United States (Boston, 1799). The Editors sign their posts "Revere" to recognize the public service of a professional forerunner better known for other things

The Latest Spin from South Korea

http://crofsblogs.typepad.com/h5n1/2008/04/some-confusion.html

So sorry but there is only one H5 virus that human beings have been

known to be infected with, and that is H5N1. Now it is true that this soldier

might be co-infected with another virus in addition to this H5 virus, or have

a bacterial infection in addition to it.

According to the World Health Organization, only four out of hundreds of

strains of avian influenza viruses are known to have caused human infections

- H5N1, H7N3, H7N7 and H9N2.

http://www.recombinomics.com/News/04230802/H5N1_Korea_Chemo.

html

The media treatment of this lab confirmed case is cause for concern.

Frequently Tamiflu treatment lowers viral load to a level that is below

detection. Similarly, virus can be quickly cleared from the nose and throat,

leading to false negatives. Since the soldier responded quickly to

treatment, detection of similar cases may be difficult.

Media reports describe the hospitalization of 15-20 cases with similar

symptoms, but these cases have tested negative. On a related note, the

military has withdrawn all troops from culling operations, even though new

confirmed cases in birds are being announced daily (see satellite map), and

testing has expanded to asymptomatic ducks.

Thus, the media comments on a culler that has been PCR confirmed,

coupled with comments on H5 confirmed poultry, raise concerns that the

level of H5N1 infections in poultry and people will be significantly under-

reported.

With permission from Effect Measure:

Important new flu paper in Cell: part II

In our previous post we set the stage for discussing the results of a significant new paper by Imai et al. and colleagues on the mechanism of lung damage from diverse pathogens, including SARS, bird flu H5N1, 1918 H1N1 flu, inhalational anthrax and Monkeypox. If this work is verified it is a major step forward in our understanding of how the devastating consequences of Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI) come about and may well provide clues about how to treat what is still an essentially untreatable and catastrophic medical condition.

There are two main parts to their elegant results. The first has to do with TLR4. Imai et al. first showed that the rapid impairment of lung function in mice caused by breathing an acid chemical depended on TLR4. They did this by exposing various inbred mouse strains and finding that one, the C3H/HeJ mouse, didn't react in the same way. It was known that this mouse also showed resistance to LPS because of a mutation in the TLR4 gene. Interesting. But the dissection of the mechanism was just beginning.

We return to the idea that TLR4 is part of cell signaling (see our previous post). While some kinds of cell signaling is relatively simple, much depends on pathways of protein - protein interactions. The receptor button gets pushed by something binding to it, say at the surface of the cell (that's the signal). Now we need a response. The binding of the receptor by the signaling molecule causes the receptor to modify another protein which then interacts with yet another protein, etc., etc., in a potentially long pathway of interactions. The path may also branch into two or more pathways. Branching allows complicated interactions and feedbacks to produce dynamics not possible with a single straight line bucket brigade style signal.

There is a branch right after TLR4 is activated. One branch starts with another protein called MD88 which then interacts with still others until it winds up activating an important cellular protein called NFkappaB. The other branch starts with a protein called TRIF. The MyD88 branch is the best studied. Surprisingly, though, when a mutant mouse deficient in MyDD88 mice was used it showed no resistance to ALI. That suggested that the ALI (remember that means Acute Lung Injury) was being mediated by the other branch, through TRIF. Sure enough, abolishing TRIF in another strain of mutant mice restored the resistance to ALI on exposure to acid mist.

They then looked at cytokine production. Cytokines are chemicals that are used for local signaling. They are released in the immune response during inflammation (among other things) and if the release is not well regulated a runaway inflammatory response can result. Local production of cytokines is characteristic of ALI. But there are a lot of cytokines and unraveling how they all interact and what part each plays is a difficult problem. In this case Imai et al. noticed that one particular cytokine, IL-6 (interleukin 6) was related to TLR4 signaling or lack of signaling. Sure enough, mice deficient in IL-6 were much more resistant to acid mist exposure than mice capable of producing IL-6. This doesn't mean other cytokines aren't also involved but it does point to a role for IL-6.

If TLR4 signaling is involved, what is pushing the TLR4 button? One thought is that because lung cells are open to oxygen, maybe oxidative damage was the signal (I am skipping their experiments to rule out any hidden LPS involvement. Suffice to say there isn't.) Cells of the innate immune system, like macrophages (present as wandering scavengers and killers of pathogens in the lung), use the production of highly reactive oxygen species to kill pathogens. They do this with a "respiratory burst," again something that has to be controlled because the same reactive species that kills pathogens can cause damage to the host cell. TLR4 is embedded in the outside of the cell membrane (the bag that holds the cell contents). We discussed the make-up of the cell membrane in some earlier posts, connecting it specifically to the receptor the flu virus uses to glom onto cells... Suffice it to say one possible consequence of a respiratory burst is some oxidative damage to the cell membrane, which is made up of a lipid bilayer composed of phospolipids (see the earlier posts for a complete explanation of phospholipids). The cell membrane is not the only place where there are abundant phospholipids in the lung, however. There is a soap-like agent in the lung, surfactant, whose main function is to reduce surface tension and make it easier for the lung to keep expanded. It is made up of 8-% to 90% phospholipid. With all these potentially oxidizable materials around, Imai et al. wondered if oxidative damage to the phospholipids might be the trigger setting TLR4 signaling in motion.

The answer is a qualified "yes." We'll discuss the evidence and the connection to H5N1, SARS and some other agents in the last post, next.

The Editors of Effect Measure are senior public health scientists and practitioners. Paul Revere was a member of the first local Board of Health in the United States (Boston, 1799). The Editors sign their posts "Revere" to recognize the public service of a professional forerunner better known for other things.

Indonesia denies seeking payment for virus samples

http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/apr2308

samples.html

(hat tip crofsblog)

It still sounds like extortion to me.

An Indonesian health official, responding to recent comments by the US health secretary, today denied that Indonesia wants financial compensation if it resumes sharing its H5N1 avian influenza virus samples.

Widjaja Lukito, an adviser to Indonesian Health Minister Siti Fadilah Supari, said the country wants governments and pharmaceutical companies to develop a mechanism to ensure that developing countries have access to affordable pandemic influenza vaccines, the Associated Press (AP) reported today.

"There are many types of benefit programs that can be discussed. One could be a kind of revolving fund developed by pharmaceutical companies," Lukito told the AP.

He also suggested that the mechanism could be a multilateral trust, financially supported by governments, vaccine producers, and individual benefactors, to ensure that vaccine production and distribution are equitable, according to the AP report.

The Dispute Over NAMRU-2 Continues

http://crofsblogs.typepad.com/h5n1/2008/04/indonesia-wants.html

http://crofsblogs.typepad.com/h5n1/2008/04/namru-2-dispute.html

NAMRU-2 has done some fine work that has been of benefit to Indonesia,

a country with many types of disease outbreaks. It is unfortunate that

Indonesia has a different point of view about this.

Indonesia had refused to give diplomatic immunity to all 20 Namru-2 staff members and was prepared to grant it to only 2 of them.

"If we give diplomatic immunity to all of them, we are afraid we will not be able to control or know the things they do or take in the research activities," Juwono said.