The clinical bird flu picture so far as reviewed in the New England Journal

In 2005 the world's bird flu doctors got together and pooled their meager knowledge about the epidemiology and clinical features of this zoonotic disase that has so far infected 350 people and killed 217 of them (latest "official" figures via WHO). In March of 2007 they got together again in Turkey and the New England Journal of Medicine (January 17, 2008 issue) has just published a joint report summarizing their discussion. Helen Branswell sets the stage:

The article, a review of data compiled on human cases to date, answers some questions about how the virus affects people. But it also makes clear that four years after the current wave of H5N1 infections began, many unsolved mysteries remain.

"I think in every area there are unanswered questions and one wants to see progress in every one of those areas, whether it's better understanding of transmission and what are the risk factors there and how often human-to-human transmission actually occurs," said senior author Dr. Frederick Hayden, a scientist with the World Health Organization's global influenza program.

The review article is based on data supplied by clinicians who have treated H5N1 and other research presented at a special WHO meeting held last March in Turkey. Hayden oversaw the project and led an international committee of experts who wrote the article, which appears in this week's New England Journal of Medicine. (Helen Branswell, Canadian Press)

The paper itself has no surprises but it's a worthwhile read, clear and concise. Here are some salient points that sum up the situation as of now:

  • Influenza A/H5N1 is now thoroughly entrenched in the poultry of large parts of Asia, Africa and the Middle East
  • It has diversified genetically and evolved into distinct lineages or clades, some with subclades (so much for the "extremely stable" virus that M. Vallat of the World Organization for Animal Health (OIE) was promoting just last week)
  • Human infections are from avian sources
  • Human effected movements of poultry and poultry products are the likely primary means of geographic spread, although migratory birds also play a part. The relative proportion of poultry versus wild birds remains uncertain, as does the importance of wild birds as a reservoir
  • Human cases are dramatically skewed toward the young (median age 18). 90% of cases are below the age of 40. Older cases have had better prognosis. Highest case fatality is in the 10 to 19 year age bracketWhether the lack of older cases is a feature of susceptibility or reduced exposure is unknown
  • Most cases were previously healthy. This is not a disease of those already at risk for other disease. Of the six pregnant women, four have died and all fetuses were lost.
  • H5N1 infections in poultry and people follow the same temporal pattern as "seasonal" flu, increasing in the cooler months
  • No "traveler" cases have yet been identified. All cases are among residents of the region where the case was diagnosed
  • Some identified risk factors for poultry handling: slaughtering, defeathering, preparing sick poultry for cooking, playing with sick birds, handling fighting cocks or ducks even when they appear to be well, consuming raw or undercoooked poultry or poultry products
  • No human cases have been described where transmission has been from a mammalian host other than another person, but there is no obvious reason why this cannot occur
  • Clusters of cases have occurred in ten countries, although the discussants judged most to be from common sources. However several highly likely cases of human to human transmission were believed to have occurred when there was very close contact between a sick individual and a caregiver or relative
  • However in fully a quarter of cases there is no clearly identified source of infection
  • In these and other cases there remains a strong possibility that infection occurred from contact with virus contaminated materials (aerosolized or self contamination with poultry feces, dust, feathers) in the environment
  • We still do not understand the factors that determine host range
  • Changes in the virus needed to make it easily transmissible between people likely involve several genes. We don't know what those changes are as yet
  • Cause of death in most cases is an overwhelming primary viral pneumonia. Exactly what tissues are infected first and how is still unknown with certainty. The effects on the immune system and reported "cytokine storm" in some patients is still not understood. No therapy for this is recommended.
  • Cases are seen first by the health care system a median of four days from onset of symptoms. Median time to death is 9 to 10 days. Only one in eight are diagnosed correctly on initial presentation, with "pneumonia" and dengue fever being among the chief incorrect diagnoses. False negatives are common. Multiple specimens are recommended when clinical and history strongly suggest a diagnosis of bird flu
  • Rapid diagnostic tests to see if a patient has "influenza" (any subtype) are insensitive and produce many false negatives.

These are some of the items that drew my attention but there is much else in this paper. I recommend it for further details (.pdf here). One of the more worrisome findings is the continued failure to find mild cases. Again, Helen Branswell:

The same test results were obtained for nearly 1,100 people in studies designed to look for missed cases of H5N1 infection. Seven new studies from Cambodia, China, Thailand and Nigeria that looked for H5N1 antibodies in the blood of poultry cullers, live animal market workers, health-care workers and others who were in contact with H5N1 cases turned up only a single positive, in a live animal market worker in China.

Most diseases have a range of severity and experts had hoped the confirmed cases of H5N1 infection represented only the tip of a much larger iceberg. If that were true - if, say, there were 10 mild or virtually symptomless cases for every one found - that would dramatically lower the death rate.

But these studies, when combined with earlier small studies that failed to find any real evidence mild infection was escaping detection, are compelling proof that this isn't the case at present with H5N1, Hayden said.

"I think it's persuasive that there was not (mild disease). Now it doesn't tell you what's going to happen in the future, of course. And that's why you need to keep looking," he said.

Thus the truly horrendous case fatality ratio of over 60% still stands as the best estimate. So this remains a bad disease. A really, really bad disease.

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Great summary. Has anyone ever seen any reports on pre-1918 H1N1, I am curious if there were animal outbreaks and/or limited human cases before the big event. Everything I have read is vague about this, essentially they conclude it jumped from an unknown host to humans. I do recall a study of tissue samples gathered from waterfowl in the period 1915-1918, and it was not present as far as they could determine.

I think the most disconcerting part of this is not just the disease but, the Helen Branswell article didn't make a single ripple except for a few flubies. Ho-hum same old thing *yawn* *thud*.

The disconnect between some researchers and clinicians and the rest of us is growing. People grab on to anything no matter how ludicrous. They convince themselves they have nothing to fear. M. Vallet is a perfect example. The information doesn't seem real. It is past time for governments and public health institutions to make it real. Fear of panic instills inertia and secrecy. The pathetic table top plans are made in a vacuum. Attempting to make preparations beyond view of the public is doomed to failure. Experts are too few and only have some of the answers. You can make book on the unexpected. Believing these experts will function effectively when the populations around them are terrified is naive. The only time this might work is under a totalitarian regime. It requires either implicit trust or, complete fear of the government. We have neither.

How many times have we been told that if only we had had a little more time we could have averted the disaster. Well I have news for you, slow motion disasters don't appear to have a much better chance of 'getting it right'.

Well said Shannon!!


As you mention above, the WHO Writing Group states:

To date, no cases of influenza A (H5N1) illness have been identified among short-term travelers visiting countries affected by outbreaks among poultry or wild birds

Understandably, WHO carefully defines what they mean by "cases."

But the definition necessarily leaves out potentially significant but unprovable instances, such as that of a Hong Kong family which traveled to Fujian Province in early 2002.

From WHO:

Influenza A(H5N1) in Hong Kong Special Administrative Region of China - Update
20 February 2003

As of 20 February the Department of Health in Hong Kong SAR confirmed that a 33-year-old man, who died in hospital in Hong Kong on February 17, had been infected with a strain of the influenza A(H5N1) virus. ( see previous report ). A nasopharyngeal aspirate taken from the man tested positive for influenza A(H5N1) in the Hong Kong SAR Government Virus Unit.

The 33-year-old man is the second confirmed case of influenza A(H5N1) virus related to this outbreak in Hong Kong SAR. The man is known to have been the father of the 9-year-old boy reported as having tested positive for influenza A(H5N1) yesterday. Both cases had travelled to Fujian Province (China) in January. Two other members of the family who accompanied the cases to Fujian in January have also been unwell. The mother of the family has now made a full recovery; the other affected member of the family (an 8-year-old girl) has died on February 4 in Fujian Province.

But according to OIE, China did not report any HPAI outbreaks in 2002...

As we read updates on what is known (and unknown) about H5N1 science, it is worth reiterating that surveillance and prompt reporting remain extremely weak links. Consider India, and weep.

By Path Forward (not verified) on 18 Jan 2008 #permalink

Correcting date error in my comment above:

"2002" should read "2003."

Sorry about that!

By Path Forward (not verified) on 18 Jan 2008 #permalink

stu, exhumations in England were scheduled for last year, but apparantly
never happened. Taubenberger is examining pre 1918-samples since more
than a year - no report.
I wonder, if they found something which they don't want us to know.


No way that Taubenberger (or most any scientist) would sit on something because "they" don't want "us" to know about it. Do you really think there's some kind of conspiracy to withhold info about what happened 90 years ago? Or that a lab (filled with rowdy and articulate students and post-docs, much less the PI himself) would allow themselves to be silenced?

Get a grip!

> defeathering

How much does it take for infection, anyone know?

What's the market for sale of down and feathers from chickens and ducks and geese these days?

Feathers are ground up and used as food. What odds that process puts dust in the air? Into human food?

Is anyone testing aerosol dust for the virus, if that's even possible? I know there's routine attention to watching for aerosol levels of, for example, polonium, e.g.

It ought to be possible to look for bird or viral genetic material in aerosol dust samples, should it not? Or is it everywhere but at low levels by now?

"Don't drink the water and don't breathe the air."
-- Tom Lehrer

By Hank Roberts (not verified) on 18 Jan 2008 #permalink

Pre-1918 - The only preliminary data available from Taubenberger at NIH is the finding of a number fragments positive for H3. He presented those early findings in this excellent videocast

Stu, there is no historical account of avian or other animal outbreaks pre-1918, although veterinary records going back to the mid 19th century described what seemed like HPAI outbreaks, which means that they were certainly aware of HPAI in 1918.

Here's an interesting recent paper on the historical accounts, from Taubenberger Discovery and characterization of the 1918 pandemic influenza virus in historical context, Antivir Ther. 2007;12(4 Pt B):581-91.

Here's the most critical issue IMHO. Among all these important and excellent questions. We just have such a long way to go. :-(

We still do not understand the factors that determine host range


yes.Remember, there was much discussion some years ago whether the 1918-sequences should be made public.
Terrorists could recreate the virus or it might escape
a lab.
Such things have to be approved by the military,
by the politicians.
And then there is the factor of scientific exclusivity,
they want first to examine all avenues themselves
before someone else does it using their data.