Published November 19, 1997 in the Eastside Week

The Killer Flu and You

By Chris Carrel

The Climate is right for a major influenza pandemic. When will it happen and where will it start?

At 35 years old, the Federal Way woman was simply too young and robust to die from the flu, judging from our normal conception of the illness. After all, it’s a minor disease.

Yet for Dr. David McEniry’s patient, a 1994 bout with the flu rapidly turned deadly. The virus eliminated large swaths of cilia, the carpet of microscopic hairlike projections that protect the lungs from infection. With her lungs’ primary defenses down, an explosive bacterial infection set in, generating a fulminant pneumonia. The woman’s alveoli, the tiny air sacs that absorb oxygen into the blood became congested with fluid and immune cells arriving to fight the infection and she had to fight for breath. She was put on a respirator immediately after being admitted to the hospital, but “her lungs were pretty much destroyed,” says Dr. McEniry, A Federal Way internist.

“People underestimate the flu,” he says with some frustration.

Underestimating the flu. That may be the medical Zeitgeist as we wind down the millennium. Tropical diseases with fancy names like Ebola, Lassa fever, and antibiotic-resistant superbacteria grab the public’s attention (thanks to TV news magazines, recent movies like Dustin Hoffman’s Outbreak, and best sellers like The Hot Zone) and spawn much medical hand wringing about the threat of emerging infectious diseases. These tropical terrors, we are told, are just a genetic mutation and plane ride away from causing horrific disease and gruesome death in temperate North America. The drug-resistant germs will get you in your hospital room.

But while these exotic killers and newly resurgent bacteria certainly do pose a threat, they pale in comparison to influenza, plain old common flu. If that sounds like a stretch, consider that during the 1918 Spanish influenza pandemic more than 1 billion people fell ill and between 21 million and 40 million people died. The virus can be quite deadly.

Now, the world is overdue for another influenza pandemic, according to scientists who study the virus., and the US is not prepared to handle one when it comes. Based on our proximity to the world’s epicenter of the flu, the Puget Sound region could be on the front line for the next big one.

Influenza is a Rodney Dangerfield killer, despite incurring a staggering body count. In an average year, the disease that gets no respect kills between 20,000 and 40,000 Americans, most of those deaths from flu-related viral or bacterial pneumonia. During pandemics, though, the body count swells.

There have been three so far this century: the 1968 Hong Kong flu pandemic (the dominant strain circulating today) that killed 111,927 in America over a four-year period; the 1957 Asian flu pandemic that killed 115,700 Americans during a three-year period; and the mother of all pandemics, the 1918 Spanish influenza that killed more than 600,000 Americans in two years.

Aside from the deaths, the flu causes widespread sickness. The resulting hospitalizations and lost workdays ding the American economy for about $10 billion a year, according to the Centers for Disease Control (CDC). In public health terms, influenza is an uncontrolled disease.

Yet, most of us dismiss the flue as a minor nuisance, a little more than a serious than a common cold, though not by much. Epidemiologists describe the flu as killing at the “epidemiological fringes,” a reassuring term for those of us not on those fringes. According to CDC statistics, 90 percent of flu-related deaths occur in people 65 or older, while the mortality rate for young adults is comfortably close to zero. Newer infectious diseases, like AIDS and Hantavirus, frighten us not because of the actual numbers they kill, but because they kill indiscriminately, taking young and old alike.

With the flu, it seems, most of us assume ourselves to be safe.

That safe zone disappeared in the 1918 Spanish influenza pandemic, when for reasons that are still not understood, the virus became as efficient at killing people between the ages of 20 and 40 as it did those older than 65. In fact, it appeared to excel in killing healthy, young adults. More than 280,000 young Americans between the ages of 20 and 39 died of flu-related pneumonia during 1918 and 1919.

In the first 10 months of the pandemic, approximately 550,000 Americans died, more than all the US combat deaths from World War I, World War II, the Korean War, and the Vietnamese War combined. Nearly as disturbing as the prodigious mortality rate, though, is the speed and gruesomeness of many of the deaths.

Victims presented normal flu symptoms – high fever, fatigue, and muscle aches – but declined rapidly, becoming confused and ashen-colored, laboring to breathe, sometimes spitting up blood, before death overtook them. The agonizing sequence sometimes took as long as two days. For some, only hours were required.

In The Coming Plague, science writer Laurie Garrett observes, “There were reports of women boarding a New York subway on Coney Island feeling little else than mild fatigue, and being found dead when the train pulled into Columbus Circle, some 45 minutes later.

Autopsies of Spanish influenza victims revealed that their lungs, which should’ve been light and buoyant, were inflamed and saturated with a thin, bloody liquid that choked off breath. The major airways seeped a frothy, bloody fluid, and corpses were known to stain bedsheets as the fluids leaked out of the bodies. These unfortunate souls literally drowned in their own fluids.

The impact of the pandemic varied from city to city. Between September 1918 and March 1919, 33,387 New Yorkers died from influenza while the city seemed not to notice. Philadelphia, where 15,785 died in the same period, hovered near collapse.

Hospitals were flooded with patients too numerous for the city’s healthy doctors and nurses to attend. Essential services like telephone, fire, police and garbage collection were hobbled by the great number of workers out sick. The city’s undertakers and its only morgue were not equal to the multitude of dead.

In the second and third week of October, when 2,600 and 4,500 died respectively, the crisis peaked. According to America’s Forgotten Pandemic, historian Alfred Crosby’s exhaustive history of the crisis, the city’s morgue, with a 36-body capacity, had the dead “piled three and four deep in the corridors and in almost every room, covered only with dirty and often blood-stained sheets. Most were unembalmed and without ice. Some were mortifying and emitting a nauseating stench.”

Seattle and environs fared much better during the pandemic than many other American cities. Approximately 2,000 Seattleites died from the flu between September 1918 and March 1919, a relatively small figure for a city of 300,000. Pure dumb luck is probably the best explanation for Seattle’s relative well-being during the plague.

The city’s brain trust tried the same anti-flu techniques that other cities did, closing dance halls and schools, requiring useless gauze masks to be worn in public, providing an equally useless anti-flu serum, and even washing the streets for the first time in many years.

The Seattle Police Department created an “influenza squad” to join its morals squad and dry squad in protecting the public from the dangers of the time. And although the influenza squad kept buys, breaking up public meetings, clearing pool halls and hotel lobbies, and arresting “promiscuous spitters,” careless coughers, and those flaunting the mask rule, there’s little reason to believe the police had any effect limiting the city’s flu epidemic.

Seattle did, however, offer the virus a free ride to remote Alaska, with supply ships spreading the killer disease into Eskimo villages. Here, Spanish influenza did some of its most horrific work in North America. Native villages were especially hard hit due to the lack of medical facilities, unfamiliarity with the disease, and the harsh climate.

According to Thomas Riggs, Jr., Alaska’s governor at the time, the native population “showed absolutely no resistance” to the flu. In Teller on the Seward Peninsula, where 70 of the village’s 150 inhabitants died, children shared cabins with their parents’ corpses because there was no one left in the village strong enough to remove and bury the dead.

In Nome, entire families froze to death because family members were too sick to keep up fires. Some remote villages were wiped out entirely by the flu. Alfred Crosby notes that “Spanish influenza did to Nome and the Seward Peninsula what the Black Death did to 14^th Century Europe.”

Indeed, Spanish influenza invites comparison only with the deadliest of infectious diseases known to humanity. It was caused by a “virus much more virulent than anything thing we’ve seen before or since,” says Baylor University influenza research Paul Glezen.

If AIDS is the standard by which we measure infectious disease in the 1990s, this was like AIDS on 78 RPM. It killed 196,000 Americans in the second month of the 1918 pandemic, more than double the death toll of the entire first decade of the AIDS epidemic in America. That this explosively lethal virus raged earlier this century brings it much too close for comfort. Because of the influenza virus’s structure, medical scientists consider a future pandemic inevitable and the probability of a 1918-like influenza too real to ignore.

A Molecular Moving Target

Influenza is a molecular moving target. “We call it influenza, and there’s types and subtypes,” says Dominick Iacuzio, influenza program officer at the National Institute of Allergy and Infections Disease (NIAID) in Bethesda, Maryland, “But because it’s a continually mutating virus, it is not the exact same virus [year after year].”

Each flu particle resembles a spiked ball. Its internal payload of viral RNA is protected by a heavy protein coat, studded with 700 protruding spikes, called surface proteins, or antigens. Influenza has two different surface proteins, hemagglutinin, known as H, and neuraminidase, known as N.

The immune system recognizes viruses by their surface proteins, and most are easily controlled this way. Once infected, or inoculated with a weakened virus, a person’s immune system will always recognize that virus’s specific surface proteins and act to fend off an infection.

But influenza has mastered a remarkably simple trick that keeps it one step ahead of the immune system. It changes frequently, altering its surface proteins ever so slightly. This so-called antigen drift prevents the immune system from getting a clear fix on the virus and is the reason we have annual epidemics. Every flu epidemic since 1968 has been a drifted version of the Hong Kong flu (H3N2) or the Russian flu (H1N1).

Pandemics occur because Type A influenza (there’s also a Type B influenza, which is far more stable and doesn’t cause pandemics; and a Type C influenza, which only causes mild respiratory infections) occasionally undergoes an even more dramatic change, called antigen shift, which results in a radically new version of its surface protein for which humans have no immunity. Influenza’s RNA strain is flimsily assembled in eight segments that fit together, and come apart, like a jigsaw puzzle.

When two different strains of influenza virus infect the same cell, the viruses sap gene segments, or re-assort, resulting in entirely new surface proteins. The 1957 Asian flu pandemic was the result of a shift from H1N1 to H2N2, while the Hong Kong pandemic was by dint of a shift from H2N2 to H3N2. Curiously, the Russian flu, H1N1, showed up in 1977, but wasn’t the result of antigenic shift. Genetic analysis revealed it to be a 1950s-era virus that had been frozen for more than 20 years before being released, likely by accident.

For genetic re-assortment to produce a viable shifted virus, it would have to mix segments of human influenza with those of an avian strain. Aquatic birds, ducks primarily, are the animal reservoir for influenza, storing a veritable warehouse of influenza strains without themselves getting sick.

There are 14 known forms of hemagglutinin and nine forms of neuraminidase found in avians. Conventional medical wisdom holds that only H1, H2, and H3 and a few of the N types can infect humans, while the rest are consigned to circulate in populations of aquatic birds. Swine, however, can be infected by both human influenza viruses and some avian influenza.

The predominant theory today is that pigs are the “mixer vessels,” where human and avian influenza commingle and re-assort, giving rise to dangerous pandemic strains. Because influenza is stable in aquatic birds (i.e. it doesn’t mutate as it does in humans), all previous pandemic strains are perfectly preserved in the avian reservoir. In other words, the virus that caused the 1918 Spanish Influenza is still out there, biding its time.

China is considered the world’s “influenza epicenter” because it’s home to more than 7 billion poultry, a great many of them ducks. Traditional agricultural practices bring pigs, ducks, and humans in close contact, encouraging re-assortment. The last two pandemics arose in China and were hybrids of human and avian viruses. China is considered the most likely source for the next pandemic, and international influenza monitoring is focusing on the People’s Republic.

There are 110 national influenza centers in 80 countries, including 10 CDC-funded laboratories in China, where researchers keep their eyes on local outbreaks and identify the virus strains circulating, forwarding the information to the Centers for Disease Control and Prevention in Atlanta as well as to the World Influenza Center in London.

By keeping an ear to the ground of the viral world, health officials can develop a reasonable estimate of which virus strains will be active in the fall flu season, information that enables pharmaceutical companies to formulate vaccines. Most importantly, if a pandemic strain emerges, early identification by this network is crucial to producing a vaccine before the pandemic gets a head of steam.

A Bird Flu?

China came close to delivering the world a new pandemic earlier this year when a Hong Kong youngster died of an entirely novel influenza strain. Though the pandemic obviously didn’t develop, the case has unsettled influenza experts.

The 3-year old Hong Kong boy died in May from acute respiratory disease and Reye’s Syndrome. The Hong Kong Health Department isolated an influenza virus in the boy’s trachea, but couldn’t identify it. The Chinese agency forwarded samples of the killer bug to the World Health Organization’s three collaborating laboratories. All three labs pegged the virus as a pure avian influenza strain, H5N1. There is not a person on Earth who would have immunity to an H5 influenza virus.

“When I think about the Hong Kong virus in May,” says Baylor’s Paul Glezen, “if that had been a virus with potential for person-to-person transmission, we would be in really bad shape…We would be in the peak of the first wave right now.”

The epidemiology investigation, though not complete, indicates that the virus lacked the ability to transmit from person to person, but it reminds us that, because of the virus’s mutability, what’s true about influenza today may not be true tomorrow.

“ We have a lot of rules and theories about what the virus can do based on past experience,” says NIAID’s Dominick Iacuzio, “evidenced by what happened [in Hong Kong] we’re still learning.”

There are two points about the H5 virus that are worth considering. First, the H5 has caused virulent epidemics in domestic poultry. A serious outbreak of an H5N2 influenza virus has killed millions of chickens on crowded Mexican poultry farms since 1995. A similar 1983 epidemic killed 17 million fowl on commercial chicken farms in Georgia.

This strain was dubbed “chicken Ebola” by influenza researcher Robert Webster because the virus abandoned its specificity for the respiratory tract, attacking cells throughout the body, including the brain. The virus caused internal hemorrhaging and central nervous system collapse, and infected flocks suffered mortality rates as high as 100 percent. With H5 adapting the ability to infect humans, its “Ebola” capacity becomes exceptionally worrisome.

Second, the conventional pandemic theory rests on pigs being a mixing vessel between human and avian viruses. If avian influenza continues infecting humans as well as pigs, then humans could conceivably become mixing vessels and the opportunities for re-assortment and pandemics would increase.

The Hong Kong situation also illustrates our vulnerability in the face of pandemics. The current system of monitoring and vaccine development works rather well for annual epidemics, but pandemics area different creature. By early February each year, health officials deliver the results of their viral watchdogging to vaccine manufacturers, describing their best estimates of what strains (and the estimates have been remarkably good in recent years) will be prevalent in the upcoming fall flu season.

The timing is crucial. Influenza vaccine is cultured on fertilized chicken eggs in a process that takes some six to eight months to complete. Vaccine manufacture must begin early in the year to be ready by the start of flu season in October (the Puget Sound area’s flu season starts later, near the first week of December).

In a normal epidemic year, health officials can be fairly certain that the vaccine won’t be needed until October. Pandemic influenza, however, moves much quicker and could arrive in the US before the vaccines are ready. The 1918 Spanish Influenza pandemic, moving about in the age of steamships, crossed the world in four months time. The 1968 Hong Kong virus reached the US only four months after emerging in China.

Of course, the nature and speed of travel between China and the US has changed dramatically since 1968. A particularly sobering thought about the H5N1 virus is that if it had proved to be communicable, it would’ve only been a 17-hour plane ride away from the Puget Sound region.

If a novel strain emerges later in the year, after vaccine production has already begun, there would be a shortage of the embryonated eggs needed for vaccine manufacture. Even if that problem could be solved, there would still be a lag time of six to eight months before large quantities of vaccine could be produced and tested.

In that case, we’d be well into the first wave of the pandemic before any vaccine would be available. If a pandemic strain emerged in a country less heavily watched than China – Southeast Asia, for instance, has no influenza-monitoring network – many of the same problems would apply.

Distribution and actual vaccination during a pandemic raise their own logistical problems as well. “You’re talking about getting [a] high proportion of people vaccinated quickly,” says Dr. Russell Alexander, chief epidemiologist at the King County Department of public Health, “and we would struggle with that.”

“We’re really not very well prepared for another pandemic,” says Baylor’s Paul Glezen, who has participated in a federal interagency working group designing an influenza pandemic preparedness plan for the country. He’s alarmed that while a plan has been drafted it has yet to be approved the Secretary of Health or sent to Congress for funding. It seems that while influenza experts view another pandemic as inevitable, the political side of our federal public health bureaucracy is acting as if it will never come.

And if the next pandemic is as severe as the 1918 Spanish Influenza experience, even our sophisticated medical technology will be of limited use. “It’s wrong to think that things have changed so that we could deal with [a 1918-type],” Glezen says. “We might save more lives but the cost would be terrible.”

One of the deadly hallmarks of the 1918 pandemics was a large number of adults dying from pneumonia-induced adult respiratory distress syndrome. In the medical journal Epidemiological Reviews, Glezen wrote, “Sufficient numbers of intensive care beds do not exist to treat a pandemic of adult respiratory distress syndrome, and if they did exist, we would bankrupt the system with the effort.”

But is it likely the world will ever again see an influenza virus as deadly as the 1918 Spanish Influenza? Despite six decades of analyzing influenza, researches are unable to predict the severity of future pandemics. Nor do they understand the molecular characteristics that define the viruses’ lethality.

However, there are conditions that give virulence an advantage. Paul Ewald, a biologist at Amherst College in Massachusetts, argues that all things begin equal, a virus that keeps its host home sick where it can’t infect anyone, will be less successful than a milder strain that allows a person to go to work and infect her co-workers.

Ewald believes that the conditions of World War I were the key to Spanish Influenza’s pathogenicity. With hundreds of thousands of soldiers crossing the Atlantic each month on crowded troopships, sick soldiers languishing in the trenches and in field hospitals, the advantage shifted to a more virulent strain of flu.

It’s a sobering thought for an overpopulated world dominated by burgeoning megacities. World population has increased from a little less than 2 billion in 1918 to nearly 6 billion (and growing) today, 45 percent of whom live in urban areas. In 1950, only New York and London had populations larger than 8 million. By 2000, more than 28 urban areas, mostly in developing countries, will surpass the 8 million mark.

If urban overcrowding can give virulent influenza strains a boost, air travel will ensure rapid dispersal throughout the world. In 1993, nearly 80 million air passengers arrived from or departed to foreign countries from US airports (Sea-Tac accounted for more than 1.5 million in 1996), a doubling of international travel from even a decade before. And since 1985, aircraft manufacturers have made cost-saving changes in air circulation systems that result in cabin air being renewed less frequently, a further boon to airborne viruses like influenza.

“Obviously, it’s much easier today for the influenza virus to spread,” say Paul Glezen. He points to a study done in 1965 that analyzed the previous three decades of influenza epidemics and concluded that Influenza A epidemics had occurred every to years and Influenza B epidemics every five. “Now epidemics occur every year, and we often have several viruses circulating each year.”

All of which makes one wonder how the Northwest will fare when the next inevitable pandemic collides with the greatly changed influenza ecology of the 1990s. Puget Sound is a major hub of trade and travel with the Pacific Rim countries, including China.

If the world is “truly a global village for microbes” as science writer Laurie Garrett observes, then the distance between Puget Sound and the world’s influenza epicenter can be measured in the hours it takes to fly a commercial jetliner between China and Sea-Tac Airport. “If there was a new [pandemic] strain…that might come on us quickly because we are an Asian port,” says King County’s Dr. Russell Alexander, “that might well be on us before we have a vaccine.”