The Great Influenza (38 page)

In 1918 especially, this question of balance played a crucial role in the war between virus and immune system, and between life and death. The virus was often so efficient at invading the lungs that the immune system had to mount a massive response to it. What was killing young adults a few days after the first symptom was not the virus. The killer was the massive immune response itself.

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The virus attaches itself normally to epithelial cells, which line the entire respiratory tract like insulation in a tube all the way to the alveoli. Within fifteen minutes after influenza viruses invade the body, their hemagglutinin spikes begin binding with the sialic-acid receptors on these cells. One after another these spikes attach to the receptors, each one a grappling hook binding the virus tighter and tighter to the cell. Generally about ten hours after the virus invades a cell, the cell bursts open, releasing between 1,000 and 10,000 viruses capable of infecting other cells. At even the lowest reproduction rate (1,000 times 1,000 times 1,000, and so on) one can easily understand how a victim could feel perfectly healthy one moment and collapse the next, just as the fifth or sixth generation of viruses matures and infects cells.

Meanwhile, the virus is also attacking the immune system directly, undermining the body's ability to protect itself; the virus inhibits the release of interferon, and interferon is usually the first weapon the body employs to fight viral infection. In 1918 the ability to inhibit the immune system was so obvious that researchers, even while overwhelmed by the pandemic, noticed that influenza victims had weakened immune responses to other stimuli; they used objective tests to prove it.

Even mild influenza viruses can utterly and entirely denude the upper respiratory tract of epithelial cells, leaving it bare, stripping the throat raw. (The repair process begins within a few days but takes weeks.)

Once an infection gains a foothold, the immune system responds initially with inflammation. The immune system can inflame at the site of an infection, causing the redness, heat, and swelling there, or it can inflame the entire body through fever, or both.

The actual process of inflammation involves the release by certain white blood cells of proteins called 'cytokines.' There are many kinds of white cells; several kinds attack invading organisms, while other 'helper' cells manage attacks, and still others produce antibodies. There are even more kinds of cytokines. Some cytokines attack invaders directly, such as interferon, which attacks viruses. Some act as messengers carrying orders. Macrophages, for example, release 'GM CSF,' which stands for 'granulocyte-macrophage colony-stimulating factor' GM CSF stimulates the production in the bone marrow of more macrophages as well as granulocytes, another kind of white blood cell. Some cytokines also carry messages to parts of the body not normally considered belonging to the immune system; several cytokines can affect the hypothalamus, which acts like the body's thermostat. When these cytokines bind to receptors in the hypothalamus, body temperature goes up; the entire body becomes inflamed. (Fever is part of the immune response; some pathogens do not grow well at higher temperatures.) In influenza, fever routinely climbs to 103, and can go higher.

But cytokines themselves also have toxic effects. The typical symptoms of influenza outside the respiratory tract, the headache and body ache, are caused not by the virus but by cytokines. A side effect of cytokines' stimulating the bone marrow to make more white cells, for instance, is likely what aches in the bone.

Cytokines can cause more serious and permanent damage as well. 'Tumor necrosis factor,' to give one example, is a cytokine that gets its name from its ability to kill cancer cells - tumors exposed to TNF in the laboratory simply melt away; it also helps raise body temperature and stimulates antibody production. But TNF is extraordinarily lethal, and not just to diseased cells. It can destroy healthy ones as well. In fact, it can kill the entire body. TNF is a toxin and a major cause of toxic shock syndrome, and it is not the only toxic cytokine.

Routinely, the body fights off the influenza virus before it gains a solid foothold in the lungs themselves. But in 1918 the virus often succeeded in infecting epithelial cells not only in the upper respiratory tract but all the way down the respiratory tract into the innermost sanctuaries of the lungs, into the epithelial cells of the alveoli. This was viral pneumonia.

The immune system followed the virus into the lungs and there waged war. In this war the immune system held nothing back. It used all its weapons. And it killed. It killed particularly with 'killer T cells,' a white blood cell that targets the body's own cells when they are infected with a virus, and it killed with what is sometimes referred to as a 'cytokine storm,' a massive attack using every lethal weapon the body possesses.

The same capillaries that moved blood past the alveoli delivered this attack. The capillaries dilated, pouring out fluid, every kind of white blood cell, antibodies, other elements of the immune system, and cytokines into the lung. Then these cytokines and other enzymes virtually obliterated the capillaries. Even more fluid poured into the lung. The cells that line the alveoli were damaged, if they survived the virus itself. Pink glassy membranes, called hyaline membranes, formed on the insides of the alveoli. Once these membranes formed, 'surfactant' (a slippery, soap-like protein that reduces surface tension and eases the transfer of oxygen into red blood cells) disappeared from the alveoli. More blood flooded the lungs. The body started producing fiberlike connective tissue. Areas of the lung became enmeshed in cell debris, fibrin, collagen, and other materials. Proteins and fluid filled the space between cells.

Macfarlane Burnet, the Nobel laureate, described what was happening inside the lungs: 'acute inflammatory injection' very rapid necrosis of most of the epithelial lining of the bronchial tree down to and especially involving the smallest bronchioles' . Essentially toxic damage to alveolar walls and exudation of blood and fluid' [C]ontinued exudation of fluid in areas where blocking of smaller bronchi had occurred would produce eventually airless regions.'

The immune system changes with age. Young adults have the strongest immune system in the population, most capable of mounting a massive immune response. Normally that makes them the healthiest element of the population. Under certain conditions, however, that very strength becomes a weakness.

In 1918 the immune systems of young adults mounted massive responses to the virus. That immune response filled the lungs with fluid and debris, making it impossible for the exchange of oxygen to take place. The immune response killed.

The influenza outbreak in 1997 in Hong Kong, when a new virus jumped from chickens to humans, killed only six people and it did not adapt to man. More than a million chickens were slaughtered to prevent that from happening, and the outbreak has been much studied. In autopsies pathologists noticed extremely high cytokine levels, discovered even that the bone marrow, lymphoid tissue, spleen (all involved in the immune response) and other organs were themselves under attack from an immune system turned renegade. They believed that this proved 'syndrome [was] not previously described with influenza.' In fact, investigators in 1918 had seen the same thing.

This was still influenza, only influenza.

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In the 1970s physicians began to recognize a pathological process in the lungs that could have many causes but, once the process began, looked the same and received the same treatment. They called it ARDS, which stands for Acute Respiratory Distress Syndrome. Almost anything that puts extreme stress on the lung can cause ARDS: near drowning, smoke inhalation, inhaling toxic fumes (or poison gas)' or influenzal viral pneumonia. Doctors today looking at pathology reports of lungs in 1918 would immediately designate the condition as ARDS.

One pulmonary expert describes ARDS as 'a burn inside the lungs.' It is a virtual scorching of lung tissue. When viral pneumonia causes the condition, the immune system toxins designed to destroy invaders are what, in effect, flame in the lung, scorching the tissue.

Whatever the causes of ARDS, even today there is no way of stopping the process of disintegration in the lung once it begins. The only care is supportive, keeping the victim alive until he or she can recover. This requires all the technology of modern intensive care units. Still, even with the best modern care, even with for example dramatically more efficient and effective administration of oxygen than in 1918, the mortality rate for ARDS patients in different studies ranges from 40 to 60 percent. Without intensive care (and hospitals have few beds in intensive-care units) the mortality rate would approach 100 percent.

(In 2003 a new coronavirus that causes SARS, 'Severe Acute Respiratory Syndrome,' appeared in China and quickly spread around the world. Coronaviruses cause an estimated 15 to 30 percent of all colds and, like the influenza virus, infect epithelial cells. When the coronavirus that causes SARS does kill, it often kills through ARDS, although since the virus replicates much more slowly than influenza, death from ARDS can come several weeks after the first symptoms.)

In ARDS, death can come from many causes. Organs outside the lungs fail because they get too little oxygen. The lungs can so fill with fluid that the right ventricle of the heart cannot empty it so the victim drowns. The strain of trying to pump blood out of the lung can cause heart failure. Or the victim can simply die from exhaustion: he or she must breathe so rapidly to get enough oxygen that muscles become exhausted. Breathing just stops.

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ARDS by no means accounts for all the influenza deaths in 1918 and 1919, or even for a majority of them. It explains only those who died in a few days, and it explains why so many young healthy people died. Although influenza almost certainly killed some people in ways that had little to do with the lungs (for example, someone whose already weak heart could not stand the additional strain of fighting the disease) the overwhelming majority of non-ARDS deaths came from bacterial pneumonias.

The destruction of the epithelial cells eliminated the sweeping action that clears so much of the respiratory tract of bacteria, and the virus damaged or exhausted other parts of the immune system as well. That gave the normal bacterial flora of the mouth unimpeded entry into the lungs. Recent research also suggests that the neuraminidase on the influenza virus makes it easier for some bacteria to attach to lung tissue, creating a lethal synergy between the virus and these bacteria. And in the lungs, the bacteria began to grow.

Bacterial pneumonias developed a week, two weeks, three weeks after someone came down with influenza, including even a seemingly mild case of influenza. Often influenza victims seemed to recover, even returned to work, then suddenly collapsed again with bacterial pneumonia.

It is impossible to know what percentage of the dead were killed by a viral pneumonia and ARDS and how many died from bacterial pneumonias. Generally speaking, epidemiologists and historians who have written about this pandemic have assumed that the overwhelming majority of deaths came from secondary invaders, from bacterial pneumonias that can be fought with antibiotics.

The conclusion of the army's pneumonia commission, however, is chilling in terms of implications for today. This commission, comprised of half a dozen of the finest scientists in America, both conducted autopsies and reviewed pathology reports of others; it found signs of what would today be called ARDS in almost half the autopsies. A separate study limited to the pathology of the disease, conducted by Milton Winternitz, a Welch protegé and later dean of the Yale Medical School, reached the same conclusion.

That overstates the proportion of victims who died from ARDS (in effect from influenzal viral pneumonia) because the army study looked only at deaths among soldiers, men who were young and otherwise healthy, the group most likely to have been killed by their own immune systems. In the total population, viral pneumonias and ARDS would not account for as high a percentage of the deaths. Most deaths almost certainly did come from secondary bacterial infections, but probably not quite so many as has been assumed. That should, however, be small comfort for those who worry about the next influenza pandemic.

The 1957 pandemic struck in the golden age of antibiotics, but even then just 25 percent of the fatalities had viral pneumonia only; three-quarters of the deaths came from complications, generally bacterial pneumonia. Since then bacterial resistance has become a major problem in medicine. Today the mortality rate for a bacterial pneumonia following influenza is still roughly 7 percent, and in some parts of the United States, 35 percent of pneumococcal infections are resistant to the antibiotic of choice. When staphylococcus aureus, a bacterium that has become particularly troubling in hospitals because of its resistance to antibiotics, is the secondary invader, the death rate (today) rises to as high as 42 percent. That is higher than the general death rate from bacterial pneumonias in 1918.

Part VII

THE RACE

CHAPTER TWENTY-TWO

N
ATURE CHOSE
to rage in 1918, and it chose the form of the influenza virus in which to do it. This meant that nature first crept upon the world in familiar, almost comic, form. It came in masquerade. Then it pulled down its mask and showed its fleshless bone.

Then, as the pathogen spread from cantonments to cities, as it spread within cities, as it moved from city to town to village to farmhouse, medical science began moving as well. It began its own race against the pathogen, moving more rapidly and with more purpose than it ever had.

Scientists did not presume to think that they would or could control this rage of nature. But they did not abandon their search for ways to control the damage of this rage. They still tried to save lives.

Worldwide their struggle, their race, commenced. In the United States that struggle would be fought by Welch, Gorgas, Cole, and their colleagues, as well as by the institutions they had built and the men and women they had trained. Neither these institutions nor these men and women had ever been tested like this. They had never imagined they would be tested like this. But any possibility of affecting the course of the disease lay in their hands.