Tuesday, 28 April 2009

Influenza - the basics

Seeing that the recent "swine flu" outbreak is catching the headlines, I thought I'd try to provide a little context - something inevitably missing from most of the terse news reports.

'Influenza' is the name of the disease caused by one of the influenza viruses.  Typical features are a fever, back and muscle aches, sore throat, headaches and a non-productive cough.  Usual strains of influenza cause an illness that lasts for about a week or two, and mortality is typically quite low - around 0.1%.  The usual cause of death is a superadded bacterial pneumonia (a bacterium, often Staph. aureus, takes advantage of the damaged lungs to cause infection there) but direct damage to the lungs by the virus is also fatal on occasion.  Mortality is highest at the extremes of age (the very old or young) and in pregnant women.

The virus is spread when a person inhales an infected respiratory droplet.  Usually, therefore, it is spread by coughs and sneezes, but the virus can also survive for short periods in the outside world, especially if encased by mucus or other secretions.  Thus, if you cough some infected droplets on to my table, I might manage to inhale them soon thereafter (probably by getting them on to my hands first, and then bringing my hands to my mouth to sneeze, eat, etc.) and still get infected. 

There are several major variants of influenza, and this is sometimes a cause of confusion. 
Influenza viruses are first divided into influenzas A, B and C, based on which version of a common antigen (the ribonucleoprotein, RNP) they have.  
  • Influenza A viruses cause epidemics and pandemics, and its natural hosts are wild aquatic birds.  However, these viruses can occasionally infect other species, including (sadly) ourselves.  Out of the three groups, influenza A viruses cause the most severe infections in humans.
  • Influenza B viruses can cause epidemics (not pandemics), and is almost entirely restricted to humans.
  • Influenza C viruses cause only small epidemics, and infect only humans and pigs; the disease is usually mild and mostly affects children. It is less common than the other two types.
Now let's back up a little to explain the terminology.  If large numbers of cases of a particular disease are found in a certain area, epidemiologists classify the pattern as endemic, epidemic or pandemic.  An endemic disease is one that is widely distributed within a particular area, but at a relatively common rate.  In other words, if malaria is endemic to Malawi, the incidence of malaria this year is roughly equal to that of last year, and can be expected to be roughly the same as next year's incidence too.

In the case of an epidemic, however, what you see is a 'spike' in the number of cases, such that significantly more people are contracting the disease in a particular area than would be expected from past years.  A pandemic is an extension of an epidemic, where the epidemic is unexpectantly seen across a very large area, such as a continent.

Why does A have the potential to cause a pandemic, whereas the others don't?  To answer that, we have to dig a little deeper.  Influenza A is further subdivided into numerous strains, based on the major variants of two glycoproteins on its surface: hemaglutinin ("H", which helps in binding the virus to the host cell and then inserting its genome) and neuraminidase ("N", which releases newly formed virions from the cell surface).  So far, we've discovered 16 types of H and 9 types of N, meaning that there are 144 combinations in theory.  The particular strain of influenza A is written as a combination of the H and N number, such as H3N2.  

Influenza A is mainly a disease of aquatic birds, and this is reflected by the fact that over 70 strains of influenza A are known to infect them.  By contrast, only a handful of strains (precisely 10, although most aren't significant) have the capacity to infect humans.  Why is "the 'flu" such a problem then - why can't we all quickly develop immunity to the major types, and never be troubled by them again?

As always with microbes, they simply evolve too quickly.  Although only 10 strains can infect humans, each of these strains evolves - sometimes a little, sometimes a lot - each year, so that they present a sort of moving target for our immune systems.  The strain of H3N2 infecting people "this" year isn't exactly the same strain (despite what its name says) as the strain of H3N2 that infected people "that" year.

There are two main mechanisms for change.  Antigenic drift is rather poorly named, but reflects the common process whereby small changes arise spontaneously and some end up being favourable to the virus.  The changes are usually favourable because they are sufficiently different from last year's strain to reinfect even those of us who developed immunity.  This new type therefore has an evolutionary advantage on the old one, and soon comes to dominate.  This process affects influenzas A, B, and C.

Influenza A can also change by means of a second method.  Antigenic shift is a rapid and dramatic change in its genome whereby two other influenza A strains can combine and form a sort of hybrid.  This new strain is likely to be so different from either of its predecessors that it can take the market (i.e. us) by storm, since our immune systems are caught totally unprepared. This is the reason that influenza A can cause large epidemics (and pandemics) and also why it often produces the worst symptoms, whereas the infections with B and C types are more small scale and/or milder.

One of the things that makes antigenic shift possilbe is that influenza A's genome is divided into 8 segments (see the red coils in the diagram above).  If two different strains infect the same animal at the same time, mixing can occur, creating the chance to form a new strain containing some genomic segments from each of the original strains.  For instance, and H3N2 and and H1N1 co-infection might create H3N1 as progeny.  Alternatively an H1N1 strain that only affects one animal (e.g. a bird) might exchange material with an H1N1 strain that affects a different animal (e.g. a pig).  In either case, this therefore a much more drastic change than the small scale tinkering that antigenic drift represents.  If this new hybrid strain happens to have the capacity to infect humans, the trouble begins.  The above diagram (from Wikipedia) summarises things nicely.

These new hybrids, formed by antigenic shift, only occur in influenza A because influenza A infects such a wide variety of animals.  Pigs, as it turns out, are often the main culprits, although by no means the only ones.  They are susceptible to avian influenza types, swine (pig) influenza types and human influenza types, and therefore are an accident waiting to happen as far as antigenic shift is concerned.  If a human influenza type picked up a few new antigens from one of the other types, the new virus would likely (a) still be able to infect humans, and (b) represent a significant antigenic change so that very few people would be immune to it.  It would therefore be a new strain of influenza to which we would be susceptible.  This is what happens from time to time in farm workers who work in close proximity to pigs.

This is not enough to cause an epidemic or a pandemic, however, since so few of us are in close contact with pigs these days.  Farm workers may suffer, but there's precious little chance of you or I getting sick from it.  However, if the virus is able to be transmitted from human to human (either from the outset, or more probably from further antigenic drift), then we have the possibility of a pandemic.

In the case of "bird flu" (or "avian flu"), we have the former situation: a rather new influenza A virus (H5N1) that kills birds by the flockful and that can, on occasion, infect humans too.  So far, we have no evidence that it can be spread from person to person, or we would be dealing with a large problem.  But this might well be, in some sense, only a matter of time. 

In the case of the newly diagnosed "swine flu", we may have breached this wall.  We appear to be dealing with a new strain of the old H1N1 influenza A virus; but one that is capable of human-to-human transmission.  It appears to be an assortment of human, swine and avian elements.  This is why the World Health Organisation is so worried right now, although there's still no reason to panic at the moment.

If you'd like to know more about the current swine flu epidemic, you can read the informative Wikipedia article, or else for a more humanised version, I'd recommend the Aetiology blog.

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