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Looking at, and thinking about, Pandemic plans in general the following are some general thoughts and observations.
Rule one in ?Grand Strategy? ? Know your enemy. Small problem we don?t.
I have posted on and around this subject several times in various threads but I would like to try and cover it again here in a little more detail.
1] The following relates to Pandemics caused by Type A influenza in humans
2] How it emerges is irrelevant it could be reassortment from seasonal flus or zoonotic emergence via shift, drift or recombination.
The crux of the problem is variability compounded by a lack of data.
Variability: Flu?s genetic strategy is the scatter gun approach.
Human genetic information is stored in our DNA, that DNA is the same in every cell in our body. As multi-cellular organisms it is very important to us that we have a mechanism that can faithfully reproduce perfect copies of that DNA each time our cells divide. To ensure this we have mirrored strands of DNA and a host of error checking and correction mechanisms. To evolve we need to acquire new genetic traits which we do by sexual reproduction. For animals the cost of producing ?a chip off the old block? is enormous so this strategy is very cautious; it makes relatively small changes per generation as failures (anything that can not get to the point of reproducing and passing on genes) are fairly disastrous.
Flu?s strategy is completely different. Firstly as it is not multi-cellular the whole copying of genetic material problem does not occur ? or only for reproduction. Secondly the reproductive cost is minimal as it is not borne by the virus but by the infected host cell. Flu?s solution is single stranded RNA genes with minimal concern for quality control. The result is staggering numbers of progeny most of which are such poor copies they just don?t work. Which leaves a very varied assortment, those identical ? or very close - to their ?parent?s? template continue on; of the rest most are just outperformed and die out. Just occasionally one of these weird and wonderful assortments finds a niche and expands into it. This ability to rapidly, and radically, shift genetic makeup, coupled with very short viral generation times, is the key to flu?s success.
From our point of view this trick is obviously not such good news. Man?s primary defence against pathogens is its immune system. It is obvious from the above that we can not out evolve the virus, generation by generation, so we have developed an immune system that can adapt to new threats within one human lifetime. This system is not specific to flu, we have one immune system to cope with all pathogens and it is optimised to cope with average pathogenic behaviour. Flu is not average it changes more quickly and is more variable than most which is what makes it one of our more troublesome adversaries. It is difficult to overstate the immune system?s complexity and impossible to overstate its ? coupled with our genetic diversity ? importance. If an individual once meets a pathogen it can not counter it dies, if a species once meets a pathogen that the genetic diversity in its immune systems can not cope with it become extinct (two provisos the pathogen must be virulent enough to cause death, if unchecked, and must be able to survive in the environment - or another species - or it may die out first once it has thinned the host out to the point it is hard to find new victims ).
The antivirus software in my computer has a database of know threats (keep downloading those updates) and a component that scans for suspicious changes - lest I be unlucky enough to be the first recipient of a newly minted virus. When it meets a known virus it is quick to respond and knows how to remove it (hopefully). If it meets a new virus it will try and class it with things it does know about and see if similar strategies work, it will also report it so it can be add to further downloads and will be quickly recognised if met again. Our immune system works on the same principle know threats are picked up early and hit hard unknown threats take longer and are therefore more likely to establish a foothold, making you more ill and take longer to bring under control. Going back to flu?s variability this means our immune system is often meeting new viruses (or at least sufficiently changed to fool the immune system) and this wide range of flu strains is accompanied by any equally variability in virulence and symptoms. To exacerbate the problem the immune system sometime gets confused and does considerable damage to the host while attempting to kill the invader. What all this leaves us with is something ? or rather lots of things - called flu some of which will kill you as readily as Ebola and others that give you a runny nose.
Data: or lack there of.
Having discussed why flu can have such a variable clinical impact pandemic planners need to make some kind of judgement about what they may meet next time. The place to start is by looking at past pandemics to try and get a feel for the range of likely possible events. Here we hit their big problem these things have happened so infrequently (only three on which we have any useful data) it is hard to draw any useful conclusions. When assessing pandemics we normally are interested in three things CAR, CFR & speed. CAR is the clinical attack rate which is the proportion of those exposed who get ill - for flu this has ranged from about 1 in 5 to 1 in 2 (normally expressed as 20-50%. CFR is the Case Fatality Rate and is the proportion of those who got clinically ill who went on to die ? the range here is from under 1% to ~ 3% (as a side note while CFR is technically a measure of fatalities it is also often used as an approximate measure of virulence). Multiply CAR by CFR and you get the proportion of the population that will die, multiply that by the population you are interested in and you have a death toll. Speed just gives you an idea of the time period these deaths are like occur over so you can calculate frequency. In past flu pandemics casualties were concentrated in waves with the bulk of the deaths occurring in 2 to 3 months.
If you ignore everything I wrote in the variability section and just plan based on the data section there does not seem to be any great problem. Take the worst case and plan for it 3/100*1/2 = 3/200 or 1.5% of the population die in a few months - pretty scary but no problem to calculate and you know what you are planning for.
Then there is the problem:
Firstly any 10 year old learning basic math should know that tossing a coin three times and making a prediction based on the outcome is not very reliable. Statistical confidence is a function of sample size. But even if we didn?t know that why are we doing all this pandemic planning at the moment anyway? Answer HPAI H5N1.
As this is only a pandemic candidate and has not achieved sustained transmission in humans, CAR and speed have no meaning but it does have a CFR ? or at least a reasonable estimate of one ? which is about 60%. How well does that fit into our target range of less than 3% - not very well.
This does not mean we should not plan, or that we should not base our plans on the only data we have, it just means we should be very sure our plans are as flexible as possible and should keep an extremely open mind on the range of clinical symptoms flu might be capable of presenting us with and of course those speed, CAR and CFR ranges.
Rule one in ?Grand Strategy? ? Know your enemy. Small problem we don?t.
I have posted on and around this subject several times in various threads but I would like to try and cover it again here in a little more detail.
1] The following relates to Pandemics caused by Type A influenza in humans
2] How it emerges is irrelevant it could be reassortment from seasonal flus or zoonotic emergence via shift, drift or recombination.
The crux of the problem is variability compounded by a lack of data.
Variability: Flu?s genetic strategy is the scatter gun approach.
Human genetic information is stored in our DNA, that DNA is the same in every cell in our body. As multi-cellular organisms it is very important to us that we have a mechanism that can faithfully reproduce perfect copies of that DNA each time our cells divide. To ensure this we have mirrored strands of DNA and a host of error checking and correction mechanisms. To evolve we need to acquire new genetic traits which we do by sexual reproduction. For animals the cost of producing ?a chip off the old block? is enormous so this strategy is very cautious; it makes relatively small changes per generation as failures (anything that can not get to the point of reproducing and passing on genes) are fairly disastrous.
Flu?s strategy is completely different. Firstly as it is not multi-cellular the whole copying of genetic material problem does not occur ? or only for reproduction. Secondly the reproductive cost is minimal as it is not borne by the virus but by the infected host cell. Flu?s solution is single stranded RNA genes with minimal concern for quality control. The result is staggering numbers of progeny most of which are such poor copies they just don?t work. Which leaves a very varied assortment, those identical ? or very close - to their ?parent?s? template continue on; of the rest most are just outperformed and die out. Just occasionally one of these weird and wonderful assortments finds a niche and expands into it. This ability to rapidly, and radically, shift genetic makeup, coupled with very short viral generation times, is the key to flu?s success.
From our point of view this trick is obviously not such good news. Man?s primary defence against pathogens is its immune system. It is obvious from the above that we can not out evolve the virus, generation by generation, so we have developed an immune system that can adapt to new threats within one human lifetime. This system is not specific to flu, we have one immune system to cope with all pathogens and it is optimised to cope with average pathogenic behaviour. Flu is not average it changes more quickly and is more variable than most which is what makes it one of our more troublesome adversaries. It is difficult to overstate the immune system?s complexity and impossible to overstate its ? coupled with our genetic diversity ? importance. If an individual once meets a pathogen it can not counter it dies, if a species once meets a pathogen that the genetic diversity in its immune systems can not cope with it become extinct (two provisos the pathogen must be virulent enough to cause death, if unchecked, and must be able to survive in the environment - or another species - or it may die out first once it has thinned the host out to the point it is hard to find new victims ).
The antivirus software in my computer has a database of know threats (keep downloading those updates) and a component that scans for suspicious changes - lest I be unlucky enough to be the first recipient of a newly minted virus. When it meets a known virus it is quick to respond and knows how to remove it (hopefully). If it meets a new virus it will try and class it with things it does know about and see if similar strategies work, it will also report it so it can be add to further downloads and will be quickly recognised if met again. Our immune system works on the same principle know threats are picked up early and hit hard unknown threats take longer and are therefore more likely to establish a foothold, making you more ill and take longer to bring under control. Going back to flu?s variability this means our immune system is often meeting new viruses (or at least sufficiently changed to fool the immune system) and this wide range of flu strains is accompanied by any equally variability in virulence and symptoms. To exacerbate the problem the immune system sometime gets confused and does considerable damage to the host while attempting to kill the invader. What all this leaves us with is something ? or rather lots of things - called flu some of which will kill you as readily as Ebola and others that give you a runny nose.
Data: or lack there of.
Having discussed why flu can have such a variable clinical impact pandemic planners need to make some kind of judgement about what they may meet next time. The place to start is by looking at past pandemics to try and get a feel for the range of likely possible events. Here we hit their big problem these things have happened so infrequently (only three on which we have any useful data) it is hard to draw any useful conclusions. When assessing pandemics we normally are interested in three things CAR, CFR & speed. CAR is the clinical attack rate which is the proportion of those exposed who get ill - for flu this has ranged from about 1 in 5 to 1 in 2 (normally expressed as 20-50%. CFR is the Case Fatality Rate and is the proportion of those who got clinically ill who went on to die ? the range here is from under 1% to ~ 3% (as a side note while CFR is technically a measure of fatalities it is also often used as an approximate measure of virulence). Multiply CAR by CFR and you get the proportion of the population that will die, multiply that by the population you are interested in and you have a death toll. Speed just gives you an idea of the time period these deaths are like occur over so you can calculate frequency. In past flu pandemics casualties were concentrated in waves with the bulk of the deaths occurring in 2 to 3 months.
If you ignore everything I wrote in the variability section and just plan based on the data section there does not seem to be any great problem. Take the worst case and plan for it 3/100*1/2 = 3/200 or 1.5% of the population die in a few months - pretty scary but no problem to calculate and you know what you are planning for.
Then there is the problem:
Firstly any 10 year old learning basic math should know that tossing a coin three times and making a prediction based on the outcome is not very reliable. Statistical confidence is a function of sample size. But even if we didn?t know that why are we doing all this pandemic planning at the moment anyway? Answer HPAI H5N1.
As this is only a pandemic candidate and has not achieved sustained transmission in humans, CAR and speed have no meaning but it does have a CFR ? or at least a reasonable estimate of one ? which is about 60%. How well does that fit into our target range of less than 3% - not very well.
This does not mean we should not plan, or that we should not base our plans on the only data we have, it just means we should be very sure our plans are as flexible as possible and should keep an extremely open mind on the range of clinical symptoms flu might be capable of presenting us with and of course those speed, CAR and CFR ranges.