MicrobiologyBytes

Rocketboom reports:

I’ve been neglecting influenza recently, and although the media may have lost interest in H5N1, people are still dying (latest data) and the threat of a pandemic has not gone away. So Maria Zambon’s review article in Nature Biotechnology is required reading (Lessons from the 1918 influenza. 2007 Nature Biotechnology 25: 433-434 subscription):

Finding a final common cellular pathway that explains the virulence of different influenza A subtypes in humans will be important for understanding the severity of human or zoonotic infections. Although a unifying hypothesis is some way off, identification of specific host genes switched on early in infection is essential for pinpointing prognostic indicators of disease severity. Immune intervention strategies are badly needed for treatment of zoonotic H5N1 and may ultimately be simpler to apply than antiviral regimes, which are currently the only countermeasure available for severe influenza infections, whether human or animal in origin.

Influenza H5N1 is still centered in the Far East, and so in the absence of an effective vaccine, antiviral drugs such as Tamiflu (Oseltamivir) are the main weapon against the virus. Unfortunately, there are some problems with using Tamiflu, particularly in Asia (Side effects of Tamiflu: clues from an Asian single nucleotide polymorphism. 2007 Cell Research 17: 309–310):

Tamiflu (Oseltamivir phosphate) seems to be a double-edged sword to some in Asia. While it is counted on against influenza and a feared avian influenza pandemic, the drug is also associated with side effects, ranging from neuropsychiatric, gastrointestinal, to hyperthermia and skin problems. According to a document from US Food and Drug Administration in 2005, 1184 cases of side effects have been reported. Interestingly 69 out of the 75 pediatric cases were from Japan, including two teen suicides. The situation seemed to have made a gloomier turn recently. It was reported in February, 2007 that two Japanese teenagers jumped from apartment buildings after taking Tamiflu and died, bringing the total number of deaths after taking Tamiflu in Japan to 54. Although no direct causal relationship had been established yet, the Japan Health Ministry warned doctors about giving the drug to teenagers. In comparison, relatively few cases of severe side effects were reported from America and European countries.

Are interactions with a single nucleotide polymorphism (SNP) in human cytosolic sialidase (HsNEU2) which occurs in 9.2% of Asian populations and, in striking contrast, not in Europeans and African Americans, responsible? The jury is still out at present…
Related:

• UK preparedness for pandemic influenza
• The Biology of Influenza
• Influenza pandemic – when?

In the worst case scenario, a pandemic of influenza in the United Kingdom would cause 750,000 excess deaths. In the short term, gross domestic product could fall by some 0.75%, and in the longer term the cost to the nation could be around £170bn (250bn; $350bn).
On 16 March 2007, the Department of Health and the Cabinet Office jointly published a new draft plan for pandemic flu. The plan builds on and replaces the October 2005 plan. It is supported by a range of additional documents related to acute hospitals, health care in the community, an “operational and strategic framework” for adults in social care, guidelines for staff in social care settings, ambulance services, and an ethical framework. Some documents offer strategic guidance, some offer operational guidance, and others guidance for individuals.

BMJ 2007 334: 965-996

Thanks to Keith for the pointer.

Influenza pandemics have been recognized for centuries, but the virus responsible was not isolated until 1933. Influenza virus particles are highly variable in shape. Mostly are spherical or oval and 80-120 nanometres (nm) in diameter, but long filamentous particles also occur (up to 2000 nm long). Different strains of virus vary in their tendency to form filaments – this property depends on the matrix protein of the virus, which lines the inner side of the virus envelope. The outer surface of the particle consists of a lipid envelope with glycoprotein spikes of two types:

Haemagglutinin (HA) and Neuraminidase (NA)

Influenza virus particles are quite fragile (they have a half-life of a few hours at room temperature), and are sensitive to drying out, sunlight and warmth. The core of the virus contains eight genome segments which consist of RNA as the genetic material plus a virus protein called the nucleoprotein or N protein.

• Influenza A viruses such as H5N1 infect a wide variety of mammals, including humans, horses, pigs, ferrets and birds. These are the main source of human infections and are associated with epidemics and pandemics. There are 15 known haemagglutinin (H) serotypes and 9 known neuraminidase (N) serotypes. Pigs and birds are believed to be particularly important reservoirs for influenza virus, generating pools of genetically and antigenically diverse viruses which may be transferred back to the human population via close contact between humans and animals.
• Influenza B viruses only infect mammals and although they cause disease, this is not generally not as severe as that cause by influenza A viruses. Unlike influenza A viruses, influenza B viruses do not have distinguishable serotypes.
• Influenza C viruses also infect mammals only, but as far as is known, do not cause disease. They are also genetically and morphologically distinct from A and B types.

Influenza viruses replicate inside host cells. Entry into the cell occurs when haemagglutinin spikes on the outside of the particle bind to receptor on the surface of the cell. This interaction can be reversed by neuraminidase spikes, which prevents the virus getting stuck on the wrong cell type.

• Online Experiment: Haemagglutination

After binding, the particle enters the cell where the RNA genome segments make their way to the nucleus. There, the proteins they encode are transcribed and expressed by three polymerase polypeptides carried in the virus particle. New virus particles which form at the surface of the cell bud out through the cell surface membrane and search for new cells to infect. Influenza virus is highly infectious and is spread is by aerosols – coughs and sneezes spread diseases. When a person becomes infected, the virus kills the cells it infects in the nose and throat. The debris released by these cells causes to body to raise an immune response and this is responsible for the symptoms of influenza: fever, chills, muscle aches and headaches. Infections usually last from 3-7 days. Deaths directly from influenza infection are rare, but damage to the lining of the respiratory tract allows secondary bacterial infections such as pneumonia to occur, which with most strains of influenza account for most deaths.

Several anti-influenza drugs exist. Amantadine and rimantadine are active against influenza A viruses (but not B viruses). Newer drugs such as Tamiflu and Relenza inhibit the neuraminidase protein of the virus.

Influenza vaccines are produced in infected hens eggs or sometimes in cell cultures. The problem is that influenza virus is highly variable and its antigenic composition changes frequently due to genetic changes. These processes are known as antigenic drift and antigenic shift. A vaccine directed against one type of influenza virus (e.g. H3N2) does not protect against infection with a different antigenic type (e.g. H5N1).

The 1918 “Spanish flu” pandemic killed between 20-40 million people. Scientists believe that another influenza pandemic is now overdue and likely to occur soon. In May 1997, a three year-old boy infected with influenza virus died in the intensive care unit of a Hong Kong hospital. This case was the first isolation of an influenza A subtype H5N1 in a human. Subtype H5 influenza viruses can cause lethal avian influenza (bird flu), a disease which can decimate flocks of domestic poultry. H5N1 influenza re-emerged in Vietnam late in 2003 and since that time has spread to many areas of the world, although it is still primarily an avian virus. Also worryingly, in March 1999 H9N2 viruses were isolated from two hospitalized children in Hong Kong. At the present time we do not know what the source of the next human influenza pandemic will be, so we are unable to prepare suitable vaccines.

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It’s getting fashionable to suggest that there may not be an influenza pandemic. The American Spectator says we should stop squaking over avian flu, and Mike the Mad Biologist thinks a pandemic is a low probability event, although he’s still worried about it.

An influenza pandemic is not a low probability event, it’s a certainty. Simple statistical analysis tells us this. The uncertainty is predicting when: this year, 10 years, 100 years time?

We’ve seen it all before:

And it might not be H5N1, it could well be H9N2, or even H2N2. The only certainty, as you can see from the timeline, is that it will happen sooner or later.

So what’s the worst that could happen?

• A pandemic of human-adapted avian influenza such as the H5N1 virus (or any of the others).
• Such a reassortant could easily have a mortality rate of 30-40%.
• Within a few months 10-25% of the world’s population could have been infected.
• 6.3 billion * 0.4 * 0.25 = over half a billion deaths.
• or worse …