Effect Measure

It’s not Labor Day yet, but I guess the Reveres have to consider their vacation over. We’re all back at our respective home stations. We admit that not watching flu evolve daily was a relief, although we did sneak peeks when we weren’t supposed to. But it also proved to be like the stock market. The daily ups and downs sometimes obscure the bigger picture. So what does it look like now?

We have two contradictory impressions. One is that the pandemic has continued to develop in a very robust fashion. So it’s a dynamic picture of change. The second is that it looks like a normal pandemic, just going about its business. We have been very struck by how , in general, we are accustomed to the experience of constant change, not just for influenza but for modern life in general and we are gestating a post on influenza as the disease of modernism par excellance. That’s another of the benefits of stepping away from the daily view. It allows for some reflection. But that’s for another day (soon, we hope). When it comes to the current status, WHO issued quite a nice one the day we were starting to pack up (August 28). Crof noted it at the H5N1 blog and Mike Coston over at Avian Flu Diary seems to have pretty much reproduced the whole thing. Both Crof’s blog and Avian Flu Diary are superior single voice flu sites and there are other group efforts and forums like Flu Wiki.do with a ton of information, more than you will ever get here. For more basic science of flu and other viruses, you can’t do better than Vincent Rancaniello and Dick Despommier’s Virology Blog. But we still want to say some more about the WHO analysis, “Preparing for the second wave: lessons from current outbreaks.”

The first thing we want to say about it is we think it’s pretty good. We have a lot of readers who really have it in for WHO and I doubt they’d approve of anything it does. But as an epidemiologist who follows flu closely, I think this is an admirable, measured and wise assessment based on experience of its member nations around the world, north and south. What does it say?

1. WHO is advising northern hemisphere countries to prepare for a second wave of pandemic spread. That’s good advice but neither WHO nor anyone else can say with certainty what’s going to happen. This is a recommendation, not a prediction, and while I have said I think the fall will see an early and bad swine flu season up north, I could well be wrong about that. But getting ready for it seems to be the only sensible thing to do. As we have commented and a recent story by Helen Branswell of Canadian Press emphasizes, a bad flu season will make itself felt in specific vulnerabilities, of which critical care facilities is one of the most obvious (along with demand for emergency room and walk-in care). WHO reports that among the fatal and severe cases is a severe form of respiratory failure (likely a primary viral pneumonia) not usually seen in seasonal flu deaths (which are mainly among the elderly). This has stressed critical care facilities and this needs attention for the upcoming flu season in the north.

But they also point out that in tropical countries the timing may be different or anomalous. Our gloss on this is two fold. It shows we still don’t understand the influence of environment very well (“seasonality” is one way to express this); the other is flu is notoriously patchy and inhomogeneous in its spatial and temporal distribution. There are lots of ways flu is unpredictable and that’s one of them.

2. The current pandemic strain is not changing much and it is tending to crowd out the seasonal strains. In our view the relative stability of the virus may be related to the fact that it is quite transmissible. The ability to make new copies is the trait that is being selected for. That’s a combination of the ability to infect a host cell (infectivity) and once that has been accomplished and lots of copies of itself made, the ability to find a new host cell to do it all over again. If changing its virulence (the ability to cause severe disease) affects transmissibility, then we might expect to see an increase in virulence. But by the looks of it, this virus has found a nice recipe and it’s sticking to it, more or less. That’s the picture at the moment. We’ll have to be watchful because flu virus never seems to do what you expect it to. For example, we’ve all been waiting for the Tamiflu resistance shoe to drop. But so far it hasn’t. It would be very surprising if this virus, like its H1N1 seasonal counterpart didn’t become completely resistant to Tamiflu. But “very surprising” seems to be what to expect.

The question of crowding out seasonal virus is interesting, and as far as I know, the mechanism isn’t completely understood. It certainly implies that co-infection is not an independent event (if it were, then we wouldn’t expect to see this kind of competitive exclusion, or so it seems to us; we’re open to alternate arguments). Until 1977 we essentially only had one subtype circulating at a time, each pandemic replacing the subtype of the previous one. Then in 1977 H1N1 and H3N2 started circulating simultaneously. We plan to discuss this, too, at a later time. In the meantime, there is a good chance next flu season will be a swine H1N1 season, not a “seasonal” H1N1 or H3N2 season. We’ll see, but that’s what WHO is reporting it is seeing in the southern hemisphere which is now well into its usual flu season.

3. In the north, particularly, there is a large reservoir of susceptibles to this novel flu virus. The under 60 crowd seems to be largely naive to the virus. The large pool of residual susceptibles is one of the main reasons we predict a bad flu season. The reason for the comparative sparing of the oldest age group is a puzzle and underscores another of WHO’s points. This isn’t seasonal flu.

4. The difference between seasonal flu and swine flu is primarily one of epidemiology, that is, the pattern and distribution of the disease in the population. Younger age groups are affected (and older ones not affected), and the increased infections in the young are producing increased severe and fatal infections. By most accounts we’ve seen, the virus doesn’t seem more virulent than seasonal flu virus. Seasonal flu always kills a certain proportion of its victims, usually in the oldest age groups. But it also does it in the younger age groups, and with so many more susceptibles in this age category we are seeing many more severe and fatal cases in previously young, health adults, adolescents and children. Usually that number is relatively small, so if you greatly increase the number of cases, the extra number and nature of fatal or severe outcomes in healthy young people has quite a psychological impact. We don’t yet have a good understanding of how or why the distribution of cases has shifted to the young in pandemics, but it could also be asked differently. Why are we not seeing a huge increase in death among the elderly? The age distribution of mortality of flu during pandemics is poorly understood. One of the most prominent features of the 1918 pandemic was its “W-shape.” In seasonal flu it is “U-shaped”, high among infants and high among the elderly but low between them. In 1918 there was a huge hump in the middle, the young adults. There have been many attempted explanations for this, but none that are conclusive or even convincing. In swine flu, the impact is in the under 50 age group with little above it, yet another pattern.

5. The attention being paid to swine flu has revealed that pregnancy is a special risk factor. This has been known but the larger number of young people being infected by this virus makes it a special problem. All societies place a special premium on the next generation and fear for the safety of babies is almost universal. It’s probably hard wired into our brains. If we didn’t have it we wouldn’t have survived as a species. But it makes the added risk in pregnant women take on added public policy significance. It also seems true that children and adolescence with well controlled underlying medical conditions like diabetes and asthma are also at risk. And a new finding, people with Body Mass Index (BMI) over 40 are also at special risk. Add to this certain populations, like indigenous peoples in various parts of the world, and we have a lot of people who may be very vulnerable to this highly transmissible virus.

6. One of the strange (and happy) early impressions, however, is that HIV positive people do not seem to be at special risk as long as they are receiving antiretroviral therapy. These people seem to have roughly the same spectrum of clinical outcomes as the non-HIV infected population. Since we are talking about 33 million people in this category, that’s good news. The bad news is that only about 15% are receiving life saving antiretrovirals.

That’s our quick once over of where we think we are as we resume active flu blogging. Not everyone will agree with our (or WHO’s) assessment. There’s lots of room for disagreement, in the large or in the small. Probably the best comment about what the fall flu season will bring came from Helen Branswell, she she said somewhere she expected it to be “complex.” Can’t argue with that.

Comments

  1. #1 Liz
    September 1, 2009

    Welcome back from vacation! I hope everyone enjoyed the well-deserved break.

  2. #2 JBH
    September 1, 2009

    Nice overview. With regard to #2, the ferret study getting press today (http://www.nih.gov/news/health/aug2009/niaid-31.htm) is evidence that H1N1 is crowding out the seasonal flu. That study reports H1N1 was transmitted much easier than seasonal flu. So it seems this virus is efficient at transmission so hopefully that strength will keep it from needing to gain virulence.

    I don’t understand why a virus would want to evolve toward greater virulence anyway, transmission efficiency would seem to me to the greatest viral strength from an evolutionary perspective.

    Also, it seems that American schools, particularly in the south, are starting to see an explosion of swine flu (according to the press reports collated at Flu Wiki). At this rate, I get the sense the United States will be at the peak of the swine flu outbreak in mid-October. Given this is so early in the normal flu season, I wonder if communities who experience such an early peak could also experience another peak later in the normal flu season (like in January/February)? Or does a communities fuel for flu get extinguished with a single peak?

    And Salt Lake City was hit particularly hard in the Spring, I wonder if they will fare better this time around.

  3. #3 revere
    September 1, 2009

    JBH: Thanks for the cite. It suggests that co-infection may be independent (or at least it happens with reasonable frequency) but transmission of virus from co-infected host cells is not. Thus there is a kind of complementarity principle here: you can get infected with one or the other or both, but you will only pass on H1N1 virus when co-infected. I don’t know if the same thing has been found for seasonal H1N1 and H3N2, although I suspect it must be to a lesser extent because they do co-circulate. These data are still preliminary and they are in ferrets, which, while a better model for human flu than mice are still not exact representations. But it is one of the viable explanations for subtype replacement that we mentioned in an earlier post on the subject.

  4. #5 Peter Perin
    September 1, 2009

    My internist announced vaccination avbailability as of September 7. Yet I’m aware of Dr Gupta’s report on CNN that the analysis of safety data, including incidence of adverse neurological events, will not be ready until mid-October. I am a long-term cancer survivor with mild respiratory impairmant. I am able to keep out crowded urban environments such as mass transit venues. My inclination is to wait for the safety data before getting vaccinated. Any comments, corrections, and/or advice will be appreciated.

  5. #6 Mathematician
    September 1, 2009

    PP: this will be seasonal flu vaccination that you’re being offered from Sept 7th I think, not pandemic vaccination. (Unless you’re in China, perhaps!)

  6. #7 BostonERDoc
    September 1, 2009

    Nice post. I would further add that data presented by Sonja Olsen at a recent IOM workshop (you can go to the web site and view the powerpoint slides and listen to the audio) showed some interesting trends in the southern hemisphere and just might give us a peek of what to expect here once the weather gets cold:
    1. new H1N1 impressively bullied out most other influenza strains–and very quickly.
    2. Most of the southern hemisphere countries experienced a “quick peak” meaning most got to the peak of the epidemic curve within a 12-20 days.
    3. Death:Hospitalization rates: In the US there appears to be 1 death for every 15 hospitalization– a similar experience in Canada and UK. However, Australia is experiencing a 1:5 ratio. I would argue that hospital care is just as good “Down Under” as it is in say Boston so is this higher death ratio in Australia a reflection of winter conditions since the virus has not changed to any appreciable extent? If so this might reflect what we are going to see when it gets colder.
    4. Critical care (ICU admissions) represent ~20% of all hospitalizations in the southern hemisphere. This also is somewhat worrisome.

  7. #8 b
    September 1, 2009

    i heard the cdc no longer thinks high bmi is a risk factor

  8. #9 Taniwha
    September 1, 2009

    As an ex-immunologist (left active research a couple of decades ago) I am fascinated by the evident difference in the target populations of H1N1 and H3N2 and the hint that H1N1 infections may tend to produce longer lasting immunity.

    I also note an interesting difference in mortality reports between the UK with 13K confirmed cases and 65 deaths versus Germany with 16K Cases and no deaths. Is this an artifact or does it indicate a problem with UK health care ?? Or may it have something to do with the ethnic diversity in the UK vs Germany (which seems to be a factor in comparing NZ and Australia)

  9. #10 M. Randolph Kruger
    September 1, 2009

    Taniwha-To answer your question it was a question that came up a week or so ago in a briefing… Its because they quit counting. They are still having deaths but mostly they are calling them the secondary cause of death. E.g. if you get pneumonia from Swine Flu and die, you call it death due to respiratory failure unless an organ failed and then you call it that.

    I dont know how long you have been reading here but just a few months ago there was a back and forth discussion about H5N1 and the counting of the cases. Its expensive to test and we postured most of us that if they didnt count (Supari) and called it something else then the deaths were due to something else and not swine flu. My assertion was that we would only have a few thousand H5N1 cases and everyone else would be suspected. HTF can anyone can square this up is impossible because OF the toe tags. You are worried about taking the vax and reactions. Well, you should be. We are going to be forced to take a very untested vaccine and to Hell with what anyone thinks. Mass is rushing a forced vaccination law through their legislature without any regards for the state constitution and the US Constitution. Is it right? I doubt it. Is it legal? Yes, unless challenged.

    Even the US government was stopped from issuing further anthrax vax as the court saw it as an illegal and uninformed consent issue. Not whether it made you sick or not.

    Peter-Here is a conundrum for you. They quit counting so now Peter Piper that picked a peck is going to hear that its only bad in the cucumber industry. But that same group is telling you to prepare for the worst based upon WHAT? The WHAT being toe tags. If we are to only go by the toe for analysis then we are going to be six kinds of screwed by the process. WHAT later on we will say it was bad and so and so died and so and so got sick and so and so never returned to work. But we will never know what the numbers are/were for future pandemics.

    Peter-Check with your doc about vaccinia. It might get you what you want which is protected, and not have to worry about these other issues.

    Another thing…. All of this political correctness has required us all to call this stuff H1N1 because it fucks up someones Chi in the pork industry. So now, its not even swine flu. Its like a numbered hurricane in the Pacific. You there…Get up off the ground. You arent dead of Swine Flu because there isnt any.

    Yep, I feel all better that this Administration has this in hand.

  10. #11 mz
    September 1, 2009

    Taniwa – it is largely an artefact as the UK (with one of the most intense outbreaks in the Northern Hemisphere) stopped counting in late June and Germany (with little in the way of community outbreaks) is still trying to count everything, though by now this makes little sense. It might be realistic to say that there have been several 100k cases in the UK, and only some 10k in Germany. The remaining difference may just be due to the statistics of small numbers on the German side of the equation.

  11. #12 Vincent Racaniello
    September 1, 2009

    Might I also add that there is clear basic science about influenza and other viruses at virology blog: virology.ws.

  12. #13 revere
    September 1, 2009

    Vincent: My apologies. Your site is a major source of important scientific information about flu that I have personally benefited from. One of the problems with listing any other sites is that you inevitably do an injustice. I am amending the post to correct this oversight, but as i do so I apologize in advance to the many other sites that do such a great job in many different ways. The fact that what you do is so valuable to my own interests and those who read here prompts this, however. As I’ve said over at your place, you’ve got a great blog. And if I remember correctly, you also spent time in Peter Palese’s lab. Peter is not only one of the great deans of flu science, but a true gentleman.

  13. #14 Marissa
    September 1, 2009

    Revere,

    hope the vac was good.

    Getting reports on Promed that a few people in Saudia Arabia are showing up testing positive for both H1N1 and H5N1. Have you heard anything more?

  14. #15 RobT
    September 2, 2009

    http://www.bmj.com/cgi/content/full/339/aug18_1/b3317?ck=nck

    Here is the url to the BMJ article discussing the lessons to take away from our experience with swine flu in Oz. Not mentioned is the surprising stat that 25% of hospital admissions went to ICU and needed lung bypass treatment so lung damage could have time to heal. They expected and planned for 10%. This exhausted the resouces of respiratory ICU units, but saved lives.

  15. #16 anon
    September 2, 2009

    how does a virus “crowd out” another one ?
    It infects first and induces host-immunity
    that hinders the other one to find hosts
    for replicating.
    (what else ?)

  16. #17 melbren
    September 2, 2009

    Oops. I meant to send that to your ferret post, Revere, should I re-post?

  17. #18 Cheetos
    September 2, 2009

    I worry that the swine flu vaccine is coming too late for a large number of us who want it. The latest word I see coming from CDC is that two doses will be necessary…given 3-4 weeks apart. If that’s the case, full protection for a lot of us won’t be achieved until December at the earliest.

  18. #19 Into the Woods
    September 2, 2009

    Links to presentation referred to by BostonERDoc above:

    Current Clinical an Epidemiological Picture of Novel
    Influenza A (H1N1) in the Southern Hemisphere

    Sonja J. Olsen, PhD
    August 12, 2009

    http://www.iom.edu/Object.File/Master/72/343/Olsen%20-%20Panel%201.pdf

    This presentation was part of an IOM workshop:

    Workshop on Personal Protective Equipment for Healthcare Workers in the Workplace Against Novel H1N1 Influenza A

    INSTITUTE OF MEDICINE Board on Health Sciences Policy

    Respiratory Protection for Healthcare Workers in the Workplace Against Novel H1N1 Influenza A

    August 11-13, 2009

    Agenda, followed by Links and Resources (selected audio and presentations).
    http://www.iom.edu/CMS/3740/71769/71867.aspx

  19. #20 Dee Alpert
    September 3, 2009

    Help! From what I’ve seen so far, school-age children with disabilities appear to be the highest risk group for potential serious effects from swine flu. Yet the American public school industry, starting with US Dept. of Education, appears unwilling or unable to get the word out and recommend or require that very serious protective measures be put into place to protect this super-vulnerable, but discrete, population.

    Many schools just for kids with severe disabilities lack staff nurses. Many lack professionally-developed cleaning and sanitization protocols. Unfortunately, many schools, both segregated special ed. schools and regular general ed. schools, have been heavily using seclusion rooms in which to lock kids with disabilities who exhibit unwanted behaviors. Without free access to toilets, these rooms are uniformly reported as “smelling urine soaked.” The other bodily fluids shed while kids are secluded in these rooms are equally dangerous from a contagious disease viewpoint.

    For all of this obvious danger, virtually nothing to protect such children while in school is being done, and virtually nothing being recommended.

    The NYC Health Dept., in a NYC govt. swine flu presentation earlier this week, noted that it would pay special attention to absences at NYC DOE special ed. schools and made plentiful references to work to be done by the “school nurse.” Yet many of these schools have no school nurse. Many kids enrolled in these “schools” actually are in segregated special ed. classes sited in regular schools, again with no nurses on staff.

    Recent research showed that the prevalence of asthma in the NYC DOE’s population of students classified as having any disability (mostly speech impairments or mild learning disabilities) was 4 times the rate of asthma in the NYC DOE’s student population overall. So why aren’t stringent measures – public health- and medically-based – being taken to protect all these kids, no matter what school buildings they attend?

    This may well wind up being the dirty little secret of the coming swine flu season. The most vulnerable children, placed in situations where contagion is extremely likely, are put at risk, while their real needs for public health and medical protection and attention are ignored because … the education industry doesn’t like being forced to “do” medical. And caste-wise, children with disabilities are typically at the bottom of the education industry heap.

    Aside from me yelling “The sky is falling, the sky is falling …,” I don’t know what can be done to bring this frightening situation rudely and effectively to the attenion to those in Washington who have some real authority to do something about it – and make sure that something effective actually gets done.

    M’aidez. Or “aidez les enfants, s’il vous plait.” Stat.

  20. #21 revere
    September 3, 2009

    Dee: I think CDC has made recommendations but the resources are local. Tax cutting and general disregard for the most vulnerable have combined to place them at special risk, as you note so eloquently. The sky is falling for them.

  21. #22 Stephen
    September 7, 2009

    @BostonERDoc (comment 7).

    According to NSW Health (which is obviously not all of Australia, but it is about 30% of the population), there have been to date:

    1203 admissions to hospital with H1N1 influenza 09.
    189 admissions to an ICU with H1N1, and
    46 deaths with H1N1.

    This is far from 5:1 admissions:death – it’s about that in ICU admissions, but not hospital admissions. In fact, it’s about 26:1.

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