Co-circulation of three human influenza A subtypes

18 May 2009

Although the new influenza H1N1 strain has been receiving a great deal of attention, apparently last season’s H1N1 and H3N2 strains continue to circulate, at least in the United States. FluView, the weekly surveillance report from the CDC, indicates that during weeks 17 and 18, seasonal influenza A (H1), A (H3), and B viruses are co-circulating with novel influenza A (H1N1). Half of all influenza viruses detected are the swine-like H1N1 viruses. The statistics are shown in this bar graph:

influenza-week-18

Seasonal influenza in the US peaked in week 6 (February) and declined by week 16. With the emergence of the new H1N1 strains, there came an upsurge in influenza activity during weeks 17 and 18.

Two aspects of these data are noteworthy. First, it is very interesting that influenza viruses of three different subtypes – H3N2, and two H1N1 – are circulating at the same time. On at least two previous occasions, the seasonal influenza strain was replaced by the new pandemic virus. In 1957, when the H2N2 strain emerged, it replaced the previously circulating H1N1 strain. Then in 1968, the H2N2 strain was replaced by the H3N2 strain. The reasons for the replacement of influenza virus strains during these two episodes of antigenic shift remain obscure. Should we expect the new H1N1 strain, if it goes on to be the pandemic strain, to replace previously circulating human influenza A viruses? When the H1N1 influenza virus re-emerged in 1977, it did not replace the H3N2 viruses – although it did not go on to be the next pandemic strain. Whether or not the new H1N1 viruses will dominate is anyone’s guess. Clues might come from which strains are isolated in the southern hemisphere in the coming weeks.

I am also intrigued by the observation that circulation of last season’s H3N2 and H1N1 strains, nearly over by week 16, has suddenly been revived along with introduction of the new H1N1 strain. Put another way, why is there a general upsurge in influenza cause by all three A subtypes? Perhaps it’s just an unusual outbreak late in the season, which has certainly happened in the past, only this time, there is a new virus thrown into the mix.

  • http://chem-bla-ics.blogspot.com/ Egon Willighagen

    Can the rise of the green and yellow types be explained by more people being tested because of mexican flue, as those numbers are absolute (left scale)?

  • phogdog

    I'm with Egon….

    How else can you explain the upsurge in influenza @ week 17 other than patients and physicians both being on high surveillance mode looking for novel H1N1 due to saturation media reporting? Could there be another explanation?

    Which begs the question of the accuracy of the normal baseline numbers. And it would be interesting to see if this reporting spike had any other particular characteristics relative to baseline: geography, race, urban/rural, income, education.

  • http://www.virology.ws profvrr

    It's possible that increased surveillance is partly responsible. I
    don't have the real numbers for now and previous periods, so it's hard
    to tell what is going on. Here is what CDC says: “The number of
    specimens tested by WHO and NREVSS collaborating laboratories during
    week 18 increased in response to the ongoing novel influenza A (H1N1)
    investigations. The increase in the percentage of specimens testing
    positive for influenza also may be due in part to changes in testing
    practices by healthcare providers, triaging of specimens by public
    health laboratories, an increase in the number of specimens collected
    from outbreaks, and other factors.”

  • http://www.virology.ws profvrr

    See my reply to Egon. It doesn't make sense to me either; why would
    isolation of the old strains rise again? But CDC isn't explaining and
    we don't have the numbers to look at.

  • http://www.facebook.com/people/Corey-Philipp/799897312 Corey Philipp

    I think that the most disturbing thing is the media focus on the 5 deaths from the novel H1N1 strain. All 5 deaths are tragic there is no doubt but the media seems to be focusing in on these deaths while ignoring the some 30,000 deaths each year in the US attributed to Influenza every year. For example the following is an extract from the fluview report for the week ending May 9th, 2009:

    Three influenza-associated pediatric deaths were reported to CDC during week 18 (Arizona, California, and Texas); one was due to influenza A virus (rapid test positive) and two were due to influenza B virus infections. The deaths reported this week occurred between April 5 and May 2, 2009. Since September 28, 2008, CDC has received 59 reports of influenza-associated pediatric deaths that occurred during the current season.

    This is very disturbing to me… The media are completely missing this tragedy because they aren't deaths caused by the new doomsday H1N1. Sorry for the cynicism but I think there is a loss of perspective here.

  • http://www.zonegrippeaviaire.com/showthread.php?t=2560 gsgs

    increase in the positives-rate for seasonal flu cannot be explained by increased testing.
    But maybe by increased information, by increased attention to the symptoms
    and thus better selection of those who are finally tested

  • http://bit.ly/UvG8i gsgs

    not only in pandemics but also in intrasubtype seasonal flu we see this replacement of strains.
    E.g. in 2002-4 the Fujian strain replaced the old H3N2, H1N1 had the 3bp deletion in HA
    at the end of the 90s , which is now in all seasonal H1N1 (but not in swine flu)
    1968 was followed by 4 years of reassortments until finally the Udorn-strain
    became dominant. Flu seems to walk through bottlenecks regularly where most strains die
    and only few strains “survive” and succeed to spread. Seasonal flu in America seems to
    die out almost every season and is introduced newly the next season from Asia.

    Maybe find the timing and location of the bottlenecks and fight flu there !
    Either by killing it or by introducing milder strains to replace virulent ones

  • David

    So let me get this straight – before 1977, only one Influenza A virus circulated in the human population?

  • Michael

    Notwithstanding the week 18 testing increase quoted, there was a reduction in positive rates for season flu.

    The increase in positive rates for season flu was in week 17. If seasonal flu positive rates continue to drop in week 19 and beyond as they did in week 18 you're looking at the expected pattern other than an across the board increase in positive rates in week 17.

    If looking for differences at week 17 it would be good to also look at the weeks just prior. If submission practices at a time of high concern overstate flu rates, then the tail end of the flu season might be a time where submission practices understate flu rates. I wonder if there are any papers on a late season under reporting effect?

  • http://bit.ly/UvG8i gsgs

    H1N1: 1918-1957 and 1977-(2009?) (same strain re-emerged)
    H2N2:1957-1968
    H3N2:1968-(2009?)

  • phogdog

    Fear garners eyeballs. Fear sells.

  • Peter Ellis

    Is there any indication that there could be co-infection with two strains, which then transmit together / cooperatively? Could some of the cases typed as “seasonal” also be carrying swine flu, perhaps at a lower level – and conversely, could some of the cases typed as “swine flu” also have seasonal flu? How is the typing done? Do they look for different flus in turn and then stop when they find one?

    This extends the “paraspecies” concept you covered a few posts ago to a wider level of grouping, with a population of different flus transmitting together.

  • http://bit.ly/UvG8i gsgs

    no reassortments found so far
    see here:
    http://www.ncbi.nlm.nih.gov/genomes/FLU/SwineFl
    how frequently they sample multiple segments

    with 100000 estimated people having Mexflu in USA and another 100000
    having seasonal flu, the chance of coinfection is only 1e-7 or 33 cases in USA

  • Peter Ellis

    I'm not talking about reassortments, What I'm asking is whether, in the absence of reassortment, a mixed simultaneous infection with two flu subtypes is possible, whether that might spread more efficiently than either subtype alone, and how that would appear to the serological testing. Could this explain why the existence of H1N1 is apparently driving up the prevalence of seasonal influenza A?

    To be crystal clear what I mean by a mixed infection I mean a single person infected with H1N1 and H3N2, who then coughs on someone else, they catch both H1N1 and H3N2, and so on. Depending on how well the two viruses replicate within the host, one patient could have “mostly” H3N2, while the next could have “mostly” H1N1, and some could have a balanced mixture. What would the serotyping tests make of that? Would they be able to pick up a mixed infection? Or would it show up as either one or the other, or a noisy “unsubtypable” category?

    Coinfection might of course lead to reassortment if a single cell is infected by both viruses, but that's not necessarily the case. The seasonal flus could be infecting the upper respiratory tract and H1N1 the lower respiratory tract. Or reassortments could simply be unstable / selected against and thus not seen.

  • Peter Ellis

    Note that not only have (seasonal) H1N1 and H3N2 gone up in absolute terms, they have also gone up relative to influenza B.

    If increased testing were the only factor, I would (naively perhaps) expect seasonal flus and influenza B to increase proportionally to each other. The fact that we see a further increase in the seasonal flus over and above the increase in influenza B is what leads me to suspect there may be something else going on here – some kind of cooperation between H1N1 and the other seasonal influenza A strains, where they facilitate each other's transmission.

  • ppga

    Questions – Today (5/20/09) there have been quotes in articles suggesting possible partial immunity to novel H1N1 for those over the age ~52, possibly due to exposure to the old H1N1 that was dominant until 1957. Assuming that this conjecture is true, wouldn't exposure to the H1N1 that resurfaced(or escaped, as it were) in 1977 afford the same immune effects, given that it was so similar to the “old” H1N1 from 1918-1957. Is the 1977 H1N1 the source of the seasonal H1N1 that has been circulating for some time now?

  • http://www.virology.ws profvrr

    See gsgs' answer to your question. The strains are mainly identified
    by nucleotide sequencing, so reassortment would be seen (although not
    every segment may be sequenced). And yes, reassortment, and
    recombination in other viruses, does add to the genetic diversity that
    occurs.

  • Peter Ellis

    See my reply to gsg :-)

    I'm not talking about reassortment but about co-infection (which might in turn lead to reassortment but doesn't necessarily do so). If a patient is infected with two strains simultaneously, will they both be picked up by testing, or will the test only pick up one of the strains?

    It's easy to construct “just so” stories which would allow two virus strains to assist each other to spread. For example, one virus could irritate the airways, causing coughing, while the other increases fluid secretion, meaning that the coughs are more productive, spread more droplets, etc. In this case, the two viruses together would transmit more efficiently than either virus alone. This is a possible reason for the unusual out-of-season spike in the seasonal H1N1 and H3N2 subtypes – if swine-H1N1 was somehow facilitating their spread (and/or vice versa).

    However, if this is true, it suggests that some proportion of the patients typed as having seasonal flu are in fact infected with (seasonal flu AND swine flu), and conversely that some proportion of the patients typed as having swine flu are in fact infected with (swine flu AND seasonal flu). I'm asking how likely it is that the serotyping procedure could be missing / mis-scoring double infections as being only one strain or the other.

  • MJ

    It's probably not an true upsurge in seasonal influenza (H1N1 and H3N2). It's more likely a surveillance artifact. Many more people with influenza-like illness are now being tested for flu (due to concerns about novel H1N1) than is typical for this late in the influenza season. Since we're looking for more flu than usual, we're finding it.

  • Claudio Vargas

    In the recent Fraser et al paper on Science they said the virus displacement occurred in the last three pandemics and that is consistent with the above information. Is there any idea about the dominant strain between 1891 and 1918?

  • Peter Ellis

    Why would that affect Flu A and Flu B differently though? In weeks 10 through 15, there is more flu B than flu A around, As soon as the novel flu comes out, that is reversed – in weeks 17/18 each of the two subtypes of flu A is being found more often than flu B. Something has happened which not only causes more flu to be detected, but dramatically changes the proportional breakdown of the different seasonal flu strains.

  • http://www.virology.ws profvrr

    The situation before 1918 is based entirely on serology, as we weren't
    able to isolate viruses (the first influenza virus wasn't isolated
    until 1930). It is believed that an H2N2 virus circulated from
    1889-1900, and an H3N8 virus from 1900 until 1918. Whether or not
    there was displacement is not known.

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  • jefvangenechten

    Is there a home test available for the H1N1 test?

  • http://www.virology.ws profvrr

    I am not aware of any for home use – only in health care provider offices.

  • caseyoconnell

    What is the rate of false positives? What testing was done and by whom to verify the rate of false positives? In particular, what is the rate of false positives given the presence of flu-like symptoms? An 80% accuracy with respect to false negatives would explain all of the 1000 positives in India (and half of those patients have already gone home.)

  • http://www.virology.ws profvrr

    CDC recently commented on the accuracy of rapid flu tests. This
    article might answer your question:
    http://www.reuters.com/article/healthNews/idUST….

  • caseyoconnell

    That helps tremendously. I'll pass that on to help calm down the extreme response to this disease. Ten times more virulent than other flus is still serious, but there are far more serious diseases that people do too little about.
    The question of false positives is not adequately answered, but the idea is supported that this is a serious disease, just not as serious as heart disease and others.

  • caseyoconnell

    That helps tremendously. I'll pass that on to help calm down the extreme response to this disease. Ten times more virulent than other flus is still serious, but there are far more serious diseases that people do too little about.
    The question of false positives is not adequately answered, but the idea is supported that this is a serious disease, just not as serious as heart disease and others.