Today’s title refers to the perhaps unexpected origins of the recent swine ’flu outbreak, that apparently  comes not from the widespread intermingling of wildfowl and table ducks in Asia but via as yet uncertain processes in the western hemisphere. In the previous blog, I summarised some of the issues of swine flu as I saw them. Meanwhile, the e-print scientific literature is starting to become populated with some epidemiological and related analyses (I thank Fiona Tomley of our Institute for Animal Health for drawing my attention to some of them). The general consensus remains that the present outbreak is of a strain that is not excessively virulent, but that during the northern summer (southern winter) a reservoir of infection (in pigs, birds and humans) will build up and the likelihood of mutations or reassortment events producing something considerably nastier will increase significantly. However, all of the uncertainties are very considerable at this stage, since the numbers of cases – and especially fatalities – are (happily) still small. Of 11 known human cases of the (probably related) ‘triple reassortment’ swine flu in the US from 2005-9, analysed via routine surveillance, all recovered. By May 5, 642 cases had been confirmed in the USA. Ferguson and colleagues have estimated R0, the basic reproduction number, of the strain as being between 1.2 and 1.6, the lower end being considered more likely from genetic and other evidence, and with the percentage of fatalities being perhaps around 0.4% (significantly more than ‘Hong Kong’ and ‘Asian’ flu but much less than the strain involved in the ‘Spanish’ flu pandemic), but the exact numbers are sufficiently small to make uncertainties very large, and the analysis is necessarily based on many assumptions about transmissibility and its homogeneity.

Irvine and Brown point out that we still do not know whether the strain of the present pandemic actually originated directly in pigs, and if so of what origin! They state, “It is not known if the particular genotype of H1N1 virus that appears putatively to have originated in Mexico is circulating in North American pigs, but its close similarity to other strains of swine influenza known to be circulating in the region (sharing 6 of 8 gene segments) has led to the assumption that this novel H1N1 strain is derived from pigs”, and “Based on current evidence from surveillance programmes in several European countries, the variant of H1N1 virus recently isolated in human beings has never been reported, and therefore does not appear to be present in the European pig population.” Certainly the situation in European and American pigs seems quite different, so plans based on a unitary model of transmission (and, when numbers of cases merit improving them, any unitary models themselves) are probably inappropriate.

Equally, it remains unclear as to why the strain circulating on North America appears to be much more virulent in Mexico than in e.g. the USA. Differences in the genetic makeup of the relevant human populations are likely a major contributor, but it could as easily be the interaction of the virus with jalapeño peppers or (more plausibly) the host nutritional status generally (which can even influence viral mutation rates) or iron status where, for instance, high iron levels can enhance virulence and virus-induced pathogenesis, iron chelation can reduce it, while increased HO-1 (haem oxygenase 1) levels are protective in mice. Note of course that statistical or experimental bias can be a powerful factor in these kinds of analysis, and there is real danger of excess stratification or ‘data dredging’ when numbers are small. As we acquire more genetic knowledge of these host populations, as well as of the viral sequences, we may get useful clues as to the biochemical bases of human resistance and susceptibility. Some possibilities are known already, e.g. MxA (=Mx1 in mice).

Many of these wide-ranging and complex problems may usefully be attacked by the tools of Science Wikinomics, as has happened in a project using a collaborative environment on the SARS coronoavirus. As is probably by now well known, the pattern of searches at Google (and presumably at other search engines) can reveal the location of potential outbreaks well in advance of their detection by biochemical assays in central locations, a useful and powerful example of Web 2.0 trends and of data-driven science. Readers may also be interested in following events via sites like the CDC flu site,  flutrackers, Medical News Today, the NCBI flu resource (paper) and the  NIAID Influenza Resource, our NHS,  the VLA swine flu site, the WHO flu site and Wikipedia.

And as to the origin of the title of this blog, the original quote, with apologies to the late Ken Kesey, its author (and participant in Jack Kerouac’s “On the road”), is of course “…one flew east, one flew west, One flew over the cuckoo’s nest”.

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