Is the 2009 H1N1 influenza virus more dangerous than we think?

15 July 2009

Mustela_putorius_furoThe results of experiments comparing the virulence in animals of the 2009 H1N1 influenza virus with seasonal strains have spawned the headline Study Suggests H1N1 Virus More Dangerous Than Suspected. In my view, the best experiment is now being done in humans: infection of millions with the pandemic virus. The results show that the virus is no more virulent than last season’s H1N1 strain.

In mice, ferrets, and non-human primates, the 2009 H1N1 swine-origin influenza virus (S-OIV) replicated more efficiently, and caused more severe lesions in the lungs than a seasonal H1N1 virus. These findings lead the lead author of the study to comment:

There is a misunderstanding about this virus. People think this pathogen may be similar to seasonal influenza. This study shows that is not the case. There is clear evidence the virus is different than seasonal influenza.

I’m puzzled by this statement. As far as I know, the 2009 H1N1 strain has so far likely infected millions of people, and most have concluded that the disease is no more severe than seasonal influenza. Are mice, ferrets, and non-human primates more reliable indicators of influenza virus virulence than humans?

I agree that the 2009 H1N1 influenza virus does seem to multiply more extensively in the respiratory tract than a seasonal H1N1 strain, as does the 1918 virus. But how many influenza virus strains have been studied in such animals? There are probably others that can replicate in the lower tract of experimental animals but are not very pathogenic in humans.

Two other research groups published the results of similar experiments in ferrets. They both found that the 2009 H1N1 virus replicated to higher titers, and more extensively in the lower respiratory tract, than seasonal H1N1 influenza virus. One of the groups concluded:

Our results indicated that the 2009 A(H1N1) influenza virus replicates efficiently in the upper and lower respiratory tract of ferrets, is associated with mild or moderate clinical signs and pathological changes and is transmitted efficiently between ferrets via aerosols or respiratory droplets. These results are in agreement with observations in humans, where generally mild disease but relatively efficient human-to human transmission has been observed

In other words, although the 2009 H1N1 replicated more efficiently, and in different parts of the lungs than seasonal H1N1 virus, these authors felt the observations were consistent with the low virulence of the virus humans.

It’s worth noting that when the authors of the Nature paper infected miniature pigs with the 2009 H1N1 influenza virus, the virus replicated without clinical symptoms. This result emphasizes the importance of remembering that animals are models for studying virus infections; they rarely duplicate the effects of a virus infection in humans. Furthermore, the virulence of a virus strain may vary dramatically depending on the dose and the route of infection, as well as on the species, age, gender, and susceptibility of the host. Virulence is a relative property. Consequently, when the degree of virulence of two very similar viruses are compared, the assays must be identical.

Do we really want to conclude that the new H1N1 strains is ‘more dangerous’ than we think based on tests in animal models which may or may not accurately reflect what occurs in humans? The ongoing infection of millions of humans with the new H1N1 virus seems a better source of data – and so far the results indicate that the new pandemic strain is no more dangerous than seasonal influenza.

Of course, it is possible that a more virulent version of the 2009 H1N1 virus could emerge in the coming months – what will happen as this virus evolves in humans is anyone’s guess – but who knows if it will retain the ability to multiply in the lower tract? The only thing that is certain is that it will be a different virus from the one that has been studied in mice, ferrets, and small pigs.

Y. Itoh1 et al. (2009). In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses Nature adv. online pub 13 July 2009.

Maines, T., Jayaraman, A., Belser, J., Wadford, D., Pappas, C., Zeng, H., Gustin, K., Pearce, M., Viswanathan, K., Shriver, Z., Raman, R., Cox, N., Sasisekharan, R., Katz, J., & Tumpey, T. (2009). Transmission and Pathogenesis of Swine-Origin 2009 A(H1N1) Influenza Viruses in Ferrets and Mice Science DOI: 10.1126/science.1177238

Munster, V., de Wit, E., van den Brand, J., Herfst, S., Schrauwen, E., Bestebroer, T., van de Vijver, D., Boucher, C., Koopmans, M., Rimmelzwaan, G., Kuiken, T., Osterhaus, A., & Fouchier, R. (2009). Pathogenesis and Transmission of Swine-Origin 2009 A(H1N1) Influenza Virus in Ferrets Science DOI: 10.1126/science.1177127

  • barnabydawson

    I don't think we really know what the actual severity is. I've seen two credible estimates with a significantly higher severity than the seasonal flu (0.4% and 0.5% CFR). All other estimates seem to assume that all deaths are detected (which is not the experience of the CDC which typically only detects ~5% of deaths from the seasonal flu).

    The claims in the popular press that this swine flu is no more severe than the seasonal flu seem to be based on flu surveilance numbers which are well known to be appalling innacurate when used as estimates.

    Furthermore the claim that this disease is less dangerous than the seasonal flu seems to require further justification to me as:

    1) This strain is infecting a much younger demographic resulting in a much greater loss of years of life per death.

    2) This strain is likely to infect many more people than seasonal flu.

    3) 1/3-1/2 of deaths are in healthy adults and about 1/4 have only got asthma.

    I think you're right about the animal models. But I think we not only need data from humans but some tolerably good analysis of this data before concluding anything about the severity in humans. I haven't seen a good attempt at estimating the CFR yet.

  • Liz788

    Another off-top question, sorry: I've heard rumors that some of the H1N1 vaccines could be made using live-attenuated viruses (Thailand seems to be testing this method). Does that indicate that there would be potentially serious side effects or that the vaccine could cause a negative viral reaction/response? I know there is an awful lot of anti-vaccine propaganda out there, so I would like to hear from an expert.

  • mdubuque

    Interesting rebuttal. Nature is an extraordinarily prestigious publication.

    Would you consider a letter to them explicating your view?

  • Pingback: Is the 2009 H1N1 influenza virus more dangerous than we think? « euraktiva

  • http://pandemicfluwatch.blogspot.com/ pandemicfluwatch

    “The results show that the virus is no more virulent than last season’s pandemic strain.”

    I assume you meant last year's seasonal strain? If so, then I would argue that your conclusion is based on a faulty comparison measure: the raw case-fatality ratio. The age distribution of hospitalization and death implies that this disease is significantly more virulent than seasonal strains, but that many of those in the >60 age group have some protective immunity. In the case of a seasonal flu, we would not normally see such a high incidence of mortality or severe morbidity in (non-infant) children and young adults.

    Age-specific mortality and hospitalization among those who are susceptible (largely, but obviously not exclusively, those 60 and under) is probably a better measure for comparing the virulence of these two strains, and using that measure I think it's clear that the pandemic strain is worse.

    I'm not trying to imply that this is anything like the monstrous 1918 virus -it isn't. (So far at least.) But while I wholeheartedly agree with you that animal models are often poor predictors of human pathology, and even worse predictors of human epidemiology, I don't think we can fairly say this pandemic strain is the equivalent of a seasonal flu.

  • http://www.virology.ws profvrr

    I meant to write 'last season's H1N1 strain'; thank for the
    correction. I agree that basing the CFR on current data is faulty; but
    I believe the CFR will decrease because it's currently based on
    lab-confirmed influenza. The CFR may be higher for specific age groups
    but I'm considering only the overall rate. But my main point is that
    the authors can't say the 2009 H1N1 strain is more dangerous than we
    think based on animal models. The best way is to look at the human
    data which should give a clear picture by next season.

  • http://www.virology.ws profvrr

    Flumist is an FDA approved live influenza virus vaccine that is quite
    safe and effective. An infectious attenuated vaccine is produced from
    a genetically altered virus, and there is always the possibility of
    mutation to a virulent phenotype. But no such 'reversion' has been
    observed with Flumist. However, the use of Flumist is far less than
    inactivated influenza vaccines for a variety of reasons, including the
    need to take it by inhalation and the perception that reversion might
    occur. Given the nature of the changes in the Flumist strain,
    reversion seems unlikely, but always formally possible. But infectious
    vaccines in theory provide more robust and long-lived immunity because
    they more accurately duplicate a natural infection with the virus. A
    good summary of this issue can be found at http://bit.ly/noN71.

  • http://www.virology.ws profvrr

    Nature is prestigious but also known to publish less than stellar
    science. The conclusions of the paper, with respect to animals, are
    correct. However, in any other year a paper comparing two different
    strains of any virus in any animal would not likely be published in
    this journal. This happens to be a pandemic strain and a great deal of
    publicity can be obtained by publishing about the virus.

  • mdubuque

    Yes. I understand their point and your informative rebuttal. Given your credentials, time permitting, it seems to this lay person that they would consider publishing your important caveats about the study in their letters section.

    Just a thought.

  • Chuck

    More than 90% of the deaths from seasonal flu are among the frail elderly over 65. Stastically, about the same number of elderly would be carried off by something even if there were no such thing as seasonal flu.

    More than 95% of the deaths so far from the 2009 H1N1 flu have been of people under 60 years old. While much has been reported about “underlying conditions”, somone with an underlying condition is only about twice as likely to have a severe case of the pandemic flu as a completely healthy person. Depending on your age and any underlying condition, a person under 60 is anywhere between 20 and 400 times more likely to die of the 2009 H1N1 than of seasonal flu.

  • h1n1_watcher

    Thanks for this well balanced article !

    The empirical evidence [i]in the human population[/i] does indeed support that the severity (in terms of CFR) of pandemic H1N1 roughly equals that of seasonal H1N1.

    Please take a look at the following two charts published at the US flu surveillance site:

    The first chart provides an estimate of the prevalence (i.e. the number of people infected)

    [url]http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/picILI27.htm[/url]

    It can be seen that the 'impact' in terms of doctor visits due to the current pandmic wave (i.e. the area under the curve since april 2009) is roughly equal (probably less) than the impact of this years sasonal flu wave.

    The second chart

    [url]http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/IPD27.htm[/url]

    shows the exact number of pediatric deaths (i.e. fatal cases among persons younger than 18 years)
    for recent seasonal flu waves as well as for the current pandemic wave.

    As can be clearly seen, the total number of deaths (abou 25) attributed to the pandmic H1N1 (pink bars) is still far less than the number of deaths caused by the seasonal flu wave (green bars) .

    So even if we conservatively estimate that we have only seen half the impact of the first pandemic H1N1 wave yet, the number of fatalities is still perfectly in line with the numbers seen during a typical flu season.

    Furthermore it is worth mentioning that the “pediatric deaths” statistics is probably much more accurate than the number of total deaths published because of the strict legal requirements in reporting the cause of deaths of children.

    Interstingly, novel H1N1 does not seem to be more severe than seasonal flu [i]even if we account for the age shift phenomenon[/i]:
    In [1] the number of excess deaths [i]in those under the age of 65[/i] of a typical bad flu season is estimated in the range of about 500-1000.
    Now compare this to the 260+ deaths caused by the first pandemic wave so far and conservatively further double the number to about 500 pandemic H1N1 deaths in the first wave, this too suggests that the impact of the first pandemic wave is roughly the same as that of the average seasonal wave, and this even so if we restrict the calculations to the younger-than-65 age group (for seasonal flu, the numbers would be more than ten-fold higher if we included the elderly
    65+ age groups)
    ———-
    [1]Lone Simonsen “Pandemic versus Epidemic Influenza Mortality: A Pattern of Changing Age
    Distribution”

  • h1n1_watcher

    Thanks for this well balanced article !

    The empirical evidence [i]in the human population[/i] does indeed support that the severity (in terms of CFR) of pandemic H1N1 roughly equals that of seasonal H1N1.

    Please take a look at the following two charts published at the US flu surveillance site:

    The first chart provides an estimate of the prevalence (i.e. the number of people infected)

    [url]http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/picILI27.htm[/url]

    It can be seen that the 'impact' in terms of doctor visits due to the current pandmic wave (i.e. the area under the curve since april 2009) is roughly equal (probably less) than the impact of this years sasonal flu wave.

    The second chart

    [url]http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/IPD27.htm[/url]

    shows the exact number of pediatric deaths (i.e. fatal cases among persons younger than 18 years)
    for recent seasonal flu waves as well as for the current pandemic wave.

    As can be clearly seen, the total number of deaths (abou 25) attributed to the pandmic H1N1 (pink bars) is still far less than the number of deaths caused by the seasonal flu wave (green bars) .

    So even if we conservatively estimate that we have only seen half the impact of the first pandemic H1N1 wave yet, the number of fatalities is still perfectly in line with the numbers seen during a typical flu season.

    Furthermore it is worth mentioning that the “pediatric deaths” statistics is probably much more accurate than the number of total deaths published because of the strict legal requirements in reporting the cause of deaths of children.

    Interstingly, novel H1N1 does not seem to be more severe than seasonal flu [i]even if we account for the age shift phenomenon[/i]:
    In [1] the number of excess deaths [i]in those under the age of 65[/i] of a typical bad flu season is estimated in the range of about 500-1000.
    Now compare this to the 260+ deaths caused by the first pandemic wave so far and conservatively further double the number to about 500 pandemic H1N1 deaths in the first wave, this too suggests that the impact of the first pandemic wave is roughly the same as that of the average seasonal wave, and this even so if we restrict the calculations to the younger-than-65 age group (for seasonal flu, the numbers would be more than ten-fold higher if we included the elderly
    65+ age groups)
    ———-
    [1]Lone Simonsen “Pandemic versus Epidemic Influenza Mortality: A Pattern of Changing Age
    Distribution”

  • gsgs

    I'd like to see the curves for estimated CFR by age of mexflu and seasonal H1N1
    in one picture so we can compare. x:age, y:CFR

  • MWR in Afghanistan

    You've got to be kidding me… Do you not see the data on the populations being hit hardest by this virus (compared to last year's H1N1)? Last year, we did not see this kind of impact on younger people and far far fewer pregnant women were seen developing severe complications (and death) compared to this year's Pandemic strain. I'm also puzzled by the complete lack of insight on the varied impact this is having on less-developed countries (where there are little or no stocks of antivirals, no ventilators, and sparse ICU services, if any at all).

  • http://www.infectiousdiseasenews.com/ Lloyd

    I've also read that H1N1 is more severe in pregnant women:
    http://bit.ly/7aYIjQ

  • http://www.infectiousdiseasenews.com/ Lloyd

    I've also read that H1N1 is more severe in pregnant women:
    http://bit.ly/7aYIjQ