Human infections with influenza H5N1 virus: How many?

7 February 2013

The lethality of avian influenza H5N1 infections in humans has been a matter of extensive debate. The >50% case fatality rate established by WHO is high, but the lethality of the virus might be lower if there are many infections accompanied by mild or no disease. One way to answer this question is to determine how many individuals carry antibodies to the virus in populations that are at risk for infection. A number of such studies have been done, and some have concluded that the results imply a low but substantial level of infection (even less than one percent of millions of people is a lot of infections). The conclusion of a new meta-analysis of H5N1 serosurveys is that most of the studies are flawed, and that the frequency of H5 infections appears to be low.

Twenty-nine different H5N1 serological studies were included in this meta-analysis. None of these are particularly satisfactory according to the authors:

None of the 29 serostudies included what we would consider to be optimal, blinded unexposed controls in their published methodologies, i.e., including in the serology runs blinded samples from individuals with essentially no chance of H5N1 infection. Serological assays can easily produce misleading results, especially when paired sera are not available.

Some of the problems identified in the serological surveys include the possibility that many H5N1 positive sera are the result of false positives, that is, cross reaction with antigens from other influenza virus strains. In addition, many studies utilized H5N1 strains that are no longer circulating.

It is clear that most of the H5N1 serosurveys have not been done as well as they should have been. The authors conclude that “it is essential that future serological studies adhere to WHO criteria and include unexposed control groups in their laboratory assays to limit the likelihood of misinterpreting false positive results.”

Let’s not forget that a completely different way of assessing H5N1 infection – by looking for virus-specific T cells – has been reported. The results provide further evidence for subclinical H5N1 infection and are not subject to the caveats noted here for antibody surveys.

I come away from this meta-analysis with an uneasy sense that the authors are not being sufficiently objective, and that they firmly believe that there are no mild or asymptomatic H5N1 infections. One reason is the authors’ use of ‘only’ to describe their findings. For example: “Of studies that used WHO criteria, only [italics mine] 4 found any seropositive results to clades/genotypes of H5N1 that are currently circulating”. The use of ‘only’ in this context implies a judgement, rather than an objective statement of fact. Furthermore, despite the authors stated problems with all H5N1 serosurveys, they nonetheless conclude that there is little evidence for asymptomatic H5N1 infection. If the studies are flawed, how can this conclusion be drawn?

My concern about the authors’ objectivity is further heightened by the fact that they are members of the Center for Biosecurity at the University of Pittsburgh. These are individuals whose job it is to find dangerous viruses that could be used as weapons. On the front page of the website for the Center for Biosecurity is a summary of the meta-analyis article which concludes that “In the article, Assessment of Serosurveys for H5N1, Eric Toner and colleagues discuss their extensive review of past studies and conclude that there is little evidence to suggest that the 60% rate is too high.”

I would argue that if the H5N1 serosurveys are flawed, then do them properly; it is incorrect to simply assume that the H5N1 virus is as lethal as WHO suggests. The World Health Organization should call for and coordinate a study that satisfies criteria established by virologists and epidemiologists for a robust analysis of human H5N1 exposure.

  • gsgs

    maybe someone can produce false positives deliberately – or are there
    such examples already – just to demonstrate the effect.
    It needn’t be H5N1.
    Or/and include other viruses in the survey for a larger sample,
    e.g. H9 or H7. I was amazed when they found antibodies to the new flu-C
    in 9% of swine and 2% of people in British Columbia.
    I mean, a study just to test the chance of false positives.
    But I don’t think this whole question is so important for the H5N1
    debate. Even if there are lots of asymptomatic or low symptomatic
    infections, the mortality is exceptionally high. You could even argue
    that asymptomatic infections were bad – they make it harder to detect
    and control and eradicate outbreaks.
    We have lowsymptomatic ducks and pigeons and … for some of the strains,
    but that doesn’t help the chickens and turkeys a lot. Au contraire.

  • http://www.virology.ws profvrr

    Deliberate false positives – that’s why you would want independent studies done, to avoid that.

    I do think the seropositive rate is important to know. Right now WHO says that the case fatality rate is over 50%, and governments are pouring money into H5N1 with the idea that if it transmits in humans it will be devastating. But what if the mortality rate isn’t anywhere near 50%? I think we need to know that to inform our investment.

    I do believe that if H5N1 ever did transmit among humans, its virulence would be substantially lower, because the changes needed for transmission would attenuate virulence.

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