Influenza: The Hundred-Year Hunt to Cure the 1918 Spanish Flu Pandemic

by Dr Jeremy Brown

She had beaten influenza, but now had another battle to fight. Patients who have a long stay in the ICU often develop a profound generalized weakness. At the rehab hospital, Autumn had to learn how to walk again, to climb stairs, and to perform a host of other daily activities that she had once taken for granted. After two weeks of rigorous exercise, she left rehab and came home. In the fall of 2014, nine months after she first caught influenza, Autumn was finally strong enough to return to work. Her medical bills were close to $2 million, but she was fortunate to have good medical insurance and was only on the hook for her $18 copay.

It is estimated that between 50 and 100 million people died during that influenza pandemic. In the United States there were 675,000 deaths, ten times as many as had died in combat in the Great War, which was ending at the same time the flu was peaking.

We all harbor the desire to see cancer cured and heart disease eliminated. I obviously share these hopes, but as an ER doctor I have found myself wishing for something far more modest: a cure for influenza. We tend to shrug off the flu as just a nasty cold, but in the United States alone it kills between 36,000 and 50,000 people each year. That’s an astonishing and depressing number. But here is even worse news: if a pandemic strain of influenza as deadly as the 1918 virus were to infect the United States today, more than 2 million people could die. No conceivable natural disaster would compare. And it’s not something we can just pretend won’t affect us. In early 2018 newspapers warned that the flu season was “the worst in nearly a decade.” All across the country there were reports of young, healthy people dying. Several hospitals were so overwhelmed with the influx of flu patients that they had to set up triage tents or turn patients away. Flu is certainly not “the emperor of all maladies,” as cancer was described by the oncologist Siddhartha Mukherjee, but it is the malady of all empires. It has been with us since the dawn of time, and it has afflicted each civilization and society in every corner of the globe.

If it doesn’t kill you immediately, carbon monoxide poisoning will cause symptoms that mimic the flu. Since flu outbreaks peak in the fall and winter—the very period in which people are running their heaters and furnaces—carbon monoxide exposure is often misdiagnosed as the flu.

There is evidence that a fever is actually beneficial, and the reason is simple: the immune system fights infections better when the body is hotter. White blood cells are released in greater numbers from the bone marrow, and the cells do a better job of fighting the infection. Fever also improves the efficacy of another group of blood cells called natural killer cells, and it increases the ability of macrophages (“big eaters” in Greek) to ingest and destroy the invading cells.

If you are a healthy person with run-of-the-mill flu, you should not ask for antibiotics, and your doctor should certainly not prescribe them. Antibiotics don’t fight viruses, and so they are completely ineffective against the flu. If, however, you have a complication and your viral flu has evolved into a bacterial pneumonia, you should certainly be treated with them. But, and it’s worth repeating, antibiotics do nothing against the flu virus. You would be amazed at how many patients ask for antibiotics when they clearly have a viral infection, and are disappointed when I decline to prescribe them. Doctors are largely responsible for this huge problem. The best data we have suggests that about half of all patients with viral infections like influenza get a completely useless antibiotic.

A virus is a box of chemicals, without the structures of a basic cell. It cannot metabolize or replicate on its own. In order to reproduce, it must invade living cells. Viruses infect bacteria and plants, reptiles, fish, birds, and mammals. They have been so intertwined with our own evolution that over millennia some became incorporated into our own genetic code. Nestled into the long strands of our DNA are sequences that originated from ancient viruses. Their genetic code was so bound with ours that the virus became a harmless part of us, freeloading off human cells as they reproduced.

viruses are submicroscopic entities twenty times smaller than a bacterium. They contain a core of genetic material covered by a protein capsule, and they reproduce exclusively within living cells.

Viruses have evolved to be very different from the cells that are found in our body. Cells contain tiny specialized organs. Viruses have nothing similar. They have no mitochondria, so they cannot make energy. They have no ribosomes, so they cannot build proteins. They also lack lysosomes, which export waste and toxins. The virus is simply an envelope containing a bundle of genes that exist only to make copies of themselves. But while a computer virus is designed to infect your laptop and cripple or compromise its functions, nature’s viruses do not target cells expressly in order to kill them. Instead, their singular purpose is to hijack a cell and use it as a copying machine. In doing so, they may injure or destroy the host cell, but that is collateral damage, not their primary objective. In fact, if a virus is too lethal, it can kill the cells before they can be used to make viral copies. The influenza virus, the human immunodeficiency virus (HIV), and the Ebola virus differ in how deadly they are, but their strategy is the same. They invade our cells, reproduce, and then must find a new victim to colonize. They may leave their host weakened or even dead, but this is incidental.

there are three influenza viruses—they go by A, B, and C. Only the A and B strains cause significant disease in humans, and it is the A strain that is responsible for pandemic flu.

Sticking out of its exterior are two important proteins that look like tiny spikes and pitchforks. The spiky protein is called hemagglutinin, or HA for short. After the virus is inhaled into our lungs, it is the HA that latches on to the surface of our cells. Now the virus has one foot in the door. The cell is tricked into absorbing the virus, and once inside the cell the viral membrane dissolves and releases its eight genes. These enter the nucleus of the invaded cell. From there they commandeer the normal machinery and direct the cell to make millions of copies of the viral particle. These baby particles then rise back to the cell membrane, like bubbles in a boiling pot. At the surface, they become tethered and must break free in order to invade other cells. This is where the second, pitchfork-shaped protein on the surface of the flu virus steps in. It is called neuraminidase, or NA. Its function is to break the bond between the surface of the cell and the surface of the virus. The viral progeny is now free to be coughed or sneezed out, to invade another victim. The whole process takes only a few hours, and it leaves behind destroyed respiratory cells. That is when the symptoms of influenza begin.

Our bodies learn to defend against new invaders all the time. Vaccination takes advantage of this by presenting our immune system with a weakened or harmless form of the pathogen. This allows us to manufacture antibodies in advance of an infection. The immune system doesn’t care whether it came across the pathogen in the normal course of events or the pathogen entered the body as a vaccine via a needle. Either way, the immune response is the same. The body is able to fight an infection more quickly and effectively the next time around. If the antigen has not been previously recognized by our immune system, we may still produce antibodies against it, but the process is slower. We become sicker for longer, and our inability to mount an immediate attack on the virus may in some cases be fatal.

A massive vaccination program was also a massive gamble. If no swine flu outbreaks occurred in the fall, health officials could be accused of waste and overreach. But there was another concern: in a letter to the New York Times, Dr. Hans Neumann from the New Haven Department of Health noted that based on the projected scale of the immunizations, within two days of getting a flu shot, about 2,300 people would have a stroke and 7,000 would have a heart attack. “Why?” he asked. “Because that is the number statistically expected, flu shots or no flu shots.” Likewise, in the week following a flu vaccine, another 9,000 people would contract pneumonia, of whom 900 would die. These would certainly occur after a flu shot, but not as a consequence of it. “Yet,” wrote Neumann, “can one expect a person who received a flu shot at noon and who that same night had a stroke not to associate somehow the two in his mind?”

Counting and predicting influenza activity is really hard. Google Flu Trends tried and failed, and there were no insights from the now defunct flu prediction markets. Data coming from clinics and labs is incomplete and sometimes misleading.

there is a rhythm and flow that is fairly predictable in an emergency room. It’s usually quiet until the late morning. The busiest times are from about noon to ten p.m. As noted earlier, on Thanksgiving and Christmas Day very few patients come in. Black Friday is just the opposite; the ER overflows with patients. When I worked in inner-city emergency departments, summertime was stabbing season. There was more happening outside, more places where people gathered, more alcohol flowing. “If it is hot enough to barbecue,” a patient of mine once told me as I sutured the knife wounds on his chest, “it’s hot enough to stab someone.”

One way to better protect seniors is to vaccinate an entirely different demographic: schoolchildren. This notion was elegantly demonstrated in a natural experiment in Japan. From 1962 to 1987 most Japanese schoolchildren were vaccinated against influenza; at one point the vaccine was mandatory for a solid decade. The vaccination rate grew to around 85 percent, but the mandatory vaccination program was discontinued in 1994. Over the next several years, there was an increase in the number of deaths in the elderly during the flu seasons. In the U.S., where there had been no change in the vaccination policy, deaths of the elderly over the same flu seasons remained unchanged. Vaccinating one part of the population, in other words, benefits another.