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Aviajn Flu Virus
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From the Lancet, Europe’s most esteemed medical journal

Europe wakes up to the threat of avian influenza
Ben Aris

It felt more like a war cabinet than a meeting of health professionals. But as the 130 delegates sat in WHO's European regional headquarters in Copenhagen 2 weeks ago (Oct 23-24), to discuss the long running problem of avian influenza virus H5N1, the daily news stories tracking the virus' advance across Europe gave the proceedings a sense of urgency.

"Can you be more specific?" lamented one harassed delegate from the Balkans who peppered the panel with questions. "You are giving us general guidelines, but I have to go back and see my health minister this week and I need to give him a concrete plan of action."

The vocabulary would have been the same if it were an army massing at Europe's eastern border. The scientists talked of making preparations in "peacetime". They studied the likely "attack rates" of the virus and the logistics of a response. They considered how long it would take to put the pharmaceutical industry on a war footing to make vaccine and what weapons we already have in our arsenal. There were even sessions on what sort of propaganda would be effective after the first wave of pandemic sweeps through Europe, largely unchecked. And of course they estimated the casualties.

"There are lots of unknowns but the experts emphasis that the possibility of a break out of the pandemic is sure", said Marc Danzon, the head of WHO's European regional office. "What is not known is when and where [it will strike first] . . . So we have to prepare the national health systems top face a potential crisis."

There is a lot of confusion too-at least in the public's mind. Avian influenza doesn't infect people easily. Millions have been exposed to the virus in Asia, but there are only 118 recorded infections (although the number of mild infections is almost certainly much higher). What is most worrying for health is that in half of these cases the victim died.

A human version of the H5N1 avian influenza may be less lethal in humans-or the pandemic may emerge from another strain entirely-and could take years to appear, but delegates were assuming the worst.

EU member states have been spurred into action as the bird flu marches across the globe like some apolitical giant. While most of western Europe has the resources to cope with an outbreak of a pandemic the poor countries adjacent to the EU are clearly worried.

"I tend to think that the pandemic virus is closer rather than further", said Massimo Ciotti, who worked on a WHO survey of preparations in member states. "We already have two out of the three features needed for a pandemic. The virus must be a new virus never seen before: we have it since H5N1 was detected in 1997. It must be a virus that infects humans and makes them very sick: we have it. And it must be a virus that learns to transmit itself easily and efficiently from human to human: we are not there yet."

If (or when) the pandemic breaks out, the prognosis is bleak. The best possible course of action is to prevent a pandemic ever appearing by stamping out avian influenza in birds. However, the virus is already it is entrenched in Asia and will take a decade to eradicate. Thanks to Europe's better animal husbandry techniques, Shigeri Omi, who head's WHO Asian office, says there is every reason to be believe avian flu can be contained in western Europe.

But if containment fails and the pandemic emerges then it will be almost impossible to stop it spreading around the globe within a few months.

The fastest industry can produce a vaccine is 6 months after the pandemic strain is isolated and there is no action government's can adopt that will slow the spread by more than a few weeks.

In the first wave of the pandemic (and several are expected) all effort is being concentrated on reducing the impact and mortality rates, but these measures rely on a very sensitive surveillance system, large stockpiles of drugs, and a logistic system that can deliver millions of courses of antiviral drugs within 2 days.

Fear the worst
Currently the world is in phase 3 of a pandemic where humans are infected, and only the cusp of phase 4 where the first human-to-human transmissions are seen.

Two cases of human-to-human transmission have been confirmed with reasonable degree of confidence (one died) and most experts at the conference assume it is only a matter of time before H5N1 "learns" to more between people more efficiently and the first clusters of infections are seen.

How long the virus will take to move through phase 4 and 5 to phase 6, where the full-blown pandemic emerges and spreads rapidly (or if it will happen at all), is a matter of guess work.

So what happens if a pandemic does appear? The scenarios put forward so far represent nothing more than a "best guess" based on the experience of previous pandemics, but Neil Fergusson from the department of infectious dieses and epidemiology at Imperial Collage, showed several models based on preliminary results that paint a grim picture.

"What statistics and modelling can tell you is that once you get about 20-30 cases then a global pandemic is almost inevitable, said Fergusson. "At that point we need to do something or we will have another pandemic."

Delegates in Copenhagen watched as computer generated maps of different countries were quickly covered with a red rash, marking infections by a fully adapted pandemic virus, before fading to green to show the survivors.

"We estimate that the outbreak would take somewhere between 120-180 days to peak in the first country it affected", says Fergusson. "But there would be a window in the first 30-40 days where one may be able to intervene."

Once the cluster in the country of origin reaches 2000 people, there is a very high chance of exporting the virus. If it occurs in a western European country, you can divide this threshold by four. With infections rising by 10-fold in 8-10 days after the index case, it is almost impossible to stop it travelling around the globe.

Policy and treatment
Models of the virus' probable path across the world assume that it will move at the same rate as previous pandemics, with each person infecting 1-8 new people and a clinical attack rate of 30-35% (ie one in three citizens will be infected). What can governments do to counter the spread of the virus?

Assuming the pandemic breaks out somewhere like Asia, the obvious strategy for countries like UK and America is to close their borders. However, Fergusson says the models suggest that even blocking 90% of the traffic buys only a 1-week delay and even cutting off 99% of the traffic buys just 2 weeks. Likewise, once the virus arrives in a country the 1918 outbreak shows that internal travel restrictions have little impact on the spread of the virus.

Most government have now adopted the simplest strategy for pandemic preparedness. They are building up stockpiles of antiviral drugs to cover a quarter of their populations. However, this policy only works if the drugs are delivered within 48 hours of the first appearance of symptoms—any longer than this and all the benefits are lost.

On top of the treatment-only policy, more proactive strategies could be adopted but most of them are impractical because they either need even bigger stockpiles of drugs or impossibly rapid responses to fresh outbreaks. For example, if antivirals are given prophylactically to everyone in area where the virus breaks out the attack rate could be reduced further.

"What the results [of modelling] showed was from about 3 million courses up you have about a 90% chance of containing a pandemic with what we estimate to be the transmissibility of past pandemics. But you need to act extremely quickly", says Fergusson.

Flooding an area with Tamiflu only works if there are less than 50 cases and you pick up and treat every new case that emerges within 2 days, which is beyond the surveillance and logistical reach of countries in Southeast Asia at the moment, says Fergusson.

And as 3 million courses would have to be given to every area where the virus appears, and the models are expecting multiple cases of pandemic to break out simultaneously around the country, this policy would quickly burn through the government's stockpile.

"Stamping on sparks; adopting a containment strategy in the west—in the US, UK or anywhere in mainland Europe—is doomed to failure", says Fergusson. "We will not have enough resources because in most of the world, where containment is not being adopted, an epidemic will be raging and new infected people will be coming into our area all the time—and we can do nothing about that."

A more general prophylactic policy, where the infected individuals and everyone in the same household are given antivirals, also has an significant impact on transmission, but still needs a stockpile equivalent to half the population—double what most countries have ordered.

Neither of these prophylactic policies are likely to be adopted, but simpler non-medical possibilities are available. Studies from Asia's SARS epidemic suggest that masks have a limited efficacy, but they do deliver indirect benefits like increasing social distancing, encouraging people to improve their personal hygiene, and reminding the population "there is a war on". Closing schools for 21 days and sending half the work force home will further reduce the attack rate of the virus, but comes at a high economic cost. However, none of these measures, even in combination, will move the epidemic's peak beyond the crucial 6-month mark after which vaccines should be available.

State of play
The models highlight the need for preparation. Once the pandemic breaks out most of the counter measures are made useless by delays in implementation of more than 2 days, so having the surveillance system ready to spot new cases and the logistics to deliver drugs to the patients the same day must be cornerstones of any pandemic plan

From WHO EURO's 52 members, 31 European states had pandemic plans in place by March this year, and another 18 countries have a finalised draft that is only waiting political approval. The laggards—mostly in eastern Europe—will have finished the process within 6 months.

Still, not one of these countries has tested their plans with a dry run and almost all the plans deal exclusively with public-health issues. Few have thought about contingency plans in case key workers in essential services like fire, police, power, and food industries are affected by the pandemic.

"All this needs a lot of resources in terms of people and materials", says Reinhard Kaiser from the European Centre for Disease Control, who worked on the survey. "It all costs money and there is a lot of building up infrastructure to do. Political commitment doesn't necessarily equal resources."

No one has yet considered the economic impact of possibility of a large portion of the population dying or closing down a nations economy for several months, which would clearly have a cataclysmic impact.

Money is also the main problem for the pharmaceutical industry that will have to make the vaccine. In order to try and shorten the 6-month gap between the emergence of the pandemic virus and the manufacture of a vaccine, the international institutions are calling for industry to submit "mock up" production plans that can be pre-approved by regulators now so when the strains of pandemic virus they can be rushed through before being put on general release.

Four manufacturers have already prepared plans and there are reports that Hungary has already begun work on a vaccine, but the problem is who is going to pay for building the capacity. Luc Hessel from industry association says that industry more than willing to help and is already in intensive talks with EU. Some government have agreed to pre-order the vaccine, which creates some of the capital needed. The international agencies have also agreed to waive fees of about €300 000 (US$360 000) but this is little more than a gesture. "It is difficult for industry to invest in a vaccine prototype (for the mock up) which may never be used," says Hessel.

The delegates returned home from the conference in a sober mood. There is much that rich European countries can to mitigate the impact of a pandemic virus if and when it comes, but the poorer aspirant European countries in the east lack the money and will have to lean on their better off cousins.

"We are assuming that there will be no vaccine or drugs [when the pandemic begins]", said a delegate from Montenegro. "If there is something then we will use what there is, but at the moment we are assuming nothing."
Ben Aris


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