Effect Measure

Pandemic flu no worse than seasonal flu?

Peter Doshi has a bone to pick with CDC . His particular idée fixe is that CDC is cooking the books on their estimates of excess mortality attributable to influenza and he aims to set the record straight. He’s done it before. Doshi is not the kind of critic CDC is used to. He is a graduate student, not an established public health figure. But he’s no shrinking violet and is getting in CDC’s face again in the latest issue of the American Journal of Public Health. This time Doshi extends his criticism to imply CDC is pandemic fear mongering, perhaps in collusion with Big Pharma. This has been interpreted in the press as saying “a new study” suggests we don’t have much to fear even if a pandemic materializes because a pandemic is no worse than seasonal influenza.

Needless to say I don’t have a lot of sympathy for this position, but Doshi’s points still need to be examined. In my view they have their roots in his misunderstanding of how and why CDC estimates excess influenza mortality. The number of deaths attributed to flu each year is far in excess of deaths attributed to flu on a death certificate. Doshi has never filled out a death certificate, but I have. It is not rocket science. In fact, there may not be much science in it at all. Only about 10% of deaths in the US have autopsies and many pneumonia deaths among the elderly are never diagnosed, either as pneumonia due to influenza or even pneumonia at all. So there is a misspecification of influenza deaths in the mortality data. Some of the deaths due to influenza may not be due to infection with the virus but other respiratory viruses. Many influenza deaths will never be classed as influenza because there is no information upon which to base the diagnosis. Classification as influenza is more likely to be true during an outbreak for purely mathematical reasons (a consequence of Bayes’ Theorem) but the relation between deaths with “influenza” as a principal or underlying cause of death is uncertain and has varied over the hundred years that Doshi surveys in his paper.

Despite the difficulty, the toll attributable to influenza remains is an important public health question and CDC has approached it by estimating excess mortality using the total of deaths classified on death certificates as due to pneumonia or influenza, so-called P&I deaths. Because we know P&I mortality has a seasonal pattern, the estimate is made using historical data on the phase and amplitude of the seasonal variation (the frequency is annual). This provides a seasonally varying baseline for what is expected. Excesses beyond the expected are the excess mortality from influenza.

Do we know all the excess is due to circulating influenza virus? Some of it is since we know a fair amount about the seasonal variation in infection from that virus (although we don’t know what produces the seasonal pattern). But as Doshi and almost everyone else notes (including CDC), other viruses are also involved. Does that mean the excess is an obvious overestimate? It would if we thought the only effect of influenza on mortality were in P&I deaths. But we also know with certainty that mortality registered as from other causes, particularly cardiovascular deaths, may be hastened, if not directly caused, by influenza infection. That is a large pool and if even a small proportion would not have occurred absent influenza infection, the P&I estimate is also an underestimate.

Doshi says in his paper he asked for CDC surveillance data on co-circulating respiratory viruses so he could take them into account in his interpretation. He claims CDC would only give him the data on condition of co-authorship. Since I have never heard of CDC doing this, I am surprised and dismayed — if it is true. I don’t consider this acceptable behavior regarding de-identified surveillance data gathered under government auspices. Doshi has a right to the data and withholding it seems petty, uncollegial and possibly unethical. Perhaps there is another side to the story, but Doshi’s version is disconcerting.

At any rate, the issues raised by Doshi have been discussed and examined many times by others, both within and outside of CDC. Experts in this area are not naive to the possibilities. They are in fact much more expert than Peter Doshi, who keeps referring to subtypes as strains and has no problem taking 100 years of deaths classified on a death certificate as influenza as reliable data (nor does he say if his data are primary cause or underlying cause or even if he knows). He sums up his “concerns” with three points. The first is that recorded influenza deaths are only a small proportion of deaths CDC attributes to influenza. That’s what we have been talking about, above. His second point is that in the 1980s and 1990s the estimate of the excess has gone up but the deaths classified as influenza have declined. He is not the first to notice this. CDC flu experts have looked for the reasons for this discrepancy and have come up with a number of plausible explanations. Whether it is trends in subtypes or reporting differences over time the questions have been asked and possible answers proposed. Some highly expert scientists have been worrying about and discussing these things for years. They are not new or suppressed questions. Doshi’s third concern is that various models come up with different estimates. As he points out, the CDC model is one of the lower, not higher, estimates. Everyone involved in this fairly difficult and somewhat arcane exercise are aware of the problems. Different estimates from different models and methods is not special to influenza. It is the rule rather than the exception in science. I know of no one except Doshi who advocates merely using the cause of death on the death certificate as the best basis for resolving the questions.

In the bird flu world, the headlines were made by his dismissive attitude to the threat of a pandemic. Using his method whereby a death is only caused by influenza if it says so on the death certificate, Doshi compares pandemic years with non-pandemic years, and finds that except for 1918 there is no clear distinction. Even on his terms, it is clear the pandemic years are among the highest but his point is that they are not the only high mortality years. There are other years where “influenza classed” mortality (his definition) is as high or higher, although he doesn’t compare the pandemic years to all years but only selected years. It is not a cogent point in my opinion. CDC’s statement that the hallmark of a pandemic is excess mortality is still true. It is just not exclusively true of pandemic years, even if we agreed on his definition of pandemic mortality.

More important, however, is a point he makes with his own data: not all pandemics are alike. The three pandemics of the last century all had significantly increased mortality but varied in severity. The reason the flu world is concerned about H5N1 is the extraordinary virulence of the virus as expressed by its case fatality ratio (Doshi mistakes pathogenicity for virulence but this is a minor point). If this flu virus becomes transmissible, even with a major reduction in virulence, the results would be horrific. We hope it won’t happen. But we have no way of knowing. Preparing for it is prudent and it would be insanity to look the other way, although that is precisely what Doshi’s hand waving dismissal encourages. Handwaving — and rank speculation that things aren’t as bad as they look — is the hallmark of Doshi’s own claims that a pandemic “may not be” a catastrophic event. True, but trivial. A pandemic may be a catastrophic event as well, and given the extreme brittleness of the medical care system (a brittleness Doshi does not seem to recognize or understand), it wouldn’t take an outlier event to make an already full bucket overflow.

This paper is a pointless exercise. Too bad it isn’t also a harmless one.

Comments

  1. #1 PalMD
    April 17, 2008

    Great post! I’ve had a number of anti-vaccine trolls at my place trying to explain how the CDC doesn’t really count influenza, as if the writer had just stumbled onto some golden idea that the best epidemiologists had never thought of. Oh, the arrogance.

    And I’ve filled out many death certificates as well—there are very few requirements as to filling out cause of death, as long as you dont say “heart failure”, or “respiratory failure”—in other words, without autopsy, there’s a lot of guess-work. At least there is if you care. There’s nothing stopping you from just writing “heart attack” and leaving it at that.

  2. #2 Rob
    April 17, 2008

    I helped write a rejoinder to Doshi’s last outing on this, two years ago in BMJ. After looking at all the back and forth on that article (http://www.bmj.com/cgi/eletters/331/7529/1412), I concluded he’s not really interested a serious scientific debate. Instead, he seems more of a crank in the Lou Dobbs mold: small understanding, thick skull, and not much willing to think about what anyone else has to say.

    Oh, well.

  3. #3 M. Randolph kruger
    April 17, 2008

    Here is a thought. If its only 5% of the entire world population thats still one Hell of a lot of people and still even more so unevenly distributed. 56,000 in my state alone and it only takes into account the primary cause of death from this being flu.

  4. #4 herman
    April 17, 2008

    If human bird flu infection existed in a vacuum, and did not interact with other organisms in the lung tissue, perhaps the mortality rate might drop somewhat during a pandemic, but I doubt it.
    In 1918, many Spanish Flu victims, whose immune systems were weakened, later died of tuberculosis. So if you calculate those who died of Spanish Flu, and then those who later died of tuberculosis, as a result of having weakened immune systems, the actual mortality rate, combining the 2 diseases, was very high.
    It is the interaction between these two diseases that is being totally ignored, and the interaction is not well understood, even by virologists. Tuberculosis is the world’s second deadliest infectious disease, after Aids.
    It infects over 9 million people in the world each year, and kills 1.7 million yearly, or about 4700 per day.
    As 6 billion people struggle to obtain food, in a world where climate change and high oil prices are causing the food supply to decrease, more and more will become vulnerable to infectious diseases, including TB, and influenza.
    Dr. Mario Raviglione, director of the WHO stop TB Department, recently stated: “If countries and the international community fail to address tuberculosis aggressively now, we will loose the battle.
    Multiple drug resistant (MDR-TB) and extreme drug resistant TB (XDR-TB)infects 500,000 per year in the world each year. They are very expensive to treat and XDR-TB is almost incurable. If you become infected with XDR-TB is the US, you have a 25% chance of dying.
    If H5N1 mutates to a form that is easily transmitted, human to human, and drug resistant TB continues to increase, these diseases may interact to increase human mortality globally.
    In Africa there are only 25 labs equiped to detect MDR-TB, and 19 are in South Africa. TB in Kyrgyz, capital Bishkek, has the highest rate in the world of drug resistant TB, with 26% of newly diagnosed cases being MDR-TB. The population is so poor, that patients do not receive adequate medication. Without medication, 50% of all TB patients will die within 2 years.
    What is the interaction between influenza A and tuberculosis in the human lung? This issue needs further investigation. If not, more will die soon as MDR-TB continues to spread, and H5N1 continues to mutate.

  5. #5 anon anon
    April 17, 2008

    You took Nature to task for the recent Ferguson piece — and while I rather agree with you, in many respects, I would note several remarkable things to find in Ferguson paper.

    one, they’re looking at a 20 year running natural experiement of routine holiday school closure, and they have real solid findings from it; the French system is truly amazing, why the US doesn’t have anything like it is a shame.

    two, they lay their assumptions out quite fairly, and they present their findings in a very cautious tone. This seems responsible, and commendable. Those who believe school closure holds a more profound potential, can argue in-line with paper findings, and focus on the difference between routine holiday closure being massively different from any kind of pandemic NPI-like closure scenarios — this variable could be huge. And the added bonus in layering other NPI on the marginal benefit they present (ie, millions of lives saved), could start to add up to real numbers (10s of millions).

    back to the Doshi polemic: how about taking AJPH to task?
    they published this paper as Research (with a capital R).

    this once fine publication looks to be on the verge of scientific irrelevance.

  6. #6 revere
    April 17, 2008

    anon anon: You make some good points. My problem is less with the paper per se (maybe I didn’t make that clear enough) than with how it was promoted, interpreted rather rashly to reporters and the publication venue. While I agree with you about AJPH, there really is no comparison between AJPH and Nature. I’ve published in AJPH but it is pretty marginal as a publication venue these days. Nature, on the other hand . . .

  7. #7 herman
    April 17, 2008

    I have waited 3 hours for someone else to post, but nobody has, so here goes:
    I wonder what Doshi would think about this:
    Darrel Slyles, doctor of veterinary medicine, in his advice to those who care for large numbers of birds, has this to say about avian tuberculosis, which is a disease of birds that can infect humans, states:

    6. Take personal precautions. When cleaning and servicing the aviary, it would be ideal to wear a face-mask and goggles or glasses to prevent eye-splash. Also, individuals with compromised immune systems should not have exposure to the birds. People with compromised immune systems would include individuals with HIV, transplant patients, individuals on chemotherapy for cancer, or anyone taking high doses of corticosteroids. The Center for Disease Control in Atlanta considers this a ubiquitous organism, meaning found everywhere in the environment. In a paper by Horsburgh et al. [I], Environmental Risk Factors for Acquisition of Mycobacterium avium Complex in Persons with Human Immunodeficiency Virus Infection; “Several other important potential sources of MAC (Mycobacterium avium Complex) were not associated with disease. These include contact with soil, having a bird, knowing a person with MAC, and having been hospitalized.”

    People with normally functioning immune systems have a high resistance to this infection. The bacteria are already in the environment due to shedding from wildlife. However, we do urge at risk individuals to take proper precautions and avoid contact or expo sure.

    We are left with the dilemma of chicks that may potentially be infected with avian TB. Your ethical responsibility is to notify the person purchasing or accepting the birds that the possibility of this infection exists.”

    Now I want to relate this to H5N1. Dr. Slyles states that in any large group of birds, there is at least one infected with avian tuberculosis.
    Now please imagine all the millions of birds in the world now infected with H5N1. Mixed within those birds, are many that are infected with both avian tuberculosis and H5N1.
    Did you know H5N1 can attach to a tuberculosis bacteria, and in that way travel from one bird to another, or from one human to another?
    Now please imagine all the millons of contacts between birds and humans that occur constantly. And those humans with weak immune systems are vulnerable to being infected with avian tuberculosis, if they do not protect themselves.
    And simultaneously, if H5N1 has attached to the TB bacteria of avian tuberculosis, they could simultaneously become infected with H5N1.
    Did you know 25% of TB in humans originates in animals? Did you know you can contact bovine tuberculosis by drinking unclean milk?
    Simultenous infections of the human lung is the norm, rather than the exception. If a human is infected with H5N1, he or she probably has other infections in the lung at the same time.
    Now please imagine a fatality rate of H5N1 in humans of 60%. Just for fun, please imagine that rate stays constant during a pandemic. As Henry Niman recently stated, that implies during a bird flu pandemic, that millions and millions would die. The Spanish Flu pandemic of 1918 only had a mortality rate in humans of 2 or 3 percent, and millions died.
    Now try to imagine birds with dual infections of avian tuberculosis and H5N1 infecting humans with weak immune systems, especially in Africa, where Aids is out of control.
    If that happens, I want to hand a shovel to Doshi, and request he please start digging all the graves that will be required for all of these millions. Do you think Doshi can did that many graves?

  8. #8 Tasha
    April 17, 2008

    This is slightly off-topic, but your comments about death certificates has me thinking…

    Is it possible that the oft-cited statistic noting that heart disease is the number one cause of death is actually eroneous, or at the very least overstated, due to inaccuracy in death certificate reporting?

  9. #9 revere
    April 17, 2008

    Tasha: I think the actual number isn’t known that precisely but it is very unlikely the rank ordering would be changed.

  10. #10 Medclinician
    April 24, 2009

    Pandemic Flu in 1918 killed more people (20,000,000-40,000,000) in one year than the entire deaths from the Bubonic Plague, World War I, or the Black Death. It occured in October making the over used term “seasonal flu” irrelavant. To say that Pandemic Flu is no worse than seaonal flu in completely incorrect. The data from 1918 show the complete opposite. If even half the death rate (63%) from WHO occurs in a Pandemic – according to one Russian doctor, over one billion people could die.

    No current health plan by any country or state, deals with realistic fatality rate from the Pandemic. The Infrastructrue would collapse at 3-5%.

    Pandemic flu and Seasonal Flu- birds of a deadly different feather.

    Medclinician