MANHATTAN, MARCH 1999
The streets are still. Theaters, office buildings and government agencies have been closed for weeks. A few pedestrians hurry by, wearing white face masks in the cool spring air. Many of those whose jobs involved extensive social contact, including bank tellers, store clerks, schoolteachers, waiters and police officers, are gone from their posts – home, dead, no one knows.
The city’s private hospitals are full. Bellevue remains open, but patients and doctors alike are stacked on gurneys along corridors. Inside their homes, several hundred thousand people have died or are terribly sick. Money confers no immunity. Luxury dwellings inhabited by the multimillionaires of Park Avenue are notable now for the absence of uniformed doormen to meet the ambulances and hearses that arrive hourly.
Trust between neighbors and within families has disintegrated. People exhibiting either extreme prostration or fever-induced deliriousness are shunned. The tabloid press, running limited editions only, publishes stories of an impending race war. Paranoia about the source of the outbreak is pervasive. A good portion of those still alive suspect that a biological-warfare experiment has run amok.
Death, when it comes, is blessedly quick. A fever that can shoot to 104 or 105 degrees in a matter of hours, accompanied by lung pain, appears suddenly. The end comes two to five days later, heralded by the victim’s blackening skin, a condition known as heliotrope cyanosis, in which the body’s tissues are starved of oxygen. Extremities sometimes turn gangrenous. Blood and mucus issue from the mouth and nose. Fluid pools in the lungs. In plain English, the patient drowns, a victim of a new strain of influenza.
A FIRE THAT SCORCHES US ALL
Eighty years ago, a sudden mutation in the virus that causes influenza initiated a worldwide epidemic – or pandemic – that in a mere 18 months killed an estimated 25 million to 40 million people around the world. Experts consider the scourge of 1918, known as the Spanish flu, to be the worst natural disaster in history. Entire villages in remote regions like Alaska and the Philippine hinterlands were decimated much the way that Native Americans were wiped out by smallpox in the 1600s. In the U.S., health officials vainly commanded citizens to wear disinfectant-soaked cotton masks in public. Nurses making house calls often encountered scenes, reminiscent of the Black Plague, in which whole families were dead or dying. In Philadelphia, the flu hit so hard that morticians couldn’t keep up with the corpses.
One of the most serious outbreaks occurred among the 45,000 recruits stationed at Camp Devens, near Boston, in September 1918. In one month, doctors identified 17,000 cases of influenza and saw nearly 800 fatalities. At another camp, a commander blew his brains out after more than 500 young soldiers died. Some historians speculate that it was Spanish influenza, not politics, that brought the armies of every nation to their knees and ended World War I. The flu of 1918 was biological warfare without rhetoric or national loyalties.
Two-thirds of those who died were young, between the ages of 20 and 40: soldiers packed into crowded troopships on their way to the war in Europe, for instance, and their betrothed, who remained behind. This wave of death shocked the medical establishment, which held that only the elderly, newborns and those already ill – “immunocompromised” in today’s medical parlance – were vulnerable to death by flu. Today it seems that the hard lessons of 1918 have been forgotten. The flu is once again considered a nuisance ailment, dangerous to only a few. Recently, however, a group of scientists who study infectious diseases has sounded a warning: Our currently held beliefs about this ancient disease are not only wrong – they’re dead wrong.
Hundreds of years ago, Europeans believed that flu outbreaks were determined, or “influenced,” by the alignment of the stars. Today we know that influenza is caused by a class of viruses that are among the most infectious pathogens known to man. Particles of influenza viruses literally float in the air for hours after a flu victim has coughed, waiting to be inhaled by other hosts, which can include not just people but also dogs, horses, ferrets, pigs, birds and even some marine mammals. The first flu virus in a human was isolated in 1933, when a laboratory-housed ferret sneezed in the face of a scientist, who then developed the symptoms of influenza.
Once inhaled, the virus infects the cells lining the respiratory tract. In susceptible hosts, the infection will cause a high fever, a painful cough that can turn into pneumonia, body aches and lung pain. A mild case of flu is often difficult to distinguish from a cold, a factor that complicates public-health officials’ efforts to determine whether a flu bug has achieved epidemic proportions. Even people who are symptom-less are capable of transmitting it. Not everyone will suffer to the same degree, but everyone is likely to be infected by a new strain, especially viral strains that have undergone significant mutations.
Pathology expert W.I.B. Beveridge, who wrote a natural history of the influenza virus in the 1970s, warned, “There is no known reason why there should not be another catastrophic [pandemic] like that of 1918 or even worse.” The flu, he warned, always has the capability of becoming “a global plague: A spark in a remote corner of the world could start a fire that scorches us all.” Should a superflu akin to that of 1918 make a comeback now that the population has quadrupled and more than a million people cross international boundaries on jets each day, experts say it could kill hundreds of millions.
“The 1918 strain at its peak killed about 42 people per thousand,” notes Robert G. Webster, a virologist at St. Jude Children’s Research Hospital, in Memphis. “But in a sense, 1918 was a babe in the woods.” Webster has studied influenza in humans and in animals for nearly 30 years and has witnessed some strains in chickens that kill 100 percent of those infected. He has found nothing in current research to dispel the possibility that a future strain could have an identical effect on people.
Rockefeller University is an oasis of verdant calmon Manhattan’s Upper East Side. Here, behind the iron gates of the Victorian-era campus, world-renowned scientists devote themselves to understanding the processes that cause disease in man. One of the university’s most esteemed scientists, 72-year-old Joshua Lederberg, won a Nobel Prize in medicine when he was 33 for his research into the genetics of bacteria. Sitting in his cluttered office on the top floor of the university’s main hall, the dapper, animated Lederberg (a former president of Rockefeller) warns that there may already be devastating new strains of influenza in the evolutionary pipeline: “One of them did horrendous harm in 1918, and there’s every reason to expect that strains like that will happen again.” Without a trace of flippancy, Lederberg adds, “It may have already started.”
Lederberg’s special interest is “emerging pathogens,” the diseases of the future, for which we are ill-prepared, he says. In fact, as the biology of the flu virus is increasingly deciphered, influenza presents itself not as a media-hyped monster in the closet, as so many infectious diseases of recent history have proved to be, but as perhaps one of the most underrated biomedical dangers facing humanity.
“There are many examples where the bugs are catching up on us, but flu is at the top of my list,” Lederberg says, pointing out that the greatly touted threat of African hemorrhagic-fever viruses like Ebola remains hypothetical. “Ebola is one of dozens of diseases that may break out, may get over here, may have patterns of transmission that we don’t understand very well. Those are all possible but conjectural. The emergence of [pandemic] flu strains is a sure thing.”
PLANNING FOR THE BIG ONE
In 1968, A Major New Influenza Strain emerged, probably from Hong Kong, and swarmed over the globe, causing 34,000 deaths in its first year in the U.S. Before that, the 1957 Asian flu pandemic killed 90,000 to 100,000 here and many more around the world. The vaccines that were created to stem the outbreaks in the U.S. were not only of low potency but also arrived too late to be of much help, according to Dr. Edwin Kilbourne, the nation’s unofficial dean of influenza research and a professor at New York Medical College, in Valhalla, N.Y. “It must be concluded,” Kilbourne writes in his definitive 1987 text, Influenza, that both pandemics were “essentially unmodified by human intervention.”
We have been living in a tenuous stasis with influenza for 30 years. Every 12 months or so, a slightly new variant of the flu virus circles the globe, bringing illness and death to a relative few. That’s because most of the population is already immune to enough of what remains, genetically speaking, of the previous year’s strain. During this “interpandemic” phase, as scientists call it, about 10 to 20 percent of the population contracts the illness each flu season, which reaches its peak in January and February in the Northern Hemisphere. One percent of those who get the flu are hospitalized; 8 percent of all hospitalized flu patients die – about 20,000 Americans annually, most of them elderly. The cause of death is typically flu-induced viral pneumonia.
Eventually, however, an “antigenic shift” will occur, producing a superflu – a strain to which no one has immunity – and initiating a pandemic with unknown consequences. The passage of 30 years without a pandemic suggests to some experts that we are long overdue.
“We all have the emotional sense that we’ve been lucky so far,” says Stephen Morse, director of the Program in Emerging Diseases at Columbia University’s School of Public Health. “And I think everyone feels that, you know, it’s there – it’s brewing. What’s tragic is that we cannot predict it…. We’re all waiting.”
One of the more remarkable aspects of the influenza virus is the way it jumps between species, often from the world’s waterfowl population – which is considered by many scientists to be influenza’s primary reservoir – into other animals and human beings, forming new recombinant viruses along the way. For this reason, influenza will never be eradicated. And given the speed with which dangerous new flu strains can evolve, most scientists consider existing flu surveillance, which includes 110 sites in 79 countries, to be grossly inadequate.
Rockefeller’s Lederberg has spoken out on the subject of the coming flu threat. In a book he co-edited, Emerging Infections: Microbial Threats to Health in the United States, he asserts that the country’s disease surveillance is markedly deficient. “The United States has no comprehensive national system for detecting outbreaks of infectious disease,” he wrote. It was this book that finally convinced government scientists that they needed to be thinking, and acting, more seriously about influenza.
They first met four years ago, a group of scientists from government health agencies – including the Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health – and academic institutions. Calling themselves the Working Group on Influenza Pandemic Preparedness and Emergency Response, or GRIPPE (the French word for the flu) for short, they began to lay the groundwork for a national strategy to cope with the next killer flu. The group of approximately 15, which meets annually, harbors no illusions about what it’s up against.
“We know we’re not going to be able to stop a pandemic,” says the CDC’s Dr. Nancy Cox, who chaired GRIPPE from 1993 to 1996. “By the time you realize things are really happening, it’s going to be too late. With a virus spread by respiratory route and with a quick onset, you’re really at a disadvantage.”
A modern superflu will spread brutally fast, according to Dr. Brian Murphy, who has experimented with flu vaccines for two decades at the National Institute of Allergy and Infectious Disease. “A local outbreak,” he says, “could go global in four to eight months.” Alfred Crosby, an American-studies professor at the University of Texas at Austin who wrote America’s Forgotten Pandemic: The Influenza of 1918, considered the definitive history of the Spanish-flu outbreak, speculates that while a killer flu might take that long to reach rural areas, “it would hit London, Beijing, Teheran, Nairobi, Paris, in a month.”
Yet developing a vaccine could take eight months or more. (The painstaking technology, which involves “training” the virus to grow in specially engineered chicken embryos, is 60 years old, and there are no new, more-efficient methods to replace it.) Weeks or even months would be needed to test for efficacy and safety. Distribution and administration of a vaccine could take even longer.
“There is a race,” says Murphy, “between the time in which the virus is isolated and the time in which vaccine can be produced in large-enough numbers. And who’s going to win that race? We don’t know.”
Journalists are not welcome at GRIPPE’s private meetings, but the group has been willing to share its formal recommendations. FDA epidemiologist Dr. Peter Patriarca, GRIPPE’s 1997 co-chairman, gave me a copy of the latest draft – the seventh version since the group began meeting. Patriarca asked that because the recommendations remain in flux, the 23-page document not be directly quoted.
In language reminiscent of the government’s calculus of death in the event of a nuclear war, the draft makes clear that no one in GRIPPE believes everyone could be saved in the event of a pandemic. The more relevant question is how to save as many people as possible. The group is hammering out issues like who should get vaccine, given the fact that whatever supply exists will most likely be inadequate to immunize the entire population. High-level government officials and members of the military top the list, along with police officers, firefighters, doctors and emergency-response teams. (Nancy Cox estimates that half of all medical personnel may be sick or dying in the event of a 1918-like pandemic.) Those who are traditionally the most vulnerable to death by flu – the elderly, newborns and women in their second or third trimesters of pregnancy – follow. Schoolchildren, who tend to bring illness home to infect entire families, are next. People ages 18 to 65 are the lowest priority, but GRIPPE says this could change if a pandemic follows the peculiar course of the 1918 outbreak, killing mostly healthy people in their prime.
Of course, concerns over who should get vaccine first will be moot if scientists don’t recognize the early warning signs. In 1918 a wave of flu in the spring failed to arouse alarm; it wasn’t until the following fall, when flu deaths began to soar, that public-health officials understood the danger.
According to the draft, the first to be notified of a pandemic strain’s emergence will be the heads of federal agencies, officials within the Department of Defense and, in due time, the president, whose task it will be to announce the pandemic’s arrival to the populace. Cox says that GRIPPE has also explored the possibility that the president and other government leaders may be counted among the dead. Unlike so-called Marxist diseases like tuberculosis, which tend to afflict the poorly housed and the malnourished, influenza has no respect for social standing.
GRIPPE member Dr. Joel Breman, a deputy director at the NIH’s Fogarty International Center, which funds scientists seeking to investigate emerging infectious diseases, says an influenza pandemic would be “worse than anything Stephen King or Richard Preston [author of the Ebola-virus book The Hot Zone] could write.”
The cough or sneeze of a flu-infected person can propel many millions of viral particles, known as droplet nuclei, 10 feet into the air at “muzzle velocity,” as one colorful chronicler of the 1918 pandemic described it. Droplet nuclei will invade the respiratory tract of anyone in the vicinity who happens to inhale.
“If you get 10 of us in a room,” says Breman, “and one person with influenza walks in and sits there for 10 minutes or so coughing up a storm, it’s possible that eight to nine of us will come down with influenza. Whereas if that person came in with Ebola and was sitting there coughing, probably none of us would get it.”
According to Breman, GRIPPE has even discussed the logistics of deploying roadside inns – specifically, the Motel 6 chain – as emergency hospital wards. He also says that quarantines of any kind would be futile by the time a pandemic is recognized: “These things sweep around the world. The incubation period we’re talking about here is two to four days. If you’re lying in bed sick, you don’t slam the quarantine sign on the bed, because it’s too late.”
So far, GRIPPE’s work has produced this sobering conclusion: “If it were to happen tomorrow,” according to the FDA’s Peter Patriarca, “we would at least have thought through what we need to do. The other side, though, is that if it actually happened, we would, in fact, be in big trouble. Because there will be chaos.”
FUNDING THE FLU GAME
A few optimistic scientists have suggested that the survival rate in the next killer-flu pandemic will be far higher because antibiotics, unknown in 1918, could be administered to quell flu-induced bacterial infections. Dr. Daniel Perl, a neuropathologist at Mount Sinai Hospital in New York and an avid student of the 1918 phenomenon, douses that ray of hope. He points out that based on clinical descriptions, most deaths in 1918 – just like most deaths that occurred during the 1968 pandemic – were from viral pneumonias not treatable with antibiotics.
Even if they could be helpful to some degree, it is unlikely that the nation’s antibiotic supplies would be adequate. “We might have 20 million cases of flu in the U.S.,” Perl says. “If you emptied out all the pharmacies, we still wouldn’t have enough antibiotics. He laughs openly at GRIPPE’s notion of converting motels into hospitals. “[They] haven’t read Crosby’s book,” he says. “These cases are going to require intensive-care units. I just don’t believe we have the supplies.”
Naturally, Joshua Lederberg believes that our energies should be directed to the early stages – to detecting the emergence of flu strains so that vaccines can be developed in time to prevent a catastrophe. Such an effort would require a greater emphasis on international surveillance. Monitoring of flu strains is done by some nations and by the World Health Organization, but there is no apparatus in place to detect and track emerging flu strains in all countries. According to the CDC’s Cox, there are just 12 sites in all of China where flu strains are being monitored by her agency, yet China has been traditionally viewed by experts as a great mixing bowl for new flu strains, due to farming practices that keep ducks, chickens, pigs and people in close proximity. Still, Cox reports, “We got 220 viruses from China last year, which is a record, and of those, we have found some important variants. In some cases, we’ve been able to get those variants into our annu-al vaccine for North America. We’re looking for anything new. The global picture is very important.”
There is very limited surveillance of emerging strains in South America, Russia and Africa. The CDC has exactly one flu-surveillance site in India, a country where as many as 17 million may have died in the 1918 pandemic. In the U.S., reporting of flu cases by doctors is voluntary, although 150 physicians have signed up as “sentinels” to report cases in their practices.
Effective surveillance takes money, and there is hardly any money to be had in the flu game. For two decades, Congress has failed to earmark funds specifically for flu surveillance or research. Currently all but about 15 percent of congres-sionally mandated money for surveillance of infectious diseases is applied to AIDS and, to a lesser degree, other sexually transmitted diseases and tuberculosis.
“I think it’s a tragedy,” says Patriarca about Congress’ shortsightedness. “We don’t have any money – we don’t have any resources.” Part of the problem, he believes, is the deceptive 30-year quiescence since the last pandemic. But a far larger roadblock sits in the middle of the research highway: the 1976 swine-flu inoculation program, in which 45 million frightened Americans were vaccinated in two months’ time for a pandemic that failed to materialize.
It’s hardly surprising that scientists grew panicky when they analyzed throat washings and sputum samples from flu cases at the Fort Dix, N.J., military base after a young recruit died in January 1976. On inspection, the strain closely resembled the 1918 virus. Curiously, however, the virus remained confined to Fort Dix, and there were no additional deaths. The phenomenon offered important lessons: Dangerous new strains may actually occur more often than was commonly thought, and such strains do not always go global.
“We don’t know why it hit so hard to begin with and then failed to spread after that,” Lederberg says. “We should be very relieved, but we should be worried that we don’t understand it.”
New York Medical College’s Edwin Kilbourne believes that the virus itself was almost certainly carried to the military base from a farm where a recruit was exposed to an influenza-afflicted pig. Nevertheless, Kilbourne describes the 1976 outbreak as “a totally fascinating biological puzzle,” one that has yet to be solved.
Most significantly, perhaps, the Fort Dix experience was, according to Columbia University’s Stephen Morse, a vivid demonstration that “we still can’t differentiate false alarms from the real thing.”
Political analysts have long suspected that the swine-flu vaccine program was among the factors that cost Gerald Ford the 1976 election; David Sencer, the director of the CDC at the time, was fired over it. Then, during the next decade, the government paid $85 billion to citizens claiming injuries from the vaccine itself, including a number of cases of Guillain-Barré syndrome, a neurological disease with some similarities to multiple sclerosis. Consequently, as much as government scientists may profess to worry about the emergence of pandemic flu strains, it’s sub-rosa policy that the disease isn’t mentioned in their annual requests for money from House and Senate appropriations panels.
Virologist Robert Webster says he and his colleagues worry about being accused of crying wolf. “If we were able to say for certain that the next one will be like 1918, we would rush to Congress,” he says.
The NIH’s Joel Breman is frank about what it would take to refocus Congress on the flu: “Of course, what helps – what always helps – is an epidemic.”
NEW CLUES FROM AN OLD SOURCE
Last March, the world’s tight-knit brethren of flu experts was struck by a thunderbolt when a team of young U.S. Army scientists, previously known for its expertise in analyzing the genetic material of breast-cancer cells, reported in the journal Science that it had been able to identify significant portions of the 1918 flu strain’s genome, or genetic structure. They found the genetic material in the preserved lung tissue of a 25-year-old soldier who had died at Fort Jackson, S.C., in September 1918, just weeks before he was to sail to France. For decades, such a discovery had been the Holy Grail of flu researchers, many of whom have always suspected that fragments of the 1918 strain, when submitted to the right technology, might offer clues to its virulence and unique predilection for the young, and lead to a vaccine.
The research was led by Dr. Jeffery Taubenberger, a 36-year-old molecular pathologist at the Armed Forces Institute of Pathology, in Washington, D.C., which is housed behind the Walter Reed Army Hospital in a six-story concrete bunker built at the height of the Cold War. The AFIP was created in response to a directive from President Lincoln, who, during the Civil War, grew disturbed by the fact that more soldiers were dying from infectious “camp diseases” than from enemy assaults. As a result, the AFIP maintains millions of tissue samples from both soldiers and civilians, some of whom died as long ago as the 1860s. Taubenberger knew there were about 100 cases of Spanish-influenza tissue samples stored in AFIP’s archives. During the 1918 outbreak, Army pathologists harvested these tissues during autopsies, embalmed them in a three-day bath of formaldehyde, embedded the tissues in wax and stuffed them into tiny, robin’s-egg-blue cardboard boxes by case number. Because influenza viruses are typically flushed from a victim within days of infection, the trick for Taubenberger was to find a patient who had died very soon after infection, while the virus was still thriving in lung fluids.
Taubenberger spoke from the cramped labs that he and his team occupy at the AFIP. “Our working hypothesis,” he says, “was that we can learn something about the virulence of the  strain through genetic analysis, but everything was stacked against us. Even if we could isolate RNA out of material that old, could we find a case that was still influenza-positive? Obviously, we were blessed.”
Taubenberger’s report seems to show that the 1918 virus entered humans directly from influenza-infected pigs and that the deadly strain contained no avianlike influenza genes, although some experts, Webster in particular, remain unconvinced that pigs were the sole reservoir. “Probably the entire virus [was] transmitted into pigs between 1910 and 1912 from an avian source,” he speculates. But, he concedes, “This is really all hand-waving. Until the entire virus is sequenced, we won’t know for sure.”
In contrast, the 1957 and 1968 pandemics resulted from combined avian-and human-influenza strains, Webster says. He believes that avian strains become more dangerous to humans once the strains have passed through pigs, and he postulates that the next killer pandemic is likely to arise from European pigs, which, since 1979, have been infected with a suspicious avian-influenza strain. Webster says this virus “is now the dominant [influenza] virus in pigs in Europe. It has reassorted with human influenza virus and made a couple of children quite sick. It is a very dangerous situation.” Worldwide, however, surveillance has focused entirely upon human rather than swine strains.
Still, Taubenberger’s stated objective – to understand why the 1918 strain was so deadly and why it targeted the world’s healthiest citizens instead of the old and sick – continues to elude him. Several experts believe that even if the entire genetic structure of the virus is recovered (so far, Taubenberger has sequenced only about 15 percent of the virus), it will reveal nothing about why the 1918 microbe was so virulent.
“It’s just the beginning of the story,” Taubenberger says. “Yes, there is a possibility that even if we had the entire gene sequence sitting in front of us, we might not be able to say, ‘That change – right there – is the reason.’ But that’s because there is still very little that’s understood about how you relate the genetic structure of different strains of viruses to their biologic behavior. I think that because this virus was so unusual in its clinical behavior and its virulence, there probably is a genetic basis and that even if we don’t understand it, in the future someone else will.”
Just before Christmas, there were reports from Hong Kong that an entirely new flu strain, which apparently jumped directly from birds to humans, had killed two people and infected at least seven others. The same virus has killed more than a million chickens in southern China. The Centers for Disease Control rushed a team of investigators to Hong Kong to determine whether the bug was being passed from person to person rather than only from birds to humans. Should the former turn out to be true, the event could spell disaster, since it would suggest that the avian flu strain had created a new “recombinant” virus by melding with an already-existing viral strain circulating in people. The result would be a brand-new subtype of flu to which the world’s population lacks immunity.
In the New York Times, Dr. Lo Wing-lok, an infectious-disease specialist in Hong Kong, expressed concern over the avian virus but was hesitant to speculate about its significance: “Up to this moment, we still do not have enough information to say this is the new virus that will cause a new worldwide epidemic.”
Not surprisingly, Joshua Lederberg is monitoring the events in Hong Kong closely. “What’s been alarming is the fact that there have been two deaths among the reported cases of this infection,” he says. “What’s not known is whether there are hundreds of infections in people who are not showing serious symptoms. So we don’t know what the case fatality in this strain is.
“This is the tip of the iceberg. Whether it is a tiny one or a huge one is unknown. It may fizzle overnight, or it may be something more serious. I don’t want to minimize the entire range of outcomes – use your imagination. But the alarm bell has rung.”