A Confluence of Concerns

I've started wondering about the worrisome overlap of countries affected by the recent tsunami in southeast Asia and reported instances of human infection with Avian Flu (H5N1).  I'm not the only one, fortunately, who is thinking about this.  Henry Niman (who knows much more virology than I) is keeping a list of interesting stories on this over at recombinomics (see the "in the news" section).  There is a 70% mortality rate in humans, which is certainly frightening, and there are now confirmed cases of human-to-human transmission between people living in close quarters, but I think it is important to delve a little deeper into what may be going there.

It isn't yet clear what changes would be necessary in the virus to make it the cause of a true pandemic.  Even the causes of the 1918 "Spanish Flu" are still under debate.  The great concern for H5N1 is that it will recombine with a strain that already easily infects humans.  This has long thought to be the way the Spanish Flu became so deadly, but recently some debate has emerged along the lines that mutation rates in some areas of the hemaggluttinin gene (HA) were accelerated instead.  That is, mutation within the genome, rather than recombination, may have created enough variation to result in the virus that killed tens of millions of people.  In order for recombination to operate, two different virus strains must simultaneously infect the same cell, providing the opportunity to mix their genes.  However, it turns out (see below) that homologous recombination among RNA viruses appears to be a low probability event.

For his part, the good Dr. Niman is quite firm about the role of recombination;

This is the key issue on the influenza pandemic.  The 1918 H1N1 virus gained its lethality by recombining, not reassorting.  The same thing has happened with H5N1.  The H5N1 in Thailand and Vietnam have already picked up pieces of genes that are not in any other H5N1 isolates.  These polymorphisms are found in mammalian isolates such as humans and pigs (and the 1918 isolate had polymorphisms normally found in humans and pigs).

Needless to say, we will never know exactly how the 1918 strain came to be.  But its transformation into a pandemic strain is of definite interest today.

There are stories running around that the 1918 flu was the result of a peculiar set of circumstances. [UPDATE: See my post The Spanish Flu Story.] I have only heard this story as hearsay, so if anyone knows where it came from give a yell (hopefully it isn't from an obvious book I should have read).  Essentially, the story blames the 1918 Flu on World War I.  Large numbers of wounded troops were being removed from disease ridden conditions on the battlefield, and then moved through various hospitals, with the most grievously ill and wounded becoming ever more concentrated along the way.  It is argued (not by me) that this provided a remarkable opportunity for the virus to thrive and evolve amidst a large number of immune suppressed patients.  As the sick and wounded were moved from hospital to hospital, they may have carried flu variants with them, and when introduced into a new ward inoculated the patients already present with new strains.  Whether or not this story is an accurate rendition of the origin of the 1918 strain, it does get the brain ticking over.

What I find particularly troublesome in current events is the confluence of the H5N1 infections with a potential malaria outbreak resulting from conditions brought about by the tsunami.  There are two potential things that must happen in order for H5N1 to become truly dangerous to large populations.  The first is that it must find initial purchase in humans in order to replicate itself, and the second is that it must replicate in sufficient numbers and diversity to produce a more virulent strain.  The former is already happening on a small scale, as the human to human transmission cases illustrate.

But it is a virtual certainty that more people have been exposed to the virus than have become ill.  The immune systems of those who have escaped illness have been able to fight off the bug.  This means H5N1 hasn't had much of a chance to adapt itself to humans as hosts.  But what happens if H5N1 has the opportunity to infect large numbers of immune suppressed (or immune challenged) people?  I fear that this may come to pass if a malaria epidemic does strike areas affected by the tsunami.  H5N1 may thrive in such conditions, and whether its genome is altered by mutation or by recombination with other strains, variation and selection will definitely both be operating.  The parallels to the hypothetical origin of the 1918 flu are alarming, particularly in the context of modern rapid travel.

It would be nice if our knowledge of epidemiology and molecular biology could help us understand the probability of H5N1 becoming a pandemic-causing strain.  But as far as I can tell, we just don't know enough yet.  The furthest I have gone down this road is reading (and digesting as much as I could) a paper entitled, "Phylogenetic analysis reveals a low rate of homologous recombination in negative-sense RNA viruses," by Chare et al, in the Journal of General Virology (2003, 84, 2691-2703).  This is a bioinformatic study of 79 gene sequence alignments from 35 negative sense RNA viruses, including the Spanish Flu. 

I can do no better to explain this paper than to quote from it;

Overall, our study reveals that recombination is unlikely to be a frequent process in negative-sense RNA viruses, with only a few clear-cut examples in the 79 gene sequence alignments studied here. While we were unable to estimate precise recombination rates from our analyses, it is clear that these rates must be lower than those of mutation, which is not the case in some other viruses. Indeed, the absence of any detectable recombination in 20 of 35 negative-sense RNA viruses suggests that they may be entirely clonal organisms, although this will clearly need to be confirmed with much larger sequence data sets.

It is important to reiterate this is essentially a theoretical study based on historical data.  The authors performed no experiments.  However nice our stories, making testable predictions and doing experiments are the only way we can get close to the truth.  If our models were better maybe we could get at a decent prediction for the behavior of H5N1.  Perhaps in turn this would enable a bit of practical planning in the field, as well as an estimate of the economic consequences of action and inaction.  The best we can do in this case is probably to marshall relevant historical, economic, and scientific stories, and perhaps combine this with some savy scenario planning.  But when it comes to nailing down details, we may just have to wait and see in this case.

We've picked up this story as an internal research project at Bio-Economic Research Associates.  If you are interested in contributing, or in supporting a more concentrated effort, let me know.