Avian Flu Uncertainties

(First, here is the NIH Focus on the Flu site.  Decent general info there.)

Klaus Stohr is the chief of the World Health Organization's global influenza program.  He is worried that we are overdue for a flu pandemic.  In this profile in The Lancet, he is attributed with the observations that flu pandemics occur on average every 27 years, that the last one hit 37 years ago in 1968, and that between 2 and 7 million people could die in the next pandemic.

As a veterinarian and influenza specialist, Dr. Stohr obviously knows a lot more about flu bugs than do I.  However, his statistics may need a second look, particularly for incidents in the past 100 years.  Arnold Monto notes in his New England Journal of Medicine perspective "The Threat of an Avian Influenza Pandemic" (27 Jan 2005) that, "There have been three influenza pandemics during the past century -- in 1918, 1957, and 1968."  It is true that the average interval between these three events is just under 30 years.  I don't know how many data points Dr. Stohr is working with, but the width of the distribution, in this case, is hardly even computable for pandemics this century.  The interval between events is just as likely to be 40 years as it is 30 (not so comforting, I admit).  In any event, given the state of modern medicine, travel, and sanitation (and the variability in all those things across the globe) nobody should be drawing firm statistical conclusions from the three most recent data points.  The point of this is that because this bug is not behaving as expected, perhaps we should reevaluate our expectations.

How much do we really know about pandemic strains?  Perhaps a good place to start is examining how similar the three 20th century strains were.  Not very, I am beginning to think.  Although each were a novel type A virus of avian origin, Monto observes that, "In 1957 and 1968, the new viruses had components of previous human viruses as well as avian viruses...it was determined retrospectively that in both cases, there had been a reassortment of avian and human genes -- most likely the result of the coinfection of a host by two different viruses."  Monto then notes that the 1918 strain appears to have resulted from mutation in an avian strain (see my post, The Spanish Flu Story).  So, we are down to two pandemic strains, out of only three total, that arose through the historically low probability process of reassortment (see the end of my post, A Confluence of Concerns).  The numbers aren't looking good for deriving general principles about potential pandemic flu strains.

Adding to the confusion is the fact that, according to Monto, "The genetic characteristics of [H5N1] are still completely avian; neither mutation nor the sharing of genetic material with a human virus has taken place."  (I don't entirely understand this statement in light of assertions that H5N1 is becoming more pathogenic in poultry -- how else would this occur than by mutation?  Or is recombination amongst avian strains the assumed mode of increase pathogenesis?)  Klaus Stohr himself, in a 27 Feb, 2005 editorial in NEJM, "Avian Influenza and Pandemics -- Research Needs and Opportunities", wonders;

Why has H5N1 not reassorted with a human influenzavirus?  It certainly has had ample opportunity to do so...Unprotected workers [destroying infected poultry have] had intense exposure, as did health care workers.  Virologic surveillance has demonstrated the concurrent circulation of human viruses.  Hence, one conclusion is tempting: if H5N1 could reassort, it should have done so by now.  The explanation may lie in sheer statistical luck.

Hmmm.  That's not so satisfying. 

The last thing I want to do here is undermine the efforts of experts to understand what is going on and to try to prevent a pandemic.  However, I can't square public statements about the risk we face with what data I find in the literature.  There is definitely a troublesome lack of information about how flu bugs work, how the evolve, and what we might do to stop them, particularly with vaccines.  This press release, dated 27 May 2004, from the National Institutes of Allergy and Infectious Disease, says vaccines against H5N1 will be made by Chiron and Aventis Pasteur using the traditional chicken egg method.  While I have informally heard that H5N1 is so lethal that it kills chicken embryos before they can produce an adequate amount of virus to use as a vaccine, I still haven't been able to confirm whether or not it is technologically possible to produce an H5N1 vaccine this way.

So what do we do?  Stohr, again; "Substantial gaps in knowledge remain, making the ability of science to guide policy imperfect at a critical time."