Evidence for influenza H5N1 infections in humans

The fatality rate for human infections with avian influenza H5N1 is widely quoted at >50%, based on the number of deaths among the fewer than 600 cases confirmed by the World Health Organization. Wang, Parides, and Palese suggest that this number is an overestimate:

…the stringent criteria for confirmation of a human case of H5N1 by WHO does not account for a majority of infections, but rather, the select few hospitalized cases that are more likely to be severe and result  in poor clinical outcome.

To address this problem, the authors summarized the results of serological surveys in which human sera were examined for the presence of antibodies to influenza H5N1 virus. Because antibodies are part of our immune defenses, they are a good indicator of a previous infection.

The authors searched the scientific literature and identified 20 studies in which human sera were examined for the presence of H5N1 antibodies according to WHO guidelines (a 4-fold or greater increase in neutralizing antibody titer in paired acute and convalescent sera, with the convalescent serum having a titer of ‰¥1:80, or an antibody titer of ‰¥1:80 in a single serum collected at day 14 or later after onset of symptoms and a positive result using a different serological assay).

Studies that used the WHO criteria included 7,304 study participants. Rates of seropositivity were from 0 – 5.3%, with one study reporting 11.7% positivity. The meta-analysis yielded a seropositivity rate of 1.2% (95% confidence interval 0.6% – 2.1%). When only poultry workers were considered, the seropositivity rate was 1.4%.

Other studies were separately analyzed that did not utilize WHO guidelines; these included 6,774 participants and yielded a seropositivity rate of 1.9% (95% confidence interval 0.5 – 3.4%).

A total of 12,677 study participants from 20 studies were included in this meta-analysis, of which 1-2% had evidence for prior H5N1 infection. The authors conclude:

…avian H5N1 viruses can cause a rate of mild or subclinical infections in humans that is not currently accounted for and thus, the true fatality rate for H5N1 influenza viruses is likely to be less than the frequently reported rate of more than 50%.

It seems very clear that standardized, large scale studies are needed to determine the real number of human H5N1 infections. This information is critical for assessing the actual threat of H5N1 influenza for humans.

15 thoughts on “Evidence for influenza H5N1 infections in humans”

  1. Did these studies include the sero tests taken during the 1997 Hong Kong outbreak? If so, I think it would skew the data, since it’s a different virus from the one that reemerged in 2003.

  2. From the paper: “If reports from the
    1997 outbreak in Hong Kong are considered separately, the
    rate of seropositivity is approximately 3.2% (4, 5, 7). Studies
    after 1997, and that use WHO criteria, show an overall
    seropositivity rate of approximately 0.5%.”

    This is considering only serosurveys in poultry workers, which yielded a seropositivity rate of 1.2%. Removing the Hong Kong data increased the percent seropositivity in this group of individuals.

  3.  I think using serology data to determine virulence of a virus can be a tricky argument to make.  Isn’t it possible that there are other virulence determinants within H5N1 viruses other than the HA antigen that  need to be present in order to confer the highly lethal phenotype? Presumably this serology data would include any and all viral reassortments that contain the H5 gene, but not other factors that may contribute to virulence, correct?  Isn’t this argument akin to lumping all H1N1 viruses together including the 19181 virus, then saying that it wasn’t that big of a deal?

  4. sometimes scientists (including myself) get overly excited about “bugs” and with a “little help” from the media, create unnecessary panic around the world…I think you guys touched that subject on your weekly discussion, I think it was on TWiV 69

  5. Of course, serology only tells you that there are antibodies to an H5 containing virus, with no information about virulence. Short of isolating viruses from individuals, it’s all we have. I agree we need to sort it out, and now, because we are spending a lot of effort on what is assumed to be a deadly virus – and it might not be.

  6.  The data from cell culture and animal models of H5N1 supports the paradigm that H5N1 is highly pathogenic.  However, similar models led to false conclusions about the 2009 pH1N1 virus.   There is absolutely a need to isolate H5N1 viruses from these less severe cases, to determine whether our models are fooling us.  My worry is that even if the statistically predominant strains of H5N1 flu viruses are less pathogenic than previously thought, we already have enough case evidence to show us that there are potentially lethal strains of H5N1.  The type of virus that emerges could be simple chance, and I’m not willing to bet the farm that it will be less pathogenic than anticipated.  All it takes is one bad virus strain (i.e. 19181 H1N1) for a catastrophe.

  7. Please explain this to me.  Why does anyone care what Mike Osterholm has to say??  This is the guy that got up at the NY Academy of Sciences and yelled out that he predicted 9/11 as a way of supporting his hype about H5N1.  He has been promoting a campaign of fear for months now and it is clearly bogus.  

  8. we need to know how many of these 7304 died.  Or better : how many
    or those who died and would have been included if they hadn’t died.
    (because they did fit the selection profile, poultry workers in that area,
    or whatever it was)

  9. “the true fatality rate for H5N1 influenza viruses is likely to be less than the frequently reported rate of more than 50%” … I have a very simple question, what would be the ‘true fatality rate for H5N1’ based on this new study?! (approximately I mean) Since I see it not enough just saying – likely to be less, without giving an estimation, and I think this is what Mike Osterholm alluded to also in the meeting, that anyways it is going to be a catastrophe.

  10. We can not exclude the possibility that naive people may have neutralizing antibodies against H5 trimer, esp those Abs targeting the no-globle head region. Thus, serological data may provide false results.

  11. I have now read the short Wang, Parides and Palese paper, and I have had time to take a look at a couple of the pimary papers. I think there are two points that need to be made.

    Firstly, some comments about the unsuitability of the current WHO definitions of H5N1 infection have claimed that the WHO only counts patients who have been hospitalized, and that therefore only represents the most extreme cases. From the WHO definition given in the supplementary data in the Wang et al. paper, this is clearly not the case. A confirmed WHO case can be defined by 
    “Body temperature > 38°C (100.3° F) with acute lower respiratory illness and dyspnea.” and some evidence of contact with infected poultry products (that is, a suspected case), which is then confirmed by some kind of lab technique. 
    This does not require the patient to be hospitalized (that is very sick), but does require access to a doctor, and to a specialized lab.

    Secondly, although the data in the Wang et al. paper is correct, they don’t take the specifics of the study population into account (as discussed in the TWIV epidemiology episode) so the extrapolation to the total number of possible infections worldwide is unwarranted. To show you what I mean, this paper (and it’s got open access)….

    Risk factors associated with subclinical human infection with avian influenza A (H5N1) virus–Cambodia, 2006.Vong S, Ly S, Van Kerkhove MD, Achenbach J, Holl D, Buchy P, Sorn S, Seng H, Uyeki TM, Sok T, Katz JM.J Infect Dis. 2009 Jun 15;199(12):1744-52…. followed up on two villages where there had been two confirmed H5N1 deaths. They sampled everyone within a 1 km radius of the two fatal cases (674 people), and found 7 more positive results from the lab serology (WHO criteria). Obviously, it is not reasonable to extrapolate the 1% seroprevalence rate found in this village (very close to a known outbreak) to the rest of Cambodia, or even to the rest of the district where the study was conducted.From this small sample, however, it is possible to say that the total number of people infected in this study population was 9, and the total number of deaths was 2. Perhaps meta-analysis of the available data along these lines would provide a more realistic estimate of the CFR for H5N1 influenza.DMc

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