Pandemic News/Awareness - Thread 3

Curious Tamiflu Resistance in Florida

http://www.recombinomics.com/News/05210804/H274Y_Florida.html

A change in a single nucleotide polymorphism (SNP) of a virus, pronounced

"snip", means that a single base in the DNA differs from the usual base at that

position. H274Y is a SNP associated with resistance to the antiviral drug, Tamiflu.

While this may be a positive adaptive change for influenza viruses, it is not good

for humans.

There is no easy explanation for this change. The evidence points to

the extensive use of Tamiflu in the countries battling H5N1 as the probable

cause.

The movement of H274Y from one genetic background to another can be

accomplished by recombination, and the timing of the initial outbreaks raise

concerns that they originated in H5N1, which has the identical change and

has been reported in patients as well as wild birds.

... these Florida isolates also share a polymorphism that is almost exclusively

found in N1 from H5N1 (see list here) again signaling recombination between N1

in H1N1 and N1 in H5N1.

...these interactions could be significant, and could explain the sudden

appearance of H274Y in H1N1 following prophylactic use if oseltamivir to control

H5N1.

http://www.recombinomics.com/News/05230801/H274Y_Fatal.html

The...translation describes two patients in the Netherlands who died from infection with Tamiflu resistant H1N1. Their immune system was compromised, and the H1N1 was not susceptible to Tamiflu (oseltamivir) treatment.

The report highlights the limitations of using Tamiflu to treat seasonal flu when the H274Y status is unknown. H274Y is common in many European countries.

Although these isolates are susceptible to Relenza, and some are still sensitive to amantadines, the reliance of Tamiflu can have deadly consequences.

Moreover, the widespread distribution of H274Y in H1N1 can impact H5N1 treatment if the polymorphissm is acquired by recombination.

Recent mild H5N1 cases raise concerns that the level of H5N1 in human populations is significantly higher than the confirmed cases reported by the WHO.

Bangladesh

http://crofsblogs.typepad.com/h5n1/2008/05/more-on-the-ban.html

This story is, oh so very strange...

They sent the samples in January. The CDC confirms it in May?

...experts from the Directorate-General of Health Services and International

Centre for Diarrhoeal Diseases Research, Bangladesh, went to see the child

on Thursday and found that he was absolutely cured.

The DGHS circulated a press note that stated that the child was infected with

bird flu in January this year and was cured after 14 days of treatment.

The government sent the sample of the child's blood and other body fluids to

the CDC Atlanta for diagnosis that very month.

About 3,700 suspected cases of the virus in human bodies were reported and

only one case was detected as bird flu in the country...

WHO Confirmation of First H5N1 Case in Bangladesh

http://crofsblogs.typepad.com/h5n1/

http://in.reuters.com/article/southAsiaNews/idINIndia-33731720080523

How can he say this with a straight face? Oh, wait a minute! He's a spin

meister, that's how.

I am thoroughly disgusted. January to May for a diagnosis? Are we stupid?

This is the agency that is going to inform us should a pandemic occur?

"The case was confirmed by CDC in Atlanta. It is the first in Bangladesh," WHO spokesman Gregory Hartl told Reuters.

The 16-month-old boy was infected in January and has since recovered, he said. Bangladesh authorities informed the United Nations agency promptly about the case but it took time for the international laboratory testing to be completed, Hartl said.

H5N1 Expanding Geographic Range

http://www.recombinomics.com/News/05220803/H5N1_Aomori.html

They were in the same Towada Lake where the first positives were found a month ago (see satellite map). These swans were on the east side of the lake and therefore in the Amori Prefecture. A new outbreak in Korea was also reported this week, suggesting a new wave of birds may be migrating through the area.

The HA is closely related to a wild bird sequence from Hong Kong in 2007 which has been selected as the clade 2.3.2 vaccine target, but the sequence has been withheld. It is not clear of the withholding is linked to publication, or if the publication centers on the fact that the isolate is a reassortant. However, both isolates from Japan are reassortants, and the identity level of 99.7% or higher suggests the isolates in Korea are also Fujian reassortants linked to wild birds in Hong Kong..

Fujian sequences have not been reported previously in long range migratory birds like whooper swans. The detection in Japan over a one month period suggest that the level of Fujian infections is high, which is supported by the record levels reported in Korea, and the first reported H5N1 case in Primore in southeastern Russia.

The repeated detection of H5N1 in whooper swans in multiple locations over a one month time period raises additional concerns regarding an expanded geographical reach of H5N1.

Prior to the lab confirmation of H5 in the soldier in South Korea, the human Fujian isolates had been limited to the large clade 2.3.4 sub-clade. Since the 2007 / 2008 wild bird sequences in Hong Kong have not been released, it is not clear when the 2.3.2 / 2.3.4 reassortant formed, but its presence in long range migratory birds in locations in Japan and Russia in regions which have not previously reported H5N1 raise concerns of a significant global expansion of Fujian H5N1, which includes migration to North America.

With permission from Recombinomics:

Global Expansion of Fujian H5N1 Confirmed

http://www.recombinomics.com/News/05230805/H5N1_Fujian_Global.html4[/url]

The match between the Fujian H5N1 sequences in Primorsky, Russia with multiple sequences from northern Japan and the record outbreak in South Korea leaves little doubt that a global expansion of Fujian clade 2.3 sequences has begun. H5N1 has never been reported in northern Japan or southeastern Russia and prior outbreaks in South Korea and Japan have been at the end of the year when birds are migrating into the region. The current outbreaks are in the spring, when birds are migrating out of the region.

The tracks of outbreaks (see satellite map) signal movement to the north and will likely migrate Fujian H5N1 into new regions. Although such movements may have happened previously, but not detected, the record levels in South Korea and the multiple locations in northern Japan suggest that the current levels are higher.

This expansion has much in common with the expansion of the Qinghai (clade 2.2) strain three years at Qinghai Lake. Those sequences migrated north to Siberia and Mongolia over the summer, and then spread to Europe, the Middle East, and Africa. To date, all H5N1 west of China has been clade 2.2. Clade 2.2 also expanded into south Asia as well as South Korea / Japan in 2006/2007.

The current outbreaks represent the first reports of the Fujian strain (clade 2.3) in Japan, South Korea, or Russia. The movement into northern Japan signals movement into North America in the upcoming weeks via the East asian flyway. Similarly, the movement into Russia signals migration into northeastern Russia, which will also feed into North America. The H5N1 in South Korea signals movement into Siberia, where there will be mixing with clade 2.2 from Europe, the Middle East, and Africa. This will lead to more rapid evolution via recombination between clade 2.2 and clade 2.3.

All public human sequences from China have been the Fujian strain, and the clade 2.3.4 sequences from the public sequences from Japan and Russia are most closely related to sequences from a human case in Guangdong province in 2006. Thus, these clade 2.3 sequences have been confirmed in human cases in China and the soldier in South Korea was H5 positive, although Korea has denied the infection because of false negatives for N1.

This global expansion has been confirmed with Fujian sequences in three countries that have never reported Fujian sequences previously. Surveillance programs, especially those that focus on healthy wild birds have been abysmal, in part because cloacal swabs are collected, and the methodologies used have been fatally flawed.

Recent results in Japan have also highlighted problems linked to false negatives generated by the rapid tests, which have a notoriously low sensitivity. Testing of dead and dying whooper swans in Japan has been successful, including testing on samples that have previously been negative by rapid test.

A more serious surveillance effort is required to accurately map the transport and transmission of Fujian H5N1 by long range migratory birds. The prompt release of sequences by labs in Japan and Russia should serve as a model for this surveillance.

The reliance on false negatives and the hoarding of sequences remain hazardous to the world's health.

A Big Bang Theory for Pandemics

An interesting piece by Scott McPherson, the Chief Information Officer (CIO)

of the Florida House of Representatives.

http://www.scottmcpherson.net/journal/2008/5/23/a-pandemic-big-bang.html

Since the child is recovering without the aid of antivirals, this means that we are probably looking at a very mild Qinghai clade 2.2 H5N1. This implies that if one toddler contracted high-path H5N1, then we need to assume others in the region bordering and including east India (a region the size and shape of the state of Maine) have also contracted H5N1. Since we have not seen a massive die-off of humans in the region, my suspicion is this mild H5N1 is being misdiagnosed as seasonal flu. If it is not tipping the scales on influenza tests, it is not evoking concern. This hypothesis is bolstered by the false negative and subsequent discovery of H5N1 by the CDC six weeks later, in the culturing of the virus.

the plot thickens. we now find that bangadesh waited one and a half

months to send a negative sample to cdc in atlanta. they tested

a child with mild flu who had no exposure to any farm because he lived

in a slum in the capital city. the initial test in bangladesh was negative but

they sent the sample anyway. why? what caused them to test him at all?

why would he fall into a routine surveillance category?

with permission from recombinomics:

mild h5n1 in bangladesh increases pandemic concerns

http://www.recombinomics.com/news/05220806/h5n1_dhaka_mild.html

the dghs, as part of its routine surveillance, sent a swab with samples from naso-pharyngeal of the 16-month-old boy to the centres for disease control and prevention in atlanta which confirmed the h5n1 infection wednesday.

"when the child came to us it was diagnosed with strain a positive but the h5 was found negative. however, one and a half months later when we sent the sample to atlanta, as part of our routine surveillance, it was confirmed after culturing the virus that it was h5 positive,"

the boy, who lives in kamalapur in dhaka, was cured without any medicine for influenza. he was provided with medicines for respiratory infection for 14 days...

the above comments describe the first h5n1 confirmed patient in bangladesh. as expected, the child had a mild case of h5n1 that initially tested negative for h5n1. although he was influenza a positive, he was not treated for influenza and recovered. the h5n1 infection was discovered through routine surveillance.

the spread of mild h5n1 has been a cause for concern. a year ago there were mild cases reported in central and southern egypt. these cases were not fatal and most patients did not develop pneumonia. thus, the h5n1 cold be more easily spread because patients were not critically ill, and testing of contacts would be rare, because most index cases would not be tested.

in bangladesh in january h5n1 was widespread in poultry and wild birds. crows had tested positive throughout the country, and dead crows were reported in dhaka. crows were h5n1 positive in other major cites such as chittagong, raising concerns that human h5n1 were markedly greater than the one confirmed case.

similarly, h5n1 was at record levels in west bengal in january, and wild birds were dying there also. villagers were eating poultry that had died, and children had developed symptoms. however, those cases were not tested. instead they were monitored. india repeatedly announced the lack of suspect cases with pneumonia, but mild cases of h5n1 infection do not develop pneumonia.

these mild cases provide opportunities for h5n1 to adapt to human hosts by recombining with seasonal flu and acquiring the ability to transmit efficiently. these types of adaptations in densely populated areas such as bangladesh or eastern india are of considerable concern.

the evidence for these infections is in the sequences of the viruses. in israel, h5n1 pb2 sequences have human polymorphisms. similarly, tamiflu resistance in human h1n1 had become widespread through the acquisition of the polymorphisms found in resistant h5n1. in seasonal flu isolates in florida, h5n1 polymorphisms have been acquired.

thus, the mild h5n1 are flying below the detection level and lead to humanization of the h5n1 as well as transfer of avian polymorphisms to seasonal flu.

antibody testing of patients in bangladesh and india who had respiratory symptoms when h5n1 activity was peaking in january and february would be useful. similarly, release of h5n1 sequences from poultry and mammals, such as dogs, cats, and jackals that died after eating h5n1 infected birds would be useful.

h5n1 continues to silently spread and evolve under the poor surveillance in these affected areas.

With permission from Effect Measure:

The Reveres on Bangladesh

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.

Bangladesh now has its first confirmed human case of avian influenza. That's news. Maybe:

Bangladesh announced its first human case of bird flu on Friday in a 16-month-old baby boy, bringing the number of countries which have recorded human infections to 15. Avian Influenza has already spread through 47 of Bangladesh's 64 districts and concerned Indian authorities say when the disease is so widespread in poultry, it is really a matter of time before humans start getting infected. (Times of India)

Specimens from the case had been sent to CDC in the US and the diagnosis confirmed by WHO. So why is it news "maybe"? This case goes back to January. The virus has been devastating poultry in the country since March 2007. Bangladesh is one of the most densely populated countries in the world and its environment is loaded with H5N1. If you think this is the first case -- if you think it's the only case -- then I have a 1995 Volvo sedan for you. Low mileage. Driven by mild mannered academic. Looks like a shitbox but don't be fooled: it's a really, really great car.

Just like this is the first and only case of bird flu in Bangladesh. Latest worldwide tally of human cases here (doesn't include this case).

[http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_04_30/en/index.html]

The WHO table also does not contain the South Korean case.

Bangladesh Prepares

http://crofsblogs.typepad.com/h5n1/2008/05/bangladesh-prep.html

They have needed all the help that they could get since at least March 2007.

I guess it takes some time to set everything up.

To diagnose the infection, the government has established a laboratory with

real-time polymerase chain reaction, a rapid method for diagnosis of all kinds

of influenza viruses

...Real-time PCR lets a scientist view the increase in DNA as it is amplified,

and allows rapid screening of samples for diagnosis and disease tracking.'

The government also ordered installing a Bio Safety Level 3 Laboratory on

the IEDCR premises to tackle incidence of influenza and other dangerous

pathogens within four to five months.

With the assistance of international financial institutions and lending agencies,

the government has already trained a large number of health professionals and

people.

...there are about 2,26,100 volunteers at the union that working to raise the

awareness of the people. They are visiting the door to door with messages and

leaflets, said health officials.

Nepal Worries and Waits...

http://crofsblogs.typepad.com/h5n1/2008/05/nepal-we-are-on.html

If I was a gambler, I would bet that it is already present, and that they just

are not aware of it yet. The birds and the virus are not deterred by borders.

Dr. Dhan R. Ratala, programme director of the Directorate of Livestock Services Training and Extension said, "We are only 15 km far from the virus and there are high possibilities of transforming virus in the country."

Firstly, we should stop the virus from entering the country, if it is not controlled, we should try and stop the transmission from one district to another, he said.

Other Bird Flu Viruses of Concern

http://afludiary.blogspot.com/2008/05/study-h7-strains-evolving.html

H7N2, H7N3, and H7N7 have already caused some human infections, and one

death. Follow the link for the list of cases.

An additional concern would be that if any of these viruses should co-infect

a host that already has H5N1, it might pick up the ability to be more easily

transmitted. You can see from the number of cases that at least one of these

viruses was rather easily transmitted. Eighty nine cases in one outbreak

would seem to indicate that it was.

...a study has been released in PNAS (Proceedings of the National Academy

of Sciences) suggesting that the RBD (receptor binding domain) of the H7N2

virus may be evolving to more easily infect humans.

RBD's are the area of a virus that allows it to attach to receptor cells in a

host's body. Different viruses are attracted to different types of cells, which

explains why some viruses that affect man, don't affect other species, or vice

versa.

Receptor cells have strands of sugar (carbohydrate) molecules on their surface.

These carbohydrate molecules - called glycans' - form a dense sugary coating

to all animal cell membranes.

When a virus meets a compatible receptor cell, they bind. And infection ensues.

http://tinyurl.com/5wfkqm

...a virus recovered from a strange H7N2 infection in the Yonkers area of New

York City. A man who had no known contact with poultry was hospitalized in

November 2003.

Several months later testing at the CDC revealed the rare infection. How the

man caught the virus remains a mystery.

Of all the H7 viruses studied for this work, the New York man's seemed most

adapted to humans. It bound more easily to the receptors found in the lining of

the human upper respiratory tract and had decreased binding to bird receptor

cells. And when ferrets were inoculated with the virus, it spread from the

infected animals to healthy animals placed in the same cages.

But in general H7 viruses from North America that have been isolated from

about 2002 onwards seem to have developed an increasing affinity for the

human-type receptors, said Dr. Terrence Tumpey, the CDC scientist who

led the work.

"Because we can look at an older North American H7 or Eurasian H7s or

H5s and they have the characteristic avian influenza binding properties. Whereas

these seem to be different and possibly changing."

Looking Back to 2003 - Yonkers, NY Case of H7, Bird Flu

http://www.recombinomics.com/News/04280802/H7N2_NY_

Reassortant.html

If they are going to get serious about looking for these avian flu viruses in

wild birds, they will need to use better testing methods including up to date

primers and testing the pharyngeal secretions as well as cloacal. The

Russians are doing a great job in testing for H5N1 in live as well as dead birds,

and reporting the results so we know that it can be done. The Japanese

have been transparent as well as timely with their reports on the recent swan

deaths pointing to the fact that H5N1 is expanding its range and heading

towards North America. So why would it take 4 years for the data on the

Yonkers case to be released over here?

This is the first report of an H7N2 reassortant with human and avian flu

genes and raises concerns of further genetic exchanges in an avian population

since the H and N genes are avian. H7 is also readily transmitted human

to human, but usually produces mild symptoms, including conjunctivitis.

This patient however had respiratory symptoms and was hospitalized. The delay

in the discovery of the H7N2 infection in this patient was because it was initially

thought to be an H1N1 infection, and testing was slow because of a low

frequency of cases in 2003/2004. However, it remains unclear why it took

four years to release the sequence data.

Surveillance of H7 in wild birds is poor. There have been H7 outbreaks

in Canada in British Columbia and Saskatchewan, but no H7 was detected in

wild birds prior to the poultry outbreaks. A recent report on H7 surveillance

indicated that the primers, designed to detect H7 in poultry, were mismatched

for H7 in wild birds.