The Threat of Pandemic Influenza

You all have read the articles and heard the news broadcasts. But in some of your nations, it has been more than just television stories. You have had people who became ill and some who died due to avian influenza. Some of you have had to make massive efforts to control avian influenza in birds and other animals. Just how bad is this avian influenza threat? Well, the worst predictions I have heard are that it could infect 40% of the world’s 6 billion people. That’s 2.6 billion sick people. About 40 million of them would die. World War II — the largest war humanity has experienced — killed between 40 and 60 million people in 5 or 6 years. The worst case projection is that pandemic avian influenza could kill nearly as many people in only five or six months.

In 1918, the world experienced the worst documented pandemic of influenza. We have reasonably accurate numbers for that 1918 pandemic in the United States: 675,000 Americans died. That’s 0.6% of the U.S. population at the time. Six-tenths of one percent of today’s U.S. population would be 1.9 million… that is the number of deaths that might occur in the U.S. alone. Extend that 0.6% to the rest of the world, and you get 36 million deaths, very nearly the death toll for World War II. These numbers capture the attention, but these huge numbers aren’t the whole story.

First of all, the word “pandemic” is not a word we use very often in polite conversation. Doctors call disease that is always present in a population “endemic,” like colds and cancer and heart attacks. “Epidemics” are when there is a dramatic change in a disease, an outbreak that spreads to more people than usual, but still not to everyone. Occasionally, a disease may spread much farther, even globally, and affect most or all of the people. It is then called a “pandemic.” In a pandemic, significant populations around the world are affected. So, when we refer to pandemic influenza, we mean influenza that has spread to the degree that it affects large populations in every region of the world.

Biology of Influenza

Influenza is classified several different ways. One grouping is by letter: A, B, and C. Group A influenza affects animals as well as people, and is the group into which avian influenza falls.

Another categorization of influenza is by the kind of animal it affects. There are many influenza viruses that affect only animals. The kind that affects birds is called “avian influenza.” The kinds that affect only humans, of course, are called “human influenza.”
Another way to group influenza is by the kinds of molecules that make up the surface of a virus. There are two main groups of molecules that are called “H” and “N” that are used for identification. Each of these has several subtypes, such as “H1, H2, H3, etc.” and “N1, N2, N3, etc.” One strain of avian influenza that has been in the news recently and is the focus of this discussion is H5N1. The kinds of human influenza that are most common at the moment are H1N1 and H3N2.

Influenza is caused by a virus, which is a very small structure that is not really living. It’s not like a bacterium or other cell because it can’t survive by itself. Cells have all the complex chemical and molecular machinery inside them that allows them to exist separately, to make energy on their own, to repair themselves, etc. Viruses, on the other hand, can not do any of that. They require other cells to survive, and they’re quite clever about how they make use of the cells.

Wrapped inside their protective outer capsule, viruses have either DNA or RNA, which are the long strings of molecules that make up genes. The outer capsules have protein “hooks” that attach to a cell within the host bird or human. In some cases, the DNA or RNA is actually injected into the cell, but more commonly — like with the influenza virus — the whole capsule is absorbed. It then breaks down and releases the RNA or DNA. Once the viral DNA or RNA is inside, the cell can’t distinguish between the viral DNA or RNA and the cell’s own DNA and RNA. The viral DNA or RNA mixes with the DNA and RNA of the cell, and the cell begins to use it just as it uses its own. The cell then makes new copies of the viral DNA or RNA in mass production and makes new capsules around the viral DNA or RNA. This is how a new virus particle is created.

When enough new viruses are made, the cell becomes fully packed with them, and its own machinery can’t function any more. The cell then dies; the viruses are released to be picked up by other cells; and the process starts all over again: One virus turns into thousands, which turn into millions, and so on, and so on, within just a few cycles.

This happens very quickly for some viruses. For influenza, it only takes hours. Other viruses can be very slow-growing, staying in a cell for months and years. This is the case with “mad cow disease,” for example. The point to remember here is that with influenza you can go from being healthy to being very sick in a matter of hours.

The influenza virus is an RNA virus. Because the virus contains only eight genes, it is missing some of the “quality control” mechanisms that other cells have. This means that it is not able to ensure that it makes accurate copies of itself. The usual mistakes are a change in the order or the type of genetic strands. When that happens, the characteristics of the virus change. This is important. It is called “reassortment” or “genetic shift,” and it’s what will make pandemic influenza possible.

The process of reassortment is unpredictable. The avian flu virus will reassort, and as a result it will change its characteristics, but the effect of this change is not clear. It could become more infectious or less infectious, and it could become more or less deadly. What is sure is that this process could be happening now. Originally, avian flu was mostly in wild birds, then it began to affect chickens. Then it was found in ducks and geese, and in pigs, and tigers. This transfer to pigs and tigers is particularly significant because they are mammals; so
are humans. Something that can infect a pig or a tiger may not have to change much more to be able to
infect humans.

Virus genes can also change spontaneously, without reassortment. When this happens, as it did with the 1918 influenza virus, a new virus type is created. Even as we speak, the virus continues to change. It kills every chicken it infects, and until recently, most of the wild ducks or geese it infected also died. Increasingly, however, more birds identified as having avian influenza are still alive. The virus has apparently changed both to infect more animals, and — for some animals — to become less deadly. It is a common pattern in biology, for something very deadly at first to gradually change into something less deadly.

I think of it this way: it’s not good to bite the hand that feeds you. Because viruses depend upon living organisms to survive, it’s probably not a good idea to kill them, because then the virus won’t be able to survive either. Viruses will do better if they only make us sick, and don’t kill us. That’s Darwin’s evolution, and it’s probably what is happening with the avian flu virus.

For human infections, here’s what has happened: in the period 2003 to 2004, avian influenza caused 44 known human infections, 32 of whom died. That was a 72% death rate. Since then, there have been 164 more cases for a total of 208, and 83 more deaths for a total of 115, which brings the death rate down to 55%.1 This may be evidence that the virus is evolving so that it is more likely to infect us without killing us. If so, that’s good news, (if we can say that a 55% death rate is ever good news).

For humans, in addition to the death rate from the virus, another key characteristic is its contagiousness. So far, the avian flu virus has not been very contagious to humans at all. The only known cases seem to be from close contact with birds, or maybe from close contact with another human who has avian influenza. Some of this close contact comes from how birds are raised with or near humans or with other market animals like pigs. Some of the close contact occurs from the sale of live chickens in markets, a common practice throughout the Asia-Pacific region. The virus does not yet seem to have increased its contagiousness to anywhere near that of human influenza, which is one of the most contagious diseases known. The potential for it to do so as it reassorts is one of the things that worries people.

As the virus evolves, we must all watch for what biologists call “sustained human-to-human transmission,” which is when the virus can be transmitted from one human to another, and that spread is sustained to additional humans. That pattern will be the only indication that the virus has changed enough to increase its contagiousness and to start a pandemic. This pattern has not been seen yet.

One concern about how quickly the virus will change to become more contagious has to do with those pigs we mentioned that have been infected with avian flu. Pigs can also be infected by human influenza. What if a pig got both at once? Both viruses infecting a pig cell, mixing their RNA, increases the chance for reassortment of the human virus RNA with the avian virus RNA, which increases the possibility of a new virus emerging that is as contagious as the human flu virus, and as deadly as the avian flu virus. The presence of the virus in mammals is therefore particularly ominous.

Another concern is how easily the virus can move from country to country in the age of air travel. Once the virus has achieved sustained human-to-human transmission, it becomes very difficult to stop its spread. We saw this in the recent SARS outbreak. SARS, or “severe acute respiratory syndrome,” is also a virus. Within 1 day of discovery of the SARS outbreak, it had spread to five countries by air travel of infected people. Within a few months it had spread to 30 countries on six continents.

Will There Be a Vaccine That Can Protect Us?

Each year in some countries people get flu shots to protect them from human flu. Why can’t we get shots to protect us from avian flu? Vaccinations only protect us from specific viruses. Each year vaccinations for the flu are created to protect us from the common viruses of recent years. A strain of virus must have already been identified in order to develop a vaccine for it, and a vaccine is based on a best guess of which strains will be common in the coming year. We can’t know the make-up of the reassorted avian flu virus until it finally emerges and shows sustained human-to-human transmission. Remember that the avian flu with which we are currently concerned is categorized as “H5N1.” If the virus reassorts, it may no longer be the same H5N1. In other words, if a vaccine were developed to protect us from the current H5N1, it may not protect us from the variation that becomes capable of sustained human-to-human transmission. There are efforts currently going on to make a vaccine against the avian flu, H5N1, as the virus currently exists. However, we know the virus will change, so it’s a gamble as to whether or not the vaccine will give good protection against any new form of the virus.

Once that new virus emerges, it will take 3 to 6
months to develop a specific vaccine against it. Once a vaccine is developed, it would have to be produced in quantities large enough to protect the populations of entire countries. However, there isn’t enough manufacturing capacity in the world today to make
that amount of vaccine.

There were two dozen vaccine makers in 1980. Today there are about six large manufacturers. The reason is primarily market-driven. The profit margin in making vaccines is low compared to making drugs. It’s hard and expensive to make vaccines, and for many countries, even if it were available, it would simply be too expensive to pay for enough vaccine to protect their whole population. All this says that we can’t rely on vaccines to help, or even to be available, at least for the first 6 months or so.

There is a drug that seems likely to work: Oseltamivir, or Tamiflu®, seems to help treat infection as well as prevent it. It is made by just one drug company, and costs about $3 per pill. Production does not equal demand; therefore, there is a waiting list for the large quantities required for national stockpiles.
Economics of a Pandemic

The graph shows the cost of some of the infectious diseases that have hit the world recently.

“BSE” is “mad cow disease.” Please note in particular the cost of SARS. Those are the costs in China, Hong Kong, Singapore, and Canada only. SARS is the closest we’ve come to pandemic influenza since the 1918 flu pandemic we talked about. SARS affected 8,422 people over 5 months, killing 916 of them, or about 10%. Compare those numbers with the pandemic influenza numbers: 2.6 billion affected, and 40 million deaths. Pandemic influenza is huge compared to SARS. Think of how big a circle we’d have to draw if we tried to picture pandemic avian influenza costs.

The graph on the facing page depicts a middle-case estimate from the U.S. Centers for Disease Control — not a worst-case estimate — of the costs of pandemic influenza in the first year of an outbreak, for the United States alone. It assumes we have no cure and no effective vaccine, which is currently the case… but that all other modern care resources are available. And these resources help: Fewer people will die.
You’ll notice that this death estimate is much less than the 2 million U.S. deaths we mentioned as the worst case, but notice also that it is a pyramid. Each death is preceded by hospitalization (which costs money), and each hospitalization is preceded by outpatient visits to doctors or other health caregivers (which also cost money). And in addition to those seeing doctors, there are many more at the bottom of the pyramid who are sick, but don’t seek medical care (and that too costs money). The first-year U. S. cost is estimated as $71 - $166 billion. This includes both the cost of medical care and the cost of likely lost work days. These are very large numbers, but still, they are only part of the real cost. In addition to medical care and lost work days, there are other factors that have costs.

Many of you remember the dramatic impact SARS had on travel in the Asia-Pacific area. Maybe you experienced it yourself. Maybe you had a trip planned, and didn’t take it because of SARS. One estimate for the total cost impact of SARS throughout the Asia-Pacific region, including this lost travel revenue, is $40 billion (U.S.).

Another set of costs arise if businesses and public services in the countries hit by pandemic influenza close. Goods are not produced, sold, or bought. Agriculture output drops as equipment and supplies become unavailable. As workers become sick or die, or are afraid to go to work, food production conceivably drops. Food shortages and malnutrition, perhaps even famine, with their own consequences on health and productivity, could be seen. Even if there are areas of the world that escape direct infection by pandemic influenza virus, their trade drops, their supply chains are damaged, and their financial markets are severely stressed. The impact is global.

Let me use the U.S. as an example: Imagine that pandemic influenza could be limited to Asia; that somehow we were successful at stopping its spread to the rest of the world. The U.S. buys more than it sells. To pay for this, money has to come from somewhere else; and it comes primarily from investments in U.S. business and U.S. Government by other nations. That means that money from foreign countries flows into the United States as investment in U.S. business. U.S. businesses use the money to operate, to expand, and to improve. Forty-five percent of this inflowing money is from Asia-Pacific countries. What if, as we’ve imagined, Asia-Pacific countries are hit by pandemic influenza? Their output will drop due to lost productivity and sick workers; their internal cost of dealing with the disease will rise quickly; they have no money left to invest abroad; money no longer flows to U.S. businesses, and U.S. businesses lose 45% of the capital they normally receive.

If that happens, I think I’d take my money out of the stock market very quickly to protect it…and, I suspect, so would others. That means that, in addition to the loss of Asia-Pacific investments, U.S. internal investment would slow or stop. Many U.S. businesses could not survive. They would close. Unemployment would rise. Living standards would drop. This line of thought brings to mind scenes of the great depression. And this is just from the cost of pandemic flu on global trade alone.

There would be other costs, including the cost of providing assistance to other nations. There will be decline in the rest of the global economy outside the United States. Other areas of the world also deal with the Asia-Pacific nations, and they will also suffer from the impact of pandemic influenza on Asia-Pacific trade. This will reduce their ability to supply goods to the U.S. and to buy U.S. goods, further magnifying the impact on U.S. business. Only by adding all this in would we get closer to actual costs. Costs of such magnitude, with the social and economic secondary effects that would be seen, may be unsupportable for any nation.

Political Implications of a Pandemic
Let’s imagine for a moment what might be the political impact of a huge death toll plus such economic devastation in a country. Governments, whether in countries with pandemic avian influenza or those just trying to cope with the economic effects, may be unable to manage. For some fragile nations who already have internal disruptions and tensions, we can imagine that the additional stress of pandemic influenza could lead to reduced government effectiveness. If governments become ineffective, then internal or foreign opponents may take advantage for their own purposes, leading to conflict between groups within the nation or conflict between nations. This is not a pretty picture. If a worst case global pandemic of influenza occurs, there is not an aspect of our lives, anywhere on the globe, that will be the same.

Suggestions for Action

I’d like to close my comments by suggesting some hopefully specific and practical things that we can all do right now to reduce the threat of the disease:

1. First and foremost, we can work together. We can each plan and share information inside our nation and with the nations around us. Avian flu does not recognize boundaries. It cannot be conquered by any one nation working alone. We must work together.

2. We can do a better job of monitoring wildlife that carry the influenza virus. With this information we can know more about where it is going and plan better how to reduce its spread.

3. We can do a better job at restricting the trade in wild animals. We know that such trade distributes the virus. This is a point for both the areas that are the source of wild animals and areas that are markets for them.

4. We can vaccinate domestic bird flocks to prevent infection and block spread. In the long run, this may prove to be a cheaper and less disruptive alternative than having to kill bird flocks once they have become infected.

5. We can improve the conditions under which market animals known to carry the virus are raised, in particular by separating them from other animals, especially pigs, and from humans. This will reduce the chance of both spread and reassortment into a form that can infect humans.

6. We can build surveillance systems to do regular sampling and monitoring for human illness that might be avian influenza, and we can share with others the results of that surveillance. This may be the key step to take now.

7. We can plan and develop stockpiles of medical supplies and drugs in preparation for an outbreak.

8. We can educate people about the virus, how to limit their risk, and how to limit its spread.

9. We can ask for and conduct cooperative planning among nations and within a nation for management of outbreaks.

10. We can plan now for emergency expansion of hospitals and hospital staffing, as well as services for care of the dead.

11. We can plan now for control of travel inside our own countries and to other countries to limit spread of the virus.

12. We can plan for emergency reinforcement of public services like police, communications, and fire.

13. Businesses can plan for maintenance of functions despite staff illness and disruption of their supply chain.

These are just some of the things that can be done. A few places are doing a few of these things. Unfortunately, no one is doing all
of them.

Endnotes
1 The numbers in this paragraph have been updated as of press time from: World Health Organization Regional Office for the Western Pacific. (2006, May). Avian influenza update number 45 (16 May 2006). Retrieved May 22, 2006 from: http://www.wpro.who.int/
NR/rdonlyres/29796653-
C765-4A5E-90FA-E0998CF8ED23/
0/AIWeekly45WPRO.pdf

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