UPDATE: As of 10am EDT today, China is at 64 confirmed cases and 14 deaths.
It's not easy being a flu blogger these days. People such as Crof and Mike Coston are engaged in what I will now coin "sweat-shop blogging." This means they are sitting at their computers, heads down, typing feverishly as if they are getting paid by the word.
Of course, the thing is: They do not make money at this. They don't work foir Huffington (and it's a good thing for them!). They do it because they are helping everyone understand and deal with the ramifications of emerging pathogens. In my opinion, they, and other respectable bloggers like them (I am looking at you, Maryn McKenna), should receive some sort of medal. Or free bandwidth. Or both.
Anyway, I cannot hope to maintain their pace. I do, however, make notes to myself to talk about things that I think have consequence.
So it is that an early dispatch from China at the beginning of this H7N9 outbreak caught my eye, and I filed it away for future reference. When assembled with another dispatch, I think it speaks volumes about why the Chinese are experimenting with different protocols in the treatment of their H7N9 patients.
It was Giuseppe Michieli, another intrepid flu blogger from Italy, who posted this article on FluTrackers.com at the onset of the H7N9 outbreak. The Chinese equivalent of the FDA gave emergency approval for peramavir to be used in the treatment of H7N9 bird flu patients.
Peramavir is the invention of Bio-Cryst Pharmaceuticals of Durham, North Carolina/Birmingham, Alabama. Back in 2007, Bio-Cryst made headlines with the news it had created an antiviral medicine, administered through the vein, that did things that Tamiflu and Relenza could not. My comprehensive blog on that topic is here.
Did I also mention it was a visionary blog? When I talked about the CDC's apparent failure to manufacture a pandemic virus in September of 2007, I asked:
...the CDC was unable to kick-start a reassortant H5N1/H3N2 virus. Thus, the CDC concluded, it was difficult to imagine such a reassortant occurring naturally. I cannot tell you why they did not try an H7 or H1 virus. You'll have to ask them.
Wow. I had forgotten that! Of course, we had an H1 pandemic (swine flu), and we are knee-deep in the hoopla surrounding an H7 pandemic candidate. Man, I am good. My blog on that subject can be found here. The blog also mentioned that peramavir had not been successful in a human trial. Multiple reasons were given. The usual suspects were rounded up.
I thought it odd, then, that peramavir should be sought by the Chinese, because it really is untested successfully on humans to the extent Tamiflu and Relenza were, and also because these first-line antivirals are still, against most influenzas, effective.
But then the news came out last week. Bloomberg even reported on the genetic sequencing of the first human H7N9 sample. When you read or hear the mainstream media talking about E627K, or in this case, R292K, you have to find that amusing and gratifying. The media is now picking up our lingo.
The Chinese kews very early on that they were dealing with the potential of a Tamiflu-and Relenza-resistant strain of bird flu. They knew of one case, and were worried that they might have a larger problem on their hands.
Subsequent samples have not shown the motation at that position on the neuraminidase strand, according to Chinese experts. Obviously, much more testing is needed before that claim can be validated. But we see Tamiflu mutations crop up, from time to time. One of my blogs on that very topic can be found here. It is expected that influenza will mutate itself around certain road blocks and barriers. But it also helps when Humankind accelerates the process.
The Chinese have a history of injecting antiviral drugs into their chickens in an effort to control bird flu, with sometimes-disastrous consequences. The former front-line antiviral amantadine was lost to science as a weapon against bird flu simply because the Chinese put it into every chicken they could find. I blogged on a University of Colorado study in 2009 which confirmed this. Amantadine is an M2 antiviral. It is closer to a "universal antiviral" in that it prevented the lipid coat of the virus from dissolving once inside a cell, permitting those antibodies to do their thing, similar to the fate Donald Pleasence met at the climax of Fantastic Voyage. Anyone still remember that movie? Being eaten alive by a white corpustle is a heckuva way to go.
But I digress. The number of confirmed Chinese cases is, as we expected, growing significantly -- as are the number of new locations where the virus has been detected. They were right to be alarmed when they sequenced a Tamiflu-resistant pandemic candidate. But there may be evidence to conclude there is ongoing use of peramavir.
The Chinese media reported on the recent Beijing H7N9 case, the first of its kind in that city. Here is how she is being treated:
The child received the drug Tamiflu as well as intravenous drips (bold mine) on Thursday night and later was transferred to an intensive care unit after condition worsened. After an oxygen therapy and other treatment, her suffocation and coughing symptoms eased markedly and body temperature fell to 37 degrees Celsius from 40.2 degrees Celsius, a spokesman with the Beijing Ditan Hospital said.
I think it odd that the press should go out of its way to say a flu patient has something in her arm, and that this substance is part of her treaatment. Bio-Cryst is reaching out to the Chinese government, possibly feeling that this outbreak might be the break they need to win regulatory approval in the US and Europe. A recent WRAL-Raleigh story sheds some light on this. Titled "Mystery surrounds China's use of BioCryst's drug to combat deadly bird flu," the story says China has not requested peramavir. Nor has China any manufacturing rights to the drug. Of course, the Chinese have never been fingered in any sort of intellectual property piracy or pirating, have they? Nah.
So the Chinese have peramavir and the American company has no idea how they got it. (They may want their infosec people to check their R&D servers.) But the simple hypothesis is that once the Chinese knew they had at least one strain of Tamiflu-resistant H7N9, they wasted no time roilling out the new stuff, regardless how they procured it.
I am pulling this directly from the proMED (Harvard) report. No claim of authorship from this corner!
UNDIAGNOSED ILLNESS - GERMANY: (HAMBURG) RESPIRATORY, FATAL, REQUEST FOR INFORMATION
A ProMED-mail post
ProMED-mail is a program of the
International Society for Infectious Diseases <http://www.isid.org>
Date: Wed 10 Apr 2013
Source: Bild [in German, machine trans., edited] <http://www.bild.de/regional/hamburg/viren/toetet-polizisten-im-uke-29943928.bild.html>
A 49 year old policeman is dead, 5 other persons are ill and doctors are puzzled by this mysterious disease just outside of Hamburg.
Andreas Breitner, Minister of the Interior, confirmed to the "Schleswig Holstein newspaper" the death of the 49-year-old policeman at the University Medical Center Hamburg-Eppendorf (UKE) on Tuesday [9 Apr 2013], after multi-organ failure.
Another policeman, aged 38 years is in critical condition. He is suffering from similar flu symptoms, including severe pneumonia.
A teacher from the Schacht Audorf area near Rendsburg has also died of multi-organ failure in the UKE, and according to unconfirmed reports,
3 other persons from the same region are seriously ill.
All are suffering from flu-like symptoms but the doctors do not know what disease is affecting them. It could be a "degenerated virus"
[?mutated], the "Schleswig Holstein" newspaper reporter quotes" an official.
District spokesperson Martin Schmedtje said: "Both policemen showed the same clinical picture. However, we do not know yet whether there is a pathogen or whether a pathogen was actually the cause."
After investigation there are no known connections between both colleagues.
Police spokesperson Sonke Hinrichs said, "the 2 policemen did not work in the same agency, were not on duty together, do not live in the same place. There is no visible connection, but naturally we are working together to try to find out what has happened."
The hospital is also investigating a possible link. UKE spokesperson Christine Jaehn said, "At present no patients with unusual infectious diseases are being treated in the UKE intensive care unit. Moreover, no accumulation of patients exists in the Rendsburg area."
Public health authorities in Rendsburg-Eckernfoerde have been activated since Friday [5 Apr 2013].
But so far nobody knows what this deadly disease is. On Wednesday evening [10 Apr 2013] the Rendsburg-Eckernfoerde District Administrator announced, " Despite the efforts of the specialists involved we have not been able to identify a pathogen."
However, the danger has been estimated as low. District spokesman Martin Schmedtje said, "a recommendation from the health services to close public facilities as a precaution is not necessary. General hygiene measures taken in times of rampant influenza, are sufficient."
[Given the heightened awareness of the public and public health community for severe acute respiratory illness (SARI) and the identification of 2 new novel organisms producing SARI -- the novel coronavirus (nCoV) identified in individuals with contact with Middle Eastern countries and the appearance of human cases of influenza H7N9, an avian influenza virus in Eastern China, a report such as the one above is potentially cause for concern. Other reports on this occurrence in Germany have been posted on FluTrackers
(<http://www.flutrackers.com>) where there is mention that the fatality referred to in the newswire above was found to be attributable to influenza, but a specific virus was not mentioned (?H1N1, H3N2).
As there is no history of travel outside of Germany, the likelihood of this being due to infection with either the nCoV or the avian influenza H7N9 is very low. More information on the results of laboratory studies and other investigations would be greatly appreciated.
Rendsburg-Eckernfoerde is a district in Schleswig-Holstein, Germany.
It is bordered by (from the east and clockwise) the city of Kiel, the district of Ploen, the city of Neumuenster, the districts of Segeberg, Steinburg, Dithmarschen, and Schleswig-Flensburg, and the Baltic Sea (see <http://en.wikipedia.org/wiki/Rendsburg-Eckernf%C3%B6rde> for a map and additional information on the District).
OK, now my biting, insightful commentary.
I called Mike Coston yesterday. Mike is FLA_MEDIC and the founder of the well-known and respected Avian Flu Diary blog. He is a buddy and it is great talking with him again. Anyway, I asked him if I could interrupt his blogging for a few minutes. He only wrote ten or so blogs yesterday (slacker!) and only writers and bloggers know how painful deadlines can truly be.
Anyway, Mike told me about this story, and I was very interested to see the proMED journal about it. Hamburg recently struggled with an outbreak of H5N3 in poultry, and it does rest on the Baltic.
It is now five days later, and we still have no explanation as to what has infected these individuals. I find that interesting, because if a simple explanation had been found, more than enough time has passed to tell everyone. One has to assume the German press remains interested in this case. Whether it is related to H7N9, NCoV, or even H5N1 is both unknown and wrong to speculate upon until answers come.
As of 9:50 AM EDT, China's H7N9 cases have jumped to 38, with 10 deaths. Overnight, five new cases were reported, along with one death. So we appear to be settling into a bit of a routine here, with a handful of new cases being reported, and an occasional death.
There still are not enough cases to determine a Case Fatality Rate without panicking everyone, but it is clear that this virus is a killer. The new cases are of people who are very, very sick, and are admitted and tested and confirmed and (hopefully) isolated.
When I worked for an IBM business partner, one of the axioms I learned there was: You Don't Know What You Don't Know. And we don't know several things.
First, a Chinese report states that of some 700+ chickens culled at Shanghai wet markets, only 20 tested positive for H7N9. Crawford Killian covers this nicely in his blog, The Silence of the Chickens. You cannot detect what isn't there. Shanghai authorities just took 111,000 birds out of the public diet for a nonexistent problem. Of course, they had to do this: It is Standard Operating Procedure for killing off a pandemic candidate virus. See Dr. Margaret Chan's decision in 1997 when a human-to-human H5N1 threatened the entire world in Hong Kong.
The cases are being found without organizing human testing. No H7N9 rapid test exists. Expensive and time-consuming reverse-PCR tests need to know what they are looking for. Needless to say, H7N9 reagents were the last things anyone was expecting to stock. So today's press release from the Chinese version of the CDC is welcome news:
Testing reagents for the avian influenza A/H7N9 virus have been distributed by China CDC to all influenza network laboratories of 31 provinces across China. As of 8 April 2013, a total of 160,000 Real-time PCR reagents have been delivered to make all areas capable of detecting human infections with avian influenza A/H7N9 virus.
The Chinese now have the tools necessary to get proactive and get ahead their arms around the scope of this new virus. We simply do not know how many Chinese have been infected; how many have truly died; and how transmissible this virus has become.
Yesterday also brought us the controversial story of Chinese scientists who theorize, in remarkable candidness and lack of censorship, that this new flu may mutate 8 times faster than normal viruses. THis conclusion was reached by looking at two H7N9 strains spaced some two weeks apart. Specifically, there were nine changes in the hemagglutinin over that two-week period. from this, the scientists concluded the virus was capable of massive, sweeping mutations in a shortened period of time.
I wonder if our CDC got tipped off on this pending story and that is why they decided the most prudent thing to do was open its EOC at level 2.
I am also reminded of the forthcoming animated film Epic; specifically, the upcoming trailer. Click on this link and forward to 2:08. Perhaps if this virus can mutate so quickly, it can mutate to the life expectancy of this fruit fly? We can hope so.
UPDATE: Flutrackers is reporting two Hong Kong residents are being monitored. This is not new and has already happened. We should get answers quickly.
The situation over the past two days has pretty much been the same. New cases, all located in the areas previously identified for H7N9 infection.
Blessedly, there are those who are looking at the data and coming up with some pretty interesting analysis. First, I refer you to Mike Coston's blog of today. Titled "Three graphic descriptions of China's H7N9 outbreak," this post collects some great information from informed sources.
The first chart comes from Dr. Ian Mackay. Dr. Mackay runs a flu blogsite in Australia. The chart shows the current (as of yesterday, and LOL on the word "Current" right now! I cannot even tell you what the current counts are.) individual H7N9 cases. As you can see, only seven of the 28 cases had definable, confirmed contact with poultry in wet markets or the actual preparation of fowl. This is problematic, because it seems to run counter to the prevailing theory that wet markets are the spawning place for H7N9 bird flu. It may suggest adaptation to a different host, mammilian in nature, as Dr. Richard Webby of St. Jude has theorized by looking at the makeup of the virus itself.
We just don't know enough yet on this front. We assume and can pretty safely state that poultry is or has been a vector. But the culling of 111,000 birds in Shanghai and adjacent wet markets has yielded little virus. If this cull had yielded virus, I have to believe the Chinese government would have trumpeted this fact and declared the outbreak over.
The second set of charts comes from veteran Flutrackers poster Laidback Al. Laidback Al is a Jedi Master of the highest order when it comes to charts and maps of bird flu outbreaks. His analysis and ability to see The Big Picture are impatiently sought and happily received when he weighs in.
His current geospacial analysis can be found at this link. I reproduce one key map below:
Look at the geographic dispersion of human cases. If this were limited to wet markets, perhaps, we would not see this level of dispersion. Of course, travel needs to be accounted for. But we are talking a huge area here. There are other charts in Laidback Al's post worth poring over. The other chart that got my eye was the mortality - versus - morbidity chart. The ratio of deaths to cases, while admittedly a very small sample, shows the virus is killing young adults and the very old. This seems to fit the mold of pandemic candidate viruses, whose proclivity is toward young adults and the elderly with their assorted contributing ailments.
We must look forward while looking back. Only testing will determine how widespread H7N9 truly is in China. A nice place to look would be the downstream rivers, streams and tributaries shown in another Laidback Al map. Looking at those areas downstream from Shanghai, and matching up those principalities with any unexplained reports of respiratory failure, might prove quite useful.
In the meantime, everyone continues to monitor the developing situation.
The photo accompanaying today's Helen Branswell MetroNews/Canadian Press story regarding H7N9 avian influenza stuck out to me like a sore thumb.
Here's the photo. Can you tell what set me off?
If you said the cat, you'd be correct. Cats have a history with bird flu. In Indonesia, cats became such a worrisome vector that the government actually ordered the testing of cats. For the story, read my blog from 2007.
"In Bangkok, Thailand, all the cats in one household are known to have died of H5N1 in 2004. Tigers and leopards in Thai zoos also died, while in 2007 two cats near an outbreak in poultry and people in Iraq were confirmed to have died of H5N1, as were three German cats that ate wild birds. In Austria cats were infected but remained healthy". Cats in Indonesia were also found to have been infected with H5N1.
The spread to more and more types and populations of birds and the ability of felidae (cats) to catch H5N1 from eating this natural prey means the creation of a reservoir for H5N1 in cats where the virus can adapt to mammals is one of the many possible pathways to a pandemic.
 October 2004
Variants have been found in a number of domestic cats, leopards and tigers in Thailand, with high lethality. "The Thailand Zoo tiger outbreak killed more than 140 tigers, causing health officials to make the decision to cull all the sick tigers in an effort to stop the zoo from becoming a reservoir for H5N1 influenza. A study of domestic cats showed H5N1 virus infection by ingestion of infected poultry and also by contact with other infected cats (Kuiken et al., 2004)." The initial OIE report reads: "the clinical manifestations began on 11 October 2004 with weakness, lethargy, respiratory distress and high fever (about 41-42 degrees Celsius). There was no response to any antibiotic treatment. Death occurred within three days following the onset of clinical signs with severe pulmonary lesions."
 February 28, 2006
 March 6, 2006
 August 2006
It was announced in the August 2006 CDC EID journal that while literature describing HPAI H5N1 infection in cats had been limited to a subset of clade I viruses; a Qinghai-like virus (they are genetically distinct from other clade II viruses) killed up to five cats and 51 chickens from February 3 to February 5, 2006 in Grd Jotyar (~10 km north of Erbil City, Iraq). Two of the cats were available for examination.
- "An influenza A H5 virus was present in multiple organs in all species from the outbreak site in Grd Jotyar (Table). cDNA for sequencing was amplified directly from RNA extracts from pathologic materials without virus isolation. On the basis of sequence analysis of the full HA1 gene and 219 amino acids of the HA2 gene, the viruses from the goose and 1 cat from Grd Jotyar and from the person who died from Sarcapcarn (sequence derived from PCR amplification from first-passage egg material) are >99% identical at the nucleotide and amino acid levels (GenBank nos. DQ435200–02). Thus, no indication of virus adaptation to cats was found. The viruses from Iraq are most closely related to currently circulating Qinghai-like viruses, but when compared with A/bar-headed goose/Qinghai/65/2005 (H5N1) (GenBank no. DQ095622), they share only 97.4% identity at the nucleic acid level with 3 amino acid substitutions of unknown significance. On the other hand, the virus from the cat is only 93.4% identical to A/tiger/Thailand/CU-T4/2004(H5N1) (GenBank no. AY972539). These results are not surprising, given that these strains are representative of different clades (8,9). Sequencing of 1,349 bp of the N gene from cat 1 and the goose (to be submitted to GenBank) show identity at the amino acid level, and that the N genes of viruses infecting the cat and goose are >99% identical to that of A/bar-headed goose/Qinghai/65/2005(H5N1). These findings support the notion that cats may be broadly susceptible to circulating H5N1 viruses and thus may play a role in reassortment, antigenic drift, and transmission."
 January 24, 2007
"Chairul Anwar Nidom of Airlangga University in Surabaya, Indonesia, told journalists last week that he had taken blood samples from 500 stray cats near poultry markets in four areas of Java, including the capital, Jakarta, and one area in Sumatra, all of which have recently had outbreaks of H5N1 in poultry and people. Of these cats, 20% carried antibodies to H5N1. This does not mean that they were still carrying the virus, only that they had been infected - probably through eating birds that had H5N1. Many other cats that were infected are likely to have died from the resulting illness, so many more than 20% of the original cat populations may have acquired H5N1."
Seeing a cat sitting outside an empty stall remined me immediately of these issues. Are the Chinese testing the cats? Are we seeing the death of cats in any significant number? Are the Chinese doing surveillance with veterinarians?
Cats eating wild birds is one thing. Cats eating diseased fowl in wet markets is another. Where are we more likely to see this?