The Plague That Won’t Go Away

By Charlotte Bruce Harvey '78 / November / December 2004
June 13th, 2007

Flu season arrived ominously this fall. On their front pages in late September, newspapers reported that British regulators had found contamination problems at a Liverpool, England, pharmaceutical plant that supplies half of the U.S. flu vaccine. The plant was shut down for three months, leaving the United States short 50 million doses of vaccine. Public health officials responded by urging otherwise healthy people to refrain from using up the available doses, so they could be given to the old, the very young, and the sick. Brown responded as did employers all around the country: by suspending its annual program of offering a free flu shot to whoever wanted it.

Most people saw this vaccine shortage as little more than a nuisance; some doubt that a flu shot makes any difference at all. But the shortfall’s potentially devastating implications lay buried in another news story that broke about the same time: the news from Thailand that a twenty-six-year-old woman had died of bird flu, which she appeared to have contracted from her daughter, who was herself dying of the disease. Tissue samples confirmed that the deadly virus was a particularly dangerous strain of avian influenza known as A(H5N1).

H5N1 first appeared in Hong Kong in 1997, when it struck birds in a live-animal market and then sickened eighteen people, six of whom died. To contain the infection, officials ordered the immediate slaughter of all poultry in the territory—1.5 million birds over the course of three days—and a drastic overhaul of the city’s markets. Hong Kong’s swift response was credited with averting a pandemic. Nevertheless H5N1 has resurfaced over the past seven years in nine Asian countries, including Korea, Japan, Malaysia, Vietnam, and Thailand. Millions of birds have died, and millions more have been culled—in a region that depends on poultry for both food and export. Still, the flu continues to spread. It is now endemic, infecting not only farmed birds, but wild waterfowl, domestic cats, pigs, and even zoo tigers according to the New York Times. Sporadically the virus manages to infect people. This year, forty-four people in the region became ill with bird flu; thirty-two of them died. While most of those victims had been around birds, several cases strongly suggest human-to-human transmission. The Thai mother is one.

These two seemingly unrelated events present a startling possibility. What would happen if a flu strain as lethal as H5N1 began to spread quickly among humans and vaccine manufacturers were caught unprepared? What if millions of people began dying?

To John M. Barry ’68 such a scenario is not a matter of if, but when. While there is no way to prevent the emergence of a deadly influenza virus, measures do exist to help prevent one from causing a pandemic. And Barry believes governments are doing too little to adopt those measures. A plague is coming, he says, and unless we do a better job of preparing for it, we have only to look to the past to see our future.

Barry is all too familiar with that past. He spent seven years researching The Great Influenza: The Epic Story of the Deadliest Plague in History, a book about just such a pandemic, which occurred in 1918–19. Since its publication in February by Viking Press, Barry has spoken widely on the subject, not only giving the requisite book-promotional interviews to radio and newspaper reporters but also addressing the world’s top infectious-disease experts. Last summer, for example, he gave the keynote speech at a National Academies conference on pandemic influenza, and he was invited to do the same at a conference on global vaccination strategies in October.

Until this fall’s vaccine shortage, Barry’s plea was heard largely by specialists. In the United States, both politicians and the public seemed oblivious to the danger of influenza. But when people couldn’t get their kids flu shots in October, just weeks after bird flu had killed a mother and daughter in Thailand, Barry’s doomsday scenario seemed increasingly plausible. Discussing H5N1 in Providence this fall, he said flatly that it “is the scariest virus I’ve heard of—far scarier than AIDS or Ebola. Its death rate is light years ahead of 1918.”

The 1918–19 pandemic was the deadliest on record, and Barry argues that now, as then, we run a lethal risk when we fail to take the flu seriously enough. The most common estimate is that the so-called Spanish flu killed 20 million people worldwide, but Barry believes that number is far too low. Today most epidemiologists agree that at least 40 million people died, and the number could be as high as 100 million. Even using the low count, Barry points out that the pandemic killed more people in twenty-four weeks than AIDS has in twenty-four years. It killed more in a single year than the Black Death of the fourteenth century, and more than the entire death toll of World War I. In the United States alone, 675,000 people died of the 1918 flu, a percentage of the population equivalent to about 1.75 million deaths today.

The disease was gruesome. Like victims of dengue, or “breakbone,” fever (with which some doctors confused it at the time) patients endured agonizing pain in their bones. They ran high fevers. They coughed violently, some so hard their ribs broke.

With most strains of influenza, the fatalities tend to be infants, old people, and others whose weakened immune systems can’t fight the virus or the secondary bacterial pneumonia it often fosters.

The 1918 flu, a strain called N1H1, also struck healthy young men and women, who died not from bacterial pneumonia but from the virus itself. Under attack, their immune systems overreacted and marshaled all defenses, decimating their lungs in the process. Autopsy reports compared their lungs to those of soldiers killed by mustard gas. The cause of death was Acute Respiratory Distress Syndrome, or ARDS. When their lung tissue broke down and their lungs filled with fluid and debris, their hearts couldn’t pump enough oxygenated blood to their organs and extremities. Without oxygen, patients’ skin turned dark blue, a condition called cyanosis. They bled from the mouth, eyes, nose, and ears. Doctors described patients struggling to clear their airways of the bloody foam in their lungs. Some patients—the ones killed by ARDS—seemed perfectly healthy just hours before they fell down dead.

The stresses of World War I only hastened the flu’s spread. Troops packed into railroad cars, slept inches from one another in icy barracks, huddled close around camp stoves, and convalesced in army hospitals filled to several times their capacity. In Europe, as many soldiers died of influenza as in the trenches. Transport ships carried the disease across the Atlantic, infecting ports from which other ships ferried it to more distant locales. Of course none of this compares to the disease-spreading capacity of modern airplanes, which cram hundreds of people into confined spaces, mixing their germs constantly, and transport this viral soup to new cities around the globe in hours.

The first European newspapers to report on the 1918 pandemic were in Spain, which is why the disease became known as the Spanish flu. U.S. newspapers, hand-tied by the Sedition Act, which was passed in May 1918, shied away from publishing flu statistics or other warnings that might imply vulnerability and be construed as treasonous. In September, after a flu-ravaged ship docked in the Philadelphia Navy Yard and the infection began to spread through the hospital, doctors urged organizers to cancel an upcoming Liberty Loan parade. The city’s public health director wouldn’t listen. The parade was designed to raise millions for the war effort, and he did not want to appear unpatriotic despite clear evidence that gathering crowds would only foment the disease.

So Philadelphia, like many cities, ran out of coffins. In scenes evocative of the Black Death, priests drove horse carts through the modern city streets calling, “Bring out your dead!” Corpses wrapped in sheets were buried in mass graves dug by steam shovel.

In the middle of the Paris peace negotiations, Woodrow Wilson contracted the flu. “Wilson had influenza, 103-degree fever, violent coughs, nausea, and diarrhea, all symptoms of influenza—not stroke as thought by later scholars,” Barry told interviewer Terry Gross on the National Public Radio program Fresh Air. “He was actually negotiating from his bed at a time when his aides said he couldn’t remember in the afternoon what had been decided before noon.” Barry speculates that Wilson’s flu-induced confusion may explain his concessions to France’s Georges Clemenceau on the strictures that hobbled Germany and led ultimately to Adolf Hitler’s rise.

Barry, whose previous books include the award-winning  Rising Tide: The Great Mississippi Flood of 1927 and How It Changed America, hypothesizes that the 1918 pandemic started in America’s farm belt, in Haskell, Kansas. There, in January and February 1918, a physician named Loring Miner was so overwhelmed by the outbreak of a particularly lethal strain of influenza that he sought advice from the U.S. Public Health Service. He reported the epidemic to the weekly journal Public Health Reports, which tracked communicable diseases worldwide. Barry found newspaper reports of soldiers—one a new enlistee and another home visiting family—who traveled in late February from Haskell to Camp Funston, where on March 4 a cook reported sick with influenza. Three weeks later 1,100 men were hospitalized. From Funston, troops carried the virus to Europe.

All flu strains normally originate as a digestive disease in birds and are spread through their droppings. After forcing their way into living cells, flu viruses replicate rampantly, recombining their tiny fragments of RNA in every manner possible. When the infected cells burst, each releases between 100,000 and a million of these recombined viral offspring—what virologists call a mutant swarm. Of all RNA viruses, Barry points out, influenza and HIV are among those that mutate the fastest. “In both, a drug-resistant mutation can emerge within days,” Barry writes in The Great Influenza. “And the influenza virus reproduces rapidly—far faster than HIV. Therefore it adapts rapidly as well, often too rapidly for the immune system to respond.”

If we humans are lucky, the virus stays in birds. But given the right combination of mutations and circumstances, it can jump species, and if avian flu invades a cell already infected with human flu virus, the two strains can exchange genetic material, forming a new hybrid. Or a bird flu may infect an intermediary host, typically a pig, which is susceptible to both avian and human influenza. This, Barry says, may be what happened in 1918. Sometimes through sheer random mutation, a strain like H5N1, the recent strain in Thailand, develops the ability to infect humans directly. The fact that the virus is widespread in Asian birds but has only infected a few dozen people indicates that it is not yet efficient at infecting humans, Barry observes. But it has proved overwhelmingly lethal to those it has managed to infect—killing 70 percent of its victims so far.

The likelihood that the Thai mother was infected by her daughter could mean that the virus has jumped another critical hurdle on the road to pandemic: moving directly from one human to another.

According to John Barry, we have failed to absorb the les-sons of 1918. Garden-variety flu causes lost workdays and kills 36,000 U.S. citizens each winter but it is nothing to the global outbreak of a new strain to which humans have no resistance. Throughout his book, Barry repeats like a drumbeat the refrain It was only influenza. The line may grow tiresome as a literary device, but his point is dead on. That the stars have not lined up for another pandemic as severe as 1918’s is due more to luck than to good public health policy. Milder pandemics struck in 1957 and in 1968 (the “Hong Kong” flu). Barry says we’re overdue.

Three avian flu strains are currently poised to infect humans, he warns in the November issue of Fortune. H5N1 is the most lethal, but a milder strain called H9N2 infected three people in Hong Kong in 1999 and 2003. And in the Netherlands, H7N7 killed one of the eighty-four people it infected in the winter of 2003.

Barry believes we could be doing more to prevent a pandemic. In 1918 and 1919, doctors raced to discover an antiserum for influenza. That research, Barry says, led to some of the century’s most important developments in biological science, including the discovery of DNA. As a result, we can now minimize influenza’s severity with antiviral drugs—notably Tamiflu—which can even prevent illness if taken long enough. Barry believes governments should be more actively stockpiling antivirals to buy time for scientists to develop vaccines for emergent flu strains.

But science is not enough. The unwitting villains in The Great Influenza were the politicians and military officers who sacrificed thousands of lives in their attempt to keep a lid on information. Many didn’t want to admit to the nation’s weakness in wartime. Others were reluctant to cede authority to doctors. Transparency is critical when facing a disease outbreak, Barry says. When China covered up the first cases of the lethal pneumonia SARS (Sudden Acute Respiratory Syndrome) in November 2002, the entire world lost vital time to contain the disease. In refusing to acknowledge the disease’s presence, China risked fueling a pandemic just as certainly as (and much more knowledgeably than) the Philadelphia health officials who decided to go ahead with a Liberty Loan parade in spite of a burgeoning epidemic.

The World Health Organization has implemented a global monitoring system to track outbreaks of influenza as they emerge, but compliance is costly and fewer than half the world’s nations can afford it. Coverage is especially thin in South America, Africa, and parts of China—places where population is dense and disease spreads quickly. “This system needs to be expanded,” Barry writes, “and poor countries should get the resources to take part.”

Furthermore, he says, governments need to get involved in vaccine production, whether directly or by providing incentives or guarantees to private-sector manufacturers. “To protect the United States against a pandemic,” he warns, “vaccine development and production facilities must be upgraded, new technology developed, and factories located in the U.S. That is a national security issue.”

A slate of legal and liability issues, as well as unpredictable market forces, undermines the private sector’s ability to guarantee an adequate vaccine supply, says Georges Peter, a Brown pediatrics professor who stepped down this summer as chairman of the National Vaccine Advisory Committee for the U.S. Department of Health and Human Services (HSS).

Because influenza vaccines take so long to manufacture, orders must be placed months before flu season hits and demand can be known. But influenza is a moving target, constantly mutating. Each February, public health experts try to anticipate which strains are most likely to dominate the following winter, and to determine the composition of the coming year’s vaccine. When the experts guess right, people are glad they were vaccinated. But when officials guess wrong, people lose faith. The next year, Peter says, adults don’t bother to get flu shots and manufacturers are stuck with unused vaccine that can’t be saved for the next year. Last fall, the flu struck early and the death of several children created a surge in demand and a resultant shortfall. This year’s more drastic shortfall has revealed the danger of having just two companies, Chiron and Adventis, produce the entire U.S. vaccine supply.

Peter is hopeful that the current shortfall will prove a boon, increasing demand for vaccines and drawing attention to the underlying problems with their production. Barry makes the same point. Last year Congress cut in half HHS’s requested vaccine budget—some of which was specifically targeted for research on emerging flu strains. Congress was preparing to do the same this fall when the vaccine crisis hit.

Since H5N1 first emerged in Hong Kong in 1997, virologists working around the world have raced to create a vaccine.  The virus is so lethal it immediately killed the chicken eggs it was injected into to develop antibodies. To give the eggs’ immune systems time to respond, researchers had to disable one of the genes in the virus. The resultant vaccine has been tested in chickens, and the next step is clinical trials in humans, which were just beginning when the mother and daughter died in Thailand this fall. Once those trials are complete, the four-month-long manufacturing process can begin. HSS announced it has contracted for two million doses.

If we manage to dodge this bullet, only one thing is certain: there’s another on its way. All we can do, John Barry says, is prepare for it.

Charlotte Bruce Harvey is the BAM’s managing editor.

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November / December 2004