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By Mandy Hall

I had a little bird,
Its name was Enza.
I opened the window,
And in-flu-enza.
-- Children's Skipping Rhyme, 1918

SOMETIME in the early spring of 1918, a new strain of influenza emerged from China. Within the next 18 months, the disease would travel the world twice, killing upwards of 20 million people before disappearing as fast as it arrived.

Very few places were spared the touch of disease and death it brought; only isolated places such as American Samoa escaped its influence. Two other flu pandemics travelled the globe within the twentieth century, one in 1957 and one just 11 years later in 1968; both of these outbreaks were of far less severity than the so-called Spanish Flu of 1918 and 1919. To give a perspective, it's now understood that 28% of the United States population got the flu, either falling ill or dying.

Now, once again, WHO and individual governments around the world are alerting the public to the threat of another influenza pandemic. This article will explore the science and history behind the current warnings, and speculate on the possible impact a future pandemic would have on our society.

Pandemics of one kind or another have been around man throughout recorded history. The word pandemic is used to describe any outbreak of contagious disease that is present over a geographically extensive area. WHO defines a pandemic to have started when the following conditions have been met: a disease new to the population emerges, the agent infects humans and causes serious illness, and lastly, the disease spreads easily and is sustainable between humans.

A notable example of how a pandemic has altered history is the Black Death of the 1300s. This pandemic killed about a third of the European population at a time and in its aftermath brought irrevocable changes to the social structure and institutions of the Continent. The Spanish Flu of 1918 is thought to have hastened the end of World War I.


History of the Spanish Flu

Early in spring 1918, influenza became epidemic in Kansas and military camps throughout the United States; however, it is for the losses in Spain, eight million in May 1918, that the outbreak is named. It travelled throughout Europe and returned to the United States in September of 1918. The illness was devastating in its course, typically striking the young and fit rather than the old and weak, and was often rapid in its course; there were many reports of individuals being struck down in the street and almost dead before they managed to return home. Another celebrated report was that of the bridge foursome that sat up too late playing cards -- by morning three of the players were dead. Most of the reports focused on the severe pneumonia that seemed to grip the infected almost from onset, a pneumonia that rapidly progressed until the patient died of asphyxiation because their lungs were so congested. People literally drowned in their own body fluids.

During the 1918 epidemic, scientists were unaware that the cause for the deaths was a virus rather than a bacterium. The causative agent was only discovered in 1932. Now we have progressed to the point where scientists have been able to extract the virus from samples obtained from the bodies of Alaskan victims of the Spanish Flu. From these samples they have been able to reconstruct the virus and determine its genetic structure. But even before this more recent development, the natural history of the influenza virus was well known. Influenza virus itself is divided into three types depending upon its internal structure. These types are A, B and C. The latter two are only found in humans. Type B can cause localised epidemics, and C only causes mild symptoms. Beside humans, influenza A-type viruses are found in a variety of animal species such as birds, horses, pigs, whales and even the cat family.

Type A influenza then divides into a series of smaller subtypes technically categorised by the particular combination of two proteins -- hemagglutinin and neuraminidase -- that are present on and in the virus and designated by the letters H and N. Examples are H5N1 or H7N7, both avian viruses, and H3N2, the 1968 Hong Kong Flu.

These two proteins are the means by which the virus enters and then exits a cell, destroying it in the process. The genetic code of influenza viruses is different from that of a normal cell. Instead of being based on DNA, it is carried within segmented RNA. This is a crucial issue to understand; because the RNA is segmented, it is relatively easy for two virus subtypes that have infected the same individual, say a pig, to exchange segments of their genetic code to produce a new subtype. This new subtype is then transmitted to a human who, having no natural immunity to this new viral subtype, gets infected and then transmits it to another human.

It is theorised that this is how the two latter pandemics in 1957 and 1968 arose, with both the subtypes that caused each pandemic acquiring portions of avian viruses by a process called reassortment.

Unlike DNA, RNA does not have the capacity to detect errors as it replicates so it is very prone to mutation. This is why the flu vaccine is only valid for one season. The next season's subtypes will be subtly different to those of the previous year, requiring immunity to be built up again. The surprising conclusion of the CDC researchers who reconstructed the 1918 virus was that it wasn't a swine virus as had long been thought, but a virus that was genetically much closer to the avian influenza A. This indicates that the 1918 pandemic wasn't caused by the type of reassortment seen in the 1957 and 1968 pandemics but by the avian virus adapting itself to a new host -- the human species. Even before this discovery, scientists were monitoring outbreaks of avian influenza across the globe.

There are 15 subtypes of influenza A circulating within the global bird population. Just as in humans, the range of illness caused in birds by these avian subtypes can range from mild to a severe and highly infectious form. As far as is known, all outbreaks of these highly pathogenic forms of the virus have been caused by just two of the 15 subtypes, H5 and H7. The highly pathogenic form of the virus causes disease that occurs suddenly, is very severe, and is virtually 100 percent fatal. Strains within the H5 and H7 subtypes are not always of the highly pathogenic type but even these have been known to suddenly change from a strain that causes mild disease to a strain that causes severe disease.

The 1983-84 US epidemic was caused by a H5 strain, H5N2, which had been circulating for about six months before the disease it caused became highly pathogenic. Similarly in Italy between 1999-2001, a H7 strain mutated from being mild to highly pathogenic in nine months.

The birds most at risk from infection and death from these highly pathogenic forms tend to be domestic poultry, chicken and turkeys. Migratory waterfowl, in particular, due to their resistance to the disease, have been implicated as the vector of transmission. Current control methods have focused on vaccination and eradication of the poultry population where the disease is endemic. This of course has a drastic effect on the economic life of the human populations dependent upon the poultry as a source of income or even food. It was thought that avian viruses did not infect any other species than pigs, where the reassortment events of 1957 and 1968 probably happened. That changed in 1997 when the first documented cases of human infection with an avian virus, H5N1, occurred.

Eighteen people in Hong Kong fell ill with a severe respiratory infection caused by H5N1, an avian virus first identified in 1959. At the same time there was an epidemic of highly pathogenic avian influenza in Hong Kong, coincidently caused by the same virus. Investigation of the outbreak showed that close contact with live infected poultry was the source of the human infection. More worryingly, genetic examination of both the human and avian H5N1 showed that the avian virus had jumped directly from birds across to humans. The authorities moved quickly and within three days the entire poultry population of the island, 1.5 million birds, was destroyed.

It is now thought that only this prompt action by the Hong Kong authorities, reducing any opportunity for further bird to human transmission, averted a pandemic. There was some limited transmission at the time to health workers but this transmission did not result in severe disease. Six of the original 18 cases died. To date there have been approximately 120 documented cases of human H5N1 infection with around half of the cases resulting in death, usually from respiratory complications. During the period since then and now, there have been documented outbreaks of bird to human transmission of two other strains of avian influenza A viruses. One outbreak occurred in the Netherlands, resulting in one death and illness in 83 others, and again in Hong Kong, where luckily there were no deaths.

The common factor in all outbreaks so far has been close contact with infected poultry; this includes handling, living with, and eating raw and undercooked infected poultry and duck products. A group of tigers at a Thai zoo became infected when fed raw infected poultry. There is little reliable evidence yet for sustained human-to-human transmission -- one of the conditions of a pandemic disease.


Similarities Between H5N1 and Spanish Flu

Some of the presenting factors of human H5N1 are eerily familiar; it has been the young and fit who have been presenting sudden onset disease that tends to progress rapidly to a viral pneumonia. In some cases, the disease progresses to severe adult respiratory distress syndrome, multi-organ failure, and death. Adult respiratory distress syndrome occurs when the normally hollow structures in the lung which are crucial for taking in oxygen and removal of waste gases become clogged with other particles such as blood, viruses and material from the immune system. The onset and course of disease is rapid with death occurring anywhere from six to 30 days after the onset of the illness.

This is not as fast as the progression of Spanish Flu, which could kill a healthy person within hours of onset.

These figures are based on individuals who present themselves for medical care; and perhaps it should be pointed out that while a 50 percent mortality rate seems high and frightening, these are recorded cases only. Human H5N1 infection presents a range of symptoms that not only include the standard flu symptoms of headache, myalgia, and sore throat, but also diarrhoea and vomiting. Patients with 'non-standard' symptoms may have been ignored or misdiagnosed in the community as presenting symptoms of some other disease.

The current 50 percent mortality rate may therefore be accurate when looking at the outcome of severe infection but it may not be indicative of the true mortality rate of the whole range of possible human H5N1 disease. The high death rate of the young, fit and healthy has been one of the scientific puzzles of the influenza story. Seasonal influenza is a disease that can be fatal to the old and chronically sick, but it appears that this is the reverse with H5N1 disease, as with Spanish Flu.

A clue to the cause of the catastrophic pulmonary (lung-related) events of severe H5N1 came with the rediscovery of the virus strain, H1N1, which caused the 1918 pandemic. Rapid onset of pulmonary disease and death in mice infected with H1N1 was found to be associated with a vigorous release of compounds called cytokines. Cytokines are part of the very complex immune system that helps prevent infection. There are several individual cytokines but they all work in one way or another to pass messages from one part of the immune system to another, target and limit the actions of the system, and overall coordinate the action of the immune system to any threat.

It is theorised that a mechanism that is being called a 'cytokine storm' occurs in some individuals in response to infection by H5N1. The precise mechanics of this so-called storm are still unknown but it appears that the delicate cytokine system is unbalanced, leading to an uncontrolled response by the immune system. Eventually the airways become clogged with immunological and other material, leading to the patient asphyxiating because of lack of oxygen.

This sort of cytokine storm is seen in other syndromes such as toxic shock syndrome and gram negative sepsis, where the inflammatory response is stuck in the 'on' position. However, it is too early to say whether this is the precise case in influenza infection. It does suggest that one way of treating or even preventing the onset of disease is to weaken the immune system so that its response to the virus is muted. However, there is always the problem in finding a balance. Weakening or suppressing the immune system with steroids or other drugs always risks the appearance of another overwhelming infection.


Preventive Measures

Research is now ongoing to evaluate the usefulness of other preparations in preventing or damping down cytokine storms. One such class of drugs being examined are the statins, primarily used at present for lowering cholesterol. Another compound that may be useful in decreasing the possibility of a cytokine storm is curcumin (turmeric). Curcumin is known to decrease the production of a specific cytokine called TNF-alpha. There is also a suggestion that Curcumin has antiviral properties too.

Another key herbal antiviral preparation is olive leaf; its constituent calcium elenolate was shown to inhibit several classes of virus including many strains of influenza virus. A detailed list of herbal and homeopathic compounds can be found at FluWiki, and of course it should be stressed that a knowledgeable practitioner is always far more informative and safer than words on a page. The lack of a human vaccine has left the manufactured therapeutics field currently open to only one class of drugs -- the antivirals.

There are two classes of antivirals in production. One class, consisting of amantadine and rimantadine, works by preventing the function of a specific protein, M2, in the virus. Unfortunately, the virus can quite easily change this protein so that the drug no longer works. Interestingly, H5 viruses circulating in South East Asia are resistant to this class of drugs, but are not resistant circulating elsewhere; so it may eventually have a role to play in the fight against human forms of this disease.

The other class, oseltamivir (Tamiflu) and zanamivir (Relenza), works by inhibiting the function of neuraminidase. This inhibition essentially stops the virus from replicating. Current recommendations are that treatment with Tamiflu is commenced within forty-eight hours of known exposure or the onset of symptoms. However, disease progression and death has been described even with early Tamiflu therapy. It has also been noted that compared with the 1997 strain, the strain in 2004 required higher doses and longer administration of Tamiflu to achieve similar antiviral results and survival rates.

The natural history of the influenza A virus and in particular, H5N1, is complex. So must our response be if we, as a global community, are to prevent or at least minimise the effects that a global pandemic would have on all our lives.

A pandemic according to WHO will only be classified as occurring if there is evidence of 'efficient and sustained human to human transmission'. One of the key strands of the WHO outbreak alert and response program is that of co-operative surveillance.

Developed regions such as Europe and North America have relatively open and well-resourced surveillance programs for both the bird and human populations. However, there is a significant difference in the number of human cases officially reported by China to WHO (3) to those that have been reported by unofficial sources (300). China did not report the full extent of the SARS epidemic until the information was leaked by one of their chief doctors. The Chinese government has recently invited an official WHO investigative team to visit the country to investigate two recent fatal cases of human H5N1 infection, so the risk of unreported infection and transmission in China may be receding for now.

Another region that WHO has declared to be at risk from H5N1 is Africa. Traditional methods of poultry production share many similarities with those of South East Asia, with large numbers of households keeping flocks that are allowed to wander at will and mingle with both wild birds and children playing. There are few existing avian disease surveillance programs and virtually no governmental disease control or compensation payments; both of these factors discourage early and open reporting. The health systems of African countries are infinitely more burdened than those of most of South East Asia due to the longstanding problems of tuberculosis, AIDS, malaria, and poverty, so access to a correct and prompt diagnosis as well as prompt treatment with the correct antivirals will be a lot harder to obtain.

It is, however, thought that South East Asia is the place where the virus may make its final adaptation to humans. Reports from northern Vietnam suggest that there are changes to the pattern of infection among contacts of patients and increases in clusters amongst families -- indications that seem to indicate that the virus is adapting to humans.

Human influenza A is very efficient at transmission. It can be inhaled, absorbed through the conjunctiva, transmitted through direct and indirect contact (say, for example, off a hard surface) and there is some evidence it can be ingested. Individuals are typically infective a day or perhaps two before the onset of symptoms and can be infective (particularly children) for up to three weeks after symptoms resolve. Infective individuals can even be asymptomatic.


Making Plans Now

The developed world of Europe and North America are proceeding to put in place contingency plans that will be brought into operation once a pandemic state has been declared. The UK Department of Health's contingency document states that once a pandemic state is declared, the virus will arrive in the UK within a maximum of a month, perhaps faster depending on where and when the change to the virus arises. Closing borders to all travellers, if this was a feasible option, would only delay its arrival by as little as two to three months. Once within the UK, it would likely spread to most major centres within two to three weeks.

While the American plan also talks of the rapidity of spread beyond the borders of affected countries, the executive has granted powers to the CDC in Atlanta to enable its officers to quarantine individuals if there is suspicion of illness or if an individual has been in contact with someone who has been in contact with the virus. President Bush has suggested in a recent speech that presidential power might be extended over the National Guard to implement such quarantines.

The Posse Comitatus Act forbids 'police action' in US territory except under very strict circumstances. Repealing this act would allow martial law to be proclaimed on a much wider basis. By contrast, the UK plan avoids mentioning the use of quarantine, and indeed explicitly states that the Department of Health has not sought any additional powers to facilitate this. US government documents admit that screening at airports and other entry points will be labour-intensive and yield dubious results -- how are they going to classify someone as infected? Real time testing equipment will yield results in about 30 minutes, but the kits cost around $20-25 US dollars.

Quarantine could be targeted at keeping affected areas 'sealed off' from the rest of the country but the restriction would have to be applied very quickly once influenza cases began to appear and even then it might already be too late, with asymptomatic and often unwitting carriers moving around the country. Contact tracing particularly in large conurbations or along crowded mass transit routes would be a next to impossible task. Both countries along with other developed nations have stressed the importance of vaccination once an effective vaccine is developed. At present, their drug of choice for prevention and treatment of influenza is Tamiflu.

It appears that national governments are not the only ones beginning to stockpile Tamiflu. Consumers in some countries are beginning to build up their own private stockpiles of the drug. There are significant problems with Tamiflu, not least of which the question regarding how effective it can be in the fight against the pandemic flu when it arrives given that some localised strains of the virus are already proving to be resistant to it. Another significant problem is the supply chain problem; starting with Roche who is the patent holder and currently the only company producing this drug. Roche is currently working at maximum capacity, and recent discussions with other companies who wish to produce a generic Tamiflu have foundered over intellectual property rights issues.

The crucial time window for giving the drug is within 48 hours after known exposure or the onset of symptoms. This makes it imperative that there is an effective chain of local distribution centres set up before a pandemic arises -- long distance travel either by air or road may not be possible during a pandemic. The British contingency plan has recognised that there may be a supply gap with Tamiflu and have drawn up a list of priority groups to receive them. Undertakers are listed as part of the second group.

Disruption to normal life will depend upon just how virulent the strain is, and we won't know how bad it will be until the virus adapts. UK planners have estimated that anywhere from 20,000 to 700,000 lives could be lost in a pandemic depending upon the virulence of the strain. In addition to the lives lost across the globe, there will be economic, and no doubt, civil disruption. Individuals will be absent from work not just because they're ill but to look after ill dependants or relatives; because they're scared to make the commute on the crowded subway or bus or because their child's school or day care facility has closed.

In most highly developed countries only a small proportion of the population lives close enough to the majority of their food supply to be unaffected by food shortages due to disruption of trucking, supply chain, or fuel supply caused by massive illness from a pandemic. As seen in other recent natural disasters, food becomes a priority quickly and if it is not plentiful or easily accessible, people become fairly desperate in a very short period of time. Military personnel may have to step in to manage and supply chains of food and medicines for the duration of a pandemic.

There may well be a shortage of medical staff and equipment to deal with the huge numbers of ill people; those patients that get significant respiratory problems are very ill people indeed. That's all right we say, they didn't have ventilators in 1918, or IVs or antibiotics. In the United States there are approximately 105,000 ventilators -- this means that there will be patients who will die of respiratory distress without accessing advanced medical care.

It's not simply the lack of ventilators that will be a problem. Seriously ill patients with the complex set of symptoms that the serious form of influenza will cause require a large and skilled team to care for them. So not only does medical and nursing staff have to be present, but also laboratory staff, x-ray staff, physical therapists and all the non-clinical support staff that keep a hospital running. Some hospital staff has been classified as being 'first responders', which should guarantee that they receive antiviral prevention/treatment first.

So how can an ordinary person on the street prepare for him or herself and family in the event of a pandemic? If possible arrange with your company to do work from home as much as possible. Limiting contact with large crowds is one of the best ways of avoiding infection. Where possible, companies should arrange to handle meetings by phone or video conference to avoid the need for people to travel. If you have to go out in large crowds, wear a suitable mask and gloves and practise very good hand hygiene.

Back at home, ensure that you have ready access to enough cash to cover your family's needs for a month or possibly two -- security staff may not be available to fill your local ATM. Of course this means that there is an added incentive for those who would take advantage of such a situation, so ensure sensible security precautions are taken. Make sure that the house is stocked with food, with plenty of non-perishable foods and alternative cooking arrangements just in case there are long periods without power. Essentially it is good, sensible disaster preparedness.

It would be unnatural for there not to be another influenza pandemic of some sort within this century. The betting is that the pandemic will be sooner rather than later. It may not be H5N1 but it could as well be as there are signs that indicate that the virus is becoming adapted to humans. Whether the illness is relatively mild as it transfers across or triggers serious respiratory problems like the 1918 virus, there will be worldwide disruption, even in the medium term. Above all remember -- coughs and sneezes really do spread diseases so use a tissue when you sneeze and throw it away carefully, cover your mouth when you cough, practice good hand hygiene, and lastly but most importantly, keep healthy.

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