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Kolkata, January 22 About 2,324 cases of people suffering from fever have been reported from the Birbhum district — Ground Zero of the bird flu outbreak in the state — in the last five days.
“The West Bengal Government is failing to understand the gravity of the situation,” said Union Minister of State for Health and Family Welfare P Lakshmi, during a visit to Birbhum on Tuesday.

Lakshmi, who is currently in the state to get a first hand assessment of the culling operations, did not find adequate health infrastructure to combat the bird flu threat. She criticised the state government for acting irresponsibly and lacking seriousness to fight the disease.

“There is no infrastructure, not even qualified doctors. We have sent pills and gear but the required equipment is not in place till date. They do not understand that this is an emergency situation and they should be prepared for it,” she added.
She blamed the state Animal Resource Development department for the spread of the virus to new areas, as it did not carry out culling operations in a swift manner.
The state government, however, maintained that there has been no case of H5N1 virus infecting humans, and tried to play down its own figures of fever cases in Birbhum.
“There is no need to panic. We do not have any reports of humans being infected. Therefore, a few hundred fever cases means nothing,” said Sanchita Bakshi, state director health services.

According to the status report, as many as 707 fever cases were reported from Birbhum district on January 18.
A day later and another 304 people were added to the list.
For January 20, which happened to be a Sunday, the report does not give any figures.
On January 21, 707 more cases were added to the existing figures and today an additional 613 cases of fever were recorded.

The report further stated that that six central rapid response teams are assisting the state government in culling operations.
Five human blood samples taken from South Dinajpur district have tested negative, the report added.

The chief antigens of the influenza virus are the hemagglutinin and neuraminidase protruding from its surface. But of all the parts of the influenza virus that mutate, the hemagglutinin and neuraminidase mutate the fastest. This makes it impossible for the immune system to keep pace.

By no means do the antigens of all viruses, even all RNA viruses, mutate rapidly. Measles is an RNA virus and mutates at roughly the same rate as influenza. Yet measles antigens do not change. Other parts of the virus do, but the antigens remain constant. (The most likely reason is that the part of the measles virus that the immune system recognizes as an antigen plays an intergral role int he function of the virus itself. If it changes shape, the virus cannot survive.) So a single exposure to measles usually gives lifetime immunity.

Hemagglutinin and neuraminidase, however, can shift into different forms and still function. The result: their mutations allow them to evade the immune system but do not destroy the virus. In fact, they mutate so rapidly that even during a single epidemic both the hemagglutinin and neuraminidase often change.

Sometimes the mutations cause changes so minor that the immune system can still recognize them, bind to them, and easily overcome a second infection from the same virus.

But sometimes mutations change the shape of the hemmagglutinin or neuraminidase enough that the immune system can't read them. The antibodies that bound perfectly to the old shapes do not fit well to the new one.

This phenomenon happens so often that it has a name: "antigen drift."

When antigen drift occus, the virus can gain a foothold even in people whose immune system has loaded itself with antibodies that bind to the older shapes. Obviously, the greater the change, the less efficiently the immune system can respond.

One way to conceptualize antigen drift is to think of a football player wearing a uniform with white pants, a green shirt, and a white helmet with a green V emblazoned on it. The immune system can recognize this uniform instantly and attack it. If the uniform changes slightly--if, for example, a green stripe is added to the white pants while everything else remains the same--the immune system will continue to recognize the virus with little difficulty. But if the uniform goes from green shirt and white pants to white shirt with green pants, the immune system may not recognize the virus so easily.

Antigen drift can create epidemics. One study found nineteen discrete, identifiable epidemics in the United States in a thirty-three-year period--more than on every other year. Each one caused between ten thousand and forty thousand "excess deaths" in the United States alone--an excess over and abouve the death toll usually caued by the diease. As a result influenza kills more people in the United States than any other infectious disease, including AIDS

Public health experts monitor this drift and each year adjust the flu vaccine to try to keep pace. But they will never be able to match up perfectly, because even if they predict the direction of mutation, the fact that influenza viruses exist as mutating swarms means some will always be different enough to evade both the vaccine and the immune system.

But as serious as antigen drift can be, as lethal an influenza as that phenomenon can create, it does not cause great pandemics. It does not create firestorms of influenza that spread worldwide such as thouse in 1889-90, in 1918-19, in 1957, and in 1968.


Pandemics generally develop only when a radical change in the hemagglutinin, or the neuraminidase, or both, occurs. When an entirely new gene coding for one or both replaces the old one, the shape of the new antigen bears little resemblance to the old one.
This is called "antigen shift."

To use the football-uniform analogy again, antigen shift is the equivilent of the virus changing from a green shirt and white pants to an orange shirt and black pants.

When antigen shift occurs, the immune system cannot recognize the antigen at all. Few people in the world will have antibodies that can protect them against this new virus, so the virus can spread through a population at an explosive rate.

Hemagglutinin occurs in fifteen known basic shapes, neuraminidase in nine, and the occur in different combinations with subtypes. Virologists use these antigens to identify what particular virus they are discussing or investigating. "H1N1," for example is the name given the 1918 virus, currently found in swine. An "H3N2" virus is circulating among people today {2004}.

Antigen shift occurs when a virus that normally infects birds attacks humans directly or indirectly. In Hong Kong in 1997 an influenza virus identified as "H5N1" spread directly from chickens to people, infecting eighteen and killing six.

Birds and humans have differeent sialic-acid receptors, so a virus that binds to a bird's sialic-acid receptor will not normally bind to--an thus infect--a human cell. In Hong Kong what most likely happened was that the eighteen people who got sick were subjected to massive exposure to the virus. The swarm of these viruses, the quasi species, likely contained a mutation that could bind to human receptors, and the massive exposure allowed that mutation to gain a foothold in the victims. Yet the virus did not adapt itself to humans; all those who got sick were infected directly from chickens.

But the virus can adapt to man. It can do so directly, with an entire animal virus jumping to humans and adapting with a simple mutation. It can also happen indirectly. For one final and unusual attribute of the influenza virus makes it particularly adept at moving from species to species.

The influenza virus not only mutates rapidly, but it also has a "segmented" genome. This means that its genes do not lie along a continuous strand of its nucleic acid, as do genes in most organisms, including most other viruses. Instead, influenza genes are carried in unconnected strands of RNA. Therefor, if two different influenza viruses infect the same cell, "reassortment" of their genes becomes very possible.

Reassortment mixes some of the segements of the genes of one virus with some from the other. It is like shuffling two different decks of cards together, then making up a new deck with cards from each one. This creates an entirely new hybrid virus, which increases the chances of a virus jumping from one species to another.

If the Hong Kong chicken influenza had infected someone who was simulatneously infected with a human influenza virus, the two viruses might easily have reassorted their genes. They might have formed a new virus that could pass easily from person to person. And the lethal virus might have adapted to humans.

The virus may also adapt indirectly, through an intermediary. Some virologists theorize that pigs provide a perfect "mixing bowl," because the sialic-acid receptors on their cells can bind to both bird and human viruses. Whenever an avian virus infects swine at the same time that a human virus does, reassortment of the two viruses can occur. And as entirely new virus can emerge than can infect man. In 1918 veterinarians noted outbreaks of influenza in pigs and other mammals, and pigs today still get influenza from a direct descendant of the 1918 virus. But it is not clear whether pigs caught the disease from man or man caught it from pigs.

And Dr. Peter Palese at Mount Sinai Medical Center in New York, one of the world's leading experts on influenza viruses, considers the mixing-bowl theory unnecessary to explain antigen shift: "It's equally likely that co-infection of avian and human virus in a human in one cell in the lung [gives] rise to the virus...There's no reason why mixing couldn't occur in the lung, whether in pig or man. It's not absoulute that there are no sialic acid receptors of those types in other species. It's not absolute that the avian receptor is really that different from the human, and, with one single amino acid change, the virus can go much better in another host."*

Antigen shift, this radical departure from existing antigens, led to major pandemics long before modern transportation allowed rapid movement of people. Thiere is mixed opinion as to whether several pandemics in the fifteenth and sixteenth centuries were influenza although most medical historians believe that they were, largely because of the speed of their movement and the number of people who fell ill. In 1510 a pandemic of pulmonary disease came from Africa and "attacked at once and raged all over Europe not missing a family and scarce a person." In 1580 another pandemic started in Asia, then spread to Africa, Europe, and America. It was so fierce "that in the space of six weeks it afflicted almost all the antions of Europe, of whom hardly the twentieth person was free of the disease," and some Spanish cities were "nearly entirely depopulated by the disease."

There is no dispute, though, that other pandemics in the past were influenza. In 1688, the year of the Glorious Revolution, influenza struck England, Ireland, and Virginia. In these places "the people dyed...as in a plague." Five years later, influenza spread again across Eruope: "all conditions of persons were attacked...[T]hose who were very storng and hardy were taken in the same manner as the weak and spoiled,...the youngest as well as the oldest." In January 1699 in Massachusetts, Cotton Mather wrote, "The sickness extended to allmost all families. Few or none escaped, and many dyed especially in Boston, and some dyed in a strange or unusual manner, in some families all weer sick together, in some towns allmost all weer sick so that it was a time of disease."

At least three and possibly six pandemics struck Europe in the eighteenth century, and at least four struck in the nineteenth century. In 1847 and 1848 in London, more people died from influenza than died of cholera during the great cholera epidemic of 1832. And in 1889 and 1890, a great and violent worldwide pandemic--although nothing that even approached 1918 in violence--struck again. In the twentieth century, three pandemics struck. Each was caused by an antigen shift, by radical changes in either the hemagglutinin or the neuraminidase antigens, or both, or by changes in some other gene or genes.

Influeza pandemics generally infect from 15 to 40 percent of a population; any influenza virus infecting that many people and killing a significant percentage would be beyond a nightmare. In recent years public health authorities have at least twice identified a new virus infecting humans but successfully prevented it from adapting to man. To prevent the 1997 Hong Kong virus, which killed six of eighteen people infected, from adapting to people, public health authorities had every single chicken then in Hong Kong, 1.2 million of them, slaughtered. (The action did not wipe out this H5N1 virus. It survives in chickens and in 2003 it infected two more people, killing one. A vaccine for his particular virus has been developed, although it has not been stockpiled.)

An even greater slaughter of animals occurred in the spring of 2003 when a new H7N7 virus appeared in poultry farms in the Netherlands, Belgium, and Germany. This virus infected eighty-three people and killed one, and it also infected pigs. So public health authorities killed nearly thirty million poultry and some swine.

This costly and dreadful slaughter was done to prevent what happened in 1918. It was done to stop either of these influenza viruses from adapting to, and killing man.


One more thing makes influenza unusual. When a new influenza vius emerges, it is highly competitive, even cannibalistic. It usually drives older types into extinction. This happens because infection stimulates the body's immune system to generate all its defenses against all influenza viruses to which the body has ever been exposed. When older viruses attempt to infect someone, they cannot gain a foothold. They cease replicating. The die out. So, unlike practically every other known virus, only one type--one swarm or quasi species--of influenza virus dominates at any given time. This itself helps prepare the way for a new pandemic, since the more time passes the fewer people's immune systems will recognize other antigens.

Not all pandemics are lethal. Antigen shift guarantees that the new virus will infect huge numbers of people, but it does not guarantee that it will kill large numbers. The twentieth century saw three pandemics.

The most recent new virus attacked in 1968, whe the H3N2 "Hong Kong flu" spread worldwide with high morbidity, but very low mortality--that is, it made many sick, but killed few. The "Asian flu," an H2N2 virus, came in 1957; while nothing like 1918, this was still a violent pandemic. Then of course there was the H1N1 virus of 1918, the virus that created its own killing fields.

*In 2001 Austrailian scientist Mark Gibbs advanced a theory that the influenza virus can also "recombine" its genes. Recombination means taking part of one gene and combining it with part of another gene. It is like cutting all the cards of two decks in pieces, taping the pieces together randomly, then assembling the first fifty-two for a new deck. Recombination has been demonstrated in the laboratory, but most virologists are skeptical of Gibbs's hypothesis.

But one cannot leave this subject without speaking to other questions: the likelihood and potential danger of another influenza pandemic, what we can learn from the one of 1918-1919, and how we can apply those lessons to the emergence of a new pathogen, whether that pathogen is a weapon of terror or a new natural menace--such as Severe Acute Respiratory Syndrome, SARS, the disease which spread from animals to man in the spring of 2003 and threatened to become a major pandemic.

The answer to the first question--the likelihood and potential danger of another influenza pandemic--is not reassuring. Every expert on influenza agrees that the abilitiy of the influenza virus to reassort genes means that another pandemic not only can happen. It almost certainly will happen.

For influenza is not like SARS, which was contained and--as this book goes to press--may have been completely eliminated. SARS, although more lethal even than the 1918 influenza virus, is less dangerous for several reasons.

First, SARS requires fairly close contact to spread, while influenza is among the most contagious of all diseases. Also, in SARS, the virus reaches maximum concentration in the upper respiratory tract, where coughs and sneezes are most likely to spread the virus, a week or longer after symptoms develop. This gives public health officials time to find, identify, and isolate cases. By contrast, the influenza virus can spread from person to person before any symptoms develop, before a victim knows he or she is sick.

If a new influenza virus does emerge, given modern travel patterns it will likely spread even more rapidly than it did in 1918. It will infect at least several hundred million, and probably more than a billion, people. In the United States alone, the Centers for Disease Control estimates that a new pandemic would make between 40 and 100 million people sick. So the prospect is threatening indeed.

If one compares the 1918-1919 pandemic to AIDS, one sees how threatening.

Today the world population exceeds 6 billion. Worldwide, in the twenty-four years since AIDS emerged as a disease, the total death toll is estimated at 24,800,000; at this writing, an estimated 42 million people are currently infected with the HIV virus. In the United States the cumulative death toll from AIDS is 467,910 people.

In 1918 the world's population was 1.8 billion, less than one-third today's. Yet the 1918 inluenza virus killed a likely 50 million and possibly as many as 100 million. The AIDS deaths occurred over twenty-four years; most of the influenza deaths occurred in less than twenty-four weeks.

There are now drugs than can contain the HIV virus; the difficulty lies in getting thouse drugs to the poorest parts of the world as well as in educating people there and in countries, such as China, that continue to minimize the disease. In the United States, those drugs limited AIDS deaths to 8,998 people in the most recent year for which statistics are available.

The U.S. Centers fro Disease Control (CDC) estimates that the annual death toll in the United States from influenza now averages 36,000 in a nonepidemic year. The 1918 virus killed 675,000 people in the United States, out of a population not much more than one third the size of today's.

In 1999 the Centers for Disease Control produced a study of what would likely happen if a new pandemic virus struck the United States. It took into account modern medical advances.

Antibiotics would of course significantly cut 1918's mortality rate for secondary bacterial infections following influenza. And several antiviral drugs have demonstrated some effectiveness against influenza. Amantadine and its more recent derivative, rimantadine, block the ability of the virus to build an ion channel between itself and the cell--in effect a tunnel into the cell--it attaches to. When these drugs work, the virus cannot get inside the cell, cannot invade it.

Two other drugs, zanamivir (Relenza), which is inhaled, and oseltamivir (Tamiflu), a pill, take a different approach. Both bind to the viral neuraminidase, so when new viruses try to escape the dead cell they get trapped onthe cell surface as if on fly paper. They can't infect other cells.

All these drugs can reduce the severity and duration of an attack, but only if taken within forty-eight hours after symptoms appear. Taken prophylactically the drugs can also prevent an attack, although the preventative effect does not last long and at this writing the Food and Drug Administration has approved only oseltamivir for this purpose. The virus has also shown some ability to develop resistance to them. So, although antiviral drugs do show progress and promise, they are not an answer.

A vaccine offers far better protection, especially for the elderly. But to make the vaccine, investigators have to aim at a moving target. Every year they try to predict which strains will dominate and the direction of antigen drift. Then they design a vaccine for these antigens. When the investigators are right, when they hit their target, the vaccine protects very well for an entire flu season, preventing many attacks and reducing the severity o fothers. But the vaccine needs to be produced in huge quantities, which takes months, and in that time the virus can mutate in a direction different form the one anticipated. And even if the vaccine inlcludes the right anitigens, given the "mutant swarm" nature of the virus, some viral strains will escape it. Vaccines using killed viruses are injected, but in 2003 a new vaccine (FluMist) was introduced that uses live virus and is inhaled.

The real danger, though, is that it may not be possible to develop and distribute a vaccine in time to protect against the new virus. Influenza viruses for vaccines are grown in chicken eggs. When scientists tried to prepare a vaccine to the H5N1 Hong Kong virus of 1997, the virus initially proved too lethal; the virus killed the eggs in which it was being grown. Ultimately the problem was solved, but developing this vaccine took more than a year. If another lethal virus jumps to humans and it takes that long to develop a vaccine, by then the virus will have done its damage.

So even with all the medical advances since 1918, the CDC estimates that if a new pandemic virus strikes, then the U.S. death toll will most likely fall between 89,000 and 300,000. It also estimates a best case scenario of 75,000 deaths and a worst case scenario in which 422,000 Americans would die.

The CDC based that range, however, on different estimates of the effectiveness and availability of a vaccine and of the age groups most vulnerable to the virus. It did not factor in the most important determinant of deaths: the lethality of the virus itself. The CDC simply figured virulence by computing an average from the last three pandemics, those in 1918, 1957, and 1968. Yet two of those three real pandemics fall outside the range of the statistical model. The 1968 pandemic was less lethan than the best case scenario, and the 1918 pandemic was more lethal than the worst case scenario. After adjusting for population growth, the 1918 virus killed four times as many as the CDC's worst case scenario, and medical advances cannot now significantly mitigate the killing impact of a virus that lethal.

If a new pandemic struck, people suffering from ARDS would quickly overwhelm intensive care units; those with ARDS who did not get true intensive care would have a mortality rate approaching that in 1918. A new virus would also feast on a population that did not exist in 1918--those with compromised immune systems, including people undergoing radiation or chemotherapy for cancer and transplant recipients, not to mention anyone with HIV.

No one has attempted to estimate the worldwide death toll of another influenza pandemic, but one could easily imagine a lethal virus--even one less virulent than that of 1918--killing tens of millions. No disease, including AIDS, poses the long-term threat of a violent explosion that influenza does.