Imagine the next flu pandemic has reached Sydney, and the infection is spiralling out of control. Health-care workers are becoming sick, and dying at the same pace as the public, and the city's hospitals are overwhelmed.
Emergency departments turn away all but the seriously ill. The rest are issued with surgical masks, sent home with antiviral drugs (while these are still in stock) and told to await mobile medical teams.
Coordination of medical services begins to unravel as the number of new cases each day quickly overtakes the availability of medical staff. People who have not yet fallen sick start to abandon Sydney in droves.
New clusters of cases arise in rural New South Wales and soon in Melbourne, Adelaide and Brisbane, and along the eastern seaboard. Schools are closed, movie theatres and restaurants are avoided and public gatherings are banned.
As the number of deaths continues to mount, reports in the media spread alarm across the country as quickly as the virus itself. The disease reaches Perth, Darwin and Tasmania.
Laboratories work around the clock to develop a vaccine targeting the new strain, but no supplies are yet available. New Zealand, as yet free from infection, closes its borders to flights from Australia. All flights in Australia, both domestic and international, are grounded.
Incoming flights are turned back and only returning Australians are allowed into the country. The police and the military are empowered to enforce the sweeping powers of the Quarantine Act (1908), allowing them to detain anyone disembarking from a pandemic country and put them in mandatory quarantine.
Borders have closed to international trade, exacerbating shortages of food, soap, paper, light bulbs, fuel and medicines, including vaccines unrelated to the pandemic.
As more and more employees call in sick, businesses close one-by one and all but essential services grind to a halt. Australia's transportation system is reduced to skeletal operations and trains and buses are cancelled to prevent further viral spread.
In major metropolitan areas, looting starts as police absenteeism becomes chronic. Unpleasant ethical dilemmas have to be faced: who should have priority access to the limited antiviral supplies? Is enough antiviral medication stockpiled to keep those involved in maintaining essential services healthy until a vaccine is ready?
When it is available, who should be first in line to receive it? What will become of the vaccinated population when the world economy disintegrates under the global pandemic? How will the immense number of dead bodies be handled when the numbers start to outstrip the ability to process them?
It's a nightmare scenario, but one that could happen, according to the World Health Organisation (WHO). Lee Jong-wook, a South Korean doctor and head of the United Nations agency, warned in September 2005 that a pandemic is likely. (Editor's note: this article was first published in Cosmos Magazine in November 2005.)
The arrival of a pandemic-grade avian influenza H5N1 – capable of being transmitted from person to person, rather than having to be caught directly from poultry – was inevitable.
The WHO director was blunt in addressing a press conference in New York, saying avian influenza H5N1 "will acquire this capability – it's just an issue of timing".
And he said the fact that the virus is spreading via migratory birds means the threat is indeed global. "Human influenza is coming, we know that. We must pounce on human pandemic outbreaks with all medicines at our disposal and at the earliest possible moment. When the pandemic starts, it is simply too late."
Better known as 'bird flu', the deadly virus may not have yet reached Australia and New Zealand, nor mutated into a strain capable of efficient transmission between people. But experts believe it won't stay that way for long. The WHO considers Highly Pathogenic Avian Influenza A Virus H5N1 (as it is officially known) to be the world's most serious health threat, far greater than severe acute respiratory syndrome (SARS) or bioterrorism.
The virus emerged in Hong Kong in 1997, and by 2003 had evolved into new strains that have infected millions of domestic poultry across 12 countries in Southeast Asia. It has expanded its territory via migratory birds into remoter parts of China, Mongolia and Russia, and is headed for Europe.
The critical question is whether the virus, now largely confined to birds and some pigs, will mutate so that it will be transmissible in humans. And whether the virulence of the altered virus will devastate a human population in sufficient numbers to cause a pandemic.
At the time of this article going to press, avian flu H5N1 had infected 116 people in Indonesia, Vietnam, Thailand and Cambodia, and killed 60 people. Speculation prevails about the number of cases of human-to-human transmission.
One confirmed case in Thailand in 2004 involved a mother who had no contact with any infected poultry but who had closely nursed her sick daughter – resulting in a double fatality.
To cause a pandemic, the bird flu virus must first develop genetic characteristics that enable efficient human-to-human transmission.
Then it must spread to as many people as possible before it kills its host. A virus with a high attack rate (high rate of infection) as well as high virulence (lethality) would be most damaging, however, highly lethal viruses don't spread well because they kill the host too quickly.
From a virus's point of view, a high attack rate and low lethality is a recipe for success – but this would be a calamity for humanity.
The Spanish flu pandemic of 1918 and 1919 was cataclysmic – its final death toll was 50 million people or more globally – because it had a death rate of 2.8 per cent.
While this low lethality might sound like a good thing, it's not: a low death rate means a high rate of transmission, allowing the virus to spread further and further, infecting many, many more people – and resulting in more deaths overall.
At least 2 million people worldwide – and as many as 7 million – could die from a new strain of pandemic flu, according to the WHO. But the true picture is anybody's guess. Epidemiologists suggest a virus could plausibly have an attack rate of 30 per cent and a mortality rate of 1 per cent; in a global population of 6.2 billion people, this translates to 18.6 million deaths worldwide.
To calculate the pandemic potential of the avian flu H5N1 virus, it's worth taking a look at its behaviour so far. The death rate across the four countries affected by human casualties has fallen considerably since the earliest outbreaks. In Vietnam, mortality has dropped from 90 per cent to 20 per cent. Whether this means the virus has mutated into a less virulent – but nevertheless more dangerous – form is open to debate.
According to a paper in the British medical journal The Lancet in May 2005, experts in Vietnam attribute the falling human death rate to widespread culls of poultry, better medical treatment and people seeking treatment at an earlier stage.
But the longer an infected host survives, the more chance the bug has to undergo genetic changes that favour its advancement: gradual evolutionary change via genetic mutation (antigenic drift), or rapid change by exchanging genes with a human influenza strain (antigenic shift).
Aileen Plant, an epidemiologist and deputy chief executive with the Australian Biosecurity Cooperative Research Centre for Emerging Infectious Disease in Brisbane, said the decreasing death rates were not necessarily good news.
"It appears that the Vietnamese strain of the virus is adapting in some way that confers an advantage to the virus," she said.
"It must be remembered that all of the people who have died so far had avian flu H5N1, not a human flu/bird flu strain. Higher survival provides opportunity for the avian and human flu viruses to mix and exchange genetic material, to become a new strain that poses a very serious threat."
This is exactly what epidemiologists fear most. Antigenic shift that would result in the birth of a new strain with the features of both viruses: fast infection capabilities from human flu, plus the deadliness of avian flu H5N1.
The bodies of people and pigs provide the best potential incubators for viruses to develop antigenic shift. Experts theorise that genetic shift is possible if an organism becomes infected with human flu and avian flu H5N1 simultaneously.
Pigs are great candidates for this because, unlike humans, they have receptors for both human and avian viruses in their respiratory tracts.
In May 2005, doctors confirmed the first cases of the H5N1 virus had been found in pigs on the Indonesian island of Java, where half the pigs tested had the disease.
Trevor Ellis, a bird-flu expert and senior research fellow at Murdoch University's veterinary school in Perth, who has recently returned from scientific discussions in Hong Kong, said pigs are being closely monitored as sources of genetic mixing.
"Although pigs are less commonly infected, they could have an important role as vehicles for dual infection, especially given their receptivity to both avian and human flu viruses and their greater genetic proximity to humans than birds," he said.
"In experimental studies, pigs that have been deliberately infected with H5N1 have shown no spread to other pigs. The virus doesn't appear to be highly transmissible between pigs at this stage, or to cause high mortalities," said Ellis.
Peter Collingnon, director of microbiology and infectious diseases at the Canberra Hospital, says once genetic reassortment has occurred, birds are no longer needed as the intermediary.
"The virus has to acquire a new genetic code that produces changes in its coating so that it sticks to human cells better, is able to evade our innate and acquired immunity, and gain entry into our cells so that it can take over and make numerous progeny," he said.
"We are looking at a pandemic if the new strain has acquired the genetic code it needs to be readily spread from person to person, particularly if it retains its virulence," he said.
Avian influenza subtype H5N1 is of particular concern because it has a knack for acquiring genes from other viruses. The key proteins involved are haemagglutinin (H), which binds to receptors on epithelial cell membranes in the respiratory tract and mediates entry of the virus into the cell; and neuraminidase (N), which aids infection by releasing virus progeny from infected cells.
If avian flu H5N1 and a human influenza strain infect the same cell concurrently, genetic strands of RNA from each strain undergo reassortment. The haemagglutinin is replaced with a novel subtype for which humans have no immunity. The consequence of this simple swap of proteins is that the human flu virus usually becomes pandemic grade.
But avian flu H5N1 may not even need to acquire genes from human viruses in order to devastate the human population. According to the world's first analysis of the full genome sequence of the Spanish flu virus, published in Nature in October 2005, the 1918–19 pandemic was wholly the result of a strain of avian influenza that had adapted to humans – not a novel bird flu/human flu hybrid.
Alan Hampson, deputy director of the WHO Collaborating Centre for Reference and Research on Influenza, in Melbourne, who initiated Australia's pandemic preparedness planning in 1997, says the country is basing its state of readiness on developments internationally.
"We are likely to see the first indication that the H5N1 virus has acquired the ability to spread between people when clusters of cases of human-to-human transmission appear in rural areas of Asia," Hampson said.
"If containment efforts were to fail at that point, the virus will start to gain speed in transmission, and quickly travel around the world. In a worst-case scenario, this virus will have touched most parts of the world in less than six months. That was the case in 1957 and 1968 – even before the era of the jumbo jet."
Containment in Asia depends on the WHO being able to quarantine outbreaks before they spread. The WHO has a stockpile of about 3 million courses of antiviral drugs. But for most of the world, antiviral medication will either be unavailable, or will be too expensive to purchase.
To date, at least 14 countries have ordered the antiviral medication Tamiflu (oseltamivir) in anticipation of an outbreak but, according to the WHO, this only represents enough medication to treat 40 million people.
In readiness for the arrival of a human strain of avian flu H5N1, Australia has one of the world's largest stockpiles of antiviral medication – totalling almost 4 million courses of the neuraminidase inhibitors Tamiflu and Relenza (zanamivir).
This would be sufficient to treat about a quarter of the Australian population with one dose twice a day; or a million workers as a preventive measure (prophylactically) for six weeks on one dose a day, to maintain a labour force.
Moira McKinnon, a senior medical adviser for biosecurity and disease control at the Australian Department of Health, says plans to designate the majority of the antiviral stockpile to prevent illness in 'essential workers' – rather than to the treatment of the sick – has raised an ethical storm.
"Health-care workers and border workers – people who have been exposed to an infected case, or who are likely to be exposed – will be issued immediately with the antiviral medication. Ten per cent of the stockpile would be used for treatment of the public in conjunction with isolation and home quarantine, which will be assessed during a pandemic. Our stand on this has drawn criticism from other developed countries," McKinnon says.
With only an estimated six weeks before antiviral stocks run out, speedy production of a vaccine will be essential. The Australian government has contracted the Melbourne-based pharmaceutical company CSL to provide up to 40 million doses of pandemic vaccine – sufficient to give every Australian two doses.
At best, it could take six weeks to produce the first batch of protective vaccine; but it might take much longer. For one thing, the manufacturer will have to determine the specific strain causing the pandemic before commencing full-scale production, to ensure the correct vaccine is developed.
"CSL commenced clinical trials [in October 2005] on four alternative formulations suitable for a candidate pandemic vaccine," said Rachel David, the avian-flu-vaccine spokeswoman for CSL.
Four hundred volunteers have signed up for the CSL trial, which is testing the effectiveness and safety of a candidate vaccine. Results are expected by the middle of 2006. The trial vaccine, which has been neutralised to prevent it from being contagious, uses a strain of avian flu H5N1 isolated from a bird-flu victim in Vietnam.
"When the WHO announces the pandemic, seed will be prepared with the key HA antigen representative of the actual pandemic strain. At a production rate of a half-million to a million doses a day, we expect a suitable vaccine to be available to the public within three months," David said.
"But if the pandemic strain of the virus is new, or the dose of active product in the vaccine required to produce an immune response is higher than expected, or yield is lower than expected, this time line could increase to six months or longer."
In the meantime, Australia has prepared a huge stockpile of 40 million surgical masks, 50 million syringes, more than 300 ventilators, 2 million respirator masks, and needles and syringes… and a number of 500-bed quarantine centres.
Authorities have also purchased 21 thermal imaging machines (which scan for elevated body temperature), for deployment to airports within hours of a pandemic being declared. Such thermal scanners were used during the SARS outbreak to detect any passengers arriving with fevers. But avian influenza H5N1 is infectious for about 10 days (compared to 48 hours for seasonal flu) before symptoms become evident. Aileen Plant points out that this lengthy symptom-free incubation period will be a major issue for infection control.
"With SARS, until you got symptoms, you weren't infectious to other people, and you didn't reach your maximum infectiousness until 10–15 days after symptoms appeared," she said. "But if someone comes into Australia harbouring avian-human [hybrid] flu, the virus could escape detection and then spread extremely rapidly to the four winds before we even know what has hit us."
Contact tracing – where patients are interviewed and the people with whom they have been in contact are tracked down – was used during the SARS outbreak in an attempt to contain the infection. But Hampson warns this strategy will be useless in a flu pandemic: "Protection against influenza is much more difficult because it is more contagious.
"SARS only involved infection from close contact. Although a few people with SARS were super-shedders [people who spread large amounts of viral particles], it is likely that everybody who contracts flu will be a good shedder. And because it's spread by aerosols – in talking, coughing, sneezing – the virus could go some distance around airports, public transport and hospital wards."
McKinnon points out that although Australia has a good track record of rapid response to public health emergencies, a pandemic could test the nation to its breaking point.
"If the volume of cases of avian-flu infection is huge, we will be overrun. Elective surgery will stop and private hospitals will be required to participate in the response. The criteria for being in hospital will increase markedly. The setting up of fever clinics in the community will assist in processing patients, who will be home-quarantined unless sick enough to be in hospital," McKinnon said.
She said the federal Department of Health has a strategy, called Maintenance of Essential Services, should the pandemic become uncontrollable. "This is most contentious because nobody can determine who is an essential worker," observes McKinnon.
"If pandemic flu is prevalent and spreading rapidly, Australia might consider turning away planes and quarantining returning Australians. Schools would close. After the recent influenza B epidemic in New Zealand, schools closed voluntarily because there was so much absenteeism. The public almost self-regulates," she said.
"During the 1918 pandemic, police road checks stopped people travelling. Victoria and New South Wales were put in quarantine, as were individual towns," McKinnon added. "If the virus arose in Western Australia, for instance, we could quarantine the state from the rest of the country because there are only two main roads. But the eastern seaboard would be more difficult."
Hampson suspects a crisis would be reached fairly quickly. "We can try 'social distancing' by minimising the number of people on public transport and in crowded environments. We can close churches, football matches and the cinemas to buy us time to allow the vaccine manufacture to churn out more product.
"The military might be used as an option if the situation becomes really serious. But as soon as the pandemic goes beyond a certain point, it's essentially going to be unstoppable," Hampson said.
Clever strategies and effective drugs won't be enough to stamp out an outbreak of flu around the world without rapid, unified national and international efforts. The WHO is aware that while most countries have disease surveillance systems, many lack the resources for a rapid response.
Poor laboratory facilities in parts of Asia will hinder swift diagnosis and treatment. Above all, glaring shortfalls in antiviral medication and vaccine supplies across the world will exacerbate the emergency. Antiviral supplies could currently treat only 14 per cent of the world's population.
Then there is the political dimension: cover-ups. The WHO has charged that authorities in several countries have attempted to conceal avian-flu outbreaks because they fear the effects on their agricultural and tourism industries.
China, especially, is accused of hiding sensitive information. Despite being at the epicentre of avian flu outbreaks in poultry, no human deaths have been reported there. Not officially. One possibility being raised by some clinicians privately is deeply troubling: what if somewhere in the vast hinterland of China, a human pandemic is already raging?
Alex Wilde is a freelance journalist in Sydney, Australia, who specialises in medicine and science.
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