Study challenges notion of 'pandemic' flu

[cartski]

Re: Study challenges notion of 'pandemic' flu

hard to imagine that something can go pandemic quickly
as seasonal flu without respiratory transmission

If it is intestingal transmission, should we not see outbreak in a similar distribution and places as other infections that require intestinal transmission?

And in the few h2h situations we've seen, these are close contact transmissions, likely (although this is without seeing the reports) with poor sanitary and protective measures. So maybe the air transmission was ineffective, but the ingesting of the virus was. So we have h2h, but not with pandemic potential.

Perhaps we should be looking for comparison not to 1918, but to other pandemics without respiratory transmission - if such a thing existed.

J.

[JJackson]

Dump the data

Gsgs:
You are quite right. It is not a good epidemic transmission method respiratory would be better. But speed is not a prerequisite. HIV is doing very nicely and is a text book pandemic but in slow motion compared to flu pandemic. I was really just trying to get people thinking more about the about the potential difference that HP?s extended tissue tropism allows for.
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I didn?t really address Doshi?s paper ? or at least the press overview in post #1 as Al had picked over most of its weaknesses. He could have added that while antibiotics would have been very useful in most seasonal flus, as a treatment for secondary pneumonia, in 1918 many of the fatal case involved primary pneumonia ? for which it would not have helped.
<o:p></o:p>
If we completely ignore all the data (this is a new scientific method I am trialling) and look at what ought to happen from first principles Doshi should be wrong (I am also going to ignore the HP/LP complication covered before).
<o:p></o:p>
Firstly there isn?t enough data to say anything very definitive from. Anything before 1900 is sketchy (I am being polite) after that the pattern is there is only one Type A strain circulating at a time and in 1918, ?57 & ?68 a new strain emerged and supplanted the incumbent. There is one exception the H1N1 strain that reigned from 1918 to 1957 suddenly reappeared in the 1970s and since then we have had both H3N2 and H1N1 (I have never understood why ? of the 144 possible Type ?A? strains - birds seem to coexist with many in parallel but we typically take ours serially). So in the history we have strains for n=3.
<o:p></o:p>
So returning to first principles the pandemic strain becomes the seasonal strain.
Case zero in a flu pandemic is infected with avian influenza but infects with human flu, by definition he, or she, is the one who transmutes the virus.
Humans, up to this point, are a dead end host and transmissibility & virulence are evolutionarily irrelevant. The starting virulence is a bit of a lottery and could be almost anything as it is a function of how ill a pathogen, in equilibrium with another species, happens to make us ? and as we can see with H5N1 an asymptomatic Mallard shedding virus can make us very sick indeed. Once the human pandemic is underway the virus will undergo rapid genetic change under the severe selection pressures imposed by a new host species. Virulence ? in humans - becomes relevant to the virus as too severe and the host does not get out and about infecting others. You can have too mild also. As the virus is hijacking your cellular machinery to produce more virus if you are not feeling ill then that means it could be hijacking more cells and making more virus i.e. it is evidence the virus is not milking you hard enough. Over time the virus and host will adjust to find equilibrium.
Going back to Doshi then you should not be able to say anything about starting virulence only about where it ends up.<o:p></o:p>

[JJackson]

n=3

On reflection I am not sure I explained the n=3 bit very well.
Al critiqued Doshi’s conclusions but in my first post I rather ignored Doshi and talked about something else(HP/LP); the reason being I did not buy the premise. On first reading I took post #1 to mean Doshi was making predictions about future pandemics based on past pandemics. Seems like a good idea but, if you only have 3 past pandemics we know anything much about, how reliable can his statistical analysis be (leave the SPSS in its box).
To put it another way if you were E.T and had landed on this planet and only ever seen three dogs a Spaniel, a Collie and a Labrador would you be able to predict a Great Dane, Dachshund or Wolf?

[Laidback Al]

Re: n=3

. . . To put it another way if you were E.T and had landed on this planet and only ever seen three dogs a Spaniel, a Collie and a Labrador would you be able to predict a Great Dane, Dachshund or Wolf?

That is a very understandable analogy.

Indeed, the main criticism I have of the structure of the article, as reported in the news release, revolves around the many hidden assumptions about pandemics.

First, he commingles the pandemic data with seasonal influenza data to study death rates. So it would seems that he has a large, statistically valid, sample for analysis. But as we know, a pandemic influenza is not just a seasonal influenza with a higher death rate. Removing seasonal influenza data from his study reduces his sample size to 3.

You are correct that a sample size of 3 (three past pandemics) is statistically meaningless, especially when trying to predict a trend. One hidden assumption in this article is that the CFR across the the past three pandemics has remained constant. He needs this hidden assumption to explain that the long term decline in associated death rates is a function of improvements in 20th century medicine rather than a variable CFR.

Doshi's notes his only outlier in excess mortality is the 1918-1919 pandemic. The estimated CFR for that pandemic is often reported to have been about 2.5%. The current CFR for H5N1 is about 63%, 25 times more fatal than the 1918 strain. If H5N1 becomes the next pandemic strain it will clearly be the Wolf in your analogy.

[Oracle]

Re: n=3

Minor glitch in grand theory of HP vs LP:

1.The 1918 strains did not have the basic amino acid cleavage site.
2. H5N1 clades show variability in basic amino acid cleavage site (acquired, then lost in some strains).

Ergo, while it may effect upper respiratory tract receptor recognition, there are other factors at work that determine pathogenicity and transmissibility.

Doshi does indeed note that the 1918 pandemic is an outlier in his plot. It is also an outlier when a plot of genetic sequence vs protein sequence polymorphisms are evaluated for a variety of mammalian HP strains (including the sequences of the last 3 human pandemics). This, Taubenberg did in a recent article; indeed, the 1918 strains are outliers in this plot, FAR removed from the comparatively wimpy CFR of the more recent pandemics.

What is missing in the defined features of pandemic versus seasonal, is the degree to which global populations are affected, in total population affected and symptom severity (a function of both host nativity and strain virulence), infectious duration and strain adaptation, reflected in a second or third wave of continued high virulence, despite the expected drop due to host adaptation.

Yes, I read the paper.

[Laidback Al]

Re: n=3

I just emailed him and asked him to participate in the discussion here.

[JJackson]

Some confusion?

Minor glitch in grand theory of HP vs LP:

1.The 1918 strains did not have the basic amino acid cleavage site.
2. H5N1 clades show variability in basic amino acid cleavage site (acquired, then lost in some strains).

<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /><o:p></o:p>

1. I clearly stated it (1918 H1N1) was LP not HP and it does not have a polybasic cleavage site (no H1s do).<o:p></o:p>
<o:p></o:p>
2. H5N1 has many variations and I made a table showing some of them a while ago which can be found here http://www.flutrackers.com/forum/showthread.php?t=8876 (I am sorry I have not been keeping it up-to-date but it gives many of the common H5N1 cleavage sites)<o:p></o:p>
<o:p></o:p>
I did not include it in my earlier post but H5N1 is also ‘available’ in a LP form usually referred to as North American (as opposed to Asian in the <?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com:office:smarttags" /><st1:stockticker>MSM</st1:stockticker>)<o:p></o:p>
<o:p></o:p>

<o:p></o:p>

Ergo, while it may effect upper respiratory tract receptor recognition, there are other factors at work that determine pathogenicity and transmissibility.

<o:p></o:p>
<o:p></o:p>
As to respiratory tract receptor recognition this is an unrelated issue. The RBS and the cleavage site are separate areas on the Hemagglutinin protein, alpha 2,3 & alpha 2,6 specificity (or intermediate values) can be found with all types of cleavage sites.<o:p></o:p>
Many things have an effect on virulence and our understanding of them is woeful, although I have been writing about H all 8 strands seem to be involved with H, NP and N probably the most important.<o:p></o:p>
<o:p></o:p>

<o:p></o:p>

Doshi does indeed note that the 1918 pandemic is an outlier in his plot. It is also an outlier when a plot of genetic sequence vs protein sequence polymorphisms are evaluated for a variety of mammalian HP strains (including the sequences of the last 3 human pandemics). This, Taubenberg did in a recent article; indeed, the 1918 strains are outliers in this plot, FAR removed from the comparatively wimpy <st1:stockticker>CFR</st1:stockticker> of the more recent pandemics.

What is missing in the defined features of pandemic versus seasonal, is the degree to which global populations are affected, in total population affected and symptom severity (a function of both host nativity and strain virulence), infectious duration and strain adaptation, reflected in a second or third wave of continued high virulence, despite the expected drop due to host adaptation.

Yes, I read the paper.

<o:p></o:p>
<o:p></o:p>
That the H1N1 1918 pandemic was of a completely different order of magnitude in terms of virulence – and so <st1:stockticker>CFR</st1:stockticker> – I do not dispute at all. It is just not relevant to anything I have written in this thread. <o:p></o:p>
I am sorry I do not follow your argument re “genetic sequence vs protein sequence polymorphisms” the proteins primary structure (amino acid sequence) is strictly coded for by the <st1:stockticker>RNA</st1:stockticker> residue sequence (being resolved via transcription & translation). Again in the next paragraph I am not sure quite what point you are trying to make but if you would like to re-phrase I will happily try and address it.<o:p></o:p>

[JJackson]

Re: Study challenges notion of 'pandemic' flu

Perhaps we should be looking for comparison not to 1918, but to other pandemics without respiratory transmission - if such a thing existed.
J.

Certainly do; HIV as mentioned but the big daddy in pandmic terms is 1348 and the Black Death. Probably Bubonic plague (a bacteria) in association with Black Rats and fleas which would not seem to be a particularly fast transmission method but seems to have worked well.

[Laidback Al]

Re: Study challenges notion of 'pandemic' flu

Peter Doshi was kind enough to send me an electronic offprint of his paper. He also pointed out that American Journal of Public Health has an open eletter submission policy so that any one can comment on published articles in that journal.

Hopefully without violating any copyright issues, I will post some of the relevant passages. I have added the bolding.

Three influenza pandemics occurred in the 20th century: in 1918?1919, 1957?1958, and 1968?1969. . . .
Despite the widespread concern over a future influenza pandemic, there has been little research on the more than 100 years of recorded influenza death data in the United States?a period that includes both pandemic and nonpandemic seasons. . .
I present an analysis of these data to describe trends in influenza mortality and, in particular, to compare pandemic and nonpandemic influenza seasons in ways that may inform present planning for the prevention and control of influenza. . .
With the notable exception of the 1918 pandemic, each influenza pandemic season [1957-1958 and 1968-1969] was less lethal than the prior one, reflecting the overall seasonal trend in influenza deaths. . . .
The heightened concern over the threat of a future influenza pandemic largely rests on the assumption that the hallmark of pandemic influenza is excess mortality. . . .
In the monthly data from over 70 influenza seasons . . . the peak monthly death rates in the 1957?1958 and 1968?1969 pandemic seasons were no higher than (and were sometimes exceeded by) those for severe nonpandemic seasons (Table 1). If these trends extend into the future, it follows that if the health care infrastructure has been capable of handling nonpandemic influenza, it will also be able to deal with pandemic influenza. . . .
Another possible explanation for the false assumption that pandemics are necessarily more deadly than nonpandemics may lie in an inaccurate understanding?and inconsistent use?the word ?pandemic.? Influenza virus circulates the globe on an annual basis, but is usually not labeled a pandemic until the strain of virus in wide circulation is substantially novel (i.e., it carries a different hemagglutinin or neuraminidase protein than the strains already circulation).
Whatever the reasons for the misconceptions, should the trends observed over the 20th century continue to hold in the 21st, the next influenza pandemic may be far from a catastrophic event.

Doshi sets up his hypothesis with a narrowly constructed definition of a pandemic on the basis of excess mortality. He marshals the influenza mortality data from the U.S. from 1900 to 2004 and demonstrates that the mortality rate from influenza declines across this period. His data also show that the mortality rate for the 1957-1958 and the 1968-1969 pandemics barely rise above the overall declining background rate of seasonal influenza deaths. He intimates, based on the declining trend in mortality from the three 20th century pandemics (1918-1919, 1957-1958, and 1968-1969), that the next pandemic will not be a catastrophic events because the trendline from these three data points is declining.

Within the parameters that Doshi has set up, he has tied his data into a neat little bundle with straightforward conclusions. He has fulfilled the journal requirements and this doctoral student now has a peer reviewed publication to add to his curriculum vitae.

But, after reading the full article, the concerns I previously posted still stand. Besides the declining trendline in the mortality rate for the past three pandemic, there is no other data presented in the article to justify a supposition that the next pandemic will also have a low mortality rate. Predicting a low mortality rate for the next pandemic from these data requires that one assume a dependency between the mortality rate for pandemics. That is, one has to assume that the mortality rate of each pandemic is dependent on the preceding pandemic and the mortality rate for the current pandemic will affect the mortality rate of the next pandemic in the future. I am not aware that anyone has proposed a dependent relationship between mortality rates for pandemics.

It is also somewhat disingenuous to imply that that a catastrophic pandemic can only be measure in terms of high mortality rates. Depending on the virility, the attack rate, and the reproductive number, the next pandemic could have a severe, world-wide crippling economic effect along with negative consequences to the current social order, even without high mortality rates. And it is clearly stretching beyond any data presented in the article to suggest that the health care system can handle a patient surge in the event of virulent, fast moving, highly infectious virological event such as a pandemic.

I don?t want to be too critical of Mr. Doshi. His research topic was very focused and his conclusions were explicitly drawn from the data he analyzed. I am more concerned about the implications of this article, with its sweeping conclusions, passing peer review in a journal that focuses on public health -- The American Journal of Public Health.

[tropical]

Re: Study challenges notion of 'pandemic' flu

"It is also somewhat disingenuous to imply that that a catastrophic pandemic can only be measure in terms of high mortality rates. Depending on the virility, the attack rate, and the reproductive number, the next pandemic could have a severe, world-wide crippling economic effect along with negative consequences to the current social order, even without high mortality rates."

Correct.
We all saw the repercussions of the oil barel under 100$ without pandemics.

Statisticaly, the Mr. Doshi research is based on very few number of pandemics, through an very short period of time: ~100 years (maybe 200), when the homo sapiens history period was in a many more vast time period, which is enaugh to put in doubt the statistical relevance of the statement of predicted low pandemic CFR trend.

What was the pandemic CFR in the previous 10.000 year period, or more?
Who knows exactly?
What we knows is that the global CFR of an pandemic can not be predicted based on an time period 100 (and more) times shorter than the real one.

100 years ~ 3 pandemics a year (supposed)
10.000 years ~ 300 pandemics -> that must be processed:

Input data: the CFR's from 300 pandemics -> global CFR probability

"He intimates, based on the declining trend in mortality from the three 20th century pandemics (1918-1919, 1957-1958, and 1968-1969), that the next pandemic will not be a catastrophic events because the trendline from these three data points is declining."

Inserting only 3 inputs (3x 20th century pand.) in an mat. model connecting the CFR of those inputs, to get an global result is not correct.

Launch a coin only 3 times, and we shall see if you got an (exact 50&#37 global probability event, or an partial probability which does not suggest in any way the real probability event - the coin can drop 2 time face, one time on the number, etc.

This case remember me a story where a guy by math. induction "founded" that the probability of other life in the whole universe is 0% ...

The starting premises/inputs are very important.

[cartski]

Re: Study challenges notion of 'pandemic' flu

But, after reading the full article, the concerns I previously posted still stand. Besides the declining trendline in the mortality rate for the past three pandemic, there is no other data presented in the article to justify a supposition that the next pandemic will also have a low mortality rate. Predicting a low mortality rate for the next pandemic from these data requires that one assume a dependency between the mortality rate for pandemics. That is, one has to assume that the mortality rate of each pandemic is dependent on the preceding pandemic and the mortality rate for the current pandemic will affect the mortality rate of the next pandemic in the future. I am not aware that anyone has proposed a dependent relationship between mortality rates for pandemics.

Excellent elucidation.

The only added value I can understand from this article is the possibility that tansmission of the virus may be at different speeds. Hence, we can have slow-spreading pandemics and fast-spreading pandemics, both with very high mortality rates, but with capacity implications for the healthcare system.

Still, as gsg points out, this is an influenza, which implies airborne transmission, so it's bound to move around the globe quickly.

Sounds like we need another 2 by 2 table that classifies pandemic types.

Constrained data sets and valid conclusions or not, this article is just as damaging, IMO, as the current 70&#37; human antibody claims in Indonesia - both are extremes that polarize opinions (don't worry, be happy vs. doom and gloom anyway) and in the end harm the community's preparatory efforts.

J.

[colormyquilt]

Re: Study challenges notion of 'pandemic' flu

Bump this.

[Emily]

Challenging thinking about modern influenza pandemic threats

ETA: I merged a this thread I started today not knowing this study had been discussed. The NIH link might be handy since it has a link to the full free text which seems to not have been available earlier.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374803/

Am J Public Health. 2008 May; 98(5): 939–945.
doi: 10.2105/AJPH.2007.119933
PMCID: PMC2374803
Trends in Recorded Influenza Mortality: United States, 1900–2004
Peter Doshi, AM
Abstract

Objectives. I sought to describe trends in historical influenza mortality data in the United States since 1900 and compare pandemic with nonpandemic influenza seasons.

Methods. I compiled a database of monthly influenza-classed death rates from official US mortality tables for the years 1900 to 2004 (1905–1909 excluded), from which I calculated adjusted influenza season (July 1–June 30) mortality rates.

Results. An overall and substantial decline in influenza-classed mortality was observed during the 20th century, from an average seasonal rate of 10.2 deaths per 100 000 population in the 1940s to 0.56 per 100 000 by the 1990s. The 1918–1919 pandemic stands out as an exceptional outlier. The 1957–1958 and 1968–1969 influenza pandemic seasons, by contrast, displayed substantial overlap in both degree of mortality and timing compared with nonpandemic seasons.

***.56 was later corrected to .44

Conclusions. The considerable similarity in mortality seen in pandemic and non-pandemic influenza seasons challenges common beliefs about the severity of pandemic influenza. The historical decline in influenza-classed mortality rates suggests that public health and ecological factors may play a role in influenza mortality risk. Nevertheless, the actual number of influenza-attributable deaths remains in doubt.

Three influenza pandemics occurred in the 20th century: in 1918–1919, 1957–1958, and 1968–1969. Today, there is widespread concern, in the medical community as well as the public, regarding the deadly potential of a future influenza pandemic. Many national governments have begun to prepare for such a future threat. In the United States, this preparation has taken the form of the multi-billion-dollar National Strategy for Pandemic Influenza.

According to the US Centers for Disease Control and Prevention (CDC), “Pandemics are different from seasonal outbreaks or ‘epidemics’ of influenza.”1(p1) “The hallmark of pandemic influenza is excess mortality.”2 One recent official US death toll projection3(p1) suggested that the next pandemic will kill 6 to 56 times more Americans than the CDC currently estimates die in an average nonpandemic influenza season.4 The World Health Organization (WHO), in a “relatively conservative estimate,”5 predicted that the next influenza pandemic could claim 4 to 30 times more lives worldwide than a typical nonpandemic season.6

Despite the widespread concern over a future influenza pandemic, there has been little research on the more than 100 years of recorded influenza death data in the United States–a period that includes both pandemic and nonpandemic seasons. I present an analysis of these data to describe trends in influenza mortality and, in particular, to compare pandemic and nonpandemic influenza seasons in ways that may inform present planning for the prevention and control of influenza.
[snip]
DISCUSSION

The heightened concern over the threat of a future influenza pandemic largely rests on the assumption that the hallmark of pandemic influenza is excess mortality. However, this study indicates that the mortality impact of pandemic and nonpandemic seasons has been similar, with considerable overlap in both seasonal and peak monthly mortality rates.

In the 1918–1919 pandemic, which stands out for its high mortality rate, although perhaps 10&#37; to 15% of deaths were attributed to acute respiratory distress syndrome,17 many if not most of fatal cases are believed to have occurred because of secondary bacterial complications.18 Had no other aspect of modern medicine but antibiotics been available in 1918, there seems good reason to believe that the severity of this pandemic would have been far reduced.

Full text at link. Topics discussed:

• Implications for Influenza Vaccines
• The Multifactorial Nature of Influenza Risk
• Hospital Surge Capacity
• Assessing the Impact of Influenza
• Explaining the Gap Between Evidence and Fear

Since that was written just before the 2009 pH1N1 emergence, here is a study on U.S. deaths from that:

http://cid.oxfordjournals.org/conten...ppl_1/S60.full

Epidemiology of 2009 Pandemic Influenza A (H1N1) Deaths in the United States, April–July 2009 Clin Infect Dis. (2011) 52(suppl 1): S60-S68 doi:10.1093/cid/ciq022
Abstract

During the spring of 2009, pandemic influenza A (H1N1) virus (pH1N1) was recognized and rapidly spread worldwide. To describe the geographic distribution and patient characteristics of pH1N1-associated deaths in the United States, the Centers for Disease Control and Prevention requested information from health departments on all laboratory-confirmed pH1N1 deaths reported from 17 April through 23 July 2009. Data were collected using medical charts, medical examiner reports, and death certificates. A total of 377 pH1N1-associated deaths were identified, for a mortality rate of .12 deaths per 100 000 population. Activity was geographically localized, with the highest mortality rates in Hawaii, New York, and Utah. Seventy-six percent of deaths occurred in persons aged 18–65 years, and 9% occurred in persons aged ≥65 years. Underlying medical conditions were reported for 78% of deaths: chronic lung disease among adults (39%) and neurologic disease among children (54%). Overall mortality associated with pH1N1 was low; however, the majority of deaths occurred in persons aged <65 years with underlying medical conditions.

Free full text at link.

[kiwibird]

Re: Challenging thinking about modern influenza pandemic threats

Malaysia Health Minister states that H7N9 Mortality rate 60% higher than H1N1, which he quotes as 0.4%. http://www.nst.com.my/latest/liow-no...aysia-1.247390

Border controls have been set in place in Malaysia.

[JJackson]

Re: Challenging thinking about modern influenza pandemic threats

Emily have you seen this thread? It had a lengthy discussion on this paper at the time. Al & I had some issues with it.