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on flu pandemics

a briefing document

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related documents on health

Index
on flu pandemics - introduction

the life and amibitions of a virus
the influenza virus
what to do if this current virus turns out to be a serious nuisance
is it a cold or is it flu?
on flu virus mutation
flu versus vaccines
how tamiflu works
on serious responses to flu and tamiflu effects
infection propagation and chain reactions
end notes

on flu pandemics

During the last few weeks, I have become interested in viruses and the immune system. Be warned that I am no expert [see linked article and reference below], but I find it all very fascinating, and thought this latest flu scare an interesting opportunity to write a little on the subject. As usual, I shall probably develop this as the notion takes me.

the life and amibitions of a virus

A successful bug has several problems to solve, if it is to have a long and happy life, and to leave many descendants to carry on its dynasty and good works. What a good virus does not do is kill you outright, it doesn’t even want to send you to bed. It wants you out there, spreading its babies. Viruses are not out to get you, they just cause their annoyance by getting on with their normal lives, eating cabbage with a side order of braised human. It is very inconvenient for the virus if you die, thus influenza has far more descendants running around the planet than ebola.

Viruses tend to specialise in terms of which part of you they fancy. Some go for the mouth-faecal route, some go from generation to generation through birth and mother’s milk, while others are rather keen on sex and snogging. The flu virus is a brilliant piece of engineering and chooses your breathing apparatus. click to return

US deaths from the 1918 flu pandemic. Source: cdc.gov
Figure 2
US deaths from the 1918 flu pandemic. Source: cdc.gov

As you will see from the graph, even at the peak fatalities of the 1918 killer flu, only approximately 1 in 100 of thirty year-olds were dying (that is, 99 in 100 were surviving), while the numbers among infants and the ancient were considerably higher.

the influenza virus

As you will notice, flu normally only kills those with an immature immune system or those over 65 with an immune system that is wearing out. In the USA, 80% of deaths from influenza are normally amongst those over 65. Most deaths are caused by secondary infections, particularly pneumonia. What is strange about the 1918 second wave was that it killed a large percentage in the 20-40 year old age group. This is still not understood.[1] One theory is a violent reaction by the immune system [for those interested, look up cytokine storm] among those at the peak ability of their immune system - a great deal of the misery that you feel from a flu attack is your immune system fighting the invader. Another possibility is a large number of young men crowded together in unhealthy conditions at the end of the war.

Influenza is what Sompayrac calls a hit-and-run virus. It dives into your body does its thing, mutates rapidly and then your immune system kills it off. Influenza is spread by the extremely efficient route of droplet infection by coughs and sneezes. It then continues to mutate and, in a year or two, or three or four, it’s back again for another trip in a form sufficiently mutated that your body takes a while to recognise and smack it down again, by cranking up the adaptive immune system memory to send the virus again on its travels.click to return

 

“Why Did the 1918 Virus Kill So Many Healthy Young Adults?”

“The curve of influenza deaths by age at death has historically, for at least 150 years, been U-shaped (Figure 2 - see above), exhibiting mortality peaks in the very young and the very old, with a comparatively low frequency of deaths at all ages in between. In contrast, age-specific death rates in the 1918 pandemic exhibited a distinct pattern that has not been documented before or since: a "W-shaped" curve, similar to the familiar U-shaped curve but with the addition of a third (middle) distinct peak of deaths in young adults ?20–40 years of age. Influenza and pneumonia death rates for those 15–34 years of age [2] in 1918–1919, for example, were >20 times higher than in previous years (35). Overall, nearly half of the influenza-related deaths in the 1918 pandemic were in young adults 20–40 years of age, a phenomenon unique to that pandemic year. The 1918 pandemic is also unique among influenza pandemics in that absolute risk of influenza death was higher in those <65 years of age than in those >65; persons <65 years of age accounted for >99% of all excess influenza-related deaths in 1918–1919. In comparison, the <65-year age group accounted for 36% of all excess influenza-related deaths in the 1957 H2N2 pandemic and 48% in the 1968 H3N2 pandemic (33).

“A sharper perspective emerges when 1918 age-specific influenza morbidity rates (21) are used to adjust the W-shaped mortality curve (Figure 3, panels, A, B, and C [35,37]). Persons <35 years of age in 1918 had a disproportionately high influenza incidence (Figure 3, panel A). But even after adjusting age-specific deaths by age-specific clinical attack rates (Figure 3, panel B), a W-shaped curve with a case-fatality peak in young adults remains and is significantly different from U-shaped age-specific case-fatality curves typically seen in other influenza years, e.g., 1928–1929 (Figure 3, panel C). Also, in 1918 those 5 to 14 years of age accounted for a disproportionate number of influenza cases, but had a much lower death rate from influenza and pneumonia than other age groups. To explain this pattern, we must look beyond properties of the virus to host and environmental factors, possibly including immunopathology (e.g., antibody-dependent infection enhancement associated with prior virus exposures [38]) and exposure to risk cofactors such as coinfecting agents, medications, and environmental agents.

'Mixing in the pig' results in a hybrid virus that can successfully infect humans. 'How pathegenic viruses work'
“ ‘Mixing in the pig’ results in a hybrid virus that can successfully infect humans.”
From How pathogenic viruses work

Avian flu is an enteric disease, whereas in humans flu is a disease of the airways. Pigs kindly mix them together for us, producing new and exciting variations for our enjoyment. This mixing is inclined to happen in poor areas where animals and humans live in close proximity. Hence the tendency for these infections to come roaring out of Asia, and now Mexico.

“One theory that may partially explain these findings is that the 1918 virus had an intrinsically high virulence, tempered only in those patients who had been born before 1889, e.g., because of exposure to a then-circulating virus capable of providing partial immunoprotection against the 1918 virus strain only in persons old enough (>35 years) to have been infected during that prior era (35). But this theory would present an additional paradox: an obscure precursor virus that left no detectable trace today would have had to have appeared and disappeared before 1889 and then reappeared more than 3 decades later.

“Epidemiologic data on rates of clinical influenza by age, collected between 1900 and 1918, provide good evidence for the emergence of an antigenically novel influenza virus in 1918 (21). Jordan showed that from 1900 to 1917, the 5- to 15-year age group accounted for 11% of total influenza cases, while the >65-year age group accounted for 6% of influenza cases. But in 1918, cases in the 5- to 15-year-old group jumped to 25% of influenza cases (compatible with exposure to an antigenically novel virus strain), while the >65 age group only accounted for 0.6% of the influenza cases, findings consistent with previously acquired protective immunity caused by an identical or closely related viral protein to which older persons had once been exposed. Mortality data are in accord. In 1918, persons >75 years had lower influenza and pneumonia case-fatality rates than they had during the prepandemic period of 1911–1917. At the other end of the age spectrum (Figure 2), a high proportion of deaths in infancy and early childhood in 1918 mimics the age pattern, if not the mortality rate, of other influenza pandemics.”

click to return There’s plenty more in the quoted article. I’ve no time to read it closely at present.


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what to do if this current virus turns out to be a serious nuisance

The numbers of cases are far too low at present to give a clear idea whether this latest outbreak is a serious threat, or just another passing bus. the bug is obviously acting very differently in Mexico than elsewhere.

  1. Anti-viral drugs taken within the first 40 hours of symptoms appearing will not stop the disease, but are likely to attenuate it. After that, they are useless. The two best known are Relenza (which is inhaled) and Tamiflu (taken orally).
  2. Wash your hands regularly well with soap and water for at least 30 seconds. The virus can be picked up from surfaces, including skin. The virus is happy on surfaces as long as it is still damp, which usually means about an hour. The flu virus is very vulnerable to detergents.
  3. Wear a mask when in company.
  4. Don’t go out and spread it around (social distancing). Doctor’s waiting rooms, crowded aeroplanes, schools and supermarkets would not be desirable locations to frequent.
  5. You will know that it is probably not an ordinary cold if your temperature goes over 100.2°F/ 37.8°C. Ordinary colds do not tend to cause fever. click to return

 

is it the common cold or is it flu?

The common cold is often confused with influenza, but is a very different animal. The common cold (rhinovirus) is normally seen off by your innate immune system within a week of invasion. The adaptive immune system is never activated. Consequently, you don’t gain immunity to the common cold so it is regularly back for another round of fun. This virus tends to infect Westerners, on average, once a year.

Both the flu virus and the rhinovirus seek out your airways, but in very different areas. Both these viruses can’t tolerate the acids and enzymes in your digestive system. Consequently, evolution has provided you with a marvellous traffic system. Cilia in the upper respiratory tract brush detritus downwards towards the throat; whereas below that level, cilia run an up escalator towards the throat. At which point, you either swallow the rubbish into an acid bath or spit it out, we hope, into a tissue and not on the street!

The rhinovirus doesn’t like your body temperature, so prefers your upper airways, in your head, where the temperature is about 91°F/32.8°C. The flu virus prefers body temperature (98.6°F/37°C). So the rhinovirus will not raise your temperature, and the old wives’ saw of keeping warm to “not catch your death of cold” has some merit. The common cold will just make you feel ‘rotten’; flu is likely to make you feel doubleplusungood rotten, aching muscles, aching bones, which drives all sane people to bed for four or five days. Notice, even here your own genes knows what’s best for you and for everyone else. In bed, your system isn’t wasting time and energy running marathons, but is working overtime to kill the foreign army. Nor is it so easy for the critters to spread around.

Both these viruses can leave you open to secondary, usually bacterial, uninvited guests, and they will normally raise your temperature; or even turn a nuisance into a danger. But yet again, the dangers are far greater with flu.click to return

 

on flu virus mutation

Various viruses use DNA, RNA or negative RNA to carry their genetic data. The flu virus uses eight strands of negative RNA. The polymerase used to copy the RNA is subject to making many errors. This is much to the advantage of the virus as it tries to outwit immune systems. The virus changes in two main ways.

The first is called antigenic drift. Occasional mistakes are made in copying the RNA. Thus the long strings of RNA gradually vary, first by one place, then by another at random.

Now most human cells display short strands of the various chemicals found within the cell, on the outside of the cell on specialised ‘billboards’ [MHC molecules]. If your immune system has previous experience and recognises one of these strings as enemy action, war against the invading virus will rapidly crank up.

But if the sequences have been sufficiently changed that the small strands are not recognised, the flu virus gets a head start and you’re off sick for several days until the adaptive system gets its full armament factories going, and other methods of attack.

The innate immune system starts to realise that something is wrong when cells start pumping out cytokine [messenger] interferon and cells start dying. This gradually winds up the adaptive immune system over a period of about a week.

The second nasty trick is called antigenic shift. This happens when the virus manages to swap a complete RNA strand. This happens when two sustantially different variants of the virus get into the same host. Thus an example is when an avian RNA strand replaces its equivalent strand in a human flu virus while both are inside a pig. When this shift happens, it becomes particularly difficult to predict what delightful surprises the new virus may have in store.

The eight RNA flu virus strands are labelled:

H hemagglutinin
N neuraminidase
NP three nucleoproteins
M four matrix proteins plus two ion channel proteins
NS two non-structural proteins
PA sub-unit of RNA polymerase
PB1 sub-unit of RNA polymerase
PB2 sub-unit of RNA polymerase

Thus you may hear references to H1N1 flu, H5N1 flu etc., referring to the two first strands listed above. These are the genes expressed on the surface of the virus, and are, thus, most relevant to immune system response.

The following is taken from an excellent and clear discussion [5-page .pdf] of flu virus resistance through mutation, relative to Tamiflu (Oseltamivir)

“According to antigenic properties, influenza virus has two functional surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). So far 16 subtypes have been identified for HA (H1 to H16) and 9 for the NA (N1 to N9)”

From the World Health Organization, A revision of the system of nomenclature for influenza viruses, WHO Memorandum Bulletin 58 (1980) 585–591:

“The A in HA refers to an a type virus. There are 3 types of human influenza viruses, labelled A, B and C. Influenza A is the most dangerous.”

For images of a model of part of the 1918 flu virus, and access to other virus model images.click to return

 

flu versus vaccines

Developing a vaccine specific to a particular form of ‘the flu virus’ will take about six months. First, the virus has to be sequenced/analysed.

The immune system seeks markers on the surface of the virus, and then sets about destroying it. The flu virus is a rapid mutator. It swaps about the markers. Some of those markers your body will probably have seen before if you are (say) middle-aged. An experienced immune system may start cranking up earlier, and repel the boarders before they get a grip. Vaccinations will also show the immune system some flu markers.

Each year, the vaccination made available is tailored for the variants forecast to be due that year.

The 2008/2009 vaccine usually contains the following three strains:

  • A/Brisbane/59/2007- This is an H1N1-like virus
  • A/Brisbane/10/2007- This is an H3N2-like virus
  • B/Florida/4/2006

It is expected that this will also be appropriate for the 2009/2010 vaccination. The swine flu variation, also a H1N1 A-type variant, is being dealt with by a separate new vaccination at the moment.

how tamiflu works

Tamiflu is a neuraminidase inhibitor! Here’s some of how it works.

Tamiflu and Relenza are sialic acid mimics to which the neuraminidase binds much more tightly than to real sialic acid. Neuraminidase is produced by the flu virus while it is working to escape the cell (the one it has infected). Getting out of the cell is a problem for flu viruses. The virus has to shave the sialic acid to escape the cell. The virus, instead of shaving real sialic acid to escape, winds up shaving the sialic acid mimic, Tamiflu or Relenza. If it didn’t shave off the sialic acid, the flu virus would get sort of glued to the infected cell.

By the time the viruses are out of the cell, Tamiflu is too late. Thus the 40-hour time limit for its use.

As with vaccinations and acquired immunity, the flu virus is capable of mutating to head off these antivirals.

 

on serious responses to flu and tamiflu effects

Summary from three recent studies.
My impression is that the whole system is becoming more responsive, and that flu is not going high in priorities as other more annoying diseases are coming under greater control. Anti-virals is becoming an advancing area of study as were antibiotics many decades ago.

“Many patients in all three regions were also given the flu medication oseltamivir phosphate (Tamiflu), with apparent benefit. In the Mexican analysis, critically ill patients who survived were seven times more likely to have received the drug than those who died.

“All three groups of critically ill patients included very few people over the age of 60 and few young children. The numbers support a widespread hypothesis that older people carry some residual immunity against H1N1 flu, Fowler says. The new data don't explain why very young children were underrepresented in these critically ill groups.

“On the other hand, the data fail to explain why people in the prime of life would be most susceptible to the lethal effects of H1N1, a trend eerily reminiscent of the 1918 flu pandemic, which was also caused by an H1N1 strain.” [Quoted from sciencenews.org]

There are two main strains of flu virus, named A and B. A includes the H1N1 strain. Meanwhile, flu mutates like billyo in normal circumstances.

The present main concerns are with the recent H1N1 strain (‘swine flu’) and Tamiflu.

“Which antiviral drugs should health care providers prescribe for chemophrophylaxis of 2009 H1N1?

“For antiviral chemoprophylaxis of 2009 H1N1 influenza virus infection, either oseltamivir or zanamivir are recommended. Currently, circulating 2009 H1N1 viruses are susceptible to oseltamivir and zanamivir, but resistant to amantadine;” [Quoted from cdc.gov]

  1. Last year there was a Tamiflu-resistant H1N1 strain. I repeat, flu mutates like billyo!!
  2. There is no time to test in the window between infection and treatment. Thus, best recommendations are made, rather than 100% prescriptions to medics.

Once it is decided which strain of flu virus is being discussed, then suitable treatments can be suggested, but as the window is longer than testing times and there are several variants around at any one time, it is a matter of guesswork which vaccinations or anti-virals are relevant.

Tamiflu is a neuraminidase inhibitor. There are two of these so far FDA approved, with trade names Tamiflu and Relenza. There are two other treatments used for flu called adamantanes, they are Amantadine and Rimantadine. These latter two are not deemed useful for B viruses (H1N1 is an A virus), and the H3N2 virus currently circulating is resistant to them.

As you will have noticed, there was an H1N1 virus around last year that was resistant to Tamiflu, while the present H1N1 (‘swine flu’) resistance has not been found - yet. The ‘N’ molecule (neuroamidase) is made up of about 467/8 amino acids. Now these complex (neuroamidase) molecules fold predictably according the amino acid sequence. Keeping in mind that the flu virus relies on rapid mutation, certain random changes in the amino acid sequence can result in the Tamiflu molecule not fitting tightly enough, or as accurately, and thus may fail to block/disrupt the neuroamidase action of the virus. This is approximately how resistance to a substance like Tamiflu develops.

Of course, a change in the neuroamidase may also make the virus ineffective - typical evolution in action. Meanwhile, the biochemists are understanding the little beggar ever better and are working on improving the inhibitor molecules and on developing new attacks on the virus.

These drugs are fall-backs if vaccination does not work, or if the current flu version gets a start. (It takes about six months to obtain a useful vaccine.) Each year, the medical warriors are trying to keep ahead or get ahead of flu, but flu is a very crafty and agile monster.

click to return

infection propagation and chain reactions

"Many factors contribute to the R0 [the reproduction number, or how contagious is a infection], such as how long you're infectious and how many virus particles are needed to make another person sick."
[Quoted from npr.org/blogs/health]

This article should also have mentioned other variables such as population density (how manny people are available for infection per square metre), and how quickly an infection kills a host.

Successful infections are generally careful not to kill hosts. The 'best' ones mutate fast so they can have another go, for example flu and the common cold. Successful infections also try to keep their hosts alive and infectious for as long as possible, as with syphilis and HIV-AIDS.

The critical reproduction number is 1. Above 1, the disease steadily expands; below 1, it steadily dies out.

end notes

  1. pandemic
    An epidemic (a sudden outbreak) that becomes very widespread and affects a whole region, a continent, or the world.
    [Source: medicinenet.com]

  2. Caution is needed when comparing these figures with those of modern society. In advanced societies, in 1920 life expectancy was about fifty five years, a good twenty years lower than at present. Secondly, families were, on average, much larger and so the age distribution of the population was very different. Further, there were no antibiotics and care was at a lower level. Diet was also more impoverished, aggravated by the deprivations of war. Conditions were also more crowded, including conditions in the military forces.


  3. Overtreated by Shannon Brownlee

    How Pathogenic Viruses Work by Lauren Sompayrac

    Jones and Bartlett Publishers, Inc, 2002
    ISBN-10: 0763720828
    ISBN-13: 978-0763720827

    $31.45 [amazon.com]

    10.99 [amazon.co.uk]

    Highly recommended as an intelligent first primer.

  4. I have seen estimates of between 20 and 100 million killed by the 1918 flu pandemic. The preponderance died in India. The reality is, nobody has much idea of the real numbers.

  5. On viruses or virii
    As an uncountable, or mass, noun, like rice or air, the word virus has no separate plural form. As a Latin second declension neuter noun ending in -us, the word virus does not decline to become something different in the plural. If the word virus did decline, as a second declension noun, its plural would be vira. The form virrii as a plural word, would imply that the same word in its singular form was virius, a word that does not exist in Latin.

    The Latin word virus probably originates from the Sanskrit visam, meaning poison, and is related to the Latin viscum, meaning sticky substance, birdlime, and the ancient Greek ios - poison and ixos - mistletoe, birdlime.

click to return


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