Effect Measure

There have been questions in the comments about where the CDC estimate of 36,000 to 40,000 influenza related deaths a year comes from. It’s a figure I’ve used a number of times here to say generally that regular old seasonal influenza may be a mild disease for some but not for many others. Even if you don’t die of flu, it can be a miserable illness and lay you low for several weeks of acute illness and months of fatigue and malaise. Now the 36,000 deaths number is taking on a life of its own, so it’s time to explain exactly what it is and what it isn’t. There are more things it isn’t that it is.

First, of all, it isn’t a count of deaths each year from flu. We don’t know how many people die of seasonal influenza each year because there is no list we can use to count them. Why not just use the death certificate information? You can see what a death certificate looks like here. The Cause of Death section has two parts. Part I. asks for the immediate cause of death (first line) and any underlying conditions that brought it about (up to four subsequent lines). The underlying causes are the “due to” components. Suppose someone dies of gram negative sepsis, a total systemic failure usually caused by a bacterial infection. The lines below the immediate cause are supposed to be the links in the causal chain leading to the sepsis. Bacterial pneumonia would be a typical cause of sepsis, so we have an immediate cause of death of gram negative sepsis due to bacterial pneumonia. Secondary infection by bacteria is a common complication of a respiratory viral infection, so the next line might be viral pneumonia or, if known, influenza infection. Unfortunately, the cause of most deaths that may be related to influenza is not verified by any virological testing for infection by the virus. Many things besides influenza virus cause pneumonia. Most often there is no evidence of what virus or other agent was the cause of death, especially for viral pneumonias. If it’s during a flu outbreak, influenza may be listed as a probable underlying cause without any lab evidence. If influenza occurs at some other time it will likely not be listed anywhere.

There is also a second part of the Cause of Death to list any conditions that might have contributed to the immediate cause of death. Influenza could also go here, if in the judgment of the person who is filling it out influenza played some role. Suppose someone dies weeks or months after an influenza infection, say, from cardiac disease. Did flu cause or hasten their deaths? It’s not implausible, but the main question is untestable: would they have died at the same time if they had not had an influenza infection? So if there are any deaths of this type, it is quite likely they aren’t counted if mention on the death certificate is required.

So using the death certificate, then, you can get everything signed off as pneumonia, which would likely include influenza deaths where the actual agent wasn’t known, or those things where influenza was mentioned as the immediate, underlying or contributing cause of death. This would allow a week by week tally of all deaths in the US from pneumonia and influenza (P&I), which would include both influenza and non-influenza deaths, but also omit many deaths where influenza played part in the sense that the person wouldn’t have died if they hadn’t gotten the flu. In order to capture them you could use a wider cause of death category, say all respiratory and circulatory deaths, or even deaths from all causes. But obviously most deaths from any of these categories, including P&I, are not all influenza deaths. We are quite sure that if we only count death certificates where influenza is mentioned somewhere we will grossly underestimate the mortality from influenza. So what do we do?

There is no question that people die of flu during flu outbreaks. It is also true that mortality from all causes waxes and wanes throughout the year in a more or less regular wave-like pattern, worse in the winter than the summer. During a moderate or bad flu season, however, the regular wave will have a spike in it corresponding to a flu outbreak. Those are excess deaths that are occurring during a heavy flu season that don’t occur at other times of the year. One of the earliest approaches to estimating the mortality from flu, Serfling’s method, was to estimate what would be expected during the winter if the regular wave-like background were the only deaths and subtract that off from what is seen in a bad flu season (I am leaving out some technical details). In other words, the spike is excess mortality during a flu outbreak. We use this because when there is a recognized (by laboratory means) flu outbreak, the excess deaths during that period have a much higher probability of being the flu deaths.

This means that in a mild flu season, with no visible spike, the excess mortality would be zero by this method, even though we are pretty sure some people are dying of flu during flu season and perhaps outside of flu season as well. So we are underestimating the effect of flu. But since we don’t have any virological confirmation, maybe some of these spikes are due to other viruses. So that would over estimate the flu burden. There are also differences depending upon whether you use only underlying cause or both underlying and contributing cause and whether the measure is P&I, the broader respiratory and circulatory, or all causes. If we want to estimate the total burden of flu mortality we will use the all cause category, but that is the most imprecise and yields estimates with the most uncertainty.

There have been modifications and elaborations of Serflings method and in recent years some additional methods that make use of information about the prevalence of influenza positive cases of influenza-like illnesses provided on a weekly basis by the CDC influenza surveillance system. The new standard is due to Thompson et al. and was used by Jon Dushoff, Lone Simonsen and colleagues may be highly relevant to the current H1N1/2009 outbreak. In a paper in 2006 in the American Journal of Epidemiology they used regression analyses and subtype specific prevalence data to again make estimates of the excess mortality contributed by influenza. The results wereconsistent with the classical Serfling method, arrived at by a different means, an average excess mortality from flu in the years 1979 to 2001 of roughly 41,000. This number is not so informative, however, when we realize that the distribution of excess deaths year by year is probably multimodal, i.e., not some smooth and symmetrical bell-shaped curve with the average in the middle, but a jagged picture with several different peaks and valleys. That means that some years are far below 41,000 and others much above it, for all deaths from all causes related to influenza.

Table 2 in the Dushoff paper (p. 185) shows a very interesting tally of all estimated deaths for the two seasonal flu subtypes (H1N1, H3N2) and influenza B. Of the 41,000 deaths, H3N2 is the nastiest, contributing (annual average over the 23 years) 29,000 of the estimated 41,000 deaths. Influenza B comes next: 8500. Bringing up the rear is the seasonal flu subtype H1N1: just under 4000. This means that the seasonal flu subtype H1N1 is by far the least virulent, less than a seventh of the estimated mortality burden of the other seasonal flu subtype, H3N2, by this method. What there is about the seasonal H1N1 that makes it less virulent (or conversely, what there is about H3N2 that makes it nasty) we don’t know, but it appears that the current swine-origin H1N1 is more like its seasonal cousin. On the other hand, the 1918 virus was also H1N1.

Is there a take home lesson here? Flu viruses, even of the same subtype, can act very differently and we don’t know why. Could H1N1 change and become nasty like H3N2 or even the 1918 H1N1? No one knows. Could it reassort and pick up something from H3N2 or even H5N1 and become really nasty? No one knows. Seeing how quickly this one is spreading underlines the importance of investing in the science, so maybe we can know better when to worry and when not to worry. For the coming months, while we wait to see if the other shoe drops, investing in public health and social support systems would help us weather an assault from this bug or any other one that comes along.

Like the smartest of the Three Little Pigs we need a house built of bricks, not straw.

Comments

  1. #1 A Passerby
    May 4, 2009

    If the 2009 H1N1 influenza is as mild as seasonal flu, why we have to take special measure to this flu but not the seasonal one?

  2. #2 revere
    May 4, 2009

    Passer by: Because there is no natural immunity to this one so it can infect many more people in a shorter period of time and overwhelm health services and absenteeism could create a serious problem.

  3. #3 A Passerby
    May 4, 2009

    Should we also distinguish how many of the lives are taken from those who are originally healthy, productive, and from those who are already suffered from serious illness and won’t live much longer without the flu, and anything in between?

  4. #4 chris
    May 4, 2009

    There seems to have been an easing of the media concern/coverage (in the UK at least) over the past 3-4 days… and the Mexican’s believe that the worst is over and are starting to re-open restuarants and cafes.

    http://news.bbc.co.uk/1/hi/world/americas/8032582.stm

    But the number of cases is still rising … 9 new ones here today – including 7 related to the same school…so the question is whether the current easing of the media message is actually justified by the statistics ?

  5. #5 Norma Cooper
    May 4, 2009

    What symtoms does the swine flu have? I have heard fever, aches, sore throat, what about the stomach side, chills, dizzyness ect, what are the symptoms exactly, as I have searched for the symtoms and can’t seem to find them.

  6. #6 phytosleuth
    May 4, 2009

    Chris, one of the problems is that the numbers are old. The backlog of samples being tested, you see. The rise in numbers was expected (by epidemiologists anyway, and by WHO, CDC).

    I think it’s going to take a week and an update on how fast the samples are being tested and then announced to see whether the cases in general are slowing or increasing.

    Remember too, that we now have clusters around the world. Maybe some of these cluster will expand. Decisions made locally are very important.

    Back in 1918 pandemic cities that instigated mitigation quickly saw less deaths and less cases. Those that did not close public places, etc. experiences higher death rates and case rates.

  7. #7 phytosleuth
    May 4, 2009

    Norma, Twitter: Diseasegeek said: WHO’s Fukuda – diarrhea reported in about 40-50% of #swineflu cases, higher than seen w/ seasonal flu. But I can’t find original source.

    For symptoms: http://www.cdc.gov/h1n1flu/swineflu_you.htm

  8. #8 Jane
    May 4, 2009

    “Even if you don’t die of flu, it can be a miserable illness and lay you low for several weeks of acute illness and months of fatigue and malaise.”

    SEVERAL (as in 3-4) weeks of acute illness? MONTHS of fatigue and malaise? How common is that severity, really?

    This is an N of 1, but I’ve never had a doctor’s test for flu, preferring to stay home when sick, but certainly have had it a number of times, judging by the fever. It’s never lasted for more than two weeks, usually less, with a few days to a week at most to get back to fully normal. Persistent cough is another thing, but that can happen with colds. The Russian saying is, “Flu, with treatment, lasts a week; without treatment, seven days”.

  9. #9 Eric
    May 4, 2009

    Hi All,

    I wonder if a lot of the confusion about this pandemic stems from the poor way the WHO pandemic alert system represents risk. Risk is usually described by the probability of something bad happening multiplied by the severity of the consequences. It is a way of thinking about and comparing low probability but very bad things with more likely but less damaging events. By weighing different risks, you can hopefully plan to mitigate them more rationally.

    Anyway, the pandemic alert system doesn’t seem to really be an assessment of risk. A pandemic does seem to be unfolding, but it is not likely to be as horrible as a bird flu pandemic. Perhaps the pandemic alert system should be more expressive of this assessment of severity. Astronomers have such an alert system for asteroid collisions, the Torino scale. It is a measure that combines probability with severity.

    Do we need something like this for pandemic flu?

  10. #10 GeorgeT
    May 4, 2009

    Eric is right. The biggest problem with the pandemic alert system as I’ve learned myself over the past 10 days is that pandemic means one thing to the general public and another thing to the experts. To the layman, Phase 6 means Black Death level plague.

    While I disagree with WHO’s handling of a few things, in general they have done a good job, but their Phases have probably hurt more than they have helped. I think the Phases are part of what is starting the (incorrect) backlash.

  11. #11 revere
    May 4, 2009

    Everything is relative. Relative to H5N1’s current virulence, this is a pussy cat. But flu is not a walk in the park, even “mild” flu like H1N1. It can overwhelm health services and cause a lot of absenteeism and occasional serious illness and death. That’s ordinary flu. But because there is no natural immunity in the population, this flu can spread to many more people in a shorter period of time and compound all those problems.

    Whatever WHO does is irrelevant for the US as we are already experiencing an outbreak. The importance of the WHO system is for all the other countries who need a signal that it’s time to get ready. WHO, CDC and the general public are learning as we go along. This event is a moving target and we need to prepare for a variety of scenarios, including the likely one where it comes back next flu season in a more severe form. That means getting ready here, too.

    Put yourself in WHO and CDC’s position. What do you think they should do?

  12. #12 phytosleuth
    May 4, 2009

    I agree. People think WHO phases are meant to warn THEM. What I see happening is a lost connection between the local county health departments (probably under- or overwhelmed already) and the residents of that county.

    This is the message:
    This flu is mild
    Wash your hands
    A vaccine won’t be available for 4-6 months
    Tamiflu is being sent to state health departments
    Don’t use Tamiflu unless you are really sick.
    Tamiflu is free if you get it from a doctor who got it from the federal stockpile; otherwise it’s $20 a day and only reduces symptoms by one day or so.

    Translated: Nothing I can do anyway. Probably just another hyped story. I’ll decide what to do if and when it happens to me. Maybe I’ll wash my hands more often.

  13. #13 merciless
    May 4, 2009

    Jane, I’m sure that your experience is one that’s been shared by many, but my experience differs greatly. All the symptoms listed, and their duration, match almost exactly my last bout of the flu. The only difference is that I also got a secondary infection that had to be treated with antibiotics, and that’s one of the reasons the flu can be deadly to those of us with such suceptibilities.

  14. #14 ML
    May 4, 2009

    Could you comment on the point that people who experience a mild infection during this current pass of the virus will likely have some protection against a more virulent form of the virus that might be circulating by next flu season? Once enough data are accumulated to conclude that the current virus is behaving similarly to the seasonal flu, maybe schools should be open (for example) to give the general population a chance to acquire some immunity?

  15. #15 GeorgeT
    May 4, 2009

    ML: if you go over the comments of the blog entries for the past week, these points have been covered multiple times. The short version:

    Nobody knows
    No, it is a VERY bad idea

  16. #16 sandy
    May 4, 2009

    1. WHO is inviting all nations to ready their pandemic plans. but nearly all those plans assume at least a 1957 level of deaths, ranging up to 1918 levels. that is not what we are seeing so far. so much of those plans may be relevant but much is not.

    2. you ignore the point made by Palese and others that prior H1N1 experience may indeed modify the deadliness of this virus. it is not established that “there is no natural immunity.” the 1976 swine vaccine trials found that anyone exposed to any prior H1 virus needed only one shot instead of two, because it acted as a booster shot to the existing generic H1 immunity.

    3.likely is too strong a term for it coming back next season in stronger form. revere you have often pointed out how unpredictable the virus is. it is plausible that it dies out entirely, or returns as typical seasonal flu, or slightly greater.

    in the US, only 1918 came back much stronger. The H1N1 viruses of 1947,1976, and 1977 did not. nor did 1957 or 1968 pandemic viruses.

  17. #17 geos
    May 4, 2009

    The authorities in Mexico are saying that the epidemic was “in its phase of decline”.

    In Mexico isn’t May a time of low flu anyway?

    Even the 1918-1919 flu was at background levels by May 1919.

  18. #18 revere
    May 4, 2009

    sandy: Peter’s point may be (is probably) correct about 1957 but so far we don’t know that. As far as we know, there is no natural immunity to this virus. And even by this scenario, those born post 1957 have no natural immunity and that’s most people. I’m not sure why your first point is relevant to anything. As for point 3, “likely’ is my judgment. No one knows. I’ll stick by it. When I think there is a reasonable plausibility about something none of us can know for sure, I reserve the right to state it.

  19. #19 Cheetos
    May 4, 2009

    The list of probable cases in WA state continues to grow…up to 35 now, I believe. It’s been a whole week since the first few ‘probable’ cases were detected and still there is no CDC confirmation on any of them. I’d really like to know…what’s taking so long? Doesn’t seem to be taking as long in many other states.

  20. #20 Mo Falk
    May 4, 2009

    One case of a girl hospitalized in Alberta.
    The cases continue to grow rapidly in Canada with the national total at this point being 140
    Here is a link
    http://www.winnipegfreepress.com/breakingnews/Canada-reports-first-severe-case-of-swine-flu-44315232.html

  21. #21 aces
    May 4, 2009

    I thought that seasonal H1N1 reappeared in 1977 after a 20-year absence and has been lingering ever since. Why would everybody born after 1957 have no immunity?

  22. #22 Lisa the GP
    May 4, 2009

    aces,

    The H1N1 has been sort of a minority virus in most flu seasons. I guess the thinking is that not enough of the general population has antibodies to make much difference in denting the potential for lots of people sick at the same time.

    I had a very bad case of flu in my 20’s, followed by a bacterial pneumonia. For weeks it was difficult for me to climb a single flight of stairs, and I had reduced energy levels for 6-8 months afterward.

  23. #23 aces
    May 4, 2009

    Thanks for the explanation, Lisa.

    Sorry to hear of your flu experience. I hope that what you had was H1N1, so you’ll be better prepared this time!

  24. #24 Lisa the GP
    May 4, 2009

    aces, that’s the experience my article ‘home alone’ on fluwiki came from.

  25. #25 karen
    May 4, 2009

    Some states (I know of Minn. & RI so far) now say they will only test hospitalized patients for the swine flu b/c the virus is no more dangerous than the seasonal flu.

  26. #26 stan
    May 5, 2009

    The seasonal flu in the US (H1N1) was resistant to Tamiflu. The Mexican flu virus (H1N1) is proving highly contagious not virulent and susceptible to Tamiflu. Governments around the globe have stockpiled almost exclusively Tamiflu. What happens if (when) the Mexican flu attains the resistance prevalent in the most recent seasonal flu? Why is Relenza not being stockpiled (in serious quantities), if only as a backup?

  27. #27 marsha
    May 5, 2009

    “Seeing how quickly this one is spreading underlines the importance of investing in the science…”

    I’ve been following posts here since the 24th, and, now have a question. This outbreak seems an excellent opportunity for researchers around the globe to study indepth, yet, how can this be done fully when health care providers are opting to test only those patients that appear very ill? The Internet nows allows the quick exchange of information from all available sources. Is this exchange being compromised by lack of testing? Although I’m just a ‘housewife’, it seems to me that in the end, whatever models are gleened will be based on a paucity of valuable information. If I were a researcher, I’d be pulling out my hair right now. Maybe it’s too much trouble to test people, but, if the scientific community winds up basing it’s final reports only on these limited confirmed cases, won’t such reports have limited their value? Maybe I’m naive, but, I can’t help but think the approach is all wrong. Is an opportunity being wasted?

  28. #28 revere
    May 5, 2009

    stan: Relenza is being stockpiled but it is not in as abundant a supply as Tamiflu because GSK didn’t promote and market it. It is also delivered by inhaler and is not a tablet. Many national stockpiles are trying to diversify their inventories but there is a production bottleneck.

    marsha: This outbreak is barely 2 weeks old. There are systematic efforts underway to design studies that will provide useful information. The testing issue is complicated because there isn’t enough capacity to confirm via PCR if everyone were tested. We have under invested in science, so the number of hands able to do this is also limited. That’s what happens when we cut taxes. Penny wise . . .

  29. #29 Stormy Dragon
    May 5, 2009

    Maybe the reason H1N1 is less virulent than H3N1 is that nearly all of the human gene lines that were particularly suceptible to it were wiped out in 1918? Conversely, the absence of a similar H3N1 pandemic has left genetic suceptibility to that version still widely distributed.

  30. #30 Gordo
    October 27, 2009

    I know this post was from way back in May. This “swine flu” has reached pandemic levels since then. I have it, my sister in law has it, my son got it, my niece and nephew got it. Let me assure you, this is not a deadly flu. I only missed one day of work (even though I should have stayed home longer to prevent spreading it to others). I got it from a coworker who didn’t miss any days of work. My sister in law did develop pneumonia from it, but that was the worst case from the people I know. I felt pretty awful for about a week, and still do not feel 100% after 3 weeks, but I’m able to function OK, just have a lot of fatigue, occasional cough and runny nose, etc. None of the people I know that got it had symptoms of nausea, but some had diarrhea, all had a fever, most only had a fever for one day, others had a low grade fever for several days, all had runny nose, sore throat, fatigue, etc.

    It has passed though many local schools where absentee rates were up to 50%, several schools closed for one day. All of these schools quickly rebounded. You get over it and its not a huge deal. I didn’t hear of a single death in my local area despite thousands that have been infected. Don’t get me wrong, it really sucks to get it, and you will feel terrible for a while, and it takes a real long time to fully recover (3-5 weeks?), but its not the end of the world.