Wednesday, May 31, 2006

Australia's best laid plans

Australia had a great pandemic flu plan. On paper. Now paper is confronting reality and reality is winning.

Like a number of other places, it seemed only common sense that the priority for Tamiflu would be essential workers. Back in October the Australian government said it had enough Tamiflu for 1,000,000:
The Federal Health Minister, Tony Abbott, has been very frank about the inadequacy of Australian stockpiles:

"Certainly, we don’t have anything like enough antivirals to protect the entire population. At present, we have enough antivirals to protect one million essential service workers for about six weeks."

He has also been very candid about supply constraints being a clear reason for the limited stockpiles:

"[A]t the moment there are no additional antivirals anywhere in the world . . . If there were more antivirals to be had, by all means [we would expand stockpiles]. But on the best evidence we have, there aren’t."

Providing such protection will be essential in order to ensure that workers such as police, doctors, nurses, water and electricity staff and airport employees turn up for work and maintain essential infrastructure. When supplies run out after 6 weeks or so, Australia will then be competing to obtain preferential treatment for a scarce resource from Roche. (Medical Journal of Australia)
It turns out even this bit of pessimism was too optimistic. Australia has reversed direction and now will give Tamiflu only to the sick and those directly exposed to the sick:
"We came to the conclusion in consultation with the states that the attempt to keep prophylaxis going for the up to 1 million people who would normally be deemed essential was simply not going to work, there would never be enough anti-virals to do so," he said. (Australian Broadcasting Corporation)
Either a lot of Tamiflu disappeared since October, or the amount of Tamiflu was overestimated, or . . . they were just blowing smoke?

Score: Reality 1, Paper Plan 0.

Message to WHO: there is no barn door to close

I try hard to be fair to WHO. They've got an exceedingly tough job and not much to work with. Every time I write an opinion or criticize them I am conscious I could be very wrong.

But this fireblanket business just exasperates me. Let's get real.
The World Health Organization (WHO) issued a step-by-step plan on Tuesday, including the rapid mass use of the antiviral Tamiflu, for containing a bird flu outbreak if the virus starts to spread rapidly among humans.

The "rapid response and containment strategy" has a chance of quashing the deadly H5N1 virus only if people in the zone at risk receive massive doses of the drug within three weeks of a confirmed outbreak, it said.

"The success of a strategy for containing an emerging pandemic virus is strictly time dependent," the WHO said in its latest containment report, based on recommendations by 70 international experts who held closed-door talks in March.

"Mathematical models have indicated that a containment strategy, based on the mass administration of antiviral drugs, has a chance of success only when drugs are administered within 21 days following the timely detection of the first case representing improved human-to-human transmission of the virus."

Under the detailed timeline laid down, a country should notify WHO of a cluster of suspicious cases suggesting sustained human-to-human spread of the virus within 24 hours of detection.

A WHO-approved laboratory has another 24 hours to confirm that the H5N1 bird flu virus has changed, either through mutation or through reassortment with human influenza.

The strategy relies on WHO's global stockpile for rapid containment, three million treatment courses of Tamiflu, donated by Swiss drugmaker Roche. Quarantine, infection control measures and contact tracing must also be carried out.

Once the WHO officially asks Roche for Tamiflu doses to be sent, they should arrive at the international airport nearest the outbreak within 24 hours, the Geneva-based agency said. (Boston Globe)
On Saturday (May 27), The Globe goes on to report, WHO asked Roche to ready the stockpile for shipment to Sumatra in Indonesia after becoming aware of the bird flu large cluster that wiped out an entire extended family and bore unmistakable marks of human to human transmission. They did this after disease transmission had already been underway for at least four weeks and three of the patients had been released from the hospital to the general community before returning to the hospital to die. If ever there was a graphic demonstation of the futility of the fireblanket approach, this was it. It's not going to work.

This doesn't necessarily mean they shouldn't try. Maybe they'll succeed in getting a couple of days grace, although it's unlikely. What worries me more is the real possibility of self-delusion. Let me say it again, as clearly as I can: It's not going to work.

I don't know if this virus will evolve into a pandemic strain or not, and if it does, where and when it will happen (although Indonesia still tops my list of likely places). But if the biology and circumstances allow it, there is nothing we can do to prevent it. The best we can do is get ready to manage the consequences.

And there's plenty we can do along those lines, things that are more likely to save lives than elaborate and futile plans to close the barn door after the horse has bolted. Because there's no barn door to close for influenza.

Tuesday, May 30, 2006

What to expect next in Indonesia

What I think we can expect from Indonesia over the coming weeks is a fair amount of confusion. Sporadic cases of bird flu continue to be reported. WHO's latest update adds six to bring the Indonesian total to 48, of which 36 have been fatal. The wide publicity given the large cluster in Sumatra is likely to increase the index of suspicion that new cases of pneumonia, if there is a history of exposure to poultry -- common in Indonesia -- will be admitted to a bird flu isolation ward as a precautionary measure.

As we noted in an earlier post, there are a huge number of pneumonias every year in Indonesia -- 186,000 cases in the under five age group in West Java alone in 2005 -- many with exposure to poultry. If even a fraction of these is pegged a "suspect" case, the wards will fill up quickly with suspect bird flu cases. The result will be detection of some more genuine cases and more reports of crowded wards full of suspect cases, all possibly without any real change in the incidence of disease.

Add to this the chaos of a devastating earthquake, a government unable to cope at any level and a world peering in with trepidation and you have a recipe for -- a fair amount of confusion.

Unfortunately, expecting to be confused does not lessen confusion.

Revere's prep

If the SHTF, I am ready to go on blogging, thanks to this 1935 beauty from modern mechanix (h/t Boingboing):

Monday, May 29, 2006

Orent gets it (mostly) right

I've been tough on journalist Wendy Orent here because I thought her widely read op-ed pieces on bird flu were wrong-headed, inaccurate and unhelpful in getting people ready for a possible pandemic. Yesterday she had another op-ed in the LA Times and I'm glad to say it's on the right track. Not that I agree with everything she says, but it's informative and helpful to readers who want to understand some of the controversies. Here's the lede:
There's a lot of bird flu virus out there. Despite encouraging news from Vietnam and Thailand, neither of which has reported any bird or human cases of the lethal H5N1 strain this year, the situation in Indonesia continues to worsen. Eight members of a family contracted the disease, and seven of them died this month. The timing suggests person-to-person transmission. Although not the first instance of such transmission, it's the single largest cluster that has been seen, according to virologist Earl Brown of the University of Ottawa. Indonesia appears to lack the resources to combat the disease.

The virus is also active in Egypt and has spread to Israel, Jordan and the territories where Palestinians live. Africa has a wide belt of infection. With the disease spread over so much of the world, more people in contact with sick birds means more opportunities for humans to catch the virus. This appears how human influenza pandemics have begun — through human contact with sick birds.

But the factors that set off a pandemic remain unknown. No one has ever tracked the evolution of a new pandemic. All we have seen — in 1918, 1957 and 1968 — is the aftermath of that evolution. Still, we are told that all it would take for H5N1 to become a pandemic would be for the virus to mutate so it could spread in a sustained way from person to person. (LA Times)
The rest is a discussion of what she and others think this talk of mutation means. I might disagree in details, but essentially I agree we don't know much about what it would take. Most scientists don't believe a chicken virus turns into an easily transmissible human virus in one step (although it's possible). But Orent goes further. Her view is that natural selection is the key to the virus's evolution and it can't happen suddenly, requiring instead a period of adaption in mammalian and probably human hosts.

This isn't an unreasonable point of view, and this adaptation might be occurring now in Indonesia and elsewhere. But I think it's wrong to believe it is the only point of view. Here are a couple of other possibilities.

Whatever genetic changes are needed for transmissibility in humans may be traveling along with some that are useful for the virus in birds. Selection pressure doesn't explain everything, as we see in the sudden emergence of amantadine resistance in virtually all flu virus in the US. Amantadine is not used much in the US, so this isn't selection. Most likely it is a "hitchiker" effect with the amino acid change conferring amantadine resistance linked with another genetic feature that conveys some selective advantage (a point made by bioinformatician EC Holmes). Here's another possibility. It takes multiple genetic switches to be flipped to produce enhanced transmissibility in humans (let's say ten) but eight or nine are already flipped, leaving only one or two to go. Since we are largely ignorant of what it takes, we are also ignorant about how many switches are flipped already. Here's yet another point. Genetic changes that enhance transmissibility don't have to confer selective advantages or be linked to them. Without such an advantage the virus will eventually be replaced by another, more fit one, but the transient period could be very nasty. None of this is not a repudiation of Darwinism. It is consistent with the current neo-Darwinian synthesis ushered in by Sewall Wright, Ernst Mayr and others in the 1930s and 1040s.

So it's good to see Ms. Orent on board. A flu-denier has now become a useful source of information. I hope she's right about her viral evolution scenario. But the distinct possibility she isn't is good enough reason to prepare.

On Memorial Day

Memorial Day and the usual talk of the bravery and sacrifice of soldiers. Soldiers are mostly ordinary people who do what they have to do in the most terrible of circumstances. In every war they have mirror images on the other side. It seems fitting, therefore, to present a memorial to all soldiers, via the lyrics of a wonderful song penned by John McCutcheon in 1984 to commemorate the Christmas Truce of 1914.
On Christmas Day, 1914, only 5 months into World War I, German, British, and French soldiers, already sick and tired of the senseless killing, disobeyed their superiors and fraternized with "the enemy" along two-thirds of the Western Front (in times of war, a crime punishable by death). German troops held Christmas trees up out of the trenches with signs, "Merry Christmas." "You no shoot, we no shoot." Thousands of troops streamed across a no-man's land strewn with rotting corpses. They sang Christmas carols, exchanged photographs of loved ones back home, shared rations, played football, even roasted some pigs. Soldiers embraced men they had been trying to kill a few short hours before. They agreed to warn each other if the top brass forced them to fire their weapons, and to aim high.

A shudder ran through the high command on either side. Here was disaster in the making: soldiers declaring their brotherhood with each other and refusing to fight. Generals on both sides declared this spontaneous peacemaking to be treasonous and subject to court martial. By March, 1915 the fraternization movement had been eradicated and the killing machine put back in full operation. By the time of the armistice in 1918, fifteen million would be slaughtered. (from Chestnut Hill Meeting House [Philly])

Christmas in the Trenches
©John McCutcheon, from his CD, Winter Solstice
My name is Francis Toliver, I come from Liverpool.
Two years ago the war was waiting for me after school.
To Belgium and to Flanders, to Germany to here
I fought for King and country I love dear.

'Twas Christmas in the trenches, where the frost so bitter hung
The frozen fields of France were still, no Christmas song was sung.
Our families back in England were toasting us that day
Their brave and glorious lads so far away.

I was lying with my messmate on the cold an rocky ground
When across the lines of battle came a most peculiar sound.
Says I, "Now listen up, me boys!" each soldier strained to hear
As one young German voice sang out so clear.

"He's singing bloody well, you know!" my partner says to me.
Soon, one by one, each German voice joined in harmony.
The cannons rested silent, the gas clouds rolled no more
As Christmas brought us respite from the war.

As soon as they were finished and a reverent pause was spent
"God Rest Ye Merry, Gentlemen" struck up some lads from Kent.
The next they sang was "Stille Nacht," "'Tis 'Silent Night,'" says I
And in two tongues one song filled up that sky.

"There's someone coming towards us!" the front line sentry cried.
All sights were fixed on one lone figure trudging from their side.
His truce flag, like a Christmas star, shone on that plain so bright
As he, bravely, strode unarmed into the night.

Soon one by one on either side walked into No Man's Land
With neither gun nor bayonet we met there hand to hand.
We shared some secret brandy and wished each other well
And in a flare lit soccer game we gave 'em hell.

We traded chocolates, cigarettes, and photographs from home.
These sons and fathers far away from families of their own.
Young Sanders played his squeezebox and they had a violin
This curious and unlikely band of men.

Soon daylight stole upon us and France was France once more
With sad farewells we each prepared to settle back to war
But the question haunted every heart that lived that wondrous night
"Whose family have I fixed within my sights?"

'Twas Christmas in the trenches where the frost, so bitter hung.
The frozen fields of France were warmed as songs of peace were sung.
For the walls they'd kept between us to exact the work of war
Had been crumbled and were gone forevermore.

My name is Francis Toliver, in Liverpool I dwell,
Each Christmas come since World War I, I've learned its lessons well,
That the ones who call the shots won't be among the dead and lame
And on each end of the rifle we're the same.
The last lines bear repeating:
That the ones who call the shots won't be among the dead and lame
And on each end of the rifle we're the same.
The Reveres, Memorial Day, 2006

Sunday, May 28, 2006

Pandemic alert: phase shift?

I don't want to get in the business of defending WHO, especially as I have much to criticize about how they have done some things. But it is important to explain and clarify what they are doing or trying to do. If that sounds like a defense, you'll have to deal with it.

Helen Branswell of Canadian Press has just put out an important story saying that WHO isn't going to change the pandemic alert from Phase 3 to Phase 4, despite the fact that Phase 4 now sounds like the most appropriate description. Instead, they are going to rewrite the description to better express what they think about the threat. Some will immediately interpret this as moving the goal line when the game is going badly. Still, the explanation merits serious consideration. The phasing rewrite is in progress so I can't report what it will look like, but from Branswell's story I can at least tell you the rationale.
The worrisome Indonesian cluster -- the largest to date and the first time person-to-person-to-person spread of the virus is believed to have taken place -- has provoked calls from some quarters to change the global pandemic alert level to Phase 4 from the current Phase 3.

Before it could consider making that change, the WHO would have to convene a panel of experts -- the task force Fukuda mentioned -- to comb through the accumulated scientific data looking for evidence H5N1 viruses are becoming more transmissible to and among people and therefore pose a greater pandemic risk.

The task force would advise the WHO. But the final decision rests with the Geneva-based global health agency.

The current pandemic phasing document is a six-step ladder going from no known pandemic threat (Phase 1) to a full-blown pandemic (Phase 6). Many experts admit it's hard to see the difference between Phase 3 (no human-to-human spread or rare instances where a person has had close contact with an infected person), Phase 4 (small clusters of limited and localized person-to-person spread) and Phase 5 (larger but still localized clusters of human-to-human spread). (Helen Branswell, Canadian Press)
With experience the defects in the original formulation of the guidelines are becoming apparent. The issue, as Fukuda points out, is whether there is new evidence of altered transmissibility of the virus, not how many clusters or even their size. Much hinges on the ability to detect this kind of change, which is certainly not an easy call given our current knowledge. On the other hand, it is not especially useful to be tied to a grading system that doesn't express the risk, especially as a change in the Phasing will have immediate consequences regarding public perception, staffing, international trade, travel and commerce and much else. It's not something you want to get wrong in either direction. WHO is between the proverbial rock and a hard place.

The significance of all this may not be apparent to those unfamiliar with WHO's role in the international system and the legal and political limitations it implies. I am hoping to write some kind of explanation of this confusing issue in the near future, but for now, let's just observe that like any entity bound by rules of conduct, WHO cannot blithely toss them aside when it suits them unless the urgency is so great there is no choice. Making that call is difficult and they only get one chance. If they guess wrong, the next time they may find they have used up all their capital.

My appreciation for the difficult position WHO finds itself in won't stop me from offering advice. They need all the advice they can get.

Let me start here: release the sequences under your control.

Indonesia: coffee's on

Tamiflu is being flown to Asia by the US, although there remains much confusion about the number of tablets, their source and who controls the tablets and where they will be located. An AP story says there are 9500 treatment courses (presumably 95,000 tablets) from a WHO stockpile, but Secretary Leavitt said it was from a stockpile controlled by the US, not WHO. AP also says the drug along with protective gear was flown into Indonesia on Friday, although rumor had it on its way to Singapore or to Clark AFB in the Philippines. WHO spokesperson Maria Chang said it was likely control would be handed over to the Indonesian government, contradicting Leavitt's claim. Since the Indonesian government is widely considered both corrupt and incompetent, this seems a questionable move. However, it is a wise rule of thumb not to believe everything being said at this point, especially if it comes from or is meant to mollify the Indonesian Ministry of Health.

Not that WHO pronouncements seem very plausible, either. WHO has alerted Tamiflu's maker, Roche, that some of a 3 million treatment course set Roche set aside for use by WHO may be called upon for use in Indonesia. Don't worry. Just routine:
No further action on the emergency supply was expected for now, according to the U.N. health agency, which called the alert part of its standard operating procedure when a case arises like that in Indonesia.

"We have no intention of shipping that stockpile," WHO spokesman Dick Thompson cautioned. "We see this as a practice run." (AP)
Standard Operating Procedure? Well they've never done it before, so I guess they are setting the standard now for the operating procedure. But what exactly is the standard (not to mention the operating procedure)?

The seven person cluster of one extended family, spread out over at least three incubation periods (all have now died), began at the end of April, with cases dying through the first three weeks in May. WHO in Jakarta was only officially notified on May 22. CDC had people in-country but they were not invited to consult until mid-May. From what I hear third hand, NAMRU2 is not invited to be part of investigations, although this may have changed. The locals are hostile to the government. Indonesia has an active volcano and just suffered a catastrophic earthquake on its main island. The government is ineffective, slow, inefficient and passive aggressive toward international scientists.

Oh, and this:
Meanwhile, Nyoman Kandun, a senior official at Indonesia's health ministry, said a WHO laboratory in Hong Kong had confirmed five more cases of human bird flu, three of which were fatal. All five had earlier tested positive for the virus in a local laboratory.

The latest confirmed deaths were a 39-year-old man from Jakarta, a 10-year-old girl from West Java and a 32-year-old man, who on Monday became the last to die in the Kubu Simbelang cluster. (AP)
WHO so far has decided not to raise the Pandemic Threat Level from 3 to 4. But the facts speak for themselves.

Wake up and smell the Indonesian coffee!

Freethinker Sunday Sermonette: feat of Clay

I can get exercised over religion with the best of them, but even I can't out do Pat Robertson. By now you probably all know of his phenomenal feat of strength -- leg pressing 2000 pounds. Here's the official announcement, via the Christian Broadcasting Network website:
Did you know that Pat Robertson, through rigorous training, leg-pressed 2,000 pounds! How did he do it?

Where does Pat find the time and energy to host a daily, national TV show, head a world-wide ministry, develop visionary scholars, while traveling the globe as a statesman?

One of Pat's secrets to keeping his energy high and his vitality soaring is his age-defying protein shake. Pat developed a delicious, refreshing shake, filled with energy-producing nutrients.

Discover what kinds of natural ingredients make up Pat's protein shake by registering for your FREE booklet today!
That must be some protein shake. As SportsLine's Clay Travis notes:
That would mean a 76-year-old man broke the all-time Florida State University leg press record by 665 pounds over Dan Kendra. 665 pounds. Further, when [Kendra] set the record, they had to modify the leg press machine to fit 1,335 pounds of weight. Plus, Kendra's capillaries in his eyes burst. Burst. Where in the world did Robertson even find a machine that could hold 2,000 pounds at one time? And how does he still have vision? (ClayNation)
Clay, duly impressed, asked to see a work-out and interview The Big Guy (not the one with the long beard in the sky; the one with the condos and limos here on earth):
After about 20 minutes on Robertson's Web site, I managed to find a way to send an e-mail without having to give my credit card information. Here was the text:
"I would like to interview Pat Robertson about his leg-press workout and protein shake. If possible, I would like to accompany Pat on his workout where I could help him stack on the 44 different 45-pound plates he would need to attach to leg press 2,000 pounds. By my calculations, his leg press of 2,000 pounds requires 22 forty-fives and one ten-pounder on each side.

I look forward to hearing back from you,

Clay Travis"
Like Travis, I am in awe of this achievement. In fact, it is so miraculous, if True, I will become a Believer. No more atheism. Just a deeply felt belief in the CBN Protein Shake and its representative here on earth, Dr. Pat Robertson.

A world-class dreck fresser ("leg presser" in Yiddish).

Saturday, May 27, 2006

I need to get this off my chest

The cost of one month of the war in Iraq, $9 billion, is approximately the same as six years of the total operating budget of the World Health Organization ($3.3 billion for the next two years). You can take this any way you want. For now, let's just say that WHO's total budget to save lives over the next year, $1.6 billion, is less than a week's worth of the US expenditure to take lives. This is a double commentary: one on the vast expenditures for killing, by a single country, deployed in a single country; the other, the pitiful expenditure to save lives in the entire globe.

Total US CDC budget for last year was $8.8 billion, $1.6 billion for infectious disease alone, the same as WHO's entire budget for everything, for the entire world.

And "everything" covers a lot. You may be unusually preoccupied with bird flu, but people are dying mostly from other things. When we criticize WHO for its performance in the bird flu , remember this is an agency that has little to work with and much to spend it on. Bird flu is just a piece of a vast and depressing picture that includes malaria, HIV/AIDS, vectorborne disease control, maternal and child health, clean food and water and much more. Without WHO we wouldn't even have known about SARS until it was on top of us. Without WHO we'd still have smallpox in the world. Without WHO tens of millions of women and their children would be dead. Without WHO you wouldn't get a properly matched flu shot every year. And they are asked to do all this on a pittance.

I'm not trying to excuse WHO for inexcusable lapses. But the demonizing of WHO going on here and elsewhere I find troubling and lacking in perspective. It is important to know who your friends are, who your enemies are, who your friends aren't and who your enemies aren't. WHO is not the enemy, no matter how you look at it. You may feel they are misguided, have made mistakes, lack transparency or honesty and many other things I think they could fairly be charged with respect regarding their performance in the rapidly evolving bird flu situation. But they are trying to cope while still carrying an extremely heavy burden through a landscape littered with political hazards, political hazards that affect many of the other things they must do to save lives. And with the most paltry of resources.

Don't worry about "getting your money's worth" from WHO, because frankly, you're not spending much on them.

I don't mind criticizing them here if I think criticism can move things in a better direction. But while I have a great deal of respect (and affection) for the little community that has grown up around Effect Measure (and I welcome the many others arriving daily), I don't mind criticizing some of you, my friends and comrades in this difficult fight, if I think it can move things in a better direction. Some of the talk about WHO here I think is poorly informed, unhelpful and really off the wall.

OK. Rant over. I feel better. And I still like you.

Nice place for a virus

CA Nidom, the Indonesian researcher who a year ago found evidence of H5N1 infection in pigs living near infected poultry on the island of Java, is now saying (h/t crofsblog) what almost everyone else is saying, that the large cluster of cases in Sumatra is human to human transmission.

I say "almost" everyone because the Indonesian Health Minister, Siti Faila Supari, is still holding out:
"The cluster bird flu case in Tana Karo cannot yet be said a human-to-human bird flu case because proof on the mutation of virus DNA [sic] which is identical with the H5N1 strain of virus that infected the nine victims has not yet been found. And there is no proof of epidemiological human-to-human infection," the minister said. (Xinhuanet)
No change in the virus is necessary because there has probably been human to human transmission going on in Indonesia since the very first cluster of three cases appeared in Tangerang in July 2005. In fact this may also have been H2H2H, with the chain starting with one of the children (no source known) going to a sibling and then to the father. Contrary to the statement, the epidemiological evidence strongly favors human to human transmission there and in Sumatra.

The statement shows graphically what has been obvioius for a long time. The Indonesian Ministry of Health is incompetent to cope with the bird flu situation and nothing they say can be relied on. An Indonesian friend said to me yeseterday that since the fall of Suharto (no pearl of great value, to be sure), there has been no functioning government in the country. It is a free for all with the spoils going to the most corrupt.

Now they have an erupting volacano and an earthquake disaster. A great place -- if you are an influenza virus.

Friday, May 26, 2006

Imploding CDC

The Atlanta Journal Constitution has another in a series of stories about poor morale at CDC. Finally the problems have attracted the attention of a congressional committee, the same one (the Senate Finance Committee) already looking into whether state bioterrorism funding has received adequate CDC oversight:
The U.S. Senate Finance Committee is investigating whether turmoil within the Atlanta-based CDC caused by a massive reorganization is "resulting in the loss of distinguished medical experts whose participation will be greatly needed in the event of future catastrophic health emergencies," committee spokeswoman Jill Kozeny said Tuesday night. (Atlanta Journal Constitution)
For some time complaints have been anonymously posted on an outside website,
Some of the complainants are career CDC employees, many with distinguished scientific records, but they have unanimously refused to be identified, saying they fear reprisals on the job. The employees contend the reorganization has created new bureaucracies that hamper their work and that key scientists have been marginalized.


"Current and former employees are reporting that morale problems caused by failure of current agency management to adequately involve employees in the ongoing reorganization are resulting in the loss of distinguished medical experts whose participation will be greatly needed in the event of future catastrophic health emergencies," Kozeny said in a written statement.
The morale problems at CDC have been an open secret for more than a year. I personally know very senior scientists who are retiring because they are fed up with a bureaucracy that makes it difficult or impossible for them to do their jobs. The AIDS group is imploding. The flu group has been reorganized and is in limbo. Professional scientists are disgusted. The place is a mess.

It's a good thing we aren't facing any serious infectious disease threats. Heck of a job, Julie.

Considering Bandung

It appears the West Java provincial capital of Bandung may be the site of another (so far) small familial cluster, two young siblings. West Java has a population of almost 40 million, the most populous province of Indonesia and the second most densely populated. Xinhua is reporting the deaths of a brother and a sister earlier this week. Local tests indicated H5N1 infection. The younger sister was reported to be 10 years old, her brother 18 years old (Adnkron). Dead chickens were seen in the environment.

If this is indeed another familial cluster, does this signal a new phase in the human bird flu story? Possibly, but probably not. The official WHO and CDC line is that there have been other familial clusters with evidence of human to human transmission and the big one in Sumatra is just another example, although unusually large. In that context, Bandung, too, would be an example. I've also heard rumors of a couple of more small clusters. Is it plausible these are just more in an ongoing story of sporadic clusters?

Plausible, yes. The problem is not that WHO and CDC are concocting an implausible explanation for the Sumatra cluster but that they had previously downplayed the existence of even limited human to human spread in clusters, preferring instead to emphasize the poultry origin of virtually all cases, a position we find misleading, probably deliberately so. WHO has a mixed record on transparency, but habit of "happy talk" hs severely dmagaed their credibility. WHO will have to work hard to recoup and for some it won't be possible. But they should try. Straightforward reporting of facts would be a good start.

Back to the clusters. If we accept the virus has not changed genetically (and we are no longer willing to do so just because they say it, unfortunately), then we must also infer that there have likely been many other clusters, probably undetected. To return to Bandung, West Java had 186,000 cases of childhood pneumonia in 2005, about 6000 of them severe. This is the haystack a bird flu needle would hide in. Plausibly clusters and sporadic cases would be missed. Now that the index of suspicion is increased with the publicity from the Sumatran cluster, we may start seeing other reports of clusters here and there.

But why such a big cluster in Sumatra? Several possibilities. The index case could have been a super spreader (as was found in some cases of SARS) or it might just have been the upper tail of a distribution of cluster sizes. We'll probably never know, as investigators got there too late. Getting into the actual village at all proved difficult because of hostility toward the central government. The Indonesian government has now asked 33 villagers to self-quarantine at home. They are being followed for any signs of illness. So far, either publicly or via several of my own sources in-country, none has appeared outside this extended family.

If there continues to be no spread beyond the extended family, this is probably what WHO and CDC are saying it is, "another cluster," larger but not different in kind. The fact that there is third generation spread, however, sets it apart from other known clusters, so while my guess is there is nothing more to it, I wouldn't bet the farm on it. WHO is trying hard to do contact follow-up.

Too bad we are losing confidence they are telling us everything.

Thursday, May 25, 2006

Clusters, sequences, trust

If there is more upset than WHO feels appropriate about the large cluster of cases in Indonesia with apparent human to human spread within an extended family, they have no one to blame but themselves. With financial markets spooked and currencies in Asia falling, WHO is saying this may not be as unusual an event as appeared at first:
But Firdosi Mehta, acting representative of the WHO in Indonesia, urged against any over-reaction, saying this was not the first cluster that the world has known.

Limited transmissions between people are caused by close and prolonged contact when the sick person is coughing and probably infectious. (Reuters)
It is certainly true this appears more serious. One reason for this is WHO's habit of reassuring the world that whatever is happening at the moment is no big deal but what could happen in the future is a big deal. Whenever their prognostications elicit too much concern they ratchet them back. There has been evidence of human to human transmission right along -- sporadic but fairly clear -- but WHO has chosen to ignore it in their public pronouncements, instead electing to emphasize (falsely) that all the evidence to date has been it required close contact with sick or dead birds to put a person at risk. It has been clear to WHO and many others that close contact with sick and dead poultry is neither a sufficient nor necessary condition for contracting the illness. Had WHO been more accurate about this, the reaction to the Indonesian cluster might not be so great.

Lack of clarity from WHO remains troublesome, particularly regarding the viral sequences from this cluster and more generally. They have the sequence information in hand. They can deposit it immediately in GenBank so others can look at it and decide whether their claims of "no change" are correct. This needs to be done with the other Indonesian isolates as well, not just human isolates but those from birds and any other animals. Here is the WHO statement from yesterday concerning the sequencing:
Full genetic sequencing of two viruses isolated from cases in this cluster has been completed by WHO H5 reference laboratories in Hong Kong and the USA. Sequencing of all eight gene segments found no evidence of genetic reassortment with human or pig influenza viruses and no evidence of significant mutations. The viruses showed no mutations associated with resistance to the neuraminidase inhibitors, including oseltamivir (Tamiflu).

The human viruses from this cluster are genetically similar to viruses isolated from poultry in North Sumatra during a previous outbreak. (WHO)
WHO spokesperson Peter Cordingley said yesterday, "There is no change in the virus whatsoever. This virus has not developed the ability to jump more easily from chickens to humans, nor spread among humans more easily." (CNN)

We assume Cordingley isn't speaking literally ("no change whatsoever") since this is improbable and different than the WHO statement there was no "significant" mutation. A quibble, perhaps, but it raises the question what WHO considers a "significant" mutation. Does the statement the virus is "genetically similar" to poultry viruses imply the cleavage site is the same as the avian one and not the one seen in humans in Indonesia? Would WHO consider an anomalous cleavage site be considered "significant" because it wouldn't be expected to affect transmissibility? What is the WHO criterion for a "significant" mutation, anyway?

Even the statement there is no reassortment with human or pig viruses is ambiguous. Was it meant to leave open the possibility there was reassortment with other bird viruses? For example, if you were to draw phylogenetic trees for each of the eight segments, would you find there has been a swapping of some of the internal gene segments from one avian clade to another in the new isolates (i.e., the isolates are a new avian genotype)? This has been advanced as an explanation for the switch from one predominant strain to another in seasonal flu, but is visible only when you consider the whole viral genome, not just the HA and NA genes. Since no one else has the sequences for the many other Indonesian viruses, no one else can draw these trees. Have they done so?

The certainty with which WHO says there is no significant change in the genetics of the virus gives the false impression they will know such a change when they see it. We have an inkling of some things that might worry us, and presumably the statement means they haven't seen any of these. But our area of ignorance is much larger than our area of knowledge, so reassurances about the lack of change of the virus are premature. It is a melancholy truth that we will know a pandemic is coming our way when we see cases piling up somewhere, not before.

WHO has brought these suspicions on themselves. Let us be as clear as we can. Unlike some others, we don't view WHO as the enemy. Without it the world would be much worse off. WHO is not a monolith or a single person. There are many hard working and dedicated people giving their "all" at WHO and we would be ungrateful not to acknowledge this. If you want to battle an emerging pandemic, this is where the action is and it is going to attract the best, the bravest and the most dedicated. But WHO is also a lot of other people working in a complicated bureaucracy that has become ever more politicized since the days Director General Marcolino Candau ruled so effectively with an iron fist (and wasn't renewed for his trouble). Many countries, including the US, mess around politically with WHO, to everyone's detriment.

With bird flu, WHO's lack of transparency, titrating public reaction and attempts to avoid offending any of its member states have resulted in a serious loss of trust. We shouldn't have to raise any questions about the genetics of the isolates. WHO should release the new sequences (and many others). And so should CDC, St. Jude's, Weybridge and the other stellar flu scientists around the world who are sitting on sequences. If isolates come to a scientist with strings attached, they should tell the source they will not be party to suppressing scientific information. They run a risk that somone else will get the isolate or that no one will. But it is the right thing to do and will change behavior of sources if legitimate scientists cooperate. Scientists who don't should be held up to censure and their papers refused publication just as with any other ethical lapse.

We wish we could take WHO's statements about the genetics of the virus at face value. It is a sad commentary that we and many others no longer do this.

When in Romania

A couple of days ago we reported on mass quarantines of an urban area in Romania's capital of Bucharest. The measure, affecting some 60,000 people all-told in the city and another town in central Romania, was so severe we asked if something extraordinary was occurring there. It turns out there was.

Extraordinary stupidity.
Officials from the World Health Organization said they believed it to be the first time that the movements of so many people were restricted because of bird flu. The Romanian authorities said the tough measures were necessary when the virus threatened an urban area, an assertion WHO disputes.


A town in central Romania, Codlea, and its 23,000 residents, were also put under quarantine. All this happened after a dead chicken was discovered to have been infected with the H5N1 virus that health officials fear might mutate into a human epidemic.


But by Tuesday afternoon, the authorities said the danger of contamination had been reduced.

The government relaxed measures in the capital and in Codlea.

International health experts questioned the necessity of placing humans under quarantine, and critics suggested the heavy-handed response was a way of covering up the government's inability to stop the virus in the first place.

"Generally we do not recommend that the movement of people is restricted to contain an animal outbreak," said Maria Cheng, spokeswoman for the World Health Organization in Geneva. (International Herald Tribune)
Not surprisingly people in the affected areas are pissed.
On Monday, Romanian television broadcast scenes of angry residents demanding that they be allowed to go to work. Several said they had to pay for food the government provided.
A combination of authoritarianism and incompetence that is the stuff of nightmares.

Heck of a job.

Wednesday, May 24, 2006

Indonesia: probably H2H2H

WHO is now saying what could be inferred from their update yesterday: it is likely that for the first time H5N1 has spread from human to human to human -- three generations of cases, possibly four. This does not mean that a pandemic strain has started but it is another warning signal.

If we take the statement that there has been no change in the virus (let's see the sequences!), then there is another inference we might make. This is just the first time WHO has acknowledged this, not the first time it has happened. Since many cases in Vietnam, China and elsewhere lack solid evidence of close contact with poultry this may have happened many times over (see our post here). The index case here was a vegetable seller in a market where there were live animals, so she wasn't in contact with poultry as an occupation. She might well have contracted the disease from sick poultry at the market but she might also have contracted it from someone else at the market (or elsewhere).

As a result of this cogent evidence in Indonesia, WHO may convene a standing committee of experts to decide if the pandemic alert level should move from the current Phase 3 to a new Phase 4. Here is a description of Phase 3, Phase 4 and Phase 5 (see Flu Wiki for more details):
Phase 3: Human infection(s) with a new subtype, but no human-to-human spread, or at most rare instances of spread to a close contact.

Phase 4: Small cluster(s) with limited human-to-human transmission but spread is highly localized, suggesting that the virus is not well adapted to humans.

Phase 5: Larger cluster(s) but human-to-human spread still localized, suggesting that the virus is becoming increasingly better adapted to humans, but may not yet be fully transmissible (substantial pandemic risk).

Note: The distinction between phase 3, phase 4 and phase 5 is based on an assessment of the risk of a pandemic. Various factors and their relative importance according to current scientific knowledge may be considered. Factors may include rate of transmission, geographical location and spread, severity of illness, presence of genes from human strains (if derived from an animal strain), and/or other scientific parameters.
Many (including us) believe we have been in Phase 4 for some time, but WHO has been reluctant to make the call. It appears now they may do so. We shall see. WHO may still decide there is as yet no sufficient evidence the virus has changed and keep the level at 3. In an interview with Helen Branswell of Canadian Press, WHO spokesperson Maria Cheng said this:
"This is the first time we have seen cases that have gone beyond one generation of human-to-human spread,'' Cheng told The Canadian Press.

"It is an evolving situation and it is possible we would convene the task force if we saw evidence the virus was changing.''


Cheng noted the pattern of infections in this cluster seems to point away from a substantial change in the transmissibility of the virus. So do the genetic sequences of two viruses retrieved from this group of people. A statement from the WHO said analysis of those viruses showed "no evidence of significant mutations.'' (Helen Branswell, Canadian Press)
Branswell also interviewed U.S. infectious disease expert D. A. Henderson who was not so sanguine. He points out that the disease spread beyond immediate caregivers to an 18 month old and a 10 year old.
"They all had contact, but it was not the kind of contact we've had described before, where the caregiver would be really heavily exposed,'' he noted.

"And from that standpoint, I find this worrisome. And I think there is an awful lot of information we need about those cases and the circumstances.''
"An awful lot of information" is not what we are getting, however. We do get much handwringing about the difficulty of getting cooperation from fearful and suspicious villagers whose relationship with the central government in Indonesia has been distant and hostile.
"We are still not getting the level of co-operation we would consider optimal,'' Cheng admitted.

Additional WHO personnel are being sent to the village. Included in the group is an expert on social mobilization -- the art of gaining local trust and co-operation in the high tension setting of an infectious disease outbreak.
While you're at it send some of those experts on social mobilization (and social responsibility) to Geneva, Atlanta, Weybridge, Hong Kong, Nashville, Los Alamos, New York. It is not just villagers that aren't cooperating. The genetic sequences need to be released, not just from this cluster but from many others WHO, CDC and individual researchers have not deposited in GenBank (discussion at Flu Wiki here). The lack of cooperation from knowledgeable international and national health officials and eminent scientists has been worse than that of the frightened villagers. It is inexcusable and irresponsible.

To my public health colleagues: Get your own house in order before blaming desperate villagers. Release the sequences and write your papers afterwards. These are not ordinary times. Your resumés are long enough.

Benzene and soda preliminary results

The US FDA has just released preliminary data on their on-going investigation of benzene in soft drinks (see previous posts here, here and here). Using a convenience sample of 100 soft drinks from retail stores in Maryland, Virginia and Michigan, they found four different drinks (eight samples items) with benzene levels above the 5 ppb drinking water standard. Crystal Light Sunrise Classic Orange led the pack with two lots with 70 - 80 ppb of benzene. Interestingly, a lot of the same drink reformulated to have less benzene came in at less than 1 ppb.

The benzene comes from a reaction between a preservative, benzoate salt (sodium or potassium) and vitamin C (ascorbic acid). Other factos such as heat and light affect benzene formation from these ingredients so it is possible to reformulate drinks to suppress benzene exposure. There was no pretense that the sampling reported yesterday was at all representative of the retail inventory or consumer choices. The results of this relatively small sample suggest that a much larger sampling effort will be needed to estimate accurately consumer exposures to benzene, a known human carcinogen. FDA goes to some lengths to say that even those products and lots found to contain high benzene do not have uniformly high levels:
These data should not be understood to be a reflection of the distribution of benzene in beverages in the US food supply. The data cover a limited number of products, a limited number of brands, and a limited geographic region. The data do not fully address the variation from one production lot of a product to another lot. For example, when additional lots of some beverage samples initially found to contain benzene levels greater than 5 ppb were analyzed, the results indicate that benzene levels can be highly variable from lot to lot. Even products from the same lot collected at different locations may have different benzene levels depending on many factors such as time at elevated temperatures and amount of light exposure during shipping, handling, and storage. (FDA)
Fair enough. Of course this also means those products and lots found to contain little benzene in this survey may turn out to have very high levels in another sample. These results were also done in the cool weather of winter and since heat and light affect benzene formation it is likely that a study done in the summer will come up with higher levels.

Benzene is found in the environment from other sources, and some like power plants or gasoline fumes cause much higher exposures. But from the public health perspective, even small exposures with small risks are significant when billions of drinks are consumer around the world (see previous posts here and subsequent linked posts; and here). Lottery tickets have a small risk of winning, too, but if enough tickets are sold, "winners" appear. And this is a lottery no one wants to win. We shouldn't be giving cancer lottery tickets with a can or bottle of soft drink.

Additional info available at the Environmental Working Group site.

Tuesday, May 23, 2006

WHO update on Indonesia cluster: not comforting

WHO has issued a new update on the Indonesian cluster and it wasn't very comforting. The 32 year old man who died yesterday was the father of a youngster (10 years old) who took ill on 5/3 and died on 5/13. The father took ill on 5/17. He had spent a great deal of time with his sick son and WHO suggests this was the source of his infection:
The case is part of a family cluster in the Kubu Sembelang village, Karo District, of North Sumatra. The man is the seventh member of an extended family to become infected with the H5N1 virus and the sixth to die. An additional person, who was the first member of the family to fall ill, died of respiratory disease on 4 May. No specimens were taken prior to her burial and the cause of her death cannot be determined. However, as her clinical course was compatible with H5N1 infection, epidemiologists at the outbreak site include this woman as the initial case in the cluster.

The newly confirmed case is a brother of the initial case. Specimens were taken on 21 May and flown the same day to Jakarta. Tests run overnight confirmed his infection. His 10-year-old son died of H5N1 infection on 13 May. The father was closely involved in caring for his son, and this contact is considered a possible source of infection.

Although the investigation is continuing, preliminary findings indicate that three of the confirmed cases spent the night of 29 April in a small room together with the initial case at a time when she was symptomatic and coughing frequently. These cases include the woman’s two sons and a second brother, aged 25 years, who is the sole surviving case among infected members of this family. Other infected family members lived in adjacent homes.

All confirmed cases in the cluster can be directly linked to close and prolonged exposure to a patient during a phase of severe illness. Although human-to-human transmission cannot be ruled out, the search for a possible alternative source of exposure is continuing. (WHO)
This last sentence is of some significance. If the 10 year old contracted it from one of the two sons or uncle who were infected by the index case (the mother who took ill on 4/27), then the father is either a tertiary or fourth generation case. This would be the first known case that has gone beyond one generation of infected human to human cases. The statement, "Although human-to-human transmission cannot be ruled out, the search for a possible alternative source of exposure is continuing" seems bizarre in this context. One would think it is the other way around: "Although human-to-human transmission seems the best current explanation, other sources of exposure cannot be ruled out."

An additional note gives some scanty information on sequencing of two viruses isolated from this cluster (presumably isolated and confirmed by NAMRU2 in Jakarta):
Full genetic sequencing of two viruses isolated from cases in this cluster has been completed by WHO H5 reference laboratories in Hong Kong and the USA. Sequencing of all eight gene segments found no evidence of genetic reassortment with human or pig influenza viruses and no evidence of significant mutations. The viruses showed no mutations associated with resistance to the neuraminidase inhibitors, including oseltamivir (Tamiflu).

The human viruses from this cluster are genetically similar to viruses isolated from poultry in North Sumatra during a previous outbreak.
If the sequencing is completed, why is it not being deposited immediately in GenBank (or is it)? It is not immediately obvious that the reassortments with pig and human viruses concern only HA and NA or also include all other segments. We are learning that there is a great deal of reassortment occurring among influenza viruses within subtypes. When the same HA and NA are present against new genetic backgrounds of internal genes, outbreaks can occur. There is some thought this is what is happening when one strain of the same subtype replaces another in seasonal influenza (e.g., replacement of A/Fujian(H3N2) with A/California(H3N2)). The statement that there are no significant mutations suggests non-significant ones have taken place. Does this mean the unique cleavage site mutation seen in the human but not avian viruses in Indonesia is not there?

Let's see the sequences. Now. With holding them from the world scientific community is unconscionable.

Stockpile information underload

Yesterday Department of Health and Human Services Michael Leavitt told the World Health Assembly, WHO's governing body, that the US was sending some of a Tamiflu stockpile to an undisclosed Asian nation. The lack of specificity has created an information vacuum that is being rapidly filled by speculation, much of it well-informed, but still by necessity, speculation.

We are left wondering whether this is WHO stockpile stored in the US or US stockpile, how much was sent, where it went and why it is being sent now. Indonesia was the first thought of many because that country presents, on its face, one of the most threatening places for a potential development of a pandemic strain. It is populous and has endemic H5N1 infection in poultry throughout the country. Human cases continue to appear, including the largest cluster to date bearing all the marks of human to human transmission. The country has very substantial numbers of pneumonia cases at any one time so that avian flu could easily be missed in the noise of background disease. A colleague made the important additional observation that cases have mainly been reported around large cities like Jakarta (and now Surabaya) where there is medical expertise. Thus there might be a major reporting bias underestimating the true number of cases and distorting their distribution.

On the other hand, two in-country informed sources told me that so far they know of no triggering event for suddenly sending Tamiflu to Indonesia. The Tamiflu could be going to more routine WHO staging locations like Bangkok or Singapore or elsewhere. Why can't we know this? Why should anyone be guessing about it?

Transparency, credibility and trust are becoming collateral damage in the bird flu battle. WHO has squandered much of their credibility and CDC is following suit. In particular, failure to release sequence information to the scientific community is not just a scandal, it's a disgrace.

Leavitt's uniformative announcement about Tamiflu was a major blunder. We are not seeing competence at a time when we need it most.

Bioterrorism whistleblower at CDC

The Atlanta Journal Constitution has an extremely interesting article (brought to my attention by a reader: thanks) about congressional investigators looking at CDC's bioterrorism division as a result of a CDC whistle-blower's complaint they were wasting taxpayer money. The investigators are with Senator Charles Grassley's (R-Iowa) Finance Committee. Grassley, a conservative who is a demon on government waste, is a strong supporter of the Federal False Claims Act which gives whistleblowers a piece of recovered funds. (There is a great book about FFCA, complete with lots of dirt about the Frist family: Giant Killers by Henry Scammell.)
The committee's inquiry involves whether the CDC is able to show that taxpayers have gotten their money's worth from the billions of dollars in grants they awarded to local health officials to protect citizens from a bioterrorism attack, according to interviews with CDC officials. (Atlanta Journal Constitution, link hat tip Robert)
Both the director of the bioterrorism division and CDC Director Julie Gerberding are said to have met with Grassley last week in Washington. CDC has dumped about $3.6 billion on states since 2002, but most public health professionals don't think we are much better off. The use of the money to strengthen state and local public health infrastructure has been hampered by restrictions on what the use of the funds, resulting in often silly purchases of equipment that couldn't be used and technologies and consultant services that provide little value to public health. The complaint that some of this money is used to plug holes in local and state public health caused by budget cuts is misplaced. That's not a waste of money, that's a necessity if we want to prevent even further deterioration of our public health infrastructure.

There is a widespread perception in public health itself, however, that huge amounts of this money have been wasted and many of us would like to see where it really went. If this is just an inquiry into whether the money went to buy hazmat suits or maternal and child health services, that would be a shame. If it is a legitimate look at how the millions of dollars sloshing around made its way to questionable state vendors and lobby-promoted biotech scam artists, that's something else. Given the corruption of this Administration, it is a real question. Grassley is usually more interested in fraud and corruption rather than misplaced priorities, but we shall see. The nature and scope of his inquiry are not known yet.

Meanwhile the CDC employee who raised the issue of poor CDC oversight has been granted official whistleblower status, affording her some degree of protection against retaliation. In Gerberding's CDC this is a necessity, as the Director is known as someone who takes criticism poorly.

We'll keep our eye on this one.

Monday, May 22, 2006

Quarantine in Bucharest: why?

Agence France Presse is reporting that Romanian military and police have sealed off 13,000 people in a quarter of Bucharest where H5N1 infected chickens have been found. Forty streets in Luica quarter have been blocked off, with the quarantine estimated to last a week to three weeks. All institutions and businesses in the area were ordered closed. An immediate slaughtering of birds in the quarter was underway.

This is an unusually vigorous response to just another poultry outbreak in Romania and immediately raises the question of what is going on or suspected of going on.

Addendum: From MediaFax:
The presence of the bird flu virus was confirmed Monday for Bucharest’s district 4, and some 13,000 people are now in first-degree quarantine, Mayor of district 4 Adrian Inimaroiu told MediaFax.

Bucharest’s general mayor Adriean Videanu also confirmed for
MediaFax that the virus has been found in district 4.

The planned quarantine in district 4 includes 40 streets, with 20 apartment blocks and tens of households, as well as factories, stores and a kindergarten which will suspend their activity for at least one week, which could be extended up to 21 days.
Available media reporting suggests this remains a poultry problem. Still…

Poultry and human bird flu

One of the most repeated "facts" about the human cases of bird flu is that virtually all cases to date come from intimate contact with sick poultry. But the evidence does not show this.

One third of the Vietnamese cases are said to be without an adequate history of poultry contact, at least a third (if not more) of the Indonesian cases, and many of the Chinese cases. WHO continually repeats the necessity of the poultry connection but knows better. The Vietnamese figure is from WHO epidemiologist Peter Horby (personal communication reported in EFSA Monograph; see earlier post here). WHO is quite familiar and distressed about the situation in Indonesia. And in an article today, Helen Branswell writes:
The WHO has been extremely concerned that none of China's 18 confirmed human cases to date have occurred in areas where outbreaks in poultry were previously reported. In most of the cases thorough investigations after the fact have pointed to some possible exposure to poultry. But the lack of obvious links disturbs international public health authorities. (Helen Branswell, Canadian Press; my emphasis)
Yet WHO continues to say publicly all evidence so far shows the principal connection is from close contact with sick or dead birds.

WHO should not say the evidence shows "close contact" with sick or dead birds is required. We don't know that and it probably isn't true. If it were it wouldn't be so hard to elicit histories of poultry exposure in so many cases. The other possibilities are less close contact through poultry dust, feces, feathers, etc. If WHO wants to call this "close contact with sick or dead poultry" they are free to do so but they are using a private language. And it is largely an inference based on the fixed idea that almost all human cases can be traced back more or less directly to birds.

Given the evidence, we should keep our minds open to other possibilities, namely, contaminated food or water, an as yet unidentified animal reservoir or vector, and of course person to person transmission. At this point I believe WHO is probably right in substance: most cases probably are of proximate bird origin. But they don't have the evidence that they claim and I find that bothersome.

This is the way obvious facts are missed: we don't see what is staring us in the face until hindsight dramatically improves our vision.

Until the Fat Lady sings

On a recent trip to a scientific meeting about something quite different than bird flu, several of my colleagues knowing of my interest in the disease wanted to know if this thing was finally over and the threat receding. This followed several optimistic news reports that Thailand and Vietnam have had few or no new cases this year and that their aggressive programs of combating the disease showed a pandemic could be avoided. Vietnam has used poultry vaccination, while Thailand has used area culling. WHO's flu czar Dr. David Nabarro has praised both countries and made cautiously optimistic sounds.

At the same time the largest cluster yet has occurred in Indonesia and the disease continues to spread uncontrolled in Africa. The latest case in that cluster is almost certainly an another example of person to person transmission. In Indonesia there is no aggressive program of any kind and two of the patients in the cluster were actually released from the hospital into the community and then readmitted to die. So much for the "fireblanket" and the computer models that suggested it was a possible strategy (also see our posts here, here, here and here):
As such, the Indonesian outbreak should serve as a stark reminder to all involved of the difficulties inherent in trying to translate the models' findings into reality, said infectious diseases expert Dr. Michael Osterholm.

"Our experiences with the virus during the last six months in Turkey, Iraq and now in Indonesia should give even the most ardent supporters of containment cause to realize why, while such an approach is an ideal, it also is a fantasy."

Osterholm has been skeptical since the modelling studies were published last summer that the optimistic outcome predicted by the work could be achieved outside of the hard drives of the computers on which they were devised.

"This was never about wanting to contain the virus. It's about the reality of what happens in everyday life," Osterholm said Saturday from Minneapolis, where he is director of the Center for Infectious Disease Research and Policy at the University of Minnesota.

"One of the problems models can't address is the impact of politics, fear, panic and lack of compliance on written guidelines for public health actions."

The models, by two international teams of scientists, suggested the WHO could contain an emerging pandemic if it discovered the virus was spreading among people within the first 20 human cases or within seven to 21 days of the start of transmission. (Helen Branswell, Canadian Press)
Last week Maryn McKenna, the Atlanta Journal Constitution's expert flu reporter, had an excellent story about the difficulties of predicting what flu is going to do. The whole things is worth a read, but here is the pertinent point:
After the Asian strain of bird flu attacked humans for the first time in Hong Kong in 1997 --- sickening 18 people and killing six of them --- it disappeared for several years. It surfaced briefly in Hong Kong in 2003, infecting two people and killing one, and then vanished again for almost a year before resurfacing in Thailand and Vietnam.

Similarly, though the virus at first spread rapidly --- causing 22 cases and 15 deaths in Vietnam by the end of February 2004, and 12 cases and eight deaths in Thailand by the end of March --- it subsequently went underground again. Five months passed before Vietnam saw another human case; in Thailand, the gap was six months.

Those gaps, like the current one, occurred as the weather warmed. Influenza is seasonal: It flourishes during winter months --- or in the rainy season in tropical countries that have no clearly-defined winter --- and disappears in the summer, said Dr. Bruce Ribner, associate professor of infectious diseases at Emory University School of Medicine.


Dr. D.A. Henderson of the University of Pittsburgh Medical Center's Center for Biosecurity, former leader of the international campaign to eradicate smallpox, warns that too little is known about the Asian avian flu.

"I don't think we can feel at all confident that because flu appears to be at a lower level in some countries it is not still spreading, at least in birds," said Henderson, who worked early in his career on the 1957 influenza pandemic that killed 70,000 Americans and about 2 million people around the world.

Behind health authorities' questioning of the Southeast Asian case numbers lies a fear that success will lead countries to drop their aggressive efforts against the virus --- a concern reinforced by memories of Thailand and Vietnam declaring premature victory against the virus in March 2004.

"We have to walk a fine line between continuing to aggressively prepare for a flu pandemic, and at the same time recognizing that people's attention span will wane if the H5N1 situation looks less threatening," [CDC Director Dr. Julie] Gerberding said. (Maryn McKenna, Atlanta Journal Constitution)
As if to underline the concern, China's vice Premier Hui Liangyu said Saturday he remained concerned about the bird flu situation in China and elsewhere:
“Summing up and analyzing the epidemic’s current development both inside and outside the country, the . . . situation is not optimistic,” Hui said at a national meeting on the prevention and control of avian flu.

His warning came as the agriculture ministry reported Saturday that a total of 308 wild migratory birds have died since a bird-flu case was reported in the northwest province of Qinghai on April 23.

As of Friday, 300 bar-headed geese and eight birds of other species had been found dead in the remote province, a statement on the ministry’s website said. (AFP via Manila Times)
Yogi Berra, relying on his deep knowledge of the opera once said, "It ain't over till the fat lady sings." Of course what happens after the fat lady sings is "curtains." (NB: This is not a prediction! It's just a way to finish off this post. You'll still have time to buy your personal 5000 gallons of bottled water later. Meanwhile contact your water utility and ask them if they have made any plans in case there's a pandemic.)

Sunday, May 21, 2006

Is the virus becoming more deadly?

The recent cases of bird flu in Indonesia have had an unusually high fatality. In the Sumatran cluster six of seven family members succumbed. Overall the case fatality in Indonesia is 78%. This has prompted a number of news sources to conclude the virus is becoming deadlier:
The bird flu is becoming more deadly, now boasting a 64 percent fatality rate.

According to the World Health Organization (WHO) 47 victims have died out of 73 cases in 2006. In 2004, however, 41 patients died out of 95 cases, which is only 43 percent.

The WHO believes that since 2003, 123 people have died from the virus, from the 217 documented cases. (All Headline News)
Maybe this is a good time for a quick review of Case Fatality Rate (CFR).

The first thing is that technically CFR isn't what epidemiologists today call a rate. Rates are the number of disease events per person per time unit or sometimes number of disease onsets in a time span. Thus a mortality rate for cancer might be 1 per 10,000 population per year. A CFR, by contrast, is a proportion. In technical terms it is an incidence proportion, a measure of average risk, in this case the average risk of dying of the disease given that you contracted it. It therefore varies between zero and 1.0 (rates vary from zero to an undetermined upper number that can be much greater than 1.0).

The CFR has a numerator (deaths from bird flu) and a denominator (all diagnosed cases of bird flu). What the number expresses is the risk of dying of bird flu once you get bird flu. From this viewpoint, that risk seems to be increasing (43% in 2004 to 64% today, overall, and 78% in Indonesia).

However there are complications. The numerator (deaths in bird flu diagnosed cases) may be accurate (death is a definite endpoint), but the CFR measures the risk of dying once counted in the denominator and that risk is subject to other factors than the deadliness of the virus--in particular care seeking behavior, timely access to medical care, the skill and resources of the care itself, and the general state of health of the patient. Thus the numerator may differ from place to place even though the virus remains exactly the same.

The denominator (diagnosed bird flu cases) is less firm than the numerator. WHO has a very strict standard for defining a case (requiring laboratory confirmation by one of its reference laboratories), so it is possible many truly existing cases are not being counted because they are not being diagnosed by anyone or are mild and do not seek medical care. This would artificially inflate the CFR by having a denominator smaller than it should be and many people thought this was a likely reason for the abnormally high CFR in this disease. Unfortunately there is no confirming evidence that many cases are being missed. While data from seroprevalence surveys is sparse (these are blood studies of the general population or contacts of confirmed cases to see if they have evidence of mild infection), so far they show stunningly little evidence of undiagnosed infection. Maybe the CFR slightly overestimates the true value, but there is as yet no convincing evidence it overestimates it by much.

Because the accuracy of both the numerator and denominator of the CFR might vary from country to country and within a country, comparing CFRs over a time period in cases from ten very different countries does not clearly measure a change in the deadliness of the virus. While it is quite possible the virus is becoming more virulent, we don't have a good way to determine that at the moment.

Treat the news headlines with the appropriate caution.

Freethinker Sunday Sermonette: the "religious left"

Firedog Lake is one of the better blogs in the left blogosphere and this weekend there was a long post by Christy Hardin Smith on the "religious left." One of the great things about lefty blogging is it doesn't all march to the same drummer. We debate, we disagree, we argue -- and in the end we work together to try to make this a better world. This is by way of preamble to disagreeing with Christy's post. Since my disagreement doesn't prevent me from winding up in the same place she does I don't know whether to call it a strong disagreement, but I think it is a fundamental one.

What did she say? She begins by registering (appropriate) discomfort with the politicization of religion on the left, noting that for most of us religious faith of whatever stripe is a private matter, not to be forced on others and to be lived out in our lives. Some of us have no religious beliefs, however, and I believe she not only mischaracterizes us but commits the same error against us she accuses "ivory-tower liberals" of: condescension. She also reinforces a right wing meme that liberals are secular boors without respect for people of faith,. This is a failure to distinguish our views of "faith" and "religion" from our views of the persons who practice them.

She begins with a long excerpt from a 2005 essay by Van Jones, an African American who writes feelingly about the importance of religion in his life growing up in the days of American apartheid. Here is some of it:
I literally have had liberals laugh in my face when I told them I was a Christian. For awhile, I felt self-conscious about telling other activists that I preferred not to meet on Sunday mornings, because I wanted to go to church.

It is still commonplace to hear so-called radicals stereotyping all religious people as stupid dupes — and spitting out the word "Christian" as if it were an insult or the name of a disease. I thought progressives were supposed to be the standard-bearers of tolerance and inclusion. (Alternet)
I rather doubt this. It is reminiscent of the stories of anti-war protesters spitting at returning Vietnam Vets. I won't say that never, ever happened but if it did, no one has been able to find an example of this urban myth and if it ever happened it hardly ever happened. I'm guessing the same is true of "literally laughing in his face" upon declaring he was a Christian. This is hyperbole. All I can say about anyone -- left, right or center -- who literally laughed in the face of another person who said they were a Christian is that they are monumental boors whose rudeness knows no political stripe. This is a red herring and an extremely harmful way to depict the left. The same for the claim that "so-called radicals" stereotype religious people as stupid dupes. People say many things about those that disagree with them (consider what we say about the right wing), but there is no special singling out religious people as stupid dupes. Stupid dupes exist and some of them are religious and some of them are Democratic candidates duped by their consultants. So what?

The Jones piece goes on to give a moving rendition of the importance of the Black church in the civil rights movement. No argument there, of course, but the context is significant. The Black church was one of the few social institutions capable of organizing the black community. It is worth noting that outside of the Black clergy the churches and synagogues of America were silent, or worse -- actively racist -- in the civil rights years, (with some notable but rare exceptions).

Jones goes on to draw the inevitable conclusion:
The implications are clear for those who seek today to rescue and redeem U.S. society. The facts are simple and profound: The last time U.S progressives captured the national debate and transformed politics, people of faith were at the center of the movement, not stuck in its closet.
This zeroes out the subsequent anti-war movement, the woman's movement, the gay and lesbian movement, the environmental movement, etc., etc. It is an understandable conceit, but a conceit nonetheless. Again, with a few notable exceptions, churches played a minor role in those movements and when they were important it wasn't because of doctrine but because they transcended doctrine.

As a progressive, what should my attitude to religion be? To the extent it is someone's private affair, it doesn't matter. It is none of my business. But to the extent it is advanced as a political principle that we should embrace "good" religious arguments and support them, I reject it. As a public health professional I believe washing your hands is good hygiene. This doesn't mean I must approve of and support the arguments of a handwashing obsessive. I don't say, yes, there are germs everywhere. I am glad you are washing your hands every five minutes because I think hand hygiene is good. Or if someone tells me they will vote for someone because they are of the same religion, I am not required to say, good, that's a sufficient reason. Whether it makes sense to try to convince someone pathogens aren't everywhere, or that voting for Joe Lieberman isn't good just because he's a Jew is a tactical question. I might just keep silent. But agreeing with either is wrong. One shouldn't violate the truth for political expediency and that's just what an embrace of the "religious left" qua religious (or spirituality or whatever else you want to call it) would be.

Unfortunately Christy goes further and reinforces right wing canards about the secular left.
Yet liberals, trapped in a long-standing disdain for religion and tone-deaf to the spiritual needs that underlie the move to the Right, have been unable to engage these voters in a serious dialogue. Rightly angry at the way that some religious communities have been mired in authoritarianism, racism, sexism and homophobia, the liberal world has developed such a knee-jerk hostility to religion that it has both marginalized those many people on the Left who actually do have spiritual yearnings and simultaneously refused to acknowledge that many who move to the Right have legitimate complaints about the ethos of selfishness in American life.
Disdain for religion? Yes. What do you want me to say. I think it's good? Because I don't. Engage them in what kind of serious dialog? Certainly the dialog cannot be in the arena of a faith in a God I don't believe in or in the virtues of religious institutions that have been overwhelmingly vicious, hateful and reactionary. This is what this strategy leads to:
[Michael] Lerner, the California-based rabbi who founded the [Network of Spiritual Progressives], said the conference is partly aimed at countering an aversion to religion among secular liberals and "the liberal culture" of the Democratic Party. "I can guarantee you that every Democrat running for office in 2006 and 2008 will be quoting the Bible and talking about their most recent experience in church," he said.

The Democratic Faith Working Group, made up of 30 members of the House and scores of aides, has begun meeting monthly on Capitol Hill to discuss faith and politics, opening each session with a prayer. Its purpose is to "work with our fellow Democrats and get them comfortable with faith issues," said its chairman, Rep. James E. Clyburn (D-S.C.), a preacher's son who was raised in the fundamentalist Church of God. (WaPo)
Is this what the country needs? I don't think so.

Christy uses Ned Lamont as an example of someone who launched a successful political challenge on the grounds of values. Fine. But where was religion in this campaign? Nowhere. The business of equating "religion" with essentially secular values runs throughout Christy's post. It is wrongheaded.

Yes, let's embrace the secular values she enumerates. If some people want to consider them spiritual or religious values that's their business. I don't have to agree nor should I be asked to any more than I would agree with the premises of a handwashing obsessive. Nor should we suggest we should in the interests of "dialog."

Because none of the values she promotes depend in any way on religion, she finishes up just where I would:
What we need is language that speaks to the hearts of these voters — to the things they hold dear, which, coincidentally, are also the things we hold dear: family, children, safety, pride, our own lives and pursuit of happiness and respect and decency.


What I do see, however, is an oppotunity for the Democratic party to speak to the values that people of faith have always held to be important and sacred duties: peace, respect for all of humankind, lifting up those who need a helping hand, nurturing those who have little or nothing, giving hope where there is currently none, shining a light in the dark places.

This was the Democratic party in which I was raised — perhaps it was a naive view of the world, but it was a wonderful lesson in the might of our souls and the ability to triumph over the darkness of selfishness and meanness.


Let us work together — instead of picking each other apart — and wherever that well of faith comes from that propels you forward, let’s harness that strength instead of squabbling amongst ourselves and trying to marginalize one faction or another. In order to right this severely listing ship of state, we have to all pull on the oars together — one nation, one people, one faith in our ability to do better and to do right by all.
If that's what she means by faith, even I can say "Amen."

Saturday, May 20, 2006

Cats, pigeons, Indonesia

There has been much talk about the possibility of domestic cats being infected with H5N1 and some cases have been described (see posts here, here and here). Cats eating infected birds is suspected as the source of infection in some of these cases.

Cats, both feral and domestic, are common inhabitants of urban environments. So are pigeons. We've been told we don't have to worry about pigeons and bird flu. But this paper (which got by me when it appeared in Emerging Infectious Diseases in April) tells a somewhat different story.
In early February 2004, during the outbreak of HPAI (H5N1) in Thailand, a carcass of a 2-year-old male cat (Felis catus) was taken in an icebox 6 hours postmortem to the Faculty of Veterinary Medicine at Kasetsart University, Nakornpathom, Thailand. The cat's owner volunteered the information that the cat had eaten a pigeon (Columba levia) carcass 5 days before illness onset. The owner reported that the cat had a temperature of 41°C, was panting, and appeared to be depressed. Furthermore, the cat had convulsions and ataxia and died 2 days after onset of illness. The cat was given a single dose of 75 mg aspirin 1 day before it died; however, its body temperature remained elevated. Many dead pigeons were found in the area where the cat lived.
H5N1 was isolated from the cat and from dead pigeons in the area. The genetic sequences of the viruses matched closely and resembled the sequences of the H5N1 circulating simultaneously in poultry and large zoo cats (tigers, leopards) in early 2004 in southeast Asia. Horizontal transmission ("cat to cat") has been described elsewhere but so far no one has shown any cases of cat to human. In April Dr. Peter Roeder, a Food and Agriculture Organization scientist working with Indonesian colleagues, was reported setting up a study to see if cats were playing a role in the Indonesian outbreak but we don't know if that study is happening or not. The Indonesians have a history of foot dragging. Earlier, the former NAMRU2 epidemiologist Dr. Andrew Jeremijenko had swabbed a kitten in Indonesia and isolated an H5N1 that was a close match for a virus isolated from a human.

It seems not a day goes by that this virus doesn't confront us with something new and unsettling.

Addendum: Several commenters have questioned the use of aspirin for the cat in this report, believing that aspirin is deadly for cats. Cats lack the enzyme glucuronyl transferase which is involved in the metabolism of aspirin but they tolerate appropriate doses of aspirin well and it is used routinely in veterinary medicine for arthritis or as a blood thinner. A common dose is a quarter of a buffered adult aspirin once every three days for arthritis. The literature says that 10 mg to 25 mg per kilogram every two or three days is safe.

Note that acetaminophen (Tylenol) and ibuprofen (Advil, Motrin) are extremely toxic to cats and will kill them. This may be the source of the idea that aspirin, too, is deadly. The dosage of 75 mg in this report seems excessive and may have contributed to the cat's demise, but the animal was also infected with H5N1 which was the main issue. [NB: Disregard this last comment. 75 mg would be about right for a 3 kg cat and it is about 1/4 of an adult aspirin tab. Thus the cat's relatives shouldn't sue the owner for malpractice.]