Scott McPherson's Web Presence

The concern within China regarding the origin of four recent human H5N1 cases is palpable. Within the past three weeks, there have been four cases of H5N1, and three of those cases have resulted in death. There are suspicions that in two of the cases, possible human-to-human transmission may have occurred, although proving this theory (or disproving it) is now almost impossible.

For example, in the case of the 2-year-old girl (to this point the lone survivor), "her mother had contact with live poultry around December 21 and she had a little fever on December 28," said an official with the public health office of Hunan Province. "Then it developed into pneumonia and she died on January 6." Hat-tip to Crof on that one.

In the case of 19-year-old Huang Yanging, the first Chinese death in almost a year: A nurse treating her was herself overcome with fever, and some 116 contacts were actively monitored by Chinese health authorities. My blog on that case can be found at: http://www.scottmcpherson.net/journal/2009/1/6/was-huang-yanqing-a-carrier-of-h2h-h5n1.html

These four cases occurred all overthe Chinese nation. To date, aside from that lone comment from the Hunan government, there is nothing linking the cases to diseased poultry -- a fact that has sent shivers down the spines of Chinese influenza and infectious disease researchers. And now, normally tight-lipped Chinese scientists are openly discussing the possibility that the virus may have mutated again (at least in China) to produce a virus that is less lethal to chickens, while retaining its lethality toward humans.

The latest article on this comes from today's Epoch Times. The article reads:

Hong Kong Expert Worries About Recent Bird Flu Cases

Four persons infected in China this year

By Lin Yi
Epoch Times Staff Jan 21, 2009

HONG KONG—In two weeks, four people in China have been confirmed infected with H5N1 bird flu virus. An expert in Hong Kong worries about the possibility of an inapparent infection,* and the risk of human-to-human transmission becoming more likely.

Currently, three of the four persons have died from the virus. Professor Paul K. S. Chan from the Department of Microbiology of the Chinese University of Hong Kong believes the situation is really worrisome because the source of the virus is still not identified. There is no apparent outbreak among the birds at the locations where the people were infected. It means the possibility of an inapparent infection. (bold mine)

“If we cannot identify which chicken or duck carries the virus, we would normally take precautions especially during close contact. It is really worrisome. Many experts want to identify whether the infection was caused by an inapparent infection (between humans) or transmission from infected poultry without symptoms, which could be the result of ongoing vaccinations (bold mine). If that is the case, the vaccine should be improved or the method of applying the vaccine should be improved.” said Professor Chan in an Epoch Times interview.

Chan pointed out that the virus has never stopped mutating. Because its human-to-human transmission efficiency is still low, there has not been a large scale outbreak among humans. However, many experts are concerned that the efficiency is gradually increasing. “The mutation from difficult human-to-human transmission to rapid human-to-human transmission could take a very short time, but could be a slow process as well.” said Chan adding that it could happen within a few months in the worst-case scenario, but it is difficult to predict. (bold mine)

Chan emphasized that the virus could spread to very distant locations by birds, so isolated human infection cases are possible. “If an outbreak happened in one province, the virus could also be carried to other provinces by the birds. I believe such things could happen.”

*not apparent clinically

Read the Original Chinese Article

OK, so we have two Chinese government agencies and several noted Chinese scientists openly speculating on the same thing: H5N1 has produced human deaths without any clue as to the vector. Of course, we have seen this in Indonesia time and time again. In fact, just today, the Indonesian government has revealed two more deaths from H5N1 in the past month. From Reuters:

Indonesia confirms two more bird flu deaths

Wed Jan 21, 2009 5:54am EST

JAKARTA, Jan 21 (Reuters) - Two Indonesians living close to the capital Jakarta have died of bird flu, the health ministry said on Wednesday, bringing the country's death toll from the disease to 115.

A 5-year-old girl from Bekasi east of Jakarta died in January, while a 29-year-old woman from Tangerang, west of Jakarta, died in December last year, the health ministry said on its website.

The girl from Bekasi got sick after her parents had bought a chicken in a market.

"The cat died after it ate the chicken they bought," the statement said.

The 29-year-old fell ill after visiting a market close to her house, the statement said, without elaborating.

Samples from the two women tested positive in two local laboratories, it said.

Indonesia, which has stopped updating bird flu deaths immediately after they occur, has the highest toll from the disease of any nation.

Including the latest two deaths, Indonesia has had 115 deaths confirmed from the deadly H5N1 virus, according to data compiled since 2003 by the World Health Organisation.

Although bird flu remains an animal disease, experts fear that the virus might mutate into a form easily passed from human to human, sparking a pandemic in which case millions could die.

(Reporting by Olivia Rondonuwu; Writing by Ed Davies; Editing by Sugita Katyal)

Note that the Tangerang province produces yet another human death from H5N1.

The year 2009, only 21 days old, has already met 2003's statistics for bird flu cases and deaths as reported to the WHO. It will undoubtedly surpass 2003's case and case fatality numbers by the end of this month.

But it this sudden, jarring appearance of H5N1 in Chinese victims that is so troubling. It may only be four cases; small change in the myriad ways Chinese citizens may meet their maker. But it is the large geographic dispersal of these cases, coupled with their lack of a vector, that makes this such a troubling problem.

One thing all the dead have in common: All the victims were under the age of 40. So it has gone since Day One of the 2003 resurgence of H5N1. So it continues:The elderly are spared while the young suffer and die.

Finally: I don't know a Replikin Count from a Palm Beach County recount, but the organization claims that we are entering a "third cycle" of H5N1 infection. And according to them, this one will surpass anything we have seen to date. Medical News Today has the press release, and I invite you to read it and tell me if this company has any standing or any track record when it comes to these matters. From the release:

The data suggests that additional increases in both Replikin Counts and consequent H9N2-H5N1 infections are anticipated in a coming third cycle. Suggesting that a third cycle has begun, after a 5 year absence, H5N1 reappeared in Hong Kong chickens in early December 2008. and an H9N2 infection in a child in Hong Kong was reported on 12/30/2008.

Since there is no mention of the four Chinese cases, one can assume this release was written prior to the Chinese cases of H5N1.   Still, in light of the past three weeks, I'd say they got it absolutely dead right.  Or a broken clock is right twice a day.  I'll defer to more seasoned analysis on this organization.  

Commentary

As you know, I have been clamoring for a raising of the WHO pandemic threat level --from 3 to 4 --for some time. My previous justifications have centered around suspected changes in the H5N1 virus itself. Also used as justification was the bullheadedness of the Indonesian government as itstill refuses to display any type of transparency when it comes to sharing virus samples orreporting human cases in a timely manner.

Allow me to build a case here.

Recall the recent reports, and my blog on same, talking about how the Chinese have unwittingly produced an amantadine-resistant form of H5N1 via inoculation of fowl with a vaccine, coupled with Amantadine, that has resulted in a viral course change?

Look at the recent speculation from two different Chinese regional governments that H5N1 may have mutated again, and is now producing (at least in China) asymptomatic chickens, still shedding H5N1 virus, but not dying?

If we are producing, either through vaccine boo-boos or via natural selection (or both) an H5N1 virus that no longer causes chickens to die in staggering numbers but still continues to shed H5N1 virus, now that is scary news.

So what if, suddenly, we have lost our most important sentinels in the fight against pandemic H5N1? What if the virus has not changed, but the conditions for infection have? I am saying that if it is true that we have asymptomatic fowl in China and in other parts of Asia, and possibly Egypt, and as a result it is becoming easier for humans to get infected simply because fowl are not doing their duty and dying to warn us, then perhaps it is time to reassess that threat level once again.

When you lose a major source of intelligence when fighting a deadly foe, what do you do? When intelligence experts lose their eyes and ears, they ratchet up the threat level to compensate while they regroup and re-establish their eyes and ears.

Perhaps it is time for the WHO to do the same.  If theories hold true, and there is H5N1 present in China and elsewhere that produces asymptomatic, virus-shedding H5N1 avian flu in birds, then we have indeed lost our eyes and ears within the most populous nation on the Earth, the font of all known infectious respiratory diseases.  Any prudent homeland security expert would exercise great caution and would raise the threat level.

It is time to have serious and real dialogue on this issue.

The news from China is not good, not good at all. And I cannot help but feel uncomfortable about what is going on there.

First, some appreciation needs to be senttoward the Chinese government for being transparent on this topic. If our scientists and researchers can get their hands on some samples, it will be even better news.

In case you have not paid attention: Since the first of the year, four Chinese residents have been struck down with H5N1 avian influenza. Of the four, apparently only one remains alive -- a 2-year-old girl. the other three cases have all perished, the latest being a 16-year-old male student.

According to the CIDRAP news release,

China reports 3 H5N1 cases, 1 death

Lisa Schnirring, Staff Writer

Jan 19, 2009 (CIDRAP News) – China's health ministry today reported three new human H5N1 avian influenza cases, one of them fatal and the other patients hospitalized in critical condition, according to a statement from the World Health Organization (WHO).

In the first case, a 27-year-old woman from Jinan City in Shandong province got sick on Jan 5, was hospitalized, and died on Jan 17, the WHO reported.

Public health officials are investigating the source of the woman's H5N1 infection, the WHO said. Shandong province is in northeastern China.(bold mine)

In the second case, a 2-year-old girl from Luliang City in Shanxi province began having symptoms on Jan 7, was hospitalized, and is in critical condition, the WHO reported.

Authorities are also exploring how the girl became infected, the WHO said. Shanxi province is in the north central part of the country.(bold mine)

The third patient, a 16-year-old boy from Huaihua City in Hunan province, became ill on Jan 8 and was hospitalized on Jan 16, where he is in critical condition, the WHO said.

An investigation into the source of the boy's illness found that he was exposed to sick and dead poultry, the WHO said. Hunan province is in south central China. (bold mine)

China's national laboratory confirmed all three of the cases, according to the WHO, which added that close contacts of the three cases are under medical observation, and all remain healthy so far.

The illnesses and death raise China's H5N1 case count to 34 and fatality total to 22, and these cases bring to four the number of cases in the country in as many weeks. On Jan 7 China's health ministry announced that a 19-year-old Beijing woman who got sick on Dec 24 and died from an H5N1 infection on Jan 5. (bold mine)

The WHO said in a press release today that it anticipates China will keep it updated on the new H5N1 cases and that the organization stands ready to provide China with technical assistance, if needed.

As more people eat chicken as part of Chinese New Year celebrations, the WHO in its statement urged people to observe routine safety precautions such as ensuring that poultry is well cooked and washing hands after contact with raw meat.

This year's Chinese New Year celebration, which lasts for 15 days, starts on Jan 26.

These latest H5N1 cases and fatality raise the world's WHO-confirmed H5N1 total to 397 cases and 249 deaths.

In related developments, China's agriculture ministry is intensifying its efforts to reduce the spread of H5N1 in poultry, according to a Bloomberg News report today. The country will strengthen poultry immunization against the virus, increase vaccine production, boost monitoring of poultry markets and other high-risk areas, and improve surveillance of poultry movements across country borders, the report said.

Meanwhile, York Chow, Hong Kong's secretary for food and health, called on China to release more epidemiological information about the recent human infections, Reuters reported today. He said that an apparent lack of information about recent poultry outbreaks in light of the recent human cases raises questions about a possible change in the virus. (bold mine)

However, about a week after the 19-year-old Beijing woman died, Chinese health officials said they had found no evidence that the virus has mutated to allow easier human-to-human transmission, according to previous media reports.

Chow also expressed concern about the possible role that asymptomatic H5N1-infected chickens might be playing in the spread of the virus, Reuters reported. (bold mine)

As mentioned above, earlier this month, 19-year-old Beijing woman Huang Yanqing died of H5N1, ostensibly acquired from a wet market just outside of Beijing.

You have four infections -- and three deaths -- occurring all over the Chinese mainland. Not confined to one singular province, and not necesarily accompanied by any known die-off of poultry. And to top it all off, the mother of the 2-year-old just died of "pneumonia." Sounds like the authorities need to go back and test for H5N1 on the dead mother, if they can.

And not to say "I told you so," but even York Chow, Hong Kong'sSecretary for Food and Health, is saying he is deeply concerned about a possible change in the virus that is making detection in poultry extremely difficult. As you know, I speculated in such a change in my recent blog In Like a Lion. York's call for investigation into possible viral mutation is echoed by Chinese viral researcher and hero Guan Yi and by the Jiangsu Department of Agriculture and Forestry. So you have two Chinese provinces officially declaring there may be something to this viral mutation stuff.

Context is important here. Note that the Chinese New Year officially begins January 26th. This event causes travel for hundreds of millions of Chinese, as they migrate back home or to relatives. The highlight is the Reunion Dinner, held on New Year's Eve. From Wikipedia:

A reunion dinner is held on New Year's Eve where members of the family, near and far away, get together for the celebration. The venue will usually be in or near the home of the most senior member of the family. The New Year's Eve dinner is very sumptuous and traditionally includes chicken and fish.

OK, let's put it all together.  We ahve at least four H5N1 human cases across China, all orccurring within the past month.  Three of the cases have been fatal, meaning this strain of H5N1 packs the same degree of lethality as before.  These cases are scattered all over mainland China, especially in the central and north/northeast regions.  People are going home, usually to the home of the most senior person, and my guess is that most senior person is in rural China.  And they eat chicken, of course, meaning rural chicken, recently slaughtered in a backyard or a wet market.

While we watch this situation closely, let us also hope we get our hands on some viral samples soon.

I don't know about the rest of Flublogia, but I am already way behind on my posts regarding what has happened in the first few days of 2009. 

We've got the possibility of vaccine-resistant Clade 7 H5N1 in Beijing; a possible human cluster of one clade or another in Vietnam; the return of H5N1 in Egypt with an accompanying fatality; the return of human H5N1 in Cambodia; huge outbreaks in poultry in India, Bangladesh and the door-to-door hunt for human H5N1 in Assam, India; and I know I have left out a report or two.

Plus, the scientific papers are churning  again, the latest the Colorado confirmation that the Chinese have wiped off amantadine as a potential panflu remedy, thanks to their selfish use of the antiviral in an ill-advised and futile effort to save their chickens.

Couple this with the revelation that the Earth may actually be in a colling cycle due to the solar minimum and the almost complete lack of sunspot activity, which apparently means a drop in global temperatures, and you have conditions that are ripe for viral intensification.

I pledge to get more rest so I may keep tempo with my peers, right after tonight's BCS championship game!  GO GATORS!  GO TEBOW!

The University of Colorado confirms what we always suspected - that the overuse of amantadine in Chinese poultry vaccines has rendered the M2 antiviral essentially useless if H5N1 "goes pandemic."

A brand-new paper from the University of Colorado at Boulder (Go Buffaloes!) has confirmed the resistance of at least 30% of the existing substrains of H5N1 avian flu to amantadine, an M2 antiviral. Further, this study declares that amantadine resistance is now (in laymens terms) part of the natural evolution of the virus, meaning it has become the norm; the standard; the template for virus evolution. Irreversible and permanent, this resistance to amantadine (and also rimantadine) is the direct result of Chinese farmers feeding it to their chickens in a futile effort to beat back H5N1. The presence of amantadine in feed and in vaccines simply hastened the virus's resistance to the antiviral.

Amantadine works against the M2 protein by preventing it from doing its duty; namely, dissolving the outer coating of the virus.  By denying the virus the chance to dissolve its coat, it cannot infect.

Researchers, using among other tools the famed Google Earth API (for Application Programming Interface), have created a template so they can watch in near real-time as viruses, including H5N1, begin to display resistance to certain antivirals and drugs. "Real time" would be defined as the time in which these findings are actually noted, meaning researcher and publication real time, and not time as the real world knows it. Further, real time in this universe is complicated by the lack of shared data, which can render this issue moot if researchers are denied information on drug resistant genetic changes and modifications in the virus itself.

Researchers also speak to the Elephant In The Room, which is Tamiflu resistance. So far, they say, there is no cause for concern. But they hasten to add that it is not yet under the influence of "positive genetic selection," meaning that it H5N1 has not yet settled in to any sort of observable trend toward Tamiflu resistance. Yet.

Of particular interest to us (and probably to Dr. Henry Niman) is the statement that resistance is not being conferred via reassortment, or the mixing of genes as the virus mingles with other copies of itself. Instead, the amantadine resistance is gaining momentum via novel genetic mutations rather than an exchange of RNA segments within cells, according to the author of the study.

Here's the news story:

Bird flu becoming more resistant to antivirals

The avian flu, an Influenza A subtype dubbed H5N1, is evolving a resistance to a group of antiviral drugs known as adamantanes, one of two classes of antiviral drugs used to prevent and treat flu symptoms, said CU-Boulder doctoral student Andrew Hill, lead study author. The rise of resistance to adamantanes -- which include the nonprescription drugs amantadine and rimantadane -- appears to be linked to Chinese farmers adding the drugs to chicken feed as a flu preventative, according to a 2008 paper by researchers from China Agricultural University, said Hill.

In contrast, resistance of the avian flu virus to the second, newer class of antiviral drugs that includes oseltamivir -- a prescription drug marketed under the brand name Tamiflu -- is present, but is not yet prevalent or under positive genetic selection, said Hill of CU-Boulder's ecology and evolutionary biology department. The CU findings should help health administrators around the world plan for the possibility of an avian flu pandemic.

The CU-Boulder study is the first to show H5N1 drug resistance to adamantanes arose through novel genetic mutations rather than an exchange of RNA segments within cells, a process known as re-assortment, said Hill. The research on the mutations, combined with molecular evolution tests and a geographic visualization technique using Google Earth, "provides a framework for analysis of globally distributed data to monitor the evolution of drug resistance," said Hill.

The CU-Boulder-led study appears online in the journal Infection, Genetics and Evolution . Co-authors included CU-Boulder Associate Professor Robert Guralnick, recent CU-Boulder graduate Meredith Wilson, Farhat Habib of Kansas State University and Daniel Janies of Ohio State University.

"As these adamantanes have gotten into nonhuman vectors like birds, the positive selection for resistance to avian flu is rising," said Hill. "If Tamiflu is ever used in the manner of adamantanes, we could conceivably see a similar resistance developing through positive selection."

The research team used an interactive "supermap" using Google Earth technology that portrays the individual gene mutations and spread of the avian flu around the globe, said Guralnick of CU-Boulder's ecology and evolutionary biology department. By projecting genetic and geographic information onto the interactive globe, users can "fly" around the planet to see where resistant H5N1 strains are occurring, said Guralnick, also Hill's doctoral adviser.

For the study, the researchers analyzed 676 whole genomes of Influenza A/H5N1 from National Institutes of Health databases of viruses isolated between 1996 and 2007. The team is comparing how often amino acid sequence changes in genes lead to mutations that affect drug resistance in the H5N1 virus and how often such changes evolve into random mutations that don't affect resistance, Hill said.

The next step is to analyze 2008 data, he said.

First detected in China in 1996, the avian flu has spread throughout Asia and to India, Russia, Pakistan, the Middle East, Africa and Europe by various carriers, including poultry and migratory waterfowl, Hill said. While H5N1 is not highly communicable to humans from birds or between humans, experts are concerned future evolution of this subtype or other subtypes, or genetic re-assortment between subtypes, could make an avian influenza strain more contagious with the potential to cause a pandemic.

"Even if H5N1 is not the flu subtype that develops into the next pandemic, this technique can help us understand the properties of flu viruses and we can use these methods to track mutations in other viruses," said Guralnick. "We can harvest genetic influenza data and monitor it in near real-time, which should give this project some traction to help governments make decisions on managing potential pandemics."

Like the legend of a road map, colors and symbols on the supermap indicate which types of hosts carry the virus or the distribution of genotypes of interest, said Hill. A click by users on viral "isolates" generates computer windows revealing H5N1 mutations linked to positive genetic selection resulting from the spread and use of adamantanes.

http://www.colorado.edu/