Swine flu: why are older people (apparently) less at risk?

There is as yet no vaccine for the novel H1N1 (swine flu) pandemic strain of influenza now causing widespread illness in North America and what appears to be the start of growing outbreaks in Japan and parts of Europe (but check out this excellent piece over at ScienceInsider). WHO says most developing nations are not able to track influenza, so what is happening in Africa and parts of Asia is not known with any confidence. While the clinical illness from this virus doesn't seem very different than seasonal flu, the fact that most of the world's population has no immunity to it means there is potential for wider and swifter spread than seasonal flu. The exception to lack of immunity may be in a specific subpopulation -- one to which I belong: the elderly (aka the "older age group"). That has been the working hypothesis for why there may be a relative sparing of the very group that seasonal influenza hits hardest, and now we have a bit of data consistent with this idea.

While hard data about transmission characteristics, virulence and the possibility of cross-protection from recent flu vaccines has been scarce, CDC and public health scientists have been at work and now we are seeing some of the first fruits. Using stored serum samples from various sources, CDC has been looking to see if they contain antibodies that might cross-react with the new virus. The sera come from children and adults vaccinated with seasonal vaccines in the 2005--06, 2006--07, 2007--08, or 2008--09 seasons. Sera both before and after vaccination for each subject were used to see if any of the seasonal vaccines induced cross-reactivity to the current swine flu virus. The bottom line is essentially, "no." But not all the information is negative. 6% of adults age 18- 40 years old had any evidence of antibody cross reacting with the new virus but 33% of adults over 60 did. And a few people in all age groups showed seroconversion after vaccination with one or the seasonal vaccines. Children had no measurable antibodies or response to seasonal vaccine against the virus. Whether these antibody reactions indicate protection is still unclear. On the other hand, it is possible there is additional protection from antibodies not measured by the assays used in this study. In any event, this is at least some data consistent with the residual immunity hypothesis. If that's the case, where would this immunity have come from?

The two main possibilities are from past infection with one or more H1N1 viruses that cross-react with the novel swine flu virus; or protection brought about by previous vaccinations (before 2005). It sounds as if CDC might be looking into the possibility that using more sera and a finer gradation of age categories could allow it to pin down the years when any protection may have been acquired. The lack of protection afforded by recent seasonal vaccines is not such a surprise. Those vaccines are very much like the recent seasonal strains (97%-98% amino acid sequence identity in the hemagglutinin protein) but only 72%-73% identity for the swine flu virus. It is likely similar results would hold for earlier H1N1 strains, at least post-1977, when H1N1 reappeared after an absence of 20 years to co-circulate with the H3N2 seasonal flu virus, but we don't know that yet. 47 million people were vaccinated with a swine flu vaccine in 1976. That strain was different, but it could conceivably be playing a part.

One suspicion is that the H1N1 that suddenly "came back" in 1977 was different from the H1N1 circulating before the H2N2 pandemic of 1957. The swine influenza virus of that era was originally from humans that jumped to pigs after the 1918 pandemic. It remains a mystery where the 1977 virus came from, but in 1978 Peter Palese's lab in New York discovered it was closely related to a Russian virus isolated in 1950. Vincent Racaniello, whose Virology Blog is always worth reading, picks up the story:

Influenza viruses of the H3N2 subtype were still circulating in humans in May of 1977 when H1N1 viruses were isolated in China and then Russia. In the winter of 1977-78 the H1N1 viruses caused epidemic infection throughout the Northern Hemisphere. The results of serological tests indicated that the HA and NA glycoproteins of the 1977 H1N1 viruses were very similar to those from viruses of the same subtype which circulated in 1950. Palese’s group compared viral RNA of one 1977 isolate, A/USSR/90/77, with RNA from a virus isolated in 1950. To their surprise, the two viral RNAs were highly related. In contrast, there was less similarity between viral RNAs from the 1977 H1N1 virus and H1N1 viruses that circulated in humans between 1947 and 1956.

Why were the viral genomes of the 1977 H1N1 isolate and the 1950 virus so similar? If the H1N1 viruses had been replicating in an animal host for 27 years, far more genetic differences would have been identified. The authors suggested several possibilities, but only one is compelling:

. . . it is possible that the 1950 H1N1 influenza virus was truly frozen in nature or elsewhere and that such a strain was only recently introduced into man.

The suggestion is clear: the virus was frozen in a laboratory freezer since 1950, and was released, either by intent or accident, in 1977. This possibility has been denied by Chinese and Russian scientists, but remains to this day the only scientifically plausible explanation.

[snip]

I was a Ph.D. student in Peter Palese’s laboratory when Katsuhisa Nakajima and Ulrich Desselberger did the work in 1978 that revealed the close identity of the H1N1 strains with isolates from 1950. It revealed to me, for the first time, how an important finding creates enormous excitement in the laboratory and in the scientific community, and how general interest is fueled by the press. (Vincent Racaniello, Virology Blog)

Red meat for the tin foil hat brigade, I know. I can't help that, although I am girding myself for the result. But even for the rest of us, a little mystery and intrigue goes a long way to spice up a dreary recital of all the things we don't know and can't predict. And it is an interesting question with possible practical consequences.

More like this

While I'm at it, here are a few other recent posts about modulating our thinking about the swine flu outbreak that is a) so far less horrid than our worst fears and b) still working its way around the globe, as it may well be doing for some time to come. Greg Laden notes that nothing has changed…
A new paper has just appeared in PLoS Medicine on an old topic: whether seasonal influenza vaccines might also cause enough cross-reactivity to protect against H5N1. The basic idea is simple. The immune system "sees" the surface proteins on the flu virus and makes protective antibodies against them…
We continue to learn a great deal about influenza infection as researchers harvest information from the recent swine flu pandemic. The pork producers don't like to call it "swine flu" but it may well be that its long sojourn in that animal since 1918 (did we give Spanish flu to pigs or did pigs…
Since I started cogitating on the apparent dominance of H1 subtypes this flu season instead of the more common H3, I've continued to look at some previous papers on the subject. The take home message I am getting is that there is quite a bit we don't know about this disease, influenza, despite its…

It remains a very interesting anomaly why those over age 55 were spared during the 1918 pandemic and appear to be during the current Mexican Flu pandemic. Like everything else about influenza, this is one are ripe with speculation but few facts.

Here is another speculation: The reason for those over age 55 being relatively protected has nothing to do with their exposure to a influenza strain in the past that provides them with partial immunity.

I will have more to say about this later.

Grattan Woodson, MD

By The Doctor (not verified) on 22 May 2009 #permalink

'The reason for those over age 55 being relatively protected has nothing to do with their exposure to a influenza strain in the past that provides them with partial immunity.'

I agree Dr. Woodson...in part because there are way too many diseases that are confused with 'stomach flu' etc.

If influenza is a more sporadic disease and coupled with the viruses inherent ability to harness its genetic instability, then immunity isn't the answer.

I'm not sure that it is more a factor of personal habits coupled with probability of infection...

...but it is another good way to quiet the masses...for the moment.

I know that in other organisms, a particularly "fit" genotype/phenotype will stabilize, sometimes over long periods. Is it possible that the viral strain was a) well-suited to some reservoir that hadn't been recognized, and b) rarely was given an opportunity to jump to humans, so could "disappear" for long periods? Not likely, perhaps, but a possible alternative to being released from a lab...

Hat Tip Wise Revere,

Because of my North American Autochtone physical origins, OjibWay (Pontiac was our Icon Grand Chief).

Having been confronted to the realities of epidemics and for us, the First Nations of the American Hemisphere we experienced it as an InHumane Bulldozers, our Contemporary calls it 'pandemic' by Today Scientists Standards.

When we look at these seeds of morbidity and mortality, isolate, manipulate, distributed, stored, studied, on and on by so many people, it just cannot be pure immunity so certainly in many cases it has been release in WirldWinds of replications, for some resons...

At daily Kos about 2 weeks ago, I was not capable of not writing and shouting "..and fu...the conspiracies.

And here is why, I happenned to have done 'deep' immersion in India and Chinese Rich Cultures. In these two Cultures I see the same look in Iroquois when pandemic is evoke.

Conspirationists seem to ignore it or just don't care of the effects it has for 2 billions people at least, I did not insert African Atmosphere.

But Revere Editorial did not evoke fear, this is something seldom, therefore what's the use of moping if it still leak.

I heard a pretty Good Shaman Once said;
"Paranoia has a narrow relation with imputability"

The Pragmatism of an inquiry of such a Public Health WatchDog has numerous advantages for the Public Health, Infrastructures,economies for Government (Feds, States, Provincials and Territorials)

First Nations knowns by experience that HHS Secretary Sebelius has the Hearth at the Righ Place as we say here.

Therefore Honorable Public Health Leaders should Gathered and explain why this inquiry should be done.

Many are tired of mopping.

Snowy

Coverage of Swine Flu now fading
http://www.dailykos.com/user/Snowy%20Owl

Grattan Woodson, MD, "It remains a very interesting anomaly why those over age 55 were spared during the 1918 pandemic and [also currently] appear to be during the [H1N1/2009] pandemic... I will have more to say about this later."

Dr. Woodson, thank you for pointing out the 1918/2009 generational anomaly. I've wondered about this myself when reading the May 21 '09 CIDRAP News article by Lisa Schnirring re: "findings from scientists at the US Centers for Disease Control and Prevention (CDC) appearing in tomorrow's edition of Morbidity and Mortality Weekly Report (MMWR)..."

Might generational differences in sialic acid production be a factor!?! Might sialic acid receptors in the respiratory tract -- potential binding sites for H1N1/2009 and H5N1 influenza -- play a role in generational rates of infection susceptibility!?!

By Jonathon Singleton (not verified) on 22 May 2009 #permalink

Darby: It is possible, but as you say, "not likely." That is why the lab explanation is considered "most likely" by some. Flu virus is a notoriously sloppy reproducer and even in the same individual host one finds genetic variation.

Jonathan: Evolution doesn't work that quickly (one or two generations). So this isn't the explanation (evolution of the host).

Revere, I was just thinking about H5N1 and applying it to H1N1/2009... I was thinking about hormonal production not evolution.

Maybe I should clarify:

I meant to write, "Might age group differences in sialic acid production be a factor!?! Might sialic acid receptors, or lack thereof, in the respiratory tract of different age groups play a role in H1N1/2009 infection susceptibility!?!

By Jonathon Singleton (not verified) on 22 May 2009 #permalink

The answer to the question may reside with young people who die of seasonal influenza and pregnant women who are very susceptible to pandemic influenza.

Both have higher relative metabolism and both probably have higher relative body temperatures to older persons.

The children who die of seasonal influenza with disease progression identical to others with pandemic influenza must have an X factor that makes them particularly susceptible.

This X factor may or may not be multi-factorial but since it probably is not strictly related to body temperature then it could be a combination of body temperature and meetabollic byproducts etc. etc.

I still believe that the cytokine storm is a normal immune reaction to a hyper-infection where the virus is for some reason allowed to infect a much higher number of cells so that when the immune system is turned on, it just does what it does best...except in this case it kills too many cells destroying lung-organ function...

...the immune system wins the battle but loses the war...as the patient dies.

Reveres--any thoughts on where a person might get tested for cross-reactive antibodies? I keep wondering if the really bad flu I had in my 20's was an H1 variety since the seasonal flu that year was mostly mild.

By Lisa the GP (not verified) on 22 May 2009 #permalink

Lisa: No, this is not a conventional assay. It would have to be done in a research lab specially for this purpose.

A couple of things that happened in '77 that are of interest are :

Nuclear-Proliferation Pact Signed
On September 21, 1977, The Nuclear-Proliferation Pact was signed by 15 countries, including the United States and the then, USSR, which was to "curb" the spread of nuclear weapons.

and....

Neutron bomb funding began
The Neutron bomb was an atomic weapon designed to spread radiation to kill people and leave buildings intact.

Flu leaves buildings intact.....

Will normal tin-foil work or does it need to be heavy weight?

Continued speculation on the unexplained difference in morbidity and mortality between young adults and older adults during influenza pandemics

First a stipulation: there could be some role for residual immunity as pointed out by Revere above. For the sake of discussion. lets suppose there is a 33% cross reactivity in older adults with the newly emergent pandemic virus. While significant, this is not high enough or specific enough to explain the observations, IMO.

Speculation #1)the reason for the difference probably lies primarily with the host not the virus, although it takes two to tango.

Speculation #2) the reason is do the effect of aging on the body. Since older people are aged by definition, this speculation is consistent with the observed facts.

Comment: What is aging? Well, this is something else we don't understand as well as we would like but one feature of aging is the imperfect DNA reproduction during life as the body replaces itself (The Hayflick Phenomenon). While we were taught in high school that this process was perfect, the facts are different. Tissue replacement occurs about every 7 years on average. This imperfect process results in DNA errors that are stored in the DNA of the daughter cells and these errors are faithfully reproduced when these body cells replace themselves again and again. Of course, there are new imperfections occurring every time this process is repeated, all adding up to a considerable quantity of partially defective but still functional tissues, enzymes, and proteins as we age. There are other reasons for the DNA to be copied imperfectly like exposure to carcinogens and infection by viruses other than flu.

With this background then, the speculative thesis would go something like this: The influenza virus is perfectly evolved and adapted to members of the mammalian and avian species. Throughout all the prior millennia this tight relationship has been maintained.

During past pandemic and seasonal flu, the vast majority of the adult members of the human species have been what we would call young today with very few living past 32 years of age. Humans this age have very little aging changes. Adults over 55 yrs have a great many aging changes.

As pointed out by Johnathan for example, sialic acid could well be affected by this process causing it to be just a little different than the "perfectly" produced form seen in young adults and older adolescents.

In virology, small changes can make big differences. In the older adult, sialic acid or any of a large number of proteins and enzymes the influenza virus relies upon for entry, reproduction and exit from the host cell have all undergone the Hayflick Phenomenon to a greater of lesser extent. So while the virus is perfectly adapted to the older adolescent and young health adult, it may not be so perfectly adapted to the aged adult with all their imperfections. It is this lack of perfect fit that may play a role in the age-related anomaly in morbidity and mortality rates seen between these two groups.

These comments are not meant to deal with the difference in mortality rates between infants, children and young adolescents compared with older adolescents and young adults. This is another age-related anomaly.

In terms of M&M these younger groups have greater M&M than seen in the older adults but much less than older adolescents and young adults.

IMO, an entirely different explanation is likely to be responsible for this anomaly. In these groups it is my speculation that the difference is related to the thymus and its control of the immune response. Immune tolerance is a characteristic of young people whose thymus is functioning and this might be a protective factor for them compared to older adolescents.

What would define the difference between an older adolescent and a younger one and partially explain the difference in M&M between these two would be thymic involution. When the thymus involutes, the individual has a "mature" immune system and enters the high risk group for pandemic influenza M&M.

I make this stuff up as I go along!

Grattan Woodson, MD

By The Doctor (not verified) on 22 May 2009 #permalink

Apologies to all about the slowness and unresponsiveness of the site. Something is affecting the Sb server and all my sciblings are also tearing their hair out. I hope it will get remedied soon. In the meantime, you will sometimes get a notice your comment didn't publish but most of the time it did. Before submitting again, check to see if it went through.

Again, we're sorry for the inconvenience. It's driving me crazy, too, because the back-end is borked.

I have been the primary caretaker of my (elderly) parents for many years--which leads me to offer up the following personal observations. I would also like to follow up with some (most likely) shockingly ignorant (non-scientist type) questions based upon these observations.

Observations:
1.Older people are more likely to be advised to get seasonal flu shots.
2.Older people are more likely to comply with such advice and actually line up in supermarket parking lots to get said flu shots.
3.Older people are more likely than younger people (mathematically speaking) to have had many seasonal flu shots-- over the course of many flu seasons.
4.Older people are more likely to be advised to get pneumonia vaccines, and also more likely to comply with that advice.

Question:
Could the possible swine flu "age anomaly" be partially explained by a combination of any such observations?

I agree that it is not our conventional understanding that seasonal flu vaccination protects against swine flu, per se. However, I have also read about a possible "memory boost" that seasonal flu vaccination might provide to a person's immune response. Even if this "memory boost" theory counted as a statistically tiny factor--couldn't a tiny factor cascade into a statistically significant effect?

In other words, if one prior seasonal flu vaccine helps boost memory for one part of one flu strain, would 20 prior seasonal flu vaccines increase the odds--even ever so slightly--that there would be a broader,though not necessarily greater, boost in memory of influenza viruses in general? So, when swine flu jumps on board-- a consistently flu-vaccinated person's immune response isn't a "hey--I know you," sort of response like it would have been toward a seasonal flu for which he/she had been vaccinated, but instead, a "hmmm...you look a vaguely familiar" sort of response that results in a less successful invasion--even by a novel virus?

Is it possible that more experience with influenza viruses (via repeated seasonal flu vaccine as well as previous exposure) just counts for something--even when the strain is completely novel? Could it be that seasonal flu vaccines are good training exercises for influenza immune response systems?

If it is a possibility, would not such an advantage compound; less of an invasion by a primary flu virus may lead to a decrease in secondary bacterial and viral infections. And, for the older people who still get the swine flu--perhaps they are not as inclined to get a secondary pneumonia because they are more inclined to have had a pneumonia vaccination.

Or is this just crazy talk?

Just to add some more semi-informed and/or wild speculation, I'm wondering about 2 possible elements in the puzzle:

1. epigenetics. The folding, packing, and scaffolding of DNA has major effects on gene expression, and these epigenetic patterns can be vertically (and perhaps laterally, in microbes) transmitted even when genes themselves have not mutated or been degraded. [self-serving commercial: see my article on this at http://tinyurl.com/dnyymh] So maybe there are some epigenetic patterns common to geezers (aging Baby Boomers)and ultra-geezers that are different from those of younger cohorts and invisible to the normal antibody testing methods. Could epigenetics be driving the cytokine storm?

2. the human microbiome. Since I learned that humans are actually superorganisms comprising mostly bacteria, whose metagenomes are 99% microbial and 1% human, it seems obvious that the understanding of any pathological condition of a "human" must take into account the role of the microbial members of the organism. Have people who become very ill with H1N1 had their microbiota altered recently by antibiotics or other drugs? Could indigenous microbiota mount a concerted defense against invasive viruses under some circumstances? Or what about the hygiene hypothesis - too much cleanliness subverts proper immune system development?

Or is this also just crazy talk?

melbren: It's not crazy talk but, alas, it isnot consistent with the data we have. There seemed to be little in the way of a boost from seasonal vaccine in the older age group, at least for the last four faccine years. It remains possible that some previous seasonal flu strain is cross reacting. That's something we need to nail down. And the sparing of the older age group is a characteristic of all the flu pandemics of the 20th century, including those that occurred before there was any, or in later years, very much in the way of vaccination.

There are a number of possible explanations for the effect and it is hard to tell them apart because the data are so scarce. We'll just have to wait for the evidence and hope it comes quickly. Unfortunately because people don't like to pay taxes (even though the US tax rate is relatively low), we don't have the data that a better surveillance and public health system might have provided. That's one of the hidden taxes that people don't admit to when they cut services.

valerie: No, not crazy talk. But at the moment, just talk. We need some data and I'm willing to wait for it. But I don't want to discourage scientific speculation from commenters, as long as its reasonable and responsible and interesting. This is a science blog. But conspiracy theories not welcome. Tin foil hatters have plenty of sites where they can hold forth, but I don't want this to be one of them.

The elder sparing effect is even more puzzling since I think I remember seeing somewhere (multiple places) that the older people get, the less immune response they mount to vaccinations.

So vaccinate, test for antibodies, don't get very many, but in general older people are spared in pandemic flu?

Or is there some selection going on; older people who get sick easily GET the flu vaccine (or join studies of same) with very little benefit while the tough oldies don't bother...and outlive us all.

older people dont go out to work or school and sadly, they mostly associate with other elderly. Maybe their exposure is less?

Valarie said:

geezers (aging Baby Boomers)

Damn! I had hoped to avoid geezerhood for a few more years...

Oops - Valerie... (Maybe geezerhood is closer than I thought.)Y'all have a good weekend.

Valarie : "the human microbiome. Since I learned that humans are actually superorganisms comprising mostly bacteria, whose metagenomes are 99% microbial and 1% human, it seems obvious that the understanding of any pathological condition of a "human" must take into account the role of the microbial members of the organism. ........ Or what about the hygiene hypothesis - too much cleanliness subverts proper immune system development?"

I have thought this fact stated above. My self-contamination strategy is eating my home-made yogurt, raw garlic, ginger, salad, mint leaves, kimchi and miso soup sometimes uncooked.

So far so good.

Oop, I can not let out sashimi, twice a month.

Never send a conspiracy where a mistake will do the job equally well.

If the 1977 strain was an escapee from a Russian lab, the history of Russian biolab accidents (for example a fairly well-known one involving anthrax that produced somewhere from 75 to 100 human cases) tells us it was most likely yet another accident. Russia does some things exceptionally well, such as building robust space vehicles, but suffers from lack of diligence in other areas such as nuclear power and bioweapons & related.

--

Re. cofactors: never underestimate the power of stress to destroy health.

In Europe and Japan, people smoke like chimneys, drink like fish, and eat things that would make American cardiologists yell. Yet they have better health outcomes than USAers. Why? Better (public single-payer) health care, and lower stress levels overall.

Hypothesis: Older Americans have lower stress levels than Americans in the prime working age range.

Hypothesis: Stress levels correlate positively with M&M.

The simplest operationalization for this would be to put a single question on the intake form for flu cases in hospital: "How much stress do you have in your life? a) little to none, b) less than average, c) about average, d) more than average, e) far too much." Then watch the outcomes in terms of days hospitalized, severity of measurable symptoms e.g. number of vomits during the course of illness, number of days of temperature above X degrees during course of illness, number of pain pills dispensed by pharmacy during course of illness, etc.

And/or has anyone done this one already?

Could it be that heightened H1N1 susceptibility is correlated with susceptibility to other things, and by age 65+, those particularly susceptible to a range of illnesses are more likely to have died off?

Elizabeth: Not plausible. It is the over 65s that get hit by seasonal flu, which would not be the case under your hypothesis. Pandemic strains have different age distributions, and this is an example.

I was wondering why people really think that this is an outbreak? lets just look at the stats. Yearly about 3-5 million people across the world get infected with the "normal" flu, compared with the 28,774 people that have been infected with the swine flue. And anywhere from 250,000-500,000 DIE from the "normal" flu, whereas 144 people have died from the swine flu. Anyone else see any problem with the "pandemic" we now have? Right about half a percent of the people who get it, die. Compared to the 2% and upwards of the "normal" flu virus. So dont worry too much if you get it, you have a 99.5% of living. Im not one of those conspiracy theorist, just and average joe that noticed something. Please email me with your replies, I do want to hear what other people have to say

THERE WAS A VERY BAD FLU IN IRELAND AT XMAS , I WAS IN BED FOR A WEEK I WAS VERY TIRED WITH SHORTNESS OF BREATH , THERE WAS NO TALK OF THIS ?

By PAUL HENRY (not verified) on 22 Jul 2009 #permalink

THERE WAS A VERY BAD FLU IN IRELAND AT XMAS , I WAS IN BED FOR A WEEK I WAS VERY TIRED WITH SHORTNESS OF BREATH , THERE WAS NO TALK OF THIS ?

By PAUL HENRY (not verified) on 22 Jul 2009 #permalink