If it is a terrifying thought that life is at the mercy of the multiplication of the minute bodies (microbes), it is a consoling hope that science will not always remain powerless before such enemies.
—Louis Pasteur
We had been in the jungle for about two weeks when a kid on a motorbike rode up and told us that the rebels had overwhelmed government forces and that all these combatants were coming our way: Laurent Kabila’s guerrillas, hot on the heels of Mobutu Sésé Seko’s army.
This was in a province called Kasai-Oriental, just about in the center of Zaire, which is just about in the center of Africa. We were there on behalf of the World Health Organization and the Centers for Disease Control and Prevention to investigate an outbreak of monkeypox, a less deadly but still highly problematic cousin of smallpox. If it could be spread indefinitely by person-to-person contact, it could become a global pandemic. So the degree of sustained transmission was the central question we were trying to resolve. But suddenly the more pressing issue was how the hell we were going to get out of there.
We called the American embassy, which advised us to wrap up our investigation and evacuate immediately. “They’ll likely take your vehicles and gear,” they told us. “But they probably won’t kill you.”
This was not an entirely reassuring assessment. We were next door to Rwanda, scene of one of the worst genocides in recent history. Mobutu’s forces were known to loot, pillage, and kill in the best of times, and the word was out that they had not been paid in months. “Why do you need to be paid?” Mobutu had scolded them once, or so the story goes. “You have guns.”
The nearest airstrip, a trail of red dirt hacked out of the ever-encroaching vegetation, was seventy-five miles away in Lodja. But that was our only way of making it back to the capital.
Our team of disease detectives had been spread out to interview the locals and to collect mice, monkeys, squirrels, and rats so we could take their blood. Despite the name, monkeypox is more often found in rodents, and the primary means by which people get sick is contact with the bodily fluids of these animals, often when captured for food.
I sent some of the local villagers out to round up our team, and once everyone was accounted for, we attacked our own camp, running back and forth collecting equipment. I was dumping out vials of liquid nitrogen, which filled the jungle with plumes of white vapor, then burning my fingers as I retrieved the supercold canisters to consolidate our samples into a single tank. We were looking over our shoulders the whole time, as one of my colleagues with a military background used the satellite phone to call his contacts in the US Department of Defense.
They said, “If need be, we can pick you up in a few hours.” My colleague asked, “How is that possible? You don’t have any assets in this part of the world.” They curtly answered, “That’s our business, not yours.”
But we weren’t sure we had two hours to spare in that location. Better to get out of there now and find a plane in a couple of days. So we left behind our trucks and piled our ten people into three 4×4s and sped off into the bush toward the nearest town, a day’s drive away.
We rumbled along for two or three hours in tense silence, worried about the abrupt ending of our study, worried about our gear, worried about the villagers who might now be targeted for having helped us.
Then when we got to the river our hearts sank—there was no bridge. For a moment, it looked like were going to have to leave everything behind and swim for it. But the locals had rigged up a rudimentary ferry system consisting of a flatbed on a giant pontoon and a cable system for pulling us hand over hand, which allowed us to get to the other side.
For the next eight hours we continued through the overgrown, mosquito infested, muddy, rough terrain until we arrived at the Catholic mission in Lodja, a low cinder-block building with all the frills of a Motel 6, but to us it could have been the Paris Ritz. Hot meals with no concern about dysentery, and hot showers where accumulated dirt ran off each of us like a muddy river. The priest and novices were wonderful people, a reminder of why the human race is worth trying to help.
But first I placed a satellite call to our contacts in Kinshasa, who told us that a French film crew would be flying in the next day to shoot a documentary.
So we were ready the next morning when a thirty-seat twin-propeller plane touched down. Unfortunately, dozens of panicked villagers trying to flee the rebels and the army had also shown up hoping to get aboard. This led to a mad scramble around the airplane with security guards firing into the air to get everyone to back off.
A few minutes later our group of scientists, guides, and our single, eccentric mammologist were buckled in and ready for takeoff. But no sooner were we airborne than the skies let loose a horrendous thunderstorm with pounding rain and vicious turbulence that had us bouncing around like the passengers in Airplane! Then the liquid nitrogen tank we had with us in the cabin broke loose and started smashing into things.
The guy to my left was praying. I looked over and saw that the French physician sitting next to me was writing a farewell note to his family. Which got me thinking. If today was my last day, was I ready to die?
When I went to medical school, becoming a geek version of Indiana Jones was not what I had in mind. I’d been inspired to study medicine by my father. He’d been a fourteen-year-old peasant farmer with an elementary school education who made the multiweek trek from a remote village in Kashmir to Bombay at the beginning of the Second World War, lied about being nineteen, and joined a Scandinavian freighter as a wiper in the engine room.
My scientific interests, immunology and infectious disease, had been spurred by childhood readings of how Louis Pasteur refuted the theory of spontaneous generation. But after my residency in pediatrics and internal medicine, I was selected for a two-year fellowship to work as a disease detective at the Centers for Disease Control and Prevention (CDC) in Atlanta, or what I lovingly refer to as CSI:Atlanta. I wound up staying for almost twenty-five years, leaving in 2014 to become dean of the College of Public Health at the University of Nebraska Medical Center.
My job during those years took me from jungle outposts, to Chilean villages reachable only on horseback, to crowded Asian cities locked down under quarantine, to the abattoirs of Persian Gulf sultanates where migrant workers slaughtered goats and sheep under appalling conditions. My colleagues and I worked to stop the spread of Ebola, SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome), and lots of other scary diseases. I was also directly involved in trying to contain the spread of anthrax after the 2001 bioterrorism attack in Washington, and in rebuilding the public health infrastructure in New Orleans after the devastation of Hurricane Katrina.
I hope these tales of my adventures in public health will be entertaining in their own right. But I tell them to dramatize and particularize the disconnect between the outbreaks of hysteria that come with huge headlines, only to be forgotten within weeks, and the very real, long-term structural dangers that should, yes, genuinely scare the pants off us, but more importantly, should lead to long-term structural change in how we address global public health.
Just as we know about (but so far have done precious little to address) huge problems with our physical infrastructure—crumbling rail lines, leaking combined sewers, bridges that are on life support—we have maintained a short-sighted and fickle approach to emerging infections and possible pandemics that have us frothed up one moment, oblivious the next. I started this manuscript just as the Ebola outbreak in West Africa began to make headlines. As the book goes to press, Ebola is a distant memory, and the world’s attention has shifted to Zika. Our failure to more deeply understand and more consistently attend to the bigger issues leaves us, as they say along the fault lines in California, just waiting for the big one.
The Centers for Disease Control and Prevention is the successor to a wartime federal agency called Malaria Control in War Areas, which was set up in 1942 to protect stateside training bases from malaria during World War II, many of which were in the South, which has been known to harbor a few mosquitoes. Just after the war, in 1946, it became the Communicable Disease Center (CDC), but was still focused on malaria and typhus. It had roughly four hundred employees, most of whom were engineers and entomologists. The following year, the center paid a token $10 to Emory University for fifteen acres of land on Clifton Road in Atlanta, where the greatly expanded CDC is still headquartered today.
The program where I got my start, the Epidemic Intelligence Service (EIS), was established in 1951 by Dr. Alex Langmuir to address biological warfare concerns that arose during the conflict in Korea. Its mission was to train epidemiologists on extant public health problems while they kept a watch for foreign germs. Since that time, the EIS has been a two-year postgraduate training program in epidemiology, with a focus on fieldwork. It’s like a traditional medical residency program in that much of the education occurs through hands-on assignments and mentoring.
Rather than making rounds in hospitals, though, EIS officers evaluate public health surveillance systems; design, conduct, and interpret epidemiological analysis; and conduct field investigations of potentially serious public health problems in the United States and around the world. EIS officers have worked on issues as varied as polio, lead poisoning, cancer clusters, smallpox, Legionnaires’ disease, toxic shock syndrome, birth defects, HIV/AIDS, tobacco, West Nile virus, E. coli contaminated water, natural disasters, and fungal meningitis. But my first assignment was not nearly so impressive.
I was a twenty-six-year-old rookie (I looked about twelve despite the mustache I’d grown in the hope of adding a few years) when I conducted my first Epi-Aid, an investigation of patients with chronic fatigue syndrome that eventually proved that a controversial study linking the illness to a retrovirus infection (like HIV that causes AIDS) was due to sloppy lab work.
This was the kind of thing that only a serious geek could get excited about. But immediately afterward I was summoned to my first real challenge in the field—I was shipped off to Hawaii to investigate an outbreak of diarrhea on a cruise ship.
Okay, so maybe this was still not the kind of thing that was going to win me a Nobel (either the Peace Prize or the award in medicine and physiology), but at least it was going to get me out of the office.
Now, very few cruise ships are registered in the United States, but this one sailed only the territorial waters of the Hawaiian Islands, so it flew the US flag, which meant that its owner, along with the state health department, were entitled to call up CDC and ask us to investigate. The only problem was that the viral diarrhea people at CDC didn’t have an EIS officer available so, for whatever reason, they asked me to go and respond, even though I knew nothing about the subject. However, I was reminded of the suitcase lore of EIS officers: the farther you to travel to an outbreak, the bigger expert you seem.
For most of the ten hours I spent flying west I was on the phone with my supervisor, trying to get up to speed on Norwalk virus (common gastroenteritis, or “stomach flu”), which, judging from the history, seemed to be the cause of the outbreak, which meant in turn getting up to speed on projectile vomiting and the fine points of evaluating the stool quality of diarrhea. This was in the early 1990s, when the only way to make a call was from what amounted to a pay phone in the back of the plane. I tend to be an animated phone talker, and I’m pretty sure I was loud enough to be heard in the cockpit.
When the plane landed in Honolulu, the captain said, “Would everybody please stay seated. We need to allow Dr. Ali Khan to get off the plane first.”
I looked around and all the passengers were staring at me, and I thought, Gee, how do they know I’m the doctor flying in on an emergency case?
Then it occurred to me that I was the jerk who’d ruined everybody’s vacation by talking diarrhea all the way across the Pacific.
A bunch of tourists with the runs may sound like something out of a Judd Apatow gross-out comedy, but it was no laughing matter to those who got sick, or to the owner of the cruise line, who might lose his business.
The outbreak had occurred at sea, so when the ship returned to port the crew threw out every scrap of food on board and scrubbed down everything until the local health department gave them the okay. Then the ship took on new passengers and set sail again. But within two days (the incubation period for Norwalk virus) this entirely new set of passengers began getting sick. Which is when the crew and the health department called for help. The crew headed back into port, then waited at anchor for their consulting epidemiologist to fly in and be motored out to them in a small boat.
Despite my complete ignorance, I planned to immediately launch into a series of fourteen-hour days inspecting the ship and developing a questionnaire.
And then matters took a turn for the worse.
I am prone to seasickness, and even with the gentle rocking of the ship at anchor I became violently ill. But I was from the federal government, and I was there to help, so I spent the first few hours lying on a banquette, surrounded by all the senior staff, moaning out directives, mumbling, turning green, and rushing to the bathroom, until the ship’s nurse yanked down my pants in front of all these people and gave me a shot of Compazine.
With my dignity compromised but my health improved, I collected the questionnaires and tabulated the data, which created a detailed picture of daily behavior that thoroughly invaded everyone’s privacy: who ate what, how much and how often; who consorted with whom; which bathrooms they used; how much each passenger drank; and on and on.
Fortunately, a bit of statistical analysis yielded one correlation of particular interest. It was the linkage between the number of cups of ice consumed and the likelihood of getting sick.
Bingo.
The ship’s ice was kept in a big open bin, then scooped up and sent to the dining room. Most likely the “index patient,” the first one to come down with gastrointestinal distress, had been an infected member (or members) of the kitchen crew who went for the ice. But dirty hands came in contact not just with the scoop but with the ice itself, and the virus was transferred and preserved. And while the ship was thoroughly cleaned after the first outbreak and passengers changed, the crew members stayed onboard to infect the ice again.
As is so often the case in matters of public health, once you’ve isolated the problem, the solution comes down to better hand washing, and to a rather simple intervention. I got them to change over to one of those machines where the ice drops down into a bucket from a dispenser. Then they were good to go, and I was free to return to the major land mass of the US mainland, which did not wobble.
But it’s funny how much our view of a disease depends on context. Among generally healthy, well-fed Westerners who can afford vacations, diarrhea may be inconvenient, and it may even be embarrassing, but generally it’s no big deal. Among small children in third-world countries, however, diarrhea accounts for some 800,000 deaths each year—more than AIDS and malaria and measles combined.
It’s also amazing how often something as mundane as an ice scoop can make all the difference.
In 1854, a London physician named John Snow (not the one from Game of Thrones) set out to investigate an outbreak of cholera in Soho. In Snow’s day, the overriding explanation for infectious disease was the miasma theory, in which the source of illness was thought to be “bad air.”
But by studying the distribution of disease and putting the cases on a dot map, Snow was able to track down the source to a water pump on what was then called Broad Street. Snow’s chemical and microscopic examination of the water could not prove that it was the culprit, but he was able to persuade the local council to remove the pump handle and thus shut off this particular water source. His work, coupled with that of others, laid the foundation for one of the mainstays of modern medicine: “germ theory.” And although he did not get the recognition he deserved at the time, Snow’s study became the founding event of the modern science of epidemiology.
OUT OF SEASON
At first blush, my next assignment might seem equally as small potatoes as the outbreak of diarrhea in Hawaii. This was June 1992, when a cluster of influenza B appeared in Fairbanks, Alaska, and the state asked CDC for help.
Influenza rarely makes the list of diseases that keep ordinary citizens awake at night. In the mind of the average person, the flu fits in more easily with everyday ailments like the common cold. But while the 2014–15 Ebola epidemic, which killed 11,000 people, became a global news event, influenza causes between 250,000 and 500,000 deaths each year, every year, worldwide. The infamous influenza pandemic of 1918 sickened 20 to 40 percent of the global population and caused anywhere from 50 to 100 million deaths, including 675,000 in the United States alone. Sad to say, there is nothing to prevent a pandemic on that scale, and that deadly, from happening again. Which is why influenza is taken very seriously, and monitored very closely, by disease detectives like me.
In 1918, the victims were often young, healthy adults in the prime of life. That’s why people who don’t know much about history will often know about the flu that began to sweep across the continents just as the mass slaughter of World War I died down. It’s the perfect plot device to kill off romantic rivals in period dramas like Downton Abbey. Anytime there’s a pretty young thing who stands in the way of true love for the hero and heroine, you can be sure that the pretty young thing is going to be toast, and you can bet she’s going to be toasted by the Spanish flu.
The US population in 1918 was 103 million people, so if a pandemic on the same scale occurred today with our current population—three times larger—we’d be looking at close to 2 million dead people in the United States alone. Which is, once again, why we epidemiologists worry about influenza, and why we’re very attentive anytime it reappears with novel characteristics.
What set off the alarm bells in Fairbanks was the fact that a cluster of cases appeared in the summer, despite the fact that flu is usually a winter phenomenon in temperate countries. It’s not that the bug isn’t around all year. It’s just that in summer people spend more time outdoors, and because they’re not packed together in closed spaces, they don’t infect one another as easily. There are cases, but they usually travel below the radar.
But in Alaska, in 1992, the state public health laboratory isolated the virus from throat swab specimens obtained from nine patients in the period from June 5 to July 5. The antigenic and molecular characteristics were unknown, so we thought it would be a good idea to find out more about what was going on.
Epidemiologists often refer to “epidemics,” “clusters,” and “outbreaks,” but which term we use is more a function of art, and of the amount of attention we want to stir up, rather than some supertechnical line of distinction. Technically, a pandemic is an epidemic that spreads worldwide or occurs over a large geographical area, crossing international boundaries, and usually affecting a large number of people. Flu pandemics are usually caused by influenza A. This summer flu in Alaska was influenza B, a kissing cousin, which made the worst-case scenario unlikely, but we were still curious. And concerned. Influenza B has a habit of sweeping through nursing homes with a scythe. And when evolution rolls the genetic dice, there always can be unpleasant surprises.
Unlike Ebola, the influenza virus can travel very efficiently via large airborne droplets when infected persons sneeze, cough, and talk. So, actually, if you were out to make a horror movie about a truly scary pathogen, it wouldn’t feature an exotic foreign star like Ebola, which generally requires direct contact with blood, saliva, semen, or other bodily fluids. Moreover, with Ebola, you’re infectious mostly toward the end of your illness, when you’re probably not in the mood to go around and do much socializing anyway. With flu, you can be infectious even before you show any signs of illness.
Yes, the lead villain in the end-of-the-world pandemic thriller would be everyday influenza, which, with its proven capacity to kill millions, can be spread by a sneeze or a handshake.
And while Ebola is scary, its terrifying reputation is out of proportion to its actual risk, in part because of the way it’s been sensationalized in the media, dating back to the urtext of Ebola narratives, Richard Preston’s The Hot Zone. There’s no doubt that Ebola is a nasty disease, but influenza is not exactly your friend.
The 1918 influenza likely killed by creating a “cytokine storm” in the bloodstream and lungs, cytokines being small proteins involved in signaling, as in the immune response. When the virus infects the lung, it overstimulates the immune system, which leads to an influx of T-cells and macrophages, cells that exist to ward off invaders. But the presence of those cells activates even more of an immune response, which stimulates the production of even more cytokines. And when you have too much of a good thing too quickly, a deadly feedback loop can start to roll, and the accumulation and concentration of immune cells—free radicals, coagulation factors, tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-10, and interleukin-1 receptor antagonists—can damage the tissues. When this happens in the lungs, the accumulation of immune cells can block off the airways. In other words, you drown in your own fluids.
The danger from flu is that it can undergo a dramatic genetic shift so that the population has no immunity to its new structure. But the flu virus also continually drifts or mutates, which means that each year we have to update the flu vaccine we plan to manufacture and distribute. To prepare for the fall onslaught, we have to make a final decision about what is in the upcoming season’s vaccine about six months ahead of time. Given that the manufacture of the vaccine relies on what is, essentially, 1940s technology—the virus is grown in eggs, inside the shell—the process is always time consuming and imperfect. So when there’s an early flu outbreak, the concern is how much this new preview strain matches the vaccine that’s already in the pipeline. Which means that even seemingly arcane or tangential information can be useful.
I left Atlanta at nine thirty on the morning of July 12 and arrived in Fairbanks at four thirty in the afternoon, local time. I’d never been to Alaska, and this being summer, there was bright sunshine with people out roller skating and playing in the park—it was quite lovely. But summer also meant that it was high tourist season, and the only accommodation I could find was what turned out to be a rattrap rooming house straight out of a Raymond Chandler novel. And the constant daylight meant there was no way I was going to get any sleep.
I drove my rental car to a rundown area of town that looked like Detroit on a bad day and parked at the three-story rooming house. The guy at the desk was covered in tattoos, and the only telephone and television were in the lobby. My room was on the first floor, and despite the open window and the fan, it smelled distinctly of vomit. The window being open, of course, meant that anybody could climb right in, and that included battalions of mosquitoes.
My job was to discover as much as I could about the strain of flu that had hit Fairbanks and to figure out if it was spreading. I was also supposed to send back specimens of the virus to Atlanta so researchers could compare it to known strains, to help refine the new vaccine then being prepared. Also, CDC had been running a viral surveillance system for the past five years, enrolling primary-care doctors all over the country to track cases of flu, then submit samples from their patients to a central facility. I had been asked to review how the system had been working in Alaska.
And, oh yes, I also needed to take back a photograph of a moose. I can’t remember who asked for it, but somebody at the office wanted to see what a moose looked like up close.
At nine fifteen that first brightly lit morning, I met with the head of the state virology lab, Don Ritter. A Chicago native, Ritter had come to Alaska as an army helicopter crew chief, mapping the state’s topography. He had developed an interest in wildlife that led to an interest in pathogens.
Sitting in his office, I listened as he filled me in on the ins and outs of the viral surveillance program: where the samples came from and how they made their way through the system. He also mentioned that they did get unusual viruses in Alaska, in part because, as Sarah Palin could tell you, they have significant traffic with Russia.
If this were a spy novel, that comment would be the tagline to end the scene, after which your hero would go on to discover deadly pathogens wafting over the Bering Strait in a devious scheme of biological warfare. But even without getting carried away into John le Carré territory, I made a note. Disease detectives have to consider all the possibilities. Especially when they make you feel like James Bond.
My next stop was the office of Dr. Alan Macfarlane, a very meticulous pediatrician; so meticulous, in fact, that he was the first and only person in my career as a public health official to ask to see my identification. Maybe some people would have said he was too thorough, because he had taken a swab of anybody who came to his practice with so much as a runny nose, then sent the samples off to be cultured. It was because of this abundance of caution that he’d been the one to detect the outbreak’s first cases, all children under nine, most of whom were his patients. He’d also put a complete description on file for each child that went something like this:
Case number one. Seven and a half years old, fever to 104. Stomachache for two days, occasionally dry cough, headaches, myalgias, no sore throat, red, puffy eyes, previous medical history of recurrent otitis and recurrent otitis media and sinusitis. Had taken some Tylenol. Did not remember being exposed to anybody with influenza. Was diagnosed with pharyngitis and fevers.
After he was satisfied that I was who I said I was—an epidemiologist from CDC, also a member of the US Public Health Service—Dr. Macfarlane gave me the addresses of the patients’ families, as well as his permission to interview them. À la John Snow, I then marked all the addresses on the local map and started thinking about logistics.
My immediate objective was to find out more about each of the children and how their paths might have crossed. Did some of them share day care? Did they attend the same schools? How many siblings did each have, and had any of them been to a doctor?
Children with influenza B are prone to Reye’s syndrome, which can cause swelling of the liver and brain, so this was also a good time to see whether or not the families knew that they shouldn’t be giving their kids aspirin, which can trigger the condition.
But getting to the bottom of an outbreak is not just about medicine or virology. It’s about the people and the community and the kind of social interactions taking place.
So this is when I went into gumshoe mode, following the same incredibly boring, door-to-door routine that is the daily bread of detectives, whether disease or homicide. I contacted day-care centers, hospitals, emergency rooms, HMOs (health maintenance organizations), and nursing homes, asking if they’d noticed increased signs of influenza-like illness. I also checked with tour groups, hotel doctors, and even prisons. Basically, I had to track down every damn doctor in this part of Alaska to try to find out what they knew. How many patients had they seen with bronchitis, pneumonia, pharyngitis, otitis, and so on, and where was it coming from?
But the big question underlying all my hundreds of small questions remained. Am I seeing something new? And then following from that: Is it something to worry about?
As to the cause for worry, here’s the thing about influenza:
Viruses exist on the border of the living and the nonliving, and there’s still some debate about which side they’re on. (I firmly believe they are alive and even collectively intelligent.) Like a living thing, a virus has the ability to replicate, but that’s about it. Unlike mainstream life forms, it doesn’t produce all the proteins it needs to make copies of itself. That’s why it invades and hijacks other cells—often yours or mine—subverting the cytoplasmic material into making more viral proteins, rather than more of whatever cellular material would have been produced ordinarily.
Migratory waterfowl serve as the natural reservoir of the influenza A virus, but it also inhabits horses, dogs, pigs, poultry, and humans, and each influenza virus, no matter which type, is made up of eight genomic segments that are very promiscuous, always mixing and matching. The other type circulating in humans is Influenza B, but it is only found in humans and seals, which limits its pandemic properties. Either way, the strain of influenza A virus that makes you sick can consist of multiple segments from multiple sources, and the virus doesn’t care if its eight genetic building blocks come from birds, humans, pigs, or a little of each. In that respect, influenza is like a lazy warehouse worker at Amazon or Zappos who just grabs whatever’s handy and sticks it in the box. The end result is often like a shipment of socks (for an octopus, perhaps), none of which are necessarily mates. As long as there are eight of them, however, the system still works, and the virus can pump out more virus. And if you have the right mismatch, you can have the next deadly mix for a new pandemic virus.
Influenza also wears a viral overcoat made of two different proteins: hemagglutinin and neuraminidase that are used to identify the different viruses. We give the resultant strains names that combine the letters “N” (for neuraminidase) and “H” (for hemagglutinin) with numbers that refer to the order in which the particular H or N within the strain was discovered. The result is monikers like H1N1 or H5N1. The hemagglutinin enables the virus to latch on to the cell and penetrate the surface; the neuraminidase punches an escape hole in the cell wall when it’s time to get back out. Every year this overcoat changes a little, in what’s called “antigenic drift.”
This jumbling and tumbling produces the standard amount of novelty we see each year in the virus. Because the surface hemagglutinin, but also the components, triggers its own quite specific immune response in the host (you or me: the flu victim), we’re in better shape to the extent that the components from last year show up again this year. The repeat of older elements means that our bodies will have developed antibodies to fight those elements. We call this “cross protection.” But even these minor changes add up, so we are no longer protected, which is why we get reinfected with the same basic strain and why we need to get vaccinated each year. With estimates of 3,000 to 49,000 deaths from influenza in the United States each year, getting vaccinated is good sense.
And what worries epidemiologists is not so much antigenic drift as what’s called “antigenic shift,” which is the complete shedding of the overcoat of influenza A viruses with a new hemagglutinin (HA) or hemaggultinin and neuraminidase (HA/N) combination. A wholesale transformation that carries with it the risk that the target population (you and I) will have no immunity whatsoever, because everything coming at us will be brand new. This total makeover happens once every couple of decades. It’s what happened in 1918, and it’s a big part of why 50 to 100 million people died. Invariably these new human viruses have an avian origin, but it can also be pigs, as we saw with the 2009 H1N1p (“p” for pandemic) outbreak.
A primary focus of all the various influenza disease-monitoring systems is to identify any such brand-new influenza viruses that may be infecting humans or causing epizootics in animals, assessing whether they pose a threat for a human pandemic, and getting a head start on producing a vaccine. The proclivity of flu viruses to swap genetic material especially if a pig is infected with more than one virus, and for the origin in animals of pandemic viruses, explains the laser-like focus on bird and pig influenza outbreaks, and the need to keep people from becoming infected with these viruses.
Humans are a natural host for influenza, so it’s not as if the virus just dies off completely when spring comes and is then reborn the next fall and winter. Flu is always being transmitted from person to person, year round, year after year.
I stayed in Fairbanks for a total of two weeks, but I left my film noir flophouse after only a couple of days. Unfortunately, the next place I stayed was even worse, a really creepy bed and breakfast run by a survivalist couple whose home-schooled children never left the house. As I recall, these people were not terribly thrilled at the idea of having a federal agent present in Alaska, let alone in their own kitchen. And I was a Pakistani American to boot. Back in the early 1990s, people weren’t as quick to suspect that someone who looked like me was a terrorist. (That would come later.) But I think my survivalist hosts were pretty sure I wasn’t a Christian, and they kept an eye on me just in case I was up to something fishy.
My detective work in Alaska was ultimately reassuring rather than alarming. There was no epidemic; there were no headlines, no radical shift in the makeup of the virus. It may have been simply that with a finer filter, in this case Dr. Macfarlane, we caught more cases. The vaccine that was in the works for that year was a strain called influenza B Panama, and our Alaska cases were right in that groove. And the minute I got a break, Don Ritter took me out into the woods and I took a picture of a moose, animals which, in case you’re interested, are huge.
But the sad truth is that the influenza vaccines we produce each year are never very good, especially among the elderly, who are at the highest risk of complications or death. We even have a special high-dose vaccine for this group. Our vaccines are better than nothing, but their narrow range of effectiveness demands such a high degree of predictive ability on the part of public health officials that we always run the risk of catastrophic failure. What we need in order to lower the stakes is a universal flu vaccine that will protect against all strains based on a different mechanism of action, or by targeting more of the conserved past of the virus.
Setting aside cytokine storms, when flu is fatal, it’s usually because it has led to pneumonia. Since 1918, we’ve developed the ability to treat pneumonia with antibiotics, once so precious that we saved the urine of those receiving penicillin in order to crystallize it back out.
Still, it’s always better not to get sick, which is why vaccines were developed.
But as I mentioned earlier, these preventive measures are still primitive, involving a highly imperfect process of picking just the right strain to replicate, then growing it in tens of thousands of eggs, and more recently in cell cultures.
The need to track viruses in order to anticipate what’s coming down the pike is why we try to gather all the information we can, including long-shot investigations like the one I conducted in Alaska. The more data we have, the less we have to rely on guesswork. But it remains a high-risk proposition, because while you don’t put all your eggs in one basket, you do put 90 percent. And we see the consequences of trying to guess the next year’s predominant influenza strain months in advance in years when we have a mismatch between the vaccine strain and the circulating flu virus. The same mistake can be made when predicting the next pandemic virus.
In 1976, a new swine flu virus was detected out of the blue in a single death and thirteen ill soldiers in Fort Dix, New Jersey. This virus was similar to the dreaded 1918 influenza virus and was feared to be the harbinger of the next global pandemic. However, the virus never persisted, but the ensuing national vaccination campaign led to about five hundred cases of a severe paralyzing neurologic illness and twenty-five deaths from Guillian-Barré syndrome—the same illness associated with Zika virus. The incident is remembered as the swine flu fiasco, and the CDC director was fired for his abundance of caution. This degree of vaccine side-effect has not been reported with other flu vaccines, and had there been an influenza pandemic along the lines of 1918’s, it would have been an acceptable outcome compared to the number of deaths that might have otherwise ensued. It’s a stark reminder that public health actions have major import, and it underscores the importance of correctly determining which of the many circulating zoonotic or animal flu viruses poses the risk of a global pandemic.
In 1918, the flu that killed 50 to 100 million people was a strain first called H1N1. Known variously as la gripe, la gripe española, or la pesadilla, it was mostly called the Spanish flu, but only because Spain was not involved in the war, which meant that it was the only European country in which the press was open about the outbreak that had been killing thousands of soldiers at the front. All the combatant nations suppressed the news to protect morale.
At some point, H1N1 made the jump from animal host to human, but at any given time multiple viruses might be invading your cells and competing to assemble the eight pieces of protein they need to create a new model of themselves. One will be better at this replication, or maybe better at getting in there in the first place, or maybe it will trigger less of an immune response. The one that does the best job of doing what viruses do will be the one to prevail against the others and make the charts at CDC and the World Health Organization.
The H1N1 from 1918 held out in the competition for forty years, replicating in humans and sometimes in pigs. But because we develop partial immunity each time a virus passes through, it became less of a threat over time, and we could think of it more like the common cold.
Then, in 1957, there was a complete shift to H2N2 prompting what became known as the Asian pandemic. While it affected mostly young children and pregnant women, it killed one to 2 million people, including 69,000 in the United States.
H2N2 remained dominant in the flu world until 1968, when H3N2 came along under the alias of “Hong Kong flu,” causing between 1 and 4 million deaths, mostly among the elderly. Absent a completely new viral overcoat, that’s the common pattern: the flu kills babies and weakened senior citizens, those who are asthmatic or who have chronic heart disease.
Then, in 1977, the old H1N1 resurfaced, probably through some sort of medical misadventure—meaning an accident in a lab, or a misguided live vaccination campaign gone astray—and it started infecting people again. Fortunately, after sixty years of cohabitation, we’d developed pretty strong immunity to it, so it was not a major pandemic.
Back in 1918, when this modern progression of influenza began, all we knew about viruses was by inference. We could tell that something other than bacteria caused certain infectious diseases but that was about it. In 1892, a Russian named Dmitry Ivanovsky had poured an extract of a diseased tobacco plant through a ceramic filter fine enough to remove all bacteria, and yet the extract remained infectious. Ivanovsky thought the infectious agent might be a “toxin” caused by the bacteria. Subsequent work by others on foot and mouth disease, and on yellow fever, gave rise to descriptions like “soluble living germ” for this mysterious infectious agent. It wasn’t until improvements in optics led to better microscopes in the 1930s that true virology got under way. In 1931, the first vaccines were cultured using fertilized chicken eggs.
In the West, the vaccines given therapeutically have relied on viruses that have been killed, leaving only the residue of proteins to trigger the immune response.
In Soviet Russia, however, virologists have followed a completely different and largely isolated course: administering viruses that were alive but “attenuated,” meaning weakened. Aside from perhaps giving more of an immunologic boost, this technique appeared advantageous in that the patient could simply inhale a tiny whiff of the vaccine rather than have an injection. Not only might this be less problematic in terms of skin reactions, but it might also be vastly cheaper for massive immunization programs, especially in developing countries.
Virologists and public health officials in the West had been wondering for quite a while if the Soviet approach made more sense. In the early 1990s, with the collapse of the USSR, we finally had a chance to compare notes, and I was the one who went over to make the comparison.
In the early nineties, CDC and Baylor College of Medicine began collaborating with the Research Institute of Influenza, St. Petersburg, and the Tarasievich State Institute for Control of Biological Products in Moscow to conduct a blind placebo-controlled study that compared the effectiveness of US inactivated split-virus and Russian live, attenuated, cold-adapted vaccines. Their test subjects were 555 schoolchildren in Vologda, Russia.
In 1992, I flew to St. Petersburg to meet with our Russian colleagues, and I was struck by how poor the country was, and how disoriented, still reeling from yet another cultural and political upheaval. Having spent seventy years in relative isolation, Russia was to science what Cuba is to 1950s American cars—a kind of living museum. And yet, the men and women in these crumbling and drafty laboratories in pre-Soviet buildings were doing good science. I had been instructed to bring along panty hose, ballpoint pens, and calculators as gifts, and as a way of greasing certain wheels. I’d also been told that sometimes getting anything to eat could be problematic.
Vologda is just south of St. Petersburg, but just east of Moscow, and several of us took the twelve-hour train ride, like characters out of Dr. Zhivago, traveling all night through forests and swamps, munching on whatever we’d brought along in paper bags.
Once we got to Vologda, we visited the schools where the studies were being carried out. When all was said and done, our technique of using killed virus led to local reactions (primarily redness at the injection site) in 27 percent of the kids. Kids in the attenuated vaccine group had coryza (inflammation around the nose) only 12 percent of the time and sore throat 8 percent of the time, so in terms of avoiding complications, score one for the Russians.
Four weeks after the vaccination, the children who’d receive our killed vaccine showed roughly 20 percent more antibodies. But on the acid test of preventing school absenteeism due to acute respiratory illness during flu season, the outcome was 56 percent for killed vaccine and 47 percent for attenuated vaccine, suggesting that the two approaches are roughly equivalent.
Ten years later, in January 2003, a live influenza vaccine was introduced in the United States. I was acting as the infectious diseases associate global director, deploying epidemiologists to investigate a marked expansion of influenza A H5N1 among birds in Eurasia and Africa with cases of severe human infection. The virus had reemerged for the first time since the deadly poultry outbreaks in Hong Kong in 1997. This is a highly pathogenic, fast-mutating strain of bird flu that continues to be found in multiple species, as well as in humans. It would go on to kill 60 percent of the 638 people infected. There is clear evidence for a handful of cases of secondary but limited human-to-human transmission, but if this had gone viral, literally and figuratively, it would have been a horrific pandemic. This one was scary given that 2.5 percent of people infected with the 1918–19 influenza pandemic died.
The pattern of bird migration back and forth to Africa put Europe squarely in the crosshairs, and part of my job was to assess how well the European Union countries were prepared in terms of surveillance and disease detection and laboratory systems. Tens of millions of birds died of influenza A (H5N1), and hundreds of millions were slaughtered and disposed of to limit the spread in Southeast Asia, Russia and Central Asia, the Caucasus, the Balkans, the Middle East, West Africa, and throughout Europe.
One thing about tracking disease outbreaks is that it teaches you humility. In the years after the influenza A (H5N1) outbreak began, we figured another outbreak was only a matter of time, and we expected it would be bird flu and that it would start in Asia, as it often had in the past.
So we were keeping an eye on the Eastern Hemisphere, waiting for bird flu, when a different strain came from the opposite direction—Mexico—and clobbered us with a variant of influenza A (H1N1)p that had originated in pigs. The strain contained genes from four different viruses: North American swine influenza, North American avian influenza, human influenza, and swine influenza viruses typically found in Europe and Asia.
This was in 2009, and it spread up to San Diego and Texas and then across the United States, where it led to seventeen thousand deaths. In Mexico, the disease was much deadlier and led to a five-day shutdown of the whole country to contain the outbreak. We had been dreading one thing and we got another, and it caught us completely by surprise.
This strain is still out there, by the way. In 2014, there were more than thirty thousand cases in India, with more than two thousand deaths. There were also deaths in California and Texas, and in Canada.
It is possible that this strain of swine flu did indeed originate in Asia; we don’t know. Either way, it drove home the point that no country can afford to isolate its public health system. It has to be part of a global public health infrastructure. You can’t get away with saying, “We’re the richest country in the world. We have good doctors and a solid health care surveillance system. We’re safe.” It just doesn’t work that way.