I don't know how many of you have caught this or done the math, but the case fatality rate (CFR) from swine flu has actually increased, at both global levels and within the United States.

The published global CFR in late June was plugging along at .002, while the US CFR was at .0045.  Now, the US CFR is .0056, and the global CFR is at .0045.  So the world has caught up with America in terms of its death rate, and the figure of .0045 places this pandemic squarely within the HHS Category Two pandemic status.  But the threshold to Category 3 status is .0051.  For the past two weeks, the US CFR has exceeded the Category 3 benchmark.  Like the hurricane that spawned this HHS analogy, those winds -- and deaths -- have to be sustained.  The next few weeks will tell us if we are seeing a drop in the CFR, or if the numbers are holding steady.  That may also signal the waning of the pandemic's first wave.

These death numbers do not sound large until you look at large numbers.  If the current CFR holds, by the end of the pandemic, we could be looking at over 400,000 dead in the United States alone.  In Florida, for example, the final death toll could reach 30,000. 

This is probably why the WHO has chosen its words very carefully when describing this pandemic as "moderate" and not as "mild."

How is this possible, you ask?  Swine H1 is "mild," the public health authorities are telling us!  You are even hearing the words "no worse than seasonal flu" mentioned!

I would answer this way:  First, read Dr. Kawaoka's analysis of swine flu in today's/tomorrow's papers.  Second, re-read my blog about totally botched risk communication, and Google/read Dr. Sandman's similar remarks about recent botched risk communication.  Third, remember we are in the beginning stages of a global health crisis that will take at least eighteen months to finally play out. 

Pandemics are not for institutions with ADD, nor are they for institutions who like quick resolutions at the end of a 60-minute show.  Nor are they for institutions who demand happy endings, unless you count the conclusion itself as happy.  They are slow, historic, and life-changing events.  We should treat them and respect them as such.

It has been two years since the death of Captain America. 

Killed by a bullet fired by his brainwashed girlfriend amidst a plot fiendishly hatched by longtime enemy the Red Skull, Cap died in June 2007.

Or did he?

Of course, the shield was picked up capably by former sidekick Bucky Barnes.  But Marvel has not forgotten the huge storm of media surrounding the assassination of its greatest hero.  And so, in just a couple of weeks, Captain America #600 comes to newsstands.

And it arrives two days early.  Normally, comics are released on Wednesdays.  But for this event, Marvel is allowing dealers to actually sell the comics on a Monday.  Clearly, Marvel is hoping for a slow news day on the 15th, and shipping the prelude to a new five-issue miniseries called "Reborn" will help create news.

I am all about creating news for Marvel, so I am doing my fair share here.  If you have not read the amazing Captain America Omnibus, which is $100 and can cause a hernia just picking it up, I recommend grabbing it (with a forklift), or read the ongoing Death of Captain America series via some other route.  But read it! Start at the beginning -- Issue #1, writtten by Ed Brubaker, released just a few years ago  -- and take it from there.  Don't freak:  Issue #600 is also kind of issue #51 in the current arc, so you're not 599 issues behind.  The current and ongoing story arc is some of the best prose out there in any format. 

And the twist that brings Bucky back is absolutely electrifying.  There used to be a saying in Comicdom that you could "never bring back Bucky."  Wellllll, not exactly.  And the way Brubaker accomplished this was incredible.   Ed, you're a genius, dude.

Bucky as Cap has done a great job representing, and the picture at the top of this blog covers that nicely.  The costume is improved, for one.  So I am hoping Steve Rogers, aka Captain America, comes back in some other capacity, at least for the time being.  He can come back as Nomad, the costume he wore for a period of time.  Or he can come back to take over the protection of the nation from Norman Osborn's Dark Reign.  What?  you don't know about the Dark Reign, formed following the Civil War and the Secret Invasion?

Get busy reading.

I just read a Tweet from my buddy Mike Coston, aka FLA_MEDIC, blogger of great repute at Avian Flu Diary. He mentioned an article in Nature by Dr. Peter Sandman, one of the world's leading risk communication experts. I encourage you to follow the link and read it now. I'll wait.

OK, welcome back. Didn't that all sound familiar? Having deja vu? that is because it sounds similar to my blog of April 28th, titled Mixed messages, cafeteria-style preparedness won't cut it in swine flu fight. In that blog, I cover many of the same themes. But Dr. Sandman puts things much more succinctly and with much greater gravitas than I ever could.

I met Dr. Sandman in February 2007 in orlando at the CIDRAP pandemic conference. The man and his work are both highly valued and woefully underutilized, I am afraid.

The thing I most remember about then-HHS Secretary Mike Leavitt, a former governor of Utah, is his suggestion -- painfully repeated over and over and over again -- that the easiest way to stock up for a pandemic was "When you go to the store to buy tuna, for every three cans you buy, get a fourth and put it under the bed." Overall, the entire Bush Administration message on pandemic preparedness was (uncharacteristically) clear, sensible, and sage. It was borne of Bush's own reading of John Barry's seminal work The Great Influenza," THE history of the 1918 pandemic.

President Obama's administration seems to have completely disregarded the role that concise risk communication must play in effective management of a flu pandemic. The role of individual responsibility needs to be played up, not downplayed in favor of "nothing to see here, move along." the American people can take it: Tell them exactly what they need to hear. Especially the part they never want you to hear: government can do very little to ensure your personal safety or health during a flu pandemic. That itself may be anathema to their way of thinking, but the truth is the truth.

From Dr. Sandman's article:

Richard Besser, the acting director of the CDC, isn't understating the risk. He says he is "very concerned", but expresses his concern with a soothing bedside manner. He doesn't have that rumpled, exhausted emergency-manager look that the Nuclear Regulatory Commission's Harold Denton perfected in the 1979 Three Mile Island crisis. Denton left people feeling that the risk was serious and that they were in good hands. Besser says it is serious but leaves us feeling that he doesn't want us to worry much.

Still, I don't fault Besser for looking and sounding reassuring. Good crisis communication means saying alarming things in a calm tone, and he is doing exactly that.

The problem is that he isn't giving us anything to do except being hygienic. He keeps telling us, accurately, that the CDC is being aggressive in its response to the outbreak. But he is not asking the public to take further action. He needs to urge citizens, schools, hospitals and local governments to follow Leavitt's advice.

Instead, we have a surreal situation in which the federal government has released one-quarter of the Strategic National Stockpile of antiviral drugs, so there will be enough oseltamivir (Tamiflu) to deploy to millions of sick Americans. But it hasn't yet asked those Americans to stock up on tinned fruit and peanut butter.

It's time to talk peanut butter, tuna and bottled water. But not for swine H1; for any calamity. As I said in my late April blog:

So what should we be telling people? We should be telling them to prepare and to learn more about influenza. I am not talking about the Romero-esque TV commercials that the Ford Administration ordered up during the 1976 swine flu scare. I am talking about telling people to get their "hurricane kits" or "earthquake kits" restocked and brought up to speed. It is time to re-educate the American people on previous pandemics and previous near-misses, such as 1946 and 1951, with viruses that were also H1N1 but were much more virulent and, some thing, either swine-like or were actual swine influenzas that jumped the species barrier back in the day.

Telling people to buy one to two weeks' worth of food, water and medicines to prepare for hurricane season -- an annual hit-or-miss proposition with a clear historical precedent of occurrences -- is not considered folly; it is considered prudent.

Great minds think alike.  Thank you for a great article, Dr. Sandman.

Intrepid reader,

Last week, I blogged about the possibilities of swine H1N1 to graft other genes onto its genetic construction. I have mentioned my concern that swine H1N1 could, in fact, easily pick up the amino acid combo which, in the aggregate, represents the Tamiflu Resistance Gene.

I also alluded to the potential for swine H1N1 to take a victory lap around the world and reassort with our old friend H5N1. Now I mentioned this only in passing. The reason should be obvious: A number of persons believe this whole H1N1 thing is either a gross overreaction by public health professionals, and/or a ploy by the Obama Administration to advance its public health agenda.

It is neither, although every time I hear an Obama official even mention health care "homes" in the same breath as H1N1, I cringe, because they need to put the Rahm Emanuel playbook down ("Rule 1: Never allow a crisisto go to waste") during this entire evolving event.  It is important to know that the Obama Administration is essentially running the Bush playbook on the management of this epidemic, and they have acknowledged as much and have been publicly grateful for its existence. So far, I have not seen any major mistakes, mea culpas or blown calls in the response to this unfolding situation out of Washington, excepting the Vice-President-in-charge-of-embarrassing-gaffes and soon to be Lame Duck, Joe Biden.  And even he was saying what everyone else was thinking, I suppose.  Still, as a recovering politician myself, I am amazed at this guy's lack of an "internal quip governor" (think NASCAR restrictor plate) and how Obama allowed him to get on the ticket. 

But I digress.  Back to the issue at hand, namely reassortment.  Bloggers have been understandably reluctant to stray too far into joining swine H1N1 with avian H5N1.  But when the world's leading influenza expert -- the "Pope of Influenza," Dr. Robert G. Webster of St. Jude in Memphis -- comes out and says what everyone else in Flublogia is thinking, I think it warrants a good blog.

Dr. Webster has dedicated his entire adult life to the understanding of influenza. He has learned much, but each answer generates a whole new set of questions. He, Edwin Kilbourne, John Oxford, and the late Graeme Laver stand as the true giants of modern influenza research. Upon their footpaths walk Kawaoka, Peiris, Webby (like Peiris, a protege of Webster) and others.

Kawaoka has taken some ribbing from this Blogger in the past, but let me assure you he knows his stuff and the world is a better place with him and all his skills on board.

When Webster talks, or even speculates, it is by definition informed, and we should do the old E. F. Hutton commercial and listen. Today, an AP article -- one of the best-researched I have read in quite some time -- speaks of the opportunity for swine H1N1 to reassort with avian H5N1 and produce -- something.  One treat is that it quotes from three of the best-known names on the influenza front, which is always fun.

I will give the article and its link later. What I want to talk about now is the situation in Egypt, and why the Egyptian government made the controversial move to slaughter all its pigs virtually overnight. Something feels Biblical in that decision, you know. It was met with hostility and violent demonstrations across the nation. Only Christians eat pork there, and the hogs slaughtered were destined only for Egyptian Christian dinnertables.

But I believe the Egyptian government had its own experience and that of Indonesia on its mind when it made the decision. The Egyptian government has been looking for a reason to wipe out the hog population since 2008, because there was and is growing concern that Egyptian pigs had become reservoirs for H5N1. Search "Egypt" on my blogsite to find everything of consequence that has happened in that country, flu-wise, since 2006. I'll wait. Especially read my January, 2008 blog here. It has a pretty graphic, too.

OK, welcome back. You should have seen the blog post fromEgyptian blogger Zeinobia, whose blog from January 2008 -- yes, I said January 2008 -- was an eerie foreshadowing of our current situation.

Short form: The Egyptian government is scared to death that H1N1 will come around and reassort with H5N1, which they believe to possibly be endemic in their pig population.  And if you look at the continuing increase in suspected and confirmed Egyptian H5N1 human bird flu cases, I think you'd agree there is much to be concerned about.

Likewise, the situation in Indonesia and in China also involoves informed speculation on behalf of animal and human influenza researchers that H5N1 may have made a small foothold in the hog populations there. Especially Indonesia, which remains Bird Flu Central for human cases and potential pandemic explosion, despite the competition from ongoing Egyptian human infections. Researchers already know that some 20% of the stray cat population in Indonesia has H5N1 antibodies. Likewise, some hogs in Indonesia have tested positive for H5N! antibodies. From the Website FluWiki, from2006:

Cat H5N1 sequences in Indonesia are apparently more similar to H5N1 sequences from humans than either are to H5N1 sequences from birds. What is the most logical interpretation of these results? I submit that there may be a mammalian reservoir for H5N1 in Indonesia and other countries and that H5N1 is under selection to adapt to mammals in this reservoir. Further, at least some of the human cases may be due to mammal-to-human infections. (See also Dr. Jeremijenko’s post at 23:14 in this thread, and here and here). In the recent large cluster of human cases in Indonesia, no infections of poultry were found in close proximity to the village where the outbreak occured. However, pigs with antibodies to H5N1 were found in this region reference. H5N1 infections in pigs would be particularly worrisome as these animals could serve as mixing vessels for the formation of a human-adapted H5N1 strain. (bold mine)

That is what everyone is worried about. That is the Elephant in the Room. That is why no one in Geneva, Atlanta or anywhere else is overreacting about this swH1H1 epidemic.

Now it is time to bring in the AP story. Here it is, in its entirety.

Top flu expert warns of a swine flu-bird flu mix

By MARGIE MASON, AP Medical Writer Margie Mason, Ap Medical Writer 2hrs29minsago

MEXICO CITY – Bird flu kills more than 60 percent of its human victims, but doesn't easily pass from person to person. Swine flu can be spread with a sneeze or handshake, but kills only a small fraction of the people it infects.

So what happens if they mix?

This is the scenario that has some scientists worried: The two viruses meet — possibly in Asia, where bird flu is endemic — and combine into a new bug that is both highly contagious and lethal and can spread around the world.

Scientists are unsure how likely this possibility is, but note that the new swine flu strain — a never-before-seen mixture of pig, human and bird viruses — has shown itself to be especially adept at snatching evolutionarily advantageous genetic material from other flu viruses.

"This particular virus seems to have this unique ability to pick up other genes," said leading virologist Dr. Robert Webster, whose team discovered an ancestor of the current flu virus at a North Carolina pig farm in 1998.

The current swine flu strain — known as H1N1 — has sickened more than 2,300 people in 24 countries. While people can catch bird flu from birds, the bird flu virus — H5N1 — does not easily jump from person to person. It has killed at least 258 people worldwide since it began to ravage poultry stocks in Asia in late 2003.

The World Health Organization reported two new human cases of bird flu on Wednesday. One patient is recovering in Egypt, while another died in Vietnam — a reminder that the H5N1 virus is far from gone.

"Do not drop the ball in monitoring H5N1," WHO Director-General Margaret Chan told a meeting of Asia's top health officials in Bangkok on Friday by video link. "We have no idea how H5N1 will behave under the pressure of a pandemic."

Experts have long feared that bird flu could mutate into a form that spreads easily among people. The past three flu pandemics — the 1918 Spanish flu, the 1957-58 Asian flu and the Hong Kong flu of 1968-69 — were all linked to birds, though some scientists believe pigs also played a role in 1918.

Webster, who works at St. Jude's Children's Research Hospital in Memphis, Tenn., said bird flu should be a worry now. Bird flu is endemic in parts of Asia and Africa, and cases of swine flu have already been confirmed in South Korea and Hong Kong.

"My great worry is that when this H1N1 virus gets into the epicenters for H5N1 in Indonesia, Egypt and China, we may have real problems," he told The Associated Press. "We have to watch what's going on very diligently now."

The U.S. Centers for Disease Control and Prevention are extraordinarily busy trying to understand the swine flu virus itself, and haven't had time to break off staff to look at the possibility of a swine flu-bird flu mix, spokesman Dave Daigle said.

Malik Peiris, a flu expert at Hong Kong University, said the more immediate worry is that swine flu will mix with regular flu viruses, as flu season begins in the Southern Hemisphere. It is unclear what such a combination would produce.

But he said there are indications that scenario is possible. Peiris noted that the swine flu virus jumped from a farmworker in Canada and infected about 220 pigs. The worker and the pigs recovered, but the incident showed how easily the virus can leap to a different species.

"It will get passed back to pigs and then probably go from pigs to humans," Peiris said. "So there would be opportunities for further reassortments to occur with viruses in pigs."

He said so far bird flu hasn't established itself in pigs — but that could change.

"H5N1 itself has not got established in pigs," he said. "If that were to happen and then these two viruses were both established in pigs in Asia, that would be quite a worrying scenario."

Michael Osterholm, an infectious disease specialist at the University of Minnesota who has advised the U.S. government on flu preparations, said while flu experts are discussing the scenario, he has yet to see specific evidence causing him to think it will happen.

"Everything with influenza is a huge guessing game because Mother Natureholds all the rules, and we don't even know what they are, so anything's possible," he said. "We don't have any evidence that this particular reassortment is that much more likely to pick up H5N1 than any other reassortment out there."

"We don't have to put these things together," he added. "This is not chocolate and peanut butter running into each other in the dark hallway."

But there is in fact discussion of putting them together — in a high-security laboratory — to see what a combination would look like, according to Webster. Similar tests have been done at the CDC mixing bird flu and seasonal human flu, resulting in a weak product, he said.

Daigle, the CDC spokesman, said the agency wants to look at the question in the future.

Webster has done groundbreaking work on both swine and bird flus in his 40-year career, and has followed the evolution of the current swine flu strain from a virus that sickened a handful of people who worked with North Carolina hogs into a bug that has spread from person to person around the world.

He is closely involved in the global effort to analyze what the virus might do next. It has killed 42 people in Mexico and two in Texas, but so far has not proven very deadly elsewhere, leading to some criticism that the World Health Organization's warnings of a potential pandemic have been overblown.

Webster said underestimating the swine flu virus would be a huge mistake.

"This H1N1 hasn't been overblown. It's a puppy, it's an infant, and it's growing," he said. "This virus has got the whole human population in the world to breed in — it's just happened. What we have to do is to watch it, and it may become a wimp and disappear, or it may become nasty."

___

AP Medical Writer Maria Cheng in London contributed to this report.

So there you go.  I hope wimp, but no one knows what it will do eventually.  However, it is this worry that, I believe, has led the Egyptian government to do what it could not do last year; namely, slaughter the mixing vessels of influenza.  They do not want the Next Pandemic to start on their doorstep.  In that regard, and now knowing what you know, let me ask you:  Have they made the correct decision?

The news stories are starting to come out of Washington, DC; Baltimore; and soon Sarasota (and that is rare to have that small retirement city mentioned in the same breath with two of the Big Cities on the East Coast!) that states just don't have enough Tamiflu to go around.

And here in sunny Florida, where we did not avail ourselves of the now-expired Federal coupon offer to buy Tamiflu at cheaper prices, people are openly questioning whether the state should, indeed, buy more.

I have a better idea. First, let me set some background.

I do not know if Roche can take enough plants offline, recommission them and start making Tamiflu again in any quantity. recall that Roche made a huge capital investment in more Tamiflu plants in 2005 and 2006, only to see global demand for Tamiflu abate as the concern evaporated regarding a bird flu pandemic. Roche then recommissioned the lion's share of these facilities to make other drugs instead.

Roche also made a huge breakthrough around that time, namely being able to synthesize the key ingredient of the antiviral drug: Something only found in Chinese star anise. Shikimic Acid. According to Wikipedia, Star Anise, under the influence of shimikic acid, fought Iron Man and Wolverine before being brought down by Captain America, who is now his old sidekick Bucky, the Winter Soldier.

No, that's not right. Damn that Wikipedia!  Anyway,Janapese star anise is right out; only Chinese star anise will work. So Chinese farmers began doing what American farmers have been doing with corn; plowing under all other crops to make the big cash (cow) crop. Chinese farmers were making the kind of money American farmers were making! BIG money from star anise, because it also took a long time to reap the fruit.

But then Roche spoiled the party by synthesizing shikimic acid, and now it can be mass-produced more cheaply. Roche will have to recommission those gleaming Tamiflu plants and also begin re-licensing other drug makers to make Tamiflu under license.

Or will they? Roche has been burned by the world's governments once already. I doubt if Roche will be as willing a corporate partner (meaning ready to heavily discount Tamiflu) as they were in 2006 and 2007. And maybe they shouldn't.

The other X-Factor (so you see a pattern here? Wolverine? X-Factor?) is the dreaded Tamiflu Resistance Gene, or the combination of mutations to neuraminidase of gene segments R292K, N294S, and H274Y. Widespread circulations of this set of anti-Tamiflu genes have rendered Tamiflu virtually useless against the non-swine H1N1 that is our seasonal bug.

In fact, a Scientific American article of March, 2009 coincidentally reminded readers of the presence of this gene set. Here's the most striking passage:

A whopping 98 percent of this year's circulating H1N1 flu strains are immune to Tamiflu, compared with only 12 percent during the 2007-2008 flu season. (bold mine)

"We don’t know what's physically happened to the virus to cause it to transmit more rapidly, but something has and even more so this year," says study author Nila Dharan, a fellow in the Centers for Disease Control and Prevention's (CDC) Epidemic Intelligence Service, which studies major disease outbreaks. Dharan tells ScientificAmerican.com that a spontaneous (natural) genetic mutation – and not overuse of Tamiflu — is to blame. She notes that additional structural changes to the virus (that scientists don’t completely understand) have enhanced the resistant strain's ability to grow and infect people.

The trend is alarming enough that Department of Health and Human Services (HHS) officials have been huddling for the past week to consider whether to adjust the composition of the federal pandemic flu drug stockpile, of which 40 million treatment courses (80 percent) is Tamiflu, says Robin Robinson, director of the Biomedical Advance Research and Development Authority(BARDA), an HHS arm that manages the stockpile.

I guaran-damn-tee you that in the back/front of every single influenza researcher's mind on this planet is the knowledge that these mutations could, at any time, by reassortment or recombination, get into the present swine H1N1. Mutations have already been seen in H5N1 avian flu, but not in large numbers.

But the movement from 12% to 98% in seasonal H1N1 is striking. And where those mutations first appeared is absolutely head-scratching. Rather than link you to all the blogs I have made on Tamiflu resistance, just search this Blogsite for the words "Tamiflu resistance." You'll read everything from the presence of Tamiflu in the water supply of Sweden to the lack of resistance in the most-prescribed Tamiflu nation on earth -- Japan.

OK, now let's assume you are a policymaker. Here are the facts:

• You are broke, out of money, laying off workers, cutting services.
• You have a pandemic-in-the-brewing called swine H1N1. Or H1H1 influenza A. Or "fluffy bunny slippers," according to this insane "let's not-p-off-the-pork-people" White House PC-silliness. Hey, let's just call this "PC FLU?"

But I digress.

• You also know you don't have enough Tamiflu to really get the job done.
• And there is this as-widespread-as-Jonas-Brothers-fever anti-Tamiflu gene that is found in 98% of all seasonal H1N1 flu this past season.
• Did I mention your state is broke?

I have a solution. Back in World War II, largely in the pacific, Corpsmen and medics were stretched to the limit on penicillin. They did not have enough to treat everyone with an infection.

Miraculously, they did have this relatively new anti-gout medicine called Probenecid. They knew one of the side effects of Probenecid was that people didn't pee as much as normal. So someone in some battlefield MASH unit said "What the Hell, let's see if it works," and co-administered Probenecid with penicillin.

And danged if it didn't work! The co-administration of Probenecid with penicillin stretched the effective supply of penicillin by a factor of 2.

A few years ago, people with long memories and concern over Tamiflu stocks began speculating about the effectiveness of Tamiflu and Probenecid. I have written about this many time before, but the definitive blog on the subject in my inventory is this shoulda-won-a-Pulitzer story:

Killing two birds with one stone

A portion of Roche's study of the use of probenecid in 2002 comes from the blogsite Smart Economy, and the story can be found at: http://smarteconomy.typepad.com/smart_economy/2005/11/smart_wartime_t.html.

Dr. Michael Greger, a person whom I communicate with occasionally, wrote in his seminal work Bird Flu: A Virus of our own Hatching:

Roche found that probenicid doubled the time that Tamiflu spent circulating in the human bloodstream, effectively halving the dose necessary to treat someone with the flu. Since probenicid is relatively safe, cheap, and plentiful, joint administration could double the number of people treated by current global Tamiflu stores. “This is wonderful,” exclaimed David Fedson, former medical director of French vaccine giant Aventis Pasteur. “It is extremely important for global public health because it implies that the stockpiles now being ordered by more than 40 countries could be extended, perhaps in dramatic fashion.”2495

So let's review:

• Probenecid is safe.
• It keeps the medicine in the body longer.
• It will effectively double our supply of Tamiflu overnight.
• It will free up Relenza for use exclusively by police, fire, EMT, emergency room staff, and otehr first responders.
• It will reduce the incidence of painful gout in Tamiflu takers.
• It will reduce the amount of Tamiflu that makes its way into the groundwater, thereby making it the "green" solution.

In short, the co-administration of Tamiflu with Probenecid is a solution that bears very close, careful scrutiny. 

Always glad to help.