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 Recombinomics Commentary
School Undercounts Raise Pandemic Concerns

Recombinomics Commentary 17:34
October 26, 2009

"It's been a combination of things," Soper said. "We do know we have the H1N1 flu up here, but there's also the seasonal flu, bronchitis, strep throat, pneumonia, it's just a combination of - the perfect storm."

The above comments represent one of many examples of media reports calling H1N1 infections something other than swine flu. Other media favorites include "bad cold", "stomach flu/bug", "allergies". This confusion is largely traced to a misunderstanding of the meaning of an influenza A positive sample, or attempts to classify swine flu patients who don't have a fever, but have one or more symptoms associated with swine flu. These misconceptions create serious media undercounts of H1N1 infections.

Although the official seasonal flu season has begun, there have been virtually no confirmed seasonal flu cases in the US, in part because the season is very young, and in part because of a crowding out of seasonal flu by swine flu. Consequently, many physicians use an influenza A test to diagnose swine flu because over 99% of influenza A positive samples are swine flu.

Confusion and misdiagnosis can largely be traced to the use of fever on the swine flu case definition. A high percentage of swine flu infections do not produce a fever, but since "fever" is in the case definition, many try to apply an alternate designation for such cases. However, these feverless cases appear at the same school and at the same time as the cases with fever, supporting multiple presentations of cases with the same etiology.

As the pandemic evolves, the number of infected students has increased at an alarming rate, leading to attack rates approaching 100% and massive school closings. In Michigan, 196 schools were closed on Friday (see map) and many schools throughout the country are reporting absenteeism rates well above 10-15%, which have been used in the past to close schools. Now many school closings are driven by a high absenteeism rate among teachers and staff, which prevent the school from functioning properly.

The high levels of infections will doubtlessly lead to more strain on the health care system, which were a factor in the declaration of a health emergency. The increases in cases lead to a lack of treatment, which produces more hospitalizations, heroic efforts, and deaths.

The high frequency of cases also raises re-infection concerns, which are supported by anecdotal evidence, increasing the likelihood that the current disruption and school closings will continue.

http://www.recombinomics.com/News/10260 ... Under.html

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Post Re: Recombinomics Commentary
US Emergency Declarations Raise Pandemic Concerns
Recombinomics Commentary 22:43
October 29, 2009

http://www.recombinomics.com/News/10290 ... tions.html

New York Gov. David Paterson has declared a state of emergency because of the rise in swine flu cases.

The executive order means that far more health care professionals - including dentists - will be permitted to administer vaccines with only brief training. The order is needed to suspend provisions of state law.

New York officials said the number of vaccine doses is also being increased. The federal government is ramping up availability of the vaccine, allowing the state to order twice as many doses as a week ago, a trend that's expected to continue.


The above comments describe the declaration of a state of emergency in New York, which follows President Barack Obama's declaration for the entire country. Although these announcements are said to be anticipatory and an attempt to streamline treatment, evidence is mounting that these steps are in response to a rapidly accelerating spread of H1N1, leading to school closings, hospitalizations, and deaths, which are straining the health care system.

Nationally, the declaration is designed to reduce red tape associated with treatment and to increase drugs under regulatory review, such as Premavir, which is currently in clinical trials as an IV treatment for influenza. However, like Tamiflu, H274Y seriously reduces the effectiveness of the drug, increasing concerns that widespread H274Y will seriously impact antiviral treatment, leading to more hospitalizations and deaths.

The latest CDC weekly report describes two patients that developed H274Y resistance in the absence of documented Tamiflu treatment. One patient is under investigation, while no linkage was established for anther. These two patients are in addition to transmission in North Carolina and Hong Kong which appear to be unrelated to Tamiflu treatment in the contact. This evolutionarily fit pandemic H1N1 parallels development of resistance in seasonal H1N1.

This week there was a dramatic increase in deaths in the United States and Canada, and this trend is being reported across the northern hemisphere.

The explosion in cases, hospitalizations, and deaths are outpacing the vaccine distribution, due in part to a realization that viral yields are lower than forecast. Delivery numbers projected for mid-October have now been pushed back to mid-November, and some countries are unconvinced that one shot will provide protection, so two shots are planned, raising concerns of more delays in the vaccine roll-out, as well as a delay in the date of protection.

Meanwhile, the CDC has reported a low reactor isolate, indicating the virus is evolving away from the vaccine. The initial CDC report was not detailed, and there was no mention of low reactor sequences in the latest report, raising concerns that such isolates are increasing. Similar, sequences from Germany and Austria were just released by Mill Hill, which were also characterized as low reactors. However, the associated HA sequences has a deletion leading to a truncated HA of 189 amino acids, so the viablilty of these isolates is unclear.

However, the rapid spread of H1N1 and the associated strain on health delivery systems is cause for concern, and may have precipitated the recent emergency declarations.

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Post Re: Recombinomics Commentary
http://www.recombinomics.com/News/10290 ... eland.html

H1N1 in Swine in Iceland Raises Pandemic Concerns
Recombinomics Commentary 21:17
October 29, 2009


Clinical signs commenced on 24 Oct 2009 with 10 sows off feed, temperature greater than 40 C, some were coughing, and 2 aborted. Two workers had had flu-like symptoms for a few days prior to the clinical signs in the pigs.

The above comments are from an OIE report on an H1N1 outbreak at a farm in Iceland. As was reported in prior outbreaks in swine in Canada, Argentina, Australia, UK, Ireland, Norway, Japan, Indonesia, and the United States, the swine infection was thought to be linked to infected workers. However, the detection of H1N1 swine in Iceland suggests that such infections worldwide are much higher than reported.

In the US, only one such outbreak has been reported. H1N1 was found in swine at a Minnesota Fair, so the number of reported outbreaks on farms remains at zero, even though the United States has reported the highest number of human cases, and outbreaks in swine producing states had been widespread and growing dramatically since the start of the new school year.

Although the USDA has chided reporters for calling swine flu swine flu, and assuring the public that the swine food supply is safe, they have provided no reports on the detection of H1N1 in swine, and unlike the above countries, have failed to file OIE reports. Reports by others have described a relative mild condition in swine, which rapidly spreads through herds and is eventually controlled through extensive culling. The failure to detect H1N1 in swine raises concerns that surveillance is minimal, which was clear in the spring when the human H1N1 sequences were released.

Those sequences clearly demonstrated that the H1N1 originated in swine. In addition to the 5 swine flu genes, there were two avian genes (PB2 and PA) and one human gene (PB1). The PB1 gene was introduced into swine in 1993, along with human H3 and N2. Subsequent H1N1 isolates swapped out the human H3 and N2 for swine H1 and N1 or human H1 and N1. Those with swine H1N1 subsequently acquired the avian PA and PB2 in the late 90's. These triple reassortants have been circulating in swine for over a decade.

However, the triple reassortants isolated from humans had evolved away from most of the sequences in American swine, reflecting the poor surveillance and limited sequence database for swine H1N1 in North America. The absence of reports of H1N1 in swine on farms in the US reflects a continuing poor surveillance of swine in the US, which provides little support for assurances that the H1N1 is not in the US swine food supply.

The same concerns exist for turkeys. H1N1 has been reported in turkeys in Chile and Canada, but there have not been reports of H1N1 in turkeys, even though human cases have been high in turkey raising states. These surveillance failures also raise concerns about H1N1 in US turkeys.

Although the vast majority of human cases of swine flu come from humans, the lack of surveillance in two well described hosts, swine and turkeys, raises concerns of silent evolution and transmission in the hosts.

A more robust surveillance system, especially in US swine, is long overdue.
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Post Re: Recombinomics Commentary
Commentary

WHO Targets Hemorrhagic H1N1 Cases in Lviv Ukraine


Recombinomics Commentary 19:54
November 3, 2009
http://www.recombinomics.com/News/11030 ... Hemor.html

Work will initially begin in Lviv region, where reported numbers of cases showing severe manifestations of acute respiratory illness have been especially high. Two virologists on the team have started working at the National Influenza Centre and the laboratories of the Central Sanitary and Epidemiological Station in Kyiv to provide diagnostic support.

The above comments from the WHO update on Ukraine strike a more serious tone than yesterday's quotes from WHO spokespersons playing down the alarming number of hospitalized and fatal cases, as well as media reports spinning political considerations, or politicians claiming only 15 confirmed H1N1 cases. As the WHO update clearly states, the dominant influenza circulating worldwide is swine H1N1 and it is assumed that most cases in the Ukraine are swine H1N1. Since the official government website lists 19,189 influenza cases (in addition to more than 235,000 ARI cases), the willingness of politicians to cite 15 confirmed cases, as well as media support in the distribution of the propaganda, is unfortunate.

The more severe manifestation of ARI cases are clearly hemorrhagic disease that fills lungs with blood and produces bleeding at all orifices, which are stark reminders of 1918 pandemic cases which were also linked to a swine H1N1.

Samples have arrived at Mill Hill in London, and sequence data should be available shortly. Since current swine H1N1 produced lethal infections in previously healthy young adults, and produced hemorrhagic disease, changes in the viral genome may be absent or minor. Therefore, release of the sequences to the entire scientific community would be useful.

Similarly, an update on the number of hemorrhagic cases would be useful. Rumors have suggested that such the number of such cases is significantly higher than the six described in media reports.

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Post Re: Recombinomics Commentary
H1N1 Doctor Deaths In Ukraine Raise Concerns
Recombinomics Commentary 22:22
November 1, 2009


Four doctors died of flu in Ukraine's Ternopol and Lvov regions, Health Minister Vasily Knyazevich said at the Sunday meeting of the operative headquarters for the prevention and treatment of A/H1N1 flu.


The above comments describe the death of four health care workers (HCWs) at two sites in western Ukraine. The government website shows a total of 53 deaths (see map), which is quite low if four HCWs have already died. HCW are trained in methods to minimize infections from patients, and they are likely to get prompt medical attention, yet four have already died. These numbers add to the confusion in Ukraine.

Initial reports denied the outbreak was due to H1N1 even though there was virtually no seasonal flu circulating in Europe (or North America). The explosion in cases of acute respiratory illness (ARI), in view of the exploding H1N1 pandemic throughout the northern hemisphere, would signal involvement in the cases in Ukraine.

However, even after H1N1 was confirmed in influenza and ARI patients in western Ukraine, Kiev was still maintaining that the cases there were not H1N1, even though 300,000 doses of Tamiflu are scheduled to arrive today, and a WHO investigative team is scheduled to arrive tomorrow.

The denials of H1N1 in obvious cases raise concerns that the number of fatalities is markedly higher that the 53 acknowledged, especially when 4 of the 53 are HCWs.

More details on the HCW deaths and on those hospitalized would be useful.

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Post Re: Recombinomics Commentary
http://www.recombinomics.com/News/11030 ... ities.html


Dr. Niman
Commentary

Belarus H1N1 Deaths Raise Concerns



Recombinomics Commentary 16:43
November 3, 2009

[b]
The first Belarusian death from swine flu was registered by health officials on Tuesday. The victim, a 37-year-old female resident of the town of Drogichin, died on Friday, but results of blood tests confirming the presence of the H1N1 virus only became available Tuesday, said Oleg Arnautov, chief doctor of the western Brest province.

The woman reportedly had visited Ukraine's western Kovel region, currently near the centre of Ukraine's flu outbreak, in early October.

In recent weeks, the Belarusian capital Minsk has seen an estimated 10 deaths of persons suffering from pneumonia preceded by flu-like symptoms. Public health workers were working to identify the virus causing the illnesses
./b]

The above translation describes the first confirmed H1N1 fatality in Belarus, as well as ten more likely swine flu deaths in Minsk.

These deaths are not surprising. Although Belarus has acknowledged 59 confirmed pandemic H1N1 cases, the flu activity is characterized as widespread, and over 99% of influenza A in Europe is swine flu.

The outbreak in western Ukraine (see map) has raised concerns that transmission and virulence has increased.

The number of cases may be related to seasonal weather changes. Flu Trends shows that the Ukraine has historically had a jump in cases at this time of year, presumably linked to colder weather and availability or lack thereof of heat for homes.

Since virtually all flu in Europe at this time is swine flu, this jump in flu cases would create a jump in swine flu cases. Moreover, the spike this year is markedly higher than prior years, which could explain the increases in hospitalizations and deaths.

However, the hospitalization of more than 15,000 raises concerns that the death toll could increase dramatically.

Today's government update has been delayed, but a local media report on Lviv described a sharp increase in cases to 104,019 and an increase in fatalities from 30 to 37.

The above reports of fatalities in neighboring Belarus raises concerns that there are also significant numbers of hospitalized and fatal cases there.

There have been some efforts of limiting border crossings out of Ukraine, but it seems likely that the H1N1 associated with these fatal cases has already spread throughout the region.

Sequence data on isolates from fatal cases in the Ukraine and Belarus would be useful.

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Post Re: Recombinomics Commentary
Clusters of Hemorrhagic H1N1 Pneumonia in Ukraine
Recombinomics Commentary 11:54

November 4, 2009

Ivano-Frankivsk Oblast

All the six dead young people had symptoms of severe hemmorhagic pneumonia. The disease starts slowly, with temperature rising to 37.2 - 37.3 degrees, slight cough and pain in joints. Nasal catarrh developed at the end of the second or third day. Autopsy revealed that the lungs were soaked with blood, the oblast chief specialist said.

The above comments are from an early story describing cases in Ukraine. The clustering of hemorrhagic cases raised concerns. The concern was increased by anecdotal reports citing a high frequency of such cases in Lviv. The recent WHO announcement that they were initially focusing of severe acute respiratory illness in Lviv also increased concerns.

Hemorrhagic pneumonia was also observed in the 1918 pandemic and was thought to be linked to cytokine storm. Consequently, those with robust immune systems (previously health young adults) disproportionately died, which has also been seen in the current outbreak (Mexico, US, and worldwide). However, the cases in Ukraine appear to be clustered, raising concerns that the virus has changed.

However, the change may be minor, since the current H1N1 has produced the above symptoms in earlier cases. More severe cases may be linked to a higher viral load, which could be linked to minor genetic changes, or simply due to concentration of virus in schools. In the US the spread of the virus has been linked to school openings, which lead to an explosion of cases and subsequent student deaths. However, now there are increases in fatalities in teachers and administrators, increasing concerns worldwide.

In Ukraine, weather changes and heating issues may have led to a surge in cases, and increased concentrations of virus could have produced conditions favoring high viral loads and increased cytokine storms.

Samples have been sent to Mill Hill, and sequence data should be released shortly. Similarly, investigations on hemorrhagic pneumonia in lviv should help resolve the mechanism for the high concentration of such cases in western Ukraine.

However, H1N1 spread in Kiev has been noted, and other countries such as Belarus have announced additional H1N1 suspect or confirmed fatalities.

Sequence analysis of these cases and an update on the frequency of hemorrhagic pneumonia in Ukraine and worldwide would be useful.

http://www.recombinomics.com/News/11040 ... sters.html
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Post Re: Recombinomics Commentary
Recombinomics Commentary 14:34
November 4, 2009


478,456 Influenza/ARI

24,003 Hospitalized

60 Ventilators

81 Deaths


The above numbers are from the latest update from Ukraine. The number of infected patients has almost doubled to just under ½ million, compared to the report two days ago (see map). Hospitalized patients also have spiked higher, to 24K from 15K. ICU cases are not listed, but 60 on ventilators are. However, most (37) of those on ventilators are Chernivisti Oblast, but Lviv, which has the most fatalities and cases, has none, suggesting the data is incomplete or there are significant shortages of ventilators. The number of dead has risen to 81, but media reports describe additional fatalities, include those in the Kiev Oblast.

The explosion of cases again raises concerns that the number of fatalities is significantly higher than the 81 listed. Media reports have described an equal number of pneumonia fatalities which were not considered flu related. The basis of these exclusions remains unclear. Similarly, anecdotal reports suggest the number of fatalities is markedly higher than the 81 in the table.

The rapid rise in reported infections, hospitalizations, and deaths in the past few days raise concerns that the virus is transmitting very efficiently. Spikes in cases have been reported throughout the northern hemisphere, but the spike in fatalities and the frequency in hemorrhagic cases in Ukraine have raised concerns.

Earlier media reports suggest that an update by WHO might be issued today and include preliminary analysis of samples sent to Mill Hill in London.

Daily updates on the rapidly evolving situation in Ukraine, including sequence analysis, would be useful.

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Post Re: Recombinomics Commentary
Quote:
Clusters of Hemorrhagic H1N1 Pneumonia in Ukraine
Recombinomics Commentary 11:54
November 4, 2009
Ivano-Frankivsk Oblast

http://www.recombinomics.com/News/11040 ... sters.html

All the six dead young people had symptoms of severe hemmorhagic pneumonia. The disease starts slowly, with temperature rising to 37.2 - 37.3 degrees, slight cough and pain in joints. Nasal catarrh developed at the end of the second or third day. Autopsy revealed that the lungs were soaked with blood, the oblast chief specialist said.

The above comments are from an early story describing cases in Ukraine. The clustering of hemorrhagic cases raised concerns. The concern was increased by anecdotal reports citing a high frequency of such cases in Lviv (see map). The recent WHO announcement that they were initially focusing of severe acute respiratory illness in Lviv also increased concerns.

Hemorrhagic pneumonia was also observed in the 1918 pandemic and was thought to be linked to cytokine storm. Consequently, those with robust immune systems (previously health young adults) disproportionately died, which has also been seen in the current outbreak (Mexico, US, and worldwide). However, the cases in Ukraine appear to be clustered, raising concerns that the virus has changed.

However, the change may be minor, since the current H1N1 has produced the above symptoms in earlier cases. More severe cases may be linked to a higher viral load, which could be linked to minor genetic changes, or simply due to concentration of virus in schools. In the US the spread of the virus has been linked to school openings, which lead to an explosion of cases and subsequent student deaths. However, now there are increases in fatalities in teachers and administrators, increasing concerns worldwide.

In Ukraine, weather changes and heating issues may have led to a surge in cases, and increased concentrations of virus could have produced conditions favoring high viral loads and increased cytokine storms.

Samples have been sent to Mill Hill, and sequence data should be released shortly. Similarly, investigations on hemorrhagic pneumonia in lviv should help resolve the mechanism for the high concentration of such cases in western Ukraine.

However, H1N1 spread in Kiev has been noted, and other countries such as Belarus have announced additional H1N1 suspect or confirmed fatalities.

Sequence analysis of these cases and an update on the frequency of hemorrhagic pneumonia in Ukraine and worldwide would be useful.


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Post Re: Recombinomics Commentary
Reported Cases in Ukraine Double Again To 871,037
Recombinomics Commentary 22:54
November 6, 2009
871,037 Influenza/ARI Cases

39,603 Hospitalized

135 Deaths

The above numbers from the latest update from Ukraine (see map) http://flutracker.rhizalabs.com/ continue to alarm. More than half of the Oblasts and cities listed exceed the epidemic threshold, including Kiev and Kiev Oblast, raising concerns that the increase in case numbers will accelerate. Moreover, hospitalization of 39,603 raises concerns that the number of deaths will also accelerate, since 11% of hospitalized cases in California died.

Although WHO has suggested that these alarming number may reflect sub-standard medical and housing conditions, the numbers remain alarming. Mill Hill indicated that at least 15 samples were H1N1 positive, indicating they now have a small database of Ukraine sequences. Although initial reports indicated there were no "major" changes, which presumably referred to reassortment, and no Tamiflu/Peramivir resistance, further analysis was required to rule out significant changes which were presumably linked to SNPs.

However, because the virus already has demonstrated an ability to cause fatal infections in a disproportionate number of children and previously healthy adults, small changes in the virus could lead to increases in viral load leading to an increase in cytokine storm frequency and hemorrhagic pneumonia, as reported for earlier cases.

Therefore release of full sequences at this time is warranted.

Similarly, more detail on the number of fatal and hospitalized cases with hemorrhagic pneumonia would be useful.

http://www.recombinomics.com/News/11060 ... ne_4X.html

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Post Re: Recombinomics Commentary
Withheld Ukraine Sequences Raise Pandemic Concerns
Recombinomics Commentary 02:30
November 7, 2009
Quote:
Right now we know that many clinical specimens and viruses have been sent to one of the WHO collaborating centres for further study. We don't know the results of those studies, and it will probably take a couple of days for the full analysis of those viruses to be available. But in the meantime, what we do not have is any evidence of viruses there or anywhere else as showing any big mutations. I raise this point because I have seen in some media reports that there are reports that WHO or other groups are saying that there are mutations and I want to point out that these are rumours and factually, untrue.


The above comments from Keiji Kukuda offer some general comments on the Ukrainian H1N1 sequences at Mill Hill in London. He specifically says WHO doesn't see any "big" mutations in the samples being sequenced, which would refer to reassortment or Tamiflu resistance. However, the changes seen in Ukraine do not require "big" mutations. Small mutations, such as SNP can have profound effects for a virus like pandemic H1N1.

That virus normally circulates in swine, and has recently jumped to humans. It already has many characteristics with the 1918 pandemic strain. Both are swine H1N1 that jumped to humans. Such species jumpers can increase efficiencies with small changes. One good example is position 627 in the PB2 gene. That position comes in two forms. When there is glutamic acid (E) at that position, the PB2 enzyme copies the viral genetic material most efficiently at 41 C, the body temperature of a bird. However, if that position has a lysine (K), the enzyme is most active at 33 C, the temperature of a human nose in the winter. The swine H1N1 has an E, which may be why it goes well in lung, which is 37 C and closer to the optimal replication temperature of 41C. However, a single change that produced the most efficient replication at 37C would lead to even higher levels in the lungs, which could lead to frequent cytokine storms, like those in 1918, instead of the less frequent level seen in Ukraine.

However, the rapid spread of H1N1 in Ukraine (see map), coupled with the high frequency of hemorrhagic pneumonia raise concerns that a small change is leading to a more virulent virus. Similarly, the rapid spread of the virus could also be affected by a small change in another gene, such as HA, which controls entry of the virus to cells and influences tissue tropism.

Mill Hill has acknowledged that they have at least 15 H1N1 positive samples from Ukraine, which would identify a Ukranian specific change. The delay in the announcement of sequence results raises concerns that such changes have been detected, and such changes are undergoing further analysis.

The number of cases in Ukraine continues to expand. The number of patients with H1N1 symptoms is now approaching 1 million. Cases have been increasing at almost 200,000 per day, so it is likely that tomorrow's report will have over 1 million cases. This rapid spread increases concern that the 15 sequences at Mill Hill contain one or more of these small changes, which has led to a delay in the announcement of sequence results.

More detail on the sequences at Mill Hill is overdue. The rapid spread of H1N1 in Ukraine demands rapid sequence results. Continued delay will only increase concerns.

http://www.recombinomics.com/News/11070 ... q_NOT.html

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Post Re: Recombinomics Commentary
Quote:
1918 RBD Polymorphsm in Ukraine H1N1?
Recombinomics Commentary 04:22
November 9, 2009

http://www.recombinomics.com/News/11090 ... _1918.html


The recent explosion of H1N1 cases in Ukraine (see map) has focused attention on sequences linked to the outbreak, especially those in the lungs of patients who developed a cytokine storm. This hemorrhagic pneumonia has been described previously in other fatal swine flu infections, but that rapid increase in reported deaths in Ukraine has raised concerns that the virus is transmitting more efficiently, or is replicating at higher levels in lung tissue.

These changes are frequently linked to changes in the receptor binding domain (RBD) in the HA protein. Changes in this domain can affect affinity for receptors and also modify tissue tropism. The recent expansion of seasonal H3N2 with M2 S31N was linked to two changes in or near the receptor binding domain, S193F and D225N.

Recent isolates from Sao Paulo, Brazil, collected from necropsy tissue from fatal cases had two changes at position 225. Two of the isolates, A/Sao Paulo/53845/2009 and A/Sao Paulo/53838/2009) had D225N (see list), the same change seen in seasonal H3N2. Interestingly, the swine H1N1 is a triple reassortant with flu genes from swine, humans, and birds. The human gene is PB1 and it was acquired in swine infected with a human H3N2. The initial isolates had three human genes, the H3 and N2 as well as the PB1. Thus, the prior association of the human PB1 in isolates with human H3,may increase the advantage offered by D225N.

However, two other isolates from Sau Paulo, A/Sau Paulo/53225/2009 and A/Sau Paulo/53206/2009, collected from the lungs of fatal cases, had another change at position 225, D225G. This polymorphism is more widespread and recent isolates have been found in Japan, Italy, and China (see list ). Moreover this polymorphism has been found in two isolates from the 1918/1919 pandemic, A/New York/1/1918 and A/London/1/1919. Thus, in 1918 the H1N1 virus usually had a D at position 225, but some of the later isolates had D225G, which parallels the data from the 2009 swine H1N1 isolates.

These RBD changes in recent isolates from Sao Paulo, as well as the presence of D225G in sequences from 1918/1919 raise concerns that the swine H1N1 is adapting to its human host by acquisition of RBD polymorphisms.

The explosion of cases in Ukraine, and delays in the release of sequences from fatal cases in Ukraine is a cause for increasing concern. Recent accelerations of deaths have been widespread across the northern hemisphere, raising concerns that receptor binding domain changes described above, as well as a third polymorphism at position 225, D225E, (see list) are gaining traction as the swine H1N1 adapts to human hosts.

An update on the Mill Hill sequences and deposit of such sequences at a public database such as GISAID, where Mill Hill recently deposited sequences from Europe, would be useful.


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Post Re: Recombinomics Commentary
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Withheld Ukraine Sequences Raise Pandemic Concerns
Recombinomics Commentary 02:30
November 7, 2009

http://www.recombinomics.com/News/11070 ... q_NOT.html



Right now we know that many clinical specimens and viruses have been sent to one of the WHO collaborating centres for further study. We don't know the results of those studies, and it will probably take a couple of days for the full analysis of those viruses to be available. But in the meantime, what we do not have is any evidence of viruses there or anywhere else as showing any big mutations. I raise this point because I have seen in some media reports that there are reports that WHO or other groups are saying that there are mutations and I want to point out that these are rumours and factually, untrue.

The above comments from Keiji Kukuda offer some general comments on the Ukrainian H1N1 sequences at Mill Hill in London. He specifically says WHO doesn't see any "big" mutations in the samples being sequenced, which would refer to reassortment or Tamiflu resistance. However, the changes seen in Ukraine do not require "big" mutations. Small mutations, such as SNP can have profound effects for a virus like pandemic H1N1.

That virus normally circulates in swine, and has recently jumped to humans. It already has many characteristics with the 1918 pandemic strain. Both are swine H1N1 that jumped to humans. Such species jumpers can increase efficiencies with small changes. One good example is position 627 in the PB2 gene. That position comes in two forms. When there is glutamic acid (E) at that position, the PB2 enzyme copies the viral genetic material most efficiently at 41 C, the body temperature of a bird. However, if that position has a lysine (K), the enzyme is most active at 33 C, the temperature of a human nose in the winter. The swine H1N1 has an E, which may be why it goes well in lung, which is 37 C and closer to the optimal replication temperature of 41C. However, a single change that produced the most efficient replication at 37C would lead to even higher levels in the lungs, which could lead to frequent cytokine storms, like those in 1918, instead of the less frequent level seen in Ukraine.

However, the rapid spread of H1N1 in Ukraine (see map), coupled with the high frequency of hemorrhagic pneumonia raise concerns that a small change is leading to a more virulent virus. Similarly, the rapid spread of the virus could also be affected by a small change in another gene, such as HA, which controls entry of the virus to cells and influences tissue tropism.

Mill Hill has acknowledged that they have at least 15 H1N1 positive samples from Ukraine, which would identify a Ukranian specific change. The delay in the announcement of sequence results raises concerns that such changes have been detected, and such changes are undergoing further analysis.

The number of cases in Ukraine continues to expand. The number of patients with H1N1 symptoms is now approaching 1 million. Cases have been increasing at almost 200,000 per day, so it is likely that tomorrow's report will have over 1 million cases. This rapid spread increases concern that the 15 sequences at Mill Hill contain one or more of these small changes, which has led to a delay in the announcement of sequence results.

More detail on the sequences at Mill Hill is overdue. The rapid spread of H1N1 in Ukraine demands rapid sequence results. Continued delay will only increase concerns.


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Post Re: Recombinomics Commentary
Ukraine Dead Increase to 239 - Still No Sequences
Recombinomics Commentary 20:26
November 12, 2009

1,253,558 Influenza/ARI

65.615 Hospitalizations

239 Deaths


The above numbers are from the latest update from the Ukraine Ministry of Health. The number of deaths increased 26 to 239, so 50 new deaths have been reported in the past 2 days. Although the virus continues to spread (only 5 of the 27 reporting areas have not topped the epidemic threshold) many of the deaths are still being reported from the hard hit areas in western Ukraine(see map). However, the biggest jump in cases was 6.096 in Kiev to 89,339.

The steady increase in the high level of deaths continues to raise concerns about genetic changes in the H1N1. In this morning's press conference the WHO discussed the need for prompt treatment with Tamiflu, but did not address genetic changes in Ukraine. Only general statements on the stability of the H1N1 were made in response to questions on genetic changes in Ukraine. Today's conference is a week after the last comments on the Ukraine H1N1 sequences which indicated that there were no large changes, but an update would be forthcoming in a "few days". It has now been over a week and no updates on genetic changes have been forthcoming.

The release of the sequences from Ukraine is long overdue.

http://www.recombinomics.com/News/11120 ... e_239.html

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Post Re: Recombinomics Commentary
Somebody check my math, but I get a CFR of .02 per cent. Wouldn't that be considered pretty low for a pandemic strain of flu?

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Post Re: Recombinomics Commentary
Total Destruction of Lungs in Ukraine Fatal H1N1 Cases


Dr. Henry Niman
Recombinomics Commentary 04:22
November 9, 2009


The symptoms are observed at different stages of disease - a fever with a temperature over 38 C, cough, respiratory disorders. When cough was characterized by negligible allocation phlegm or dry unproductive cough with blotches of blood. All the patients come to hospital on average by 3-7 days of onset, were in serious condition. Period of time from onset to death averaged from 4 to 7 days. In all patients during a hospital for signs of respiratory insufficiency of various degrees, which quickly rose and manifested accelerated respiration rate, shortness of breath and effectiveness of independent breathing. X-ray studies were performed on 1-2 day hospitalization. Most patients experienced a double-headed particles of lower lung lesion, followed by a trend towards total destruction.


The above translation is from an announcement today from the Ukraine Ministry of Health describe 90 fatalities (see map) associated with community acquired pneumonia. The full report included the age distribution, which exactly match distribution reported previously by other countries for swine H1N1. 52/90 fatalities were in the age group of 19-40, followed by 26/90 in the 41-55 age group.

Coughing up blood followed the "total destruction" of lungs again gives a clinical picture of hemorrhagic pneumonia caused by H1N1 swine flu.

However, although the 90 recent fatalities described above are clearly due to H1N1, many reports continue to cite a low number of H1N1 lab confirmed cases, which is more reflective of limited testing than actual cases.

Earlier reports cited pneumonia deaths not associated with the influenza/ARI category and the basis for the classification of approximately half of such deaths into a separate category remains unclear.

The above description of these fatalities increase the need for the immediate release of sequences from H1N1 isolated from the lungs of these fatal cases.

Samples were sent to Mill Hill a week ago and only a minimal description (no "large" changes and no anti-viral resistance) of the sequence data. As the number of reports of sequences with receptor binding domain changes in isolates from lungs of fatal H1N1 cases increase, the need for full and rapid disclosure of sequences from large outbreaks such as the one in Ukraine become a major health care imperative.

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Post Re: Recombinomics Commentary
Audio: Nov6 Nov9 Nov16 Nov 18 twitter
Live feed of underlying pandemic map data here
Commentary

D225G Lung Tropism Driving H1N1 False Negatives?
Recombinomics Commentary 23:17
November 19, 2009


The recently released H1N1 Ukraine sequences by Mill Hill provide additional insight into the evolution of H1N1. Ten isolates were sequenced, including HA from all 10. Four had the predicted receptor binding domain change D225G, which has been found on multiple H1N1 genetic backgrounds. All four of the sequences with D225G were from the four fatal cases. Although it is possible that there are two distinct H1N1 viruses in circulation, it is more likely that the virus is present as a mixture and those with higher concentration of D225G produce high concentrations of virus in lungs, leading to cytokine storms and deaths. Isolates with mixed signals coding for position 225 in H1N1 have been deposited at Genbank, supporting the mixture hypothesis.

These mixtures could be generating false negatives in cases where the level of D225G is high. Virus with D225G would quickly move to the lower respiratory tract and the low levels of wild type in the upper respiratory tract would be clear by the host's immune response. These patients would be infected and seriously ill, but the reduction or absence of virus in the upper respiratory tract would test negative. The CDC has warned that rapid tests have a sensitivity of 10-70% . Thus, in some circumstances only 10% of H1N1 infected sample test positive. This low sensitivity seems to be somewhat linked to H1N1 samples.

The negative data would lead to more testing for other respiratory viruses, which may explain the data reported for rhinoviruses in the Philadelphia area. No unusual strain has emerged, suggesting that the viruses may simply represent opportunistic infections associated with the H1N1 infection that is testing negative.

The detection of such opportunistic infections is similar to results generated when SARS first emerged. Since there was no direct test for the SARS CoV initially, many additional tests were run, and different labs would find different candidate respiratory viruses. However, after the SARS CoV was discovered and developed into a diagnostic test it was clear that SARS was cause by SARS CoV and the other viruses were just opportunistic passengers.

The rapid movement of influenza virus to the lungs has parallels with the H5N1 outbreak in Turkey in late 2005/early 2006. In that outbreak another receptor binding domain change, S227N was predicted and it was found in the first confirmed H5N1 cases. However, the index case had initially tested negative, as did his sibling, on nose and throat swab. H5N1 was confirmed from lung samples in each case. However, that infection also appeared to involve mixtures. Although the index case was positive for S227N, his sister was negative. Eventually 4 sequences were released and one of the two subsequent isolates also had S227N, further suggesting that mixtures were in circulation and collection/isolation issues determined if S227N was detected.

A tissue specific D225G in swine H1N1 could be generating higher frequencies of false negatives if the ratio of D225G to wild type was high.

More testing of post-mortem samples would be useful to better understand the true level of D225G in circulation.

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Post Re: Recombinomics Commentary
1918 RBD Polymorphsm in Ukraine H1N1?
Recombinomics Commentary 04:22
November 9, 2009

The recent explosion of H1N1 cases in Ukraine (see map) has focused attention on sequences linked to the outbreak, especially those in the lungs of patients who developed a cytokine storm. This hemorrhagic pneumonia has been described previously in other fatal swine flu infections, but that rapid increase in reported deaths in Ukraine has raised concerns that the virus is transmitting more efficiently, or is replicating at higher levels in lung tissue.

These changes are frequently linked to changes in the receptor binding domain (RBD) in the HA protein. Changes in this domain can affect affinity for receptors and also modify tissue tropism. The recent expansion of seasonal H3N2 with M2 S31N was linked to two changes in or near the receptor binding domain, S193F and D225N.

Recent isolates from Sao Paulo, Brazil, collected from necropsy tissue from fatal cases had two changes at position 225. Two of the isolates, A/Sao Paulo/53845/2009 and A/Sao Paulo/53838/2009) had D225N (see list), the same change seen in seasonal H3N2. Interestingly, the swine H1N1 is a triple reassortant with flu genes from swine, humans, and birds. The human gene is PB1 and it was acquired in swine infected with a human H3N2. The initial isolates had three human genes, the H3 and N2 as well as the PB1. Thus, the prior association of the human PB1 in isolates with human H3,may increase the advantage offered by D225N.

However, two other isolates from Sau Paulo, A/Sau Paulo/53225/2009 and A/Sau Paulo/53206/2009, collected from the lungs of fatal cases, had another change at position 225, D225G. This polymorphism is more widespread and recent isolates have been found in Japan, Spain, and China (see list ). Moreover this polymorphism has been found in two isolates from the 1918/1919 pandemic, A/New York/1/1918 and A/London/1/1919. Thus, in 1918 the H1N1 virus usually had a D at position 225, but some of the later isolates had D225G, which parallels the data from the 2009 swine H1N1 isolates.

These RBD changes in recent isolates from Sao Paulo, as well as the presence of D225G in sequences from 1918/1919 raise concerns that the swine H1N1 is adapting to its human host by acquisition of RBD polymorphisms.

The explosion of cases in Ukraine, and delays in the release of sequences from fatal cases in Ukraine is a cause for increasing concern. Recent accelerations of deaths have been widespread across the northern hemisphere, raising concerns that receptor binding domain changes described above, as well as a third polymorphism at position 225, D225E, (see list) are gaining traction as the swine H1N1 adapts to human hosts.

An update on the Mill Hill sequences and deposit of such sequences at a public database such as GISAID, where Mill Hill recently deposited sequences from Europe, would be useful.

http://www.recombinomics.com/News/11090 ... _1918.html
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Post Re: Recombinomics Commentary
Media Myths Cloud Joint Hearings on Pandemic Vaccine
Recombinomics Commentary 17:17
November 19, 2009

Look at Ukraine, for example, where public awareness went from "zero" this summer to "panic" this autumn. Late last month, politicians began to speak of mass illness and mass death. The government quarantined several provinces, shut down parliament and banned mass gatherings. When the dust began to settle last week, it appeared that, yes, there had been a small outbreak of swine flu, but also that, no, most of the people who got sick didn't have the H1N1 virus. Swine flu death rates in Ukraine are no higher than those for flu or pneumonia in other years.

The above Ukraine comments are from a Washington Post story cited by Senator Joe Lieberman on the first day of joint hearings on the pandemic vaccine shortfall. He was "surprised" that there were an estimated 22 million cases in the United States and the emphasis was on shortfalls linked to over promises on delivery dates and amounts of vaccine.

However, the hearings failed to capture the events in Ukraine, which was deemed a "non-event" in the above piece by op-ed writer Anne Applebaum, even though the importance of Ukraine was hard to miss. Even the most casual observer could look at the WHO H1N1 updates and see that some in Ukraine was attracting significant attention. WHO began issuing updates last April, when H1N1 was discovered in patients in Mexico and the United States. Thus the first two updates named the two countries in the title. However, subsequent updates were just number, with no county named. Initially these updates came out daily and then settle down to one update a week. The 72nd update was on Oct 30, but two days later a new update was issued on Ukraine. Another Ukraine update was issued on Nov 3 Two days later a second Ukraine update was released and on Nov 17, the date of the above article a third Ukraine update was issued.

In addition to media reports quoting WHO spokesperson, Ukraine also came up in WHO weekly teleconferences on Nov 5 and 12. These notices were carefully worded to exclude large changes in the virus, but left open small changes, including receptor binding domain changes. Such changes were of interest because hundreds of patients had died at a rate and level markedly higher than any other European country, and the descriptions of the fatal cases were detailed, noting severe hemorrhage, as well as the total destruction of both lungs. Patients had been arriving at emergency departments coughing up blood and dying within a few days. Moreover, most of the patients were previously healthy young adults.

The gruesome descriptions and the large number of fatal cases led to wild speculation by conspiracy theorists on one hand and media and political reports such as the one above, claiming that the Ukraine outbreak was small and not unusual.

However, the careful wording of WHO updates clearly left open the possibility of small changes including the receptor binding domain and the D225G change had been predicted, based on the high number of fatalities involving lung hemorrhaging and disintegrating.

Yesterday, the sequences from 10 isolates were released at GISAID by Mill Hill and the predicted change, D225G was confirmed. This change had been "in play" and was appearing on multiple H1N1 genetic backgrounds signaling recombination and selective advantage. The recent update of demographics for the 10 patients demonstrated that the four isolates with D225G were the four patients who had died, further raising concerns that D225G on a Ukrainian H1N1 background, or other H1N1 backgrounds could lead to more severe cases and deaths. Moreover the same change had been observed during the 1918-1919 pandemic, which also involved swine H1N1 jumping and adapting to humans.

Thus, the genetic change(s) in H1N1 in Ukraine is of considerable concern, media reports and Senator comments, notwithstanding

http://www.recombinomics.com/News/11190 ... gs_MM.html

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Post Re: Recombinomics Commentary
All Fatal Ukraine Cases at GISAID Have RBD D225G
Recombinomics Commentary 14:17
November 19, 2009

The patient data associated with the 10 Ukraine isolates sequenced by Mill Hill and deposited at GISAID has been updated with demographic information, suggesting that the samples were from 10 individuals and four of the samples were from deceased patients. These are the same four samples that have D225G (see list below). This association suggests that swine H1N1 with D225G is more aggressive and is cause for concern.

As noted earlier, D225G has been appended onto multiple genetic backgrounds via recombination, and the data from Ukraine adds further support. Samples from Ternopil and Khmelnitsky (see updated map) have a regional marker that is found in swine but no other human isolates. This marker is on all 6 Termopil isolates, indicating it was an early acquisition, but only the two fatal cases have D225G indicating it was appended onto the Ternopil genetic background. However, it is also found in the two fatal cases from Lviv, which do not have the regional marker. Similarly, earlier isolates with D225G represent distinct genetic backgrounds with D225G.

It was the jumping of D225G that allowed for prediction of the marker in Ukraine prior to release of the sequences by Mill Hill. This type of jumping has been described in detail for H5N1 and seasonal H1N1. This type of jumping via recombination and identification of markers that make frequent jumps are the underlying concepts that allow for the D225G prediction.

However, it is likely that D225G jumps will continue and the lethal marker will spread via Ukraine-like viruses, as well as virus that acquire D225G by recombination. Moreover, the absence of D225G in the nasal washes may signal mixtures of H1N1, with wild type dominating in the upper respiratory tract, and versions with D225G being expressed at highest levels in the lung, leading to false negatives in nasopharyngeal swabs, and cytokine storms in lung tissues where the aggressive virus with D225G is at high concentrations.

A/Khmelnitsky/1/2009
A/Ternopil/19/2009
A/Ternopil/11/2009
A/Ternopil/6/2009
A/Ternopil/5/2009
A/Lviv/N6/2009*#
A/Ternopil/N11/2009*#
A/Ternopil/N10/2009*#
A/Lviv/N2/2009*#
A/Kyiv/N1/2009

* D225G

# Deceased

http://www.recombinomics.com/News/11190 ... D225G.html

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Post Re: Recombinomics Commentary
D225G in Fatal H1N1 Lung Cases in Norway and Ukraine
Recombinomics Commentary 16:05
November 20, 2009

WHO says same mutation (at 222 on the HA) seen elsewhere, sometimes in fatal, other times in mild cases. Signifi of change unclear.

The above comment from a Helen Branswell tweet indicates the polymorphism in Norway is position 222, which would correspond to position 225 using H3 numbering.

Although there have been examples of D225N, D225E, and D225G, the recently released sequences from Ukraine were D225G and associated with fatal lung infections and D225G is clearly "in play", using recombination to jump from background to background in Brazil, Australia, China, Spain, Japan, and Russia.

Therefore, the "mutation" in Norway is also almost certainly D225G.

http://www.recombinomics.com/News/11200 ... raine.html

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Post Re: Recombinomics Commentary
Large Tamiflu Resistant Cluster in Wales UK

Recombinomics Commentary 17:50
November 20, 2009
http://www.recombinomics.com/News/11200 ... Wales.html

The cases have been reported among nine patients in a hospital in Wales. Five cases are "known to be resistent to oseltamivir", the generic name for Tamiflu, the HPA said today in an e-mailed statement.

The above comments describe a large cluster of Tamiflu resistant swine H1N1 in a hospital in Wales. Earlier reports had described resistance in 2 immuno-compromised patients, but the updated report of 5-9 patients leaves little doubt that the virus is transmitting human to human. All prior examples of resistance in swine H1N1 involved H274Y, which is almost certainly the case for this outbreak. Previously there have been multiple reports of clusters of two, including recent outbreak in Edinburgh, and this large outbreak raises concerns that H1N1 with H274Y will become far more common.

Although prior cases were said to be due to "spontaneous mutation, by Roche and agency reports, there was little data to support that conclusion. All resistance involved the same change, H274Y, on multiple H1N1 backgrounds and appearance was too soon to support a spontaneous origin. Instead the rapid appearance supported circulation of H274Y as a minor population which was below detection limit in the absence of Tamiflu selection, but rapidly appeared after treatment. The appearance of 5-9 cases at the same facility indicates the detected H274Y was not due to independent mutations and reinforces concerns that H274Y is widespread and efficiently transmitting..

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Post Re: Recombinomics Commentary
D225G in Fatal H1N1 Cases in Norway? Recombinomics Commentary 14:05
November 20, 2009

Laboratory tests from 70 patients are examined, of which eight patients have died. Total is the mutation found in five of the patients. Two of them are dead, while the other three have been hospitalized with serious illness in intensive care units.

The new mutated virus thrives further down the respiratory system than the original. It shuts down the lungs of patients, which means more severe disease than the original virus, which first affects the throat and upper respiratory tract.

Since the new virus in the lungs and is only detected in patients who have been admitted to hospital, experts expect that it is less contagious than has affected most who are infected so far.

Both the vaccine and Tamiflu as a treatment will work also for this variant of the virus, "says director Geir Stene-Larsen at the NIPH.


The above translation suggests that D225G has been found in the lungs of dead and dying patients in Norway. An investigation into the excessive H1N1 deaths in Norway had been ordered and a news conference has been called to discuss the "mutation". The description sounds like the D225G found in fatal cases in Ukraine.

http://www.recombinomics.com/News/11200 ... y_225.html

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Post Re: Recombinomics Commentary
Commentary

Ukraine Dead Increase to 354 - Fatal H1N1 Cases Have D225G

Recombinomics Commentary 14:05
November 20, 2009
http://www.recombinomics.com/News/11200 ... e_354.html

1,540,514 Influenza/ARI

88,744 Hospitalized

354 Dead


The above numbers represent the latest figures from the Ukraine Ministry of Health. The increase in deaths is 10, which is lower than recent increases and more Oblasts have fallen below the epidemic threshold, but Live still leads in daily increases in cases (from 114,211 to 118,256) suggesting the outbreak has moved east (see map). Similarly, Kiev recorded the largest increase in fatalities (14 to 18 ).

Recently, Mill Hill in London released sequences from 10 patients in Ukraine and most were in the areas hit hard at the beginning of the outbreak, Ternopil and Lviv. Four of the ten were sequences from deceased patients and all four had D225G, which was not present in the six HA sequences from patients who survived.

This correlation between the receptor binding domain change, D225G and fatal cases is cause for concern, and recent reports describe large increases in cases and fatalities in Poland, raising concerns that this change has significantly spread to the west of western Ukraine also.

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Post Re: Recombinomics Commentary
Evidence on H1N1 D225G in Lung Cases in Norway and Ukraine
Recombinomics Commentary 11:29
November 21, 2009

The WHO said the mutation does not appear to spread and the public health significance of the finding is unclear.

"Although further investigation is under way, no evidence currently suggests that these mutations are leading to an unusual increase in the number of H1N1 infections or a greater number of severe or fatal cases," the agency said.


The above WHO comments on the receptor binding domain change D225G (cited as position 222 in some reports using H1 numbering) is curious. Although WHO claimed that there were no significant changes in the sequences from Ukraine, none of the Ukraine situation updates excluded a receptor binding domain change, and when 10 HA sequences were published at GISAID by WHO regional lab Mill Hill, there was clear evidence of an association of D225G with fatal cases. Of the 10 sequences released, four were listed as deceased, and all four had D225G. None of the six samples which came from patients that were labeled with age and gender but had no deceased designation had D225G. Moreover, three of the four samples from deceased patients were lung samples and all three lung samples had D225G. The samples which had closely related sequences but lacking D225G were predominantly nasal washes, which also presented concerns that the swine H1N1 was differentially detected, due in part to changes in receptor binding specificity.

This concern was based on published data on sequences from samples from 1918 patients. In 1918 the same change occurred. Most samples had a D at position 225, while two samples had D225G (from 1918 and 1919). The tested sample with D225G had a different binding specificity, which would be expected to show differential binding to various tissue types.

Moreover, the D225G identified from Ukraine was in both of the hard hit areas, Ternopil and Lviv. Two samples from each area were positive, indicating the change had spread. Ukraine has already acknowledged over 350 dead patients and initial reports described hemorrhagic lungs that were totally destroyed. This destruction was in multiple media reports as well as an agency report describing 90 fatal cases.

Moreover, the evidence was not limited to Ukraine. Earlier samples from lung tissues from deceased patients in Sao Paulo also had D225G, as did patients in multiple countries. Most cases were not described in detail, but the case from China was from the first severe case in Zheijiang Province and although the patient survived, she was hospitalized for several weeks.

In addition, the presence of the same change on multiple backgrounds indicated the polymorphism was being acquired via recombination. The sudden appearance of the same polymorphisms on multiple backgrounds has been described previously, including a silent change in H5N1 and H274Y in seasonal flu. These changes allowed for the prediction of D225G in the Ukraine patients prior to release of the sequences.

The above comments were made after D225G was found in samples from deceased or severe cases in Norway, which provided further evidence of spread and association with lung samples.

Thus, there was and is ample evidence of D225G in severe and fatal cases. Like 1918, it is not in all samples from fatal cases, and as with all infectious disease, not all infections are fatal. If the initial dose is low, or the hosts mounts and effective early defense, the clinical course may be mild, as has been seen with virtually all influenza infections, including H5N1 infections such as those in Egypt.

Thus, the presence of the 1918 receptor binding domain change in an H1N1 swine virus that has jumped to humans is cause for concern, and a more comprehensive survey of lung samples is useful, as well as release of new receptor binding data.

http://www.recombinomics.com/News/11210 ... dence.html

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