Scott McPherson's Web Presence

This afternoon, Nature's Declan Butler has one of the more fascinating -- and ominous -- dispatches since the H7N9 outbreak in China occurred. Nature bills itself as the international weekly journal of science.  It is one of the most respected publications of its kind in the world. 

And Declan Butler is not one to go around sounding alarms.  His articles are reasoned and insightful. SO it was with great concern that one of my IT people (shout-out Sean Nickerson) came into my office (my door is always open, insert Bob Newhart quip here).  He had just gotten an email with a link to the Nature story.

Here is a snippet:

There is still no evidence of any sustained human-to-human spread of the H7N9 virus. But the World Health Organisation confirmed on Saturday that Chinese authorities are investigating two suspicious clusters of human cases. Though these can arise by infection from a common source, they can also signal that limited human-to-human transmission has occurred.

"I think we need to be very, very concerned" about the latest developments, says Jeremy Farrar, director of the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam.

....The Beijing Municipal Health Bureau also announced today that a 4-year-old contact of a 7-year-old girl who had been hospitalized with the virus tested positive for the virus too, despite showing no symptoms. (bold mine) This is the first asymptomatic case. Along with several mild cases already reported, it suggests that the virus might be more widespread among humans than the numbers of reported cases suggest.

Perhaps counterintuitively, such mild cases are "very worrying", says Farrar. That is because reduced virulence can often point to further genetic adaptation of the virus to infection of human beings — and thus greater potential to spread.

 Marc Lipsitch is an epidemiologist at the Harvard School of Public Health in Boston, Massachusetts. Declan quotes him:

"It's too soon to say how big a threat H7N9 poses because we don't know how many animals of which species have it, how genetically diverse it is, or what the geographic extent is," says Lipsitch, "It looks as though it will be at least as challenging as H5N1."

A few years ago, back in January 2009 (and six months before the swine flu pandemic),  I wrote a blog regarding H5N1 and the potential for chickens to be asymptomatic carriers of a pandemic candidate virus. 

If you performed a Find and Replace using "H7N9" for "H5N1" in that blog post, you would instantly have a very topical blog.  So please read that blog from four years ago, and change the virus subtype in your head as you go along.

Now, I vector you to today's disclosure that 64 human H7N9 cases exist in six different provinces, including two fabled cases in the city of Beijing.  There are 14 deaths.  As I mentioned in one of my earliest blogs on the subject of human H7N9, barely a week ago:

Dr. Yin of the Bill and Melinda Gates Foundation.  Apparently Dr. Yin is the Foundation's leader in China.  And it was quite satisfying, knowing Bill and Melinda are spending funds in  China, including, but not limited to, surveillance.  Dr. Yin's statement is worth paraphrasing.  He said, basically, if you don't test for H7N9, you won't find it.  But if you do test for it, you'll find it.  The inference is that there have been numerous unexplained and undiagnosed severe respiratory ailments there this season.  Retroactive testing of samples, based on Dr. Yin's inference, will yield a significant increase in the number of H7N9 human cases. 

Indeed, with more than 400 labs across China testing away, they are finding more cases in more geographic locations.  Simultaneously, more deaths are being reported.  Fortunately, the deaths are not increasing in proportion to the number of confirmed cases.  We all believed that the case fatality rate would not be as high as the initial reports would have indicated; the sample was too low and the data, therefore, did not support (yet) a high CFR.

But I found it interesting that as of this morning, the WHO has not yet established a pandemic alert system for H7N9. Dedicated Web page, yes.  But the WHO has not started an alert system. 

WHO has an alert system in place for H5N1, and had one for pH1N1, a.k.a. The Virus Formerly Known As Swine Flu.  Perhaps it is too early for such an alert system.  After all, the virus is only in one region of one nation (albeit a region that is host to more than 300,000,000 Chinese).  I also understand the reluctance the WHO must feel regarding this disease.  The WHO took significant credibility hits after swine flu, some referring to the WHO as "chicken little."  These criticisms are unfair and undeserved.  No one had any idea that pH1N1 would have been as mild as it was.

And "mild" is a misnomer.  The words "mild virus" are of great consolation to virus experts, public policymakers and public health professionals who look at The Big Picture; but those words are of little consolation to the parents of children who died during the pandemic. 

A Reuters story from June of last year paints that smaller picture.

(Reuters) - The swine flu pandemic of 2009 killed an estimated 284,500 people, some 15 times the number confirmed by laboratory tests at the time, according to a new study by an international group of scientists.

The study, published on Tuesday in the London-based journal Lancet Infectious Diseases, said the toll might have been even higher - as many as 579,000 people.

The original count, compiled by the World Health Organization, put the number at 18,500....

The results paint a picture of a flu virus that did not treat all victims equally.

It killed two to three times as many of its victims in Africa as elsewhere. Overall, the virus infected children most (4 percent to 33 percent), adults moderately (0 to 22 percent of those 18 to 64) and the elderly hardly at all (0 to 4 percent).

Even though the elderly were more likely to die once infected, so few caught the virus that 80 percent of swine flu deaths were of people younger than 65.

In contrast, the elderly account for roughly 80 percent to 90 percent of deaths from seasonal influenza outbreaks. They were probably spared the worst of 2009 H1N1 because the virus resembled one that had circulated before 1957, meaning people alive then had developed some antibodies to it.

The relative youth of the victims meant that H1N1 stole more than three times as many years of life than typical seasonal flu: 9.7 million years of life lost compared to 2.8 million if it had targeted the elderly as seasonal flu does."

So swine flu was much more of a force than anyone (especially the critics) thought it was.

Here in April of 2013, we have a big problem.  No one knows how long this new H7N9 virus was circulating among wild birds, poultry and (especially) people in China.  In fact, we didn't know Diddley until March 31st, when the Chinese sprung the news upon the world.  Exactly when the Chinese knew it had H7N9 in people is cause for speculation, but I think we can excuse the Chinese for demanding confirmation before telling the whole world (to their credit) that a new pandemic candidate was emerging within their borders.

In fact, nothing may have ever been known, had the cases involving the three male family members not caused some doctor or technician to begin testing for something.  My guess is they speculated it was  seasonal influenza or H5N1 bird flu, then moved to SARS, then moved to the new novel coronavirus NCoV, and then reverse PCR testing revealed the presence of H7N9. 

Thank the Maker that someone had the curiosity and the desire to test in a wider spectrum!

Adding to the drama is the report from Beijing last week that a 4-year-old boy tested positive for H7N9.  He is not sick and displays no symptoms, yet he is an asymptomatic carrier of bird flu. This means wider testing is essential -- of humans, pigs and birds.  The testing net needs to be cast very widely in order for everyone to get their arms around the problem. 

And that, folks, is why I believe the USA's CDC opened its Emergency Operations Center at Level 2.  Since the CDC EOC alert levels only go from 3 to 1, the opening at Level 2 was considered by some to be controversial.

Knowing now what we do, and analyzing their decision in the current light, we should say this was an important and prudent decision.  Because, folks, we don't really know if this virus has come to America or not. And the only way we are going to know anytime soon is through weekly surveillance of mortality and morbidity.

From Wikipedia:

 United States

On April 9th, 2013 the Centers for Disease Control and Prevention (CDC) activated its Emergency Operations Center (EOC) in Atlanta at Level II, the second-highest level of alert.^[30] Activation was prompted because the novel H7N9 avian influenza virus has never been seen before in animals or humans and because reports from China have linked it to severe human disease. EOC activation will "ensure that internal connections are developed and maintained and that CDC staff are kept informed and up to date with regard to the changing situation."^[31]

From the Medscape article:

The Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, received a specimen of the H7N9 virus from China yesterday. On April 9, the CDC activated the Emergency Operation Center (EOC) at Level 2 (there are 3 levels, with 1 as the highest) to support the management of the emerging H7N9 situation, Sharon KD Hoskins, MPH, senior press officer at the CDC told Medscape Medical News in an email.

Researchers used real-time reverse-transcriptase-polymerase-chain-reaction assays, viral culturing, and sequence analyses to test the patients' respiratory specimens for influenza and other respiratory viruses.

....In an accompanying perspective, Timothy M. Uyeki, MD, MPH, MPP, and Nancy J. Cox, PhD, from the Influenza Division, National Center for Immunization and Respiratory Diseases at the CDC, commented on the article, noting that this outbreak "is of major public health significance."

"The hemagglutinin (HA) sequence data suggest that these H7N9 viruses are a low-pathogenic avian influenza A virus and that infection of wild birds and domestic poultry would therefore result in asymptomatic or mild avian disease, potentially leading to a 'silent' widespread epizootic in China and neighboring countries," Drs. Uyeki and Cox write. The HPAI H5N1 virus usually causes rapid death in infected chickens.

I am not certain, but I am pretty confident that most labs in the United States are currently incapable of subtyping anything other than the prevaling seasonal flus of pH1N1, H3N2, B, and swine H3N2 (nice call, CDC). Anything other than these substrains are lumped into one or more catagories of A: "Subtyping not performed," or A "Unable to subtype."   However, the CDC is also beginning to catalog incidences of other novel influenzas.  From their April 6th report:

Novel Influenza A Virus

No new human infections with novel influenza A viruses in the United States were reported to CDC during week 14.

A total of 312 infections with variant influenza viruses (308 H3N2v viruses, 3 H1N2v viruses, and 1 H1N1v virus) have been reported from 11 states since July 2012. More information about H3N2v infections can be found at http://www.cdc.gov/flu/swineflu/h3n2v-cases.htm.

Assuming few, if any, US labs can currently quickly detect H7N9 bird flu, the only other capability the CDC has is to monitor and initiate surveillance of the public's health.  This means both ramping up a central monitoring presence dealing with day-to-day issues, and also ramping up state health departments to begin watching for unusual spikes in ILI, or Influenza-Like-Illness.

By activating their EOC at level 2, the CDC is able to pull in disparate elements and to begin the process of surveillance in earnest. Things you just cannot do sitting at a desk, you can do in a central coordinating facility, open-air, with people at their posts.  Having been in the State of Florida EOC many times, including pandemic exercises, actual hurricane tracking and the afternoon of 9/11 (and for days afterward), the ability to sort information and make decisions does not happen in a better environment.

On April 2nd, I formally activated the State of Florida CIO Association's Pandemic Committee.  It had stood in informal recess since the Swine Flu pandemic was declared over in 2010.  However, I decided that once the chickens were not doing their duty and dying, we had a real conundrum on our hands!

In fact, just last week, the Florida Department of Health announced that they were beginning monitoring the China H7N9 situation.  I suspect other state health organizations are ramping up, if for no other reason than to give the CDC timely and accurate information, should there be spikes in respiratory illness.

So what would a spike look like?  The spike would look something like this:

  
Hmmm.  This is the actual CDC Pneumonia and Influenza Mortality chart for April 6th, 2013. 

The top black line represents the epidemic threshhold.  The bottom black line represents the seasonal baseline.

The red line represents the actual reported cases.  As you can see, the red line is at the highest point since a spike at the beginning of calendar 2011, six months after the end of the Swine Flu Pandemic. In fact, the chart had suddenly spiked to a level higher than at any point since 2009.

Not sure of what was going on, but knowing this occurred before my rebirth as a flu blogger, I reached out to Mike Coston (again). I asked Mike about what had happened? 

Mike told me that the CDC immediately looked into the situation. In fact, he blogged on both the mortality spike and the CDC's response. Apparently, what happened is that H3N2 drifted.  If you need a primer on antigenic shift vs. antigenic drift, click here.

Anyway, what happened is that, apparently, the H3N2 seasonal flu drifted.  And seniors, who may not have been vaccinated as often as recommended, had no immunity to the drifted virus -- immunity they might have had, if they had goten regular flu shots.  H3N2 is a nasty bug for anyone, but especially for the elderly, who died in numbers sufficient to trigger the uptick that you just saw.

A similar uptick, especially coming now as flu season wanes, would trigger a pretty quick CDC response.  This is why the CDC activated.  This is why state departments of health are getting ready to ramap up their surveillance. 

To recap:

• The chickens are not doing their duty and dying.
• China has no real idea how widespread the virus is.
• Nobody else does, either.
• There is currently no reason to suspect there is H7N9 in North America.
• That having been said, there is always the possibility that infected, asymptomatic travelers have come into the United States via any of the Pacific ports of call and airports. Unlikely, but not impossible.
• Certainly, we would have seen the virus in Hong Kong before we would have seen it here.
• Currently, there is no inexpensive, routine way to test in doctors' offices or public health departments in the USA for H7N9. 
• H7N9 would appear as "Type A, Unable to subtype" or "Type A, subtyping not performed."
• We have a long way to go with this situation.

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.

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.

Dr. Henry Niman may have stumbled onto something interesting.  In his Recombinomics commentary of Saturday, he has identified a cash settlement from the hospital treating the first known H7N9 patients. 

Dr. Niman cited an article from the South China Morning Post.  Here's the headline and some copy: