Effect Measure

Early returns on what is happening in the southern hemisphere suggest that novel H1N1 is crowding out the expected seasonal strains, something that pandemic strains have usually done. In 1918 there was a pandemic with the H1N1 subtype that settled down as the dominant seasonal flu virus until the “Asian flu” pandemic of 1957 when it was bumped by H2N2. That subtype ruled the seasonal flu roost for only 9 years when a new subtype, H3N2 took its place in the Hong Kong flu pandemic of 1968. Both pandemics were much less severe than 1918 but still resulted in millions of excess deaths globally. In 1977 the pattern was interrupted with the return of H1N1, which didn’t take the place of H3N2 but co-circulated with it. Since then we’ve seen mixtures of H3N2 and H1N1 each flu season, with sometimes one subtype much more prevalent, sometimes the other (a hybrid H1N2 made a sporadic appearance in 2002 but never gained a foothold and didn’t represent a novel appearing virus to the population). Sometimes H1N1 and H3N2 would switch places at some point in the flu season, but those two, along with influenza B have made up seasonal influenza since 1977.

Now we have a novel H1N1 added to the mix. While novel H1N1 and seasonal H1N1 have the same subtype designation, the swine origin of the new virus means that the hemagglutinin (H) and neuriminidase (N) proteins on its surface are sufficiently different from the human adapted counterparts that it looks like a very different flu virus to most of the population. Despite its swine origin it is infecting humans and being easily transmitted from person to person. It is also continuing to circulate in the northern hemisphere at a time when most seasonal flu is at a very low level. The seasonal flu strains are essentially gone up north, almost all flu A being novel H1N1. Is this just because seasonal flu went away by itself (and we emphasize, again, the reasons for flu’s seasonality remains a mystery)? Will they return, with or without novel H1N1 during next flu season up north?

We are looking to what is happening in the southern hemisphere for some clues. Australia is one of the most hard hit countries and also has a well functioning influenza surveillance system similar to one in the US. And it appears the new virus is pushing out the seasonal strains that were expected to be the main circulating flu viruses:

Tests on 138 type-A flu samples collected by a network of doctors confirmed 60 cases of the new A/H1N1 variant and only five of seasonal influenza in the eight weeks ended June 21, according to a report today by the Victorian Infectious Diseases Reference Laboratory in Melbourne.

[snip]

?We are seeing a big increase compared to the same stage of the flu season last year, and the increase is predominantly in 5- to 16-year-olds,? Kerry Chant, chief health officer for New South Wales, said in a statement today. Two children are in intensive care and two other people hospitalized, she said.

The eastern state, Australia?s most populous, has 653 confirmed cases of swine flu, the second highest number in the nation after neighboring Victoria state.

Health officials in Victoria have recorded 1,509 cases from laboratory tests and stopped analyzing specimens from patients with mild disease earlier this month as part of the state?s response to the virus.

[snip]

Victoria?s influenza sentinel surveillance network diagnosed flu-like illness in 21.9 of every 1,000 patients seen in the week ended June 21, the report showed. That?s up from 17 per 1,000 a week earlier.

The network comprises 87 general practitioners across the state who test a portion of their patients for flu to give authorities an indication of flu activity in the community.

Unlike seasonal flu, from which the elderly suffer the most death and disease, the new bug is targeting the young and causing potentially fatal complications in otherwise healthy people aged 30 to 50, pregnant women and those with asthma, diabetes and obesity, according to the WHO. (Jason Gale, Bloomberg)

Not only is the virus taking the place of the seasonal strains, it is acting like a pandemic strain usually acts, moving the age distribution to the left (younger age groups). So while the virus is not clinically very different from seasonal flu, it is epidemiologically different.

So what will happen? The most likely outcome in our view is that henceforth flu season will be dominated by a single viral lineage, the current swine origin H1N1. That may take a couple of seasons and during the transition we could have some very unpleasant flu seasons, with lots more illness than usual and increased morbidity and mortality among younger members of the population. That epidemiological difference will make this flu virus seem different and more frightening. But I’m guessing.Flu never does what we expect it to, so there are many other possibilities, some much nastier.

Over at Avian Flu Diary Mike Coston also reflects on this. He’s an astute flu observer and always worth reading, no less so this time.

Comments

  1. #1 Jon Schultz
    June 27, 2009

    For what it’s worth, here’s what Dr. Henry Niman is saying over at FluTrackers:

    “[N]ovel H1N1 just means H1N1 that isn’t human H1N1. The use of the term ‘novel’ is just more politics. Its really swine H1N1, as the CDC used to call it, becasue it clearly came from swine, even if found in a human. The use of the term ‘novel’ just creates a lot of confusion and actually ignores the fact that 1918 started as swine H1N1 that moved into humans. There is a fairy tale out there claimimg that the swine H1N1 was avian, but that’s nonsense. Almost all of 1918 sequence in all 8 gene segments can be created with just two sequences, a human H1N1 (WSN/33) and a swine H1N1 (swine/Iowa/15/31).
    The 2009 pandemic is a re-run of the 1918 pandemic. The swine H1N1 will recombine with human H1N1 and create a recombinant that is a more efficient killer in the fall.”

    That was in response to a question about the meaning of “novel.”

  2. #2 SusanC
    June 27, 2009

    Here’s a thought. We keep saying flu is unpredictable. And it is.

    OTOH, this novel virus is, in many ways, behaving as one would expect a pandemic flu virus to behave, including shifting the age distribution to younger age groups and crowding out circulating seasonal strains. Or being more lethal to pregnant women, just to name a few.

    We may not know WHY the virus behaves this way, but it sure looks like things may not be THAT unpredictable, after all.

  3. #3 SusanC
    June 27, 2009

    So my question is, given the complexities of trying to vaccinate millions of people for seasonal flu AND this new H1N1, if this ‘crowding out’ is confirmed in other southern hemisphere countries, is there a case for at least considering dropping the seasonal flu vaccine this year?

  4. #4 revere
    June 27, 2009

    Jon: I don’t see it matters much. I’ve called it both swine and novel. As far as the immune system goes, it’s novel. It comes from swine. Of all the things to argue about, this is pretty far down the list for me. But Henry is entitled to his views and I don’t really care about this point.

    SusanC: You make an excellent point. Clinically it also looks like flu. However if it departed from other flu virus behaviors in some respects, we wouldn’t be surprised to be surprised. The problem is we don’t know if it will crowd out other strains and if it does, why. Maybe it will be temporary or partial or who knows what. So it will be a gamble, as it always is.

  5. #5 karen
    June 27, 2009

    My question is how this novel H1N1 compares to the last 2 pandemic viruses in 1957 & 1968 – in those pandemics were there the same kind of cases of quick/sudden death in relatively young & healthy people that we’ve seen in the current outbreak? (ie: there’s an article out today from Argentina where the doctors describe the lungs of young & healthy people being “burned” or “on fire” within a matter of hours http://www.lanacion.com.ar/nota.asp?nota_id=1144216 – doctors in Utah & Manitoba had described similar findings)

  6. #6 raven
    June 27, 2009

    There are a couple of differences between 1918 and the Asian and Hong Kong pandemics and this one.

    We now have a lot more knowledge and this could make a difference.
    1. We have two antiviral drugs, Tamiflu and Relenza. Right now we wish we had more as those will work until resistance arises.

    2. The ability to rapidly make novel flu vacccines has improved as well as production capacity. The CDC and companies are now saying that they will have vaccine ready in early September or a little later. Besides eggs, there are cell substrates and live virus attenuated recombinants. Some people think the timelines are too optimistic and may be correct.

    So, will these two developments make a difference? Who knows? Wait and see.

  7. #7 maryinhawaii
    June 27, 2009

    Revere, A question about this: “The network comprises 87 general practitioners across the state who test a portion of their patients for flu to give authorities an indication of flu activity in the community.”

    So does this mean that this testing is done randomly to all patients of these GPs who come to see the doctors for any reason, rather than testing only those coming specifically with ILI? Just trying to figure out what those stats of 21.9 per 1000 patients actually indicate re flu season severity and transmission rate.

  8. #8 revere
    June 27, 2009

    mary: I don’t know the precise details of the Australian system. The idea is to get a representative sample of ILI specimens for virologic testing. Exactly what the protocol is I don’t know. Maybe another reader can help?

  9. #9 bostonERDoc
    June 27, 2009

    I am beginning to think that this pandemic strain will continue to be a nuisance during the summer in the northern hemisphere and it is far from mild. Last week I treated a 14 yo healthy no medical problems female who presented to me in shock (lack of proper oxygen delivery to vital organs) and low grade fever. We were able to get a palpable pulse after 3 Lt IV fluid resuscitation. She stabilized after 7 Lt and was transferred to an another hospital since my hospital does not have a pediatric intensive care unit. She started to complain of symptoms 48 hours prior and was seen by her pediatrician who thought it was a simple summer viral syndrome. The rapid flu that was carried out when she presented to me was positive. She had no pneumonia but a significant metabolic acidosis and and elevated lactate level. If this is happening in the summer are we ever in for it in the fall– I have told my colleagues to have a great summer because there is going to be some real doctor hurt in the fall and winter. In MA we are seeing an 8 percent hospitalization rate–far above the worst case scenario planning of 1-2 %.

  10. #10 Doug
    June 27, 2009

    With an agreeable nod to Revere’s opinion that it doesn’t matter very much what we call this novelly swinish H1N1, I think it’s interesting to contemplate Henry Niman and speculate as to why he seems somewhat energized by such a seemingly negligible matter. By his own account, at least, Henry Niman is widely thought to be heterodox within his scholarly subspecialty. If that’s true, he’s probably spent much of his life cultivating a habit of monitoring himself and his surroundings for signs of pressure to conform to others’ thinking or to be quiet about his own opinions. A dispute about mere names resembles a dispute about what opinions may be spoken publicly, and a dispute about what may be said resembles a dispute about what may be thought. Niman may have become so habitually vigilant and aggressive in his defense of inquiry against conformity, that it’s now sometimes difficult for him to shrug off a relatively unimportant matter. He has the vice of his virtue.

  11. #11 SusanC
    June 27, 2009

    bostonERDoc,

    Thanks for your post. That kind of rapid deterioration is scary.

    In MA we are seeing an 8 percent hospitalization rate–far above the worst case scenario planning of 1-2 %.

    Can you elaborate on this please? As in, 8% of what and how is it arrived at? Just curious and trying to understand. Thanks again!

  12. #12 passerby
    June 27, 2009

    I heard that the estimated number of people who have caught the novel H1N1 flu is already up to 1 million, and half of them are from NYC. Is it reliable? It’s already 1 in 300 people who have caught it within 2 months of circulation.

  13. #13 MoM
    June 27, 2009

    “We are seeing a big increase compared to the same stage of the flu season last year, and the increase is predominantly in 5- to 16-year-olds,” Kerry Chant

    One of the things I thought I heard at Buffalo a couple of weeks ago was that H1N1′s in general preferred younger people, and that in this regard, the current “novel” strain wasn’t so novel after all.

    I ask if anyone else has seen/heard similar statements, or if it was simply the result of too many chicken wings.

    MoM

  14. #14 revere
    June 27, 2009

    passerby: CDC’s Anne Schuchat mentioned the 1 million estimate at the press briefing on Friday. It is based on some CDC modeling, details not given, and considered a likely underestimate. It is only for symptomatic cases. The estimate for NYC was 500,000 and makes up a lot of the total. That’s all I know.

    MoM: While the age distribution of H1N1 skews slightly younger than H3N2, not like this virus. Moreover its novelty refers to its immune appearance, not its behavior, although they are related.

  15. #15 Jean
    June 27, 2009

    raven, we may have more knowledge, but not necessarily enough equipment. In Winnipeg, near where I live, H1N1 patients in ICU have needed to stay on ventilators for a long time–earlier, a doctor was quoted as saying he’s never seen this kind of lung damage and only hopes it’s possible to support patients until their lungs repair. Today’s paper referred to a teenage boy who has been on the ventilator for so long his muscles are wasting. That suggests if more people are sicker during the next flu season many won’t be able to get the care they need.

  16. #16 passerby
    June 27, 2009

    But if that’s already 1 in 300, many of them must have very mild symptoms. Then, how do we know the weak symtoms are necessarily related to the novel flu but not cold or something else?

  17. #17 revere
    June 27, 2009

    passer: It’s an extrapolation using some known data. Just like a political poll.

  18. #18 raven
    June 27, 2009

    we may have more knowledge, but not necessarily enough equipment. In Winnipeg, near where I live, H1N1 patients in ICU have needed to stay on ventilators for a long time-

    Ouch. Well, if we get an effective vaccine in time, that may help a lot.

    What is really alarming is if it gets into the third world, where most people live. How much equipment per capita does Africa, China, or India have compared to North America?

    General nutrtition and condition can make a big difference in outcomes. Measles kills 3 out of 1000 in the first world. In some third world epidemics, mortality was as high as 28%, two orders of magnitude difference.

    I usually skip flu shots. Not going to skip swine flu shots.

  19. #19 anon
    June 28, 2009

    so, do you think there would be more oldflu now in Australia without newflu ?
    How would oldflu know that there is newflu ? Could only happen when already
    lots of people are infected and newflu had peaked already. When newflu doesn’t
    weaken other newflu yet, then it doesn’t weaken oldflu.

    > Flu never does what we expect it to,

    that would make it soo predictable

  20. #20 SusanC
    June 28, 2009

    raven,

    Most people will not get the vaccine ‘in time’ to make a difference in their outcome.

    HHS has placed an order for bulk antigens enough for 40 million doses of H1N1 vaccine. Production of this vaccine will start once the manufacturers have finished with their current seasonal vaccine production, which is expected to be middle of July. After that, it takes at least 4 months before the first lots of vaccines are available. Take a look at this timeline for vaccine production

    The first doses will be given to those in tier 1 based on the draft guidance on vaccine prioritization (scroll down to see chart). 40 million doses will cover tier 1 and tier 2, but remember these will come out in lots, ie not all 40 million will be available at the same time. If you are a non-elderly adult with no pre-existing conditions, and you don’t work in ‘critical’ occupations, you have about 200 million people ahead of you in the queue.

    Now, they are also stockpiling adjuvants, which theoretically may stretch the vaccine doses so that you can vaccinate more people with the same stockpile, but there are serious concerns about the safety of adjuvants .

    All of the above is also limited by the vaccination capability of local public health.

    In other words, don’t hold your breath.

  21. #21 Tom DVM
    June 28, 2009

    Maybe we could combine an ‘appropriate’ study to determine the true efficacy of influenza vaccines.

    If the high risk group is being vaccinated…that would be a good place to start.

  22. #22 raven
    June 28, 2009

    Production of this vaccine will start once the manufacturers have finished with their current seasonal vaccine production, which is expected to be middle of July.

    Are you sure about that timeline? According to a recent article, they are expecting the first batches in September. There is more capacity now and a newer, faster method of making vaccine, cell based rather than eggs.

    If the peak flu season is November to February, they might have time.

    We will just have to wait and see. Better than nothing.

    AP story about 1 million US cases, June 25, 2009

    The average age of swine flu patients is 12, the average age for hospitalized patients is 20, and for people who died, it was 37. It seems to be deadliest to people 65 and older, with deaths in more than 2 percent of elderly people infected, Finelli said.

    Also at the meeting, CDC officials made projections about flu vaccines expected to be available to protect against both seasonal and swine flu this fall.

    More than 25 million doses of seasonal flu vaccine should be available by early September, CDC officials and vaccine manufacturers said.

    The same five manufacturers that make the seasonal vaccine are producing swine flu vaccine as well. As many as 60 million doses of vaccine to protect against the new virus could be ready by September, said Robin Robinson, an official with the federal agency that oversees vaccine manufacture and distribution. That prediction seemed a bit optimistic, others at the meeting said.

    The vaccinations might be given as two shots, spaced 21 days apart. But the vaccine has to be tested before it’s made available to the public.

  23. #23 SusanC
    June 28, 2009

    raven,

    Are you sure about that timeline? According to a recent article, they are expecting the first batches in September.

    Well, the best thing to do is to look at their own data. Here’s a slide showing the timeline presented at the May 22 teleconference of the National Biodefense Science Board, also presented by Robin Robinson.

    Also, notice that ‘could be ready’ is not the same as ‘expected to be ready’. Note also that others in that AP story thought that the 60 million doses prediction to be ‘a bit optimistic’.

    There is more capacity now and a newer, faster method of making vaccine, cell based rather than eggs.

    A recent Congressional Budget Office report states that only 50 million of the 120 million seasonal flu vaccine doses were produced domestically, for the flu season 2006-07. But that’s a trivalent vaccine, ie it contains 3 strains with 15ug each.

    With the new H1N1 vaccine, how many doses will be available depends on your assumptions. If we assume that 15ug per dose produces sufficient immune response, then the annual capacity becomes 150 million doses. If 2 doses per person are required, at 15ug per dose, you’d have 75 million people vaccinated, with the full annual production capacity, ie assuming they won’t make any other seasonal vaccine after the current batches are out.

    However, there’s no guarantee that 15ug per dose would be enough. It may, it may not. The H5N1 vaccine is notoriously non-immunogenic, and 90ug per dose is needed for immune response. So, we won’t know till the vaccine is made and tested.

    All that, is egg-based and without adjuvants. And, as I said, based on the full production capacity for the duration as outlined on the timeline.

    The cell-based vaccines are, as you can see from the CBO report, mostly still in Phase I to II development. The furthest advanced is Novartis, which says it expects to do clinical trials in July and file for licensure in the fall. However, note that their cell-based production plant in the US is not yet up and running. From their press release:

    The Novartis state of the art cell-culture vaccine production facility is located in Marburg, Germany. As well as speed, another advantage of cell-based production is the ability to rapidly increase production, so the facility has the potential to produce millions of doses of vaccine each week. A second facility, in collaboration with the US Department of Health and Human Services, is under construction in Holly Springs, North Carolina[1].

    The US government has worked under the assumption that in a pandemic, any vaccines produced overseas are unlikely to be available as countries fulfill their own needs first. Whether or not you agree with this philosophy, the US has not placed orders with companies abroad.

    There is a third option (beyond egg and cell-based), and that is a recombinant vaccine, by a small company called Protein Sciences. I wrote about it here and here. Because this technology requires a much shorter timescale, they have already started production. However, they can make only 100,000 doses per week, which is quite respectable but obviously not enough.

    The most interesting (and IMO the most promising) part of this recombinant vaccine is that it can be produced in existing pharmaceutical plants that use bioreactors. As you mentioned, if we think we are in bad shape, think about all the developing countries. Well, efforts are under way to license this technology to developing countries, so that they can rapidly make their own vaccines. More details on Flu Wiki. Of course, the licensing can also happen domestically, which would greatly expand capacity very quickly, but I’m not sure that process has started.

  24. #24 Dr Attila Danko
    June 29, 2009

    In regards to the sentinel influenza surveillance data from Victoria here in Australia: Sentinel GP’s (about 89 participating practices statewide) swab everyone with an “influenza like illness” These are then tested for the most common respiratory viruses. They then compile tables of the data including for other respiratory viruses and update them weekly. Here’s the latest:
    http://www.vidrl.org.au/surveillance/flu%20reports/flurpt09/html_files/flu0908.htm

    Unfortunately they take about a week at present to get the data out. I’m thinking of becoming a sentinel myself.

  25. #25 g336
    July 2, 2009

    Questions about the prioritization of vaccine:

    I’m a PBX engineer (design & implementation of office telephone systems and telecommuter/telework systems). That would seem to put me in Critical Infrastructure: Telephony, which is pretty high up the list to get vaccinated.

    On the other hand I practice what I preach and telecommute most days, so I’m not as exposed to crowds etc. as most people. And I’ve been ferocious about basic preps such as using hand sanitizer, washing hands generally, avoiding crowds, etc. etc.

    Should I seek to get priority access to vaccine on the basis of the critical nature of my work? Or should I defer access on the basis that I telecommute and so am at lower risk than those who have to be exposed to crowds?

  26. #26 revere
    July 2, 2009

    g336: Of course there is no fixed answer to your question. The need for vaccine is both risk based and function based. If you get sick, how important is that to the system seems to be the question. I don’t think any of us can be unlinked to the virus.