Karl Johnson, one of the pioneers of Ebola outbreak response, whose credentials I’ve already sketched, offered a similar but even more pointed reaction, expressed with his usual candor. We were talking—in my own office, this time—during one of his periodic trips to Montana for fly-fishing. We had become friends and he had coached me a bit, informally, on how to think about zoonotic viruses. Finally I got him to sit for an interview, and The Hot Zone inescapably came up. Waxing serious, Karl said: “Bloody tears is bullshit. Nobody has ever had bloody tears.” Furthermore, Karl noted, “People who die are not formless bags of slime.” Johnson also concurred with Pierre Rollin that the bloodiness angle has been oversold. If you want a really bloody disease, he said, look at Crimean-Congo hemorrhagic fever. Ebola is bad and lethal, sure, but not bad and lethal precisely that way.
In the real world, as described in the scientific literature, the list of major symptoms of Ebola virus disease goes like this: abdominal pain, fever, headache, sore throat, nausea and vomiting, loss of appetite, arthralgia (joint pain), myalgia (muscle pain), asthenia (weakness), tachypnea (rapid breathing), conjunctival injection, and diarrhea. Conjunctival injection means pink eye, not bloody tears. All these symptoms tend to show up in many or most fatal cases. Additional symptoms including chest pain, hematemesis (vomiting of blood), bleeding from the gums, bloody stools, bleeding from needle-puncture sites, anuria (inability to pee), rash, hiccups, and ringing in the ears have appeared in a smaller fraction of cases. During the Kikwit outbreak, 59 percent of all patients didn’t bleed noticeably at all, and bleeding in general was no indicator of who would or wouldn’t survive. Rapid breathing, urine retention, and hiccups, on the other hand, were ominous signals that death would probably come soon. Among those patients who did bleed, blood loss never seemed massive, except among pregnant women who spontaneously aborted their fetuses. Most of the nonsurvivors died stuporous and in shock. Which is to say: Ebola virus generally killed with a whimper, not with a bang or a splash.
Despite all these data, gathered amid woeful and dangerous conditions while the primary mission was not science but saving lives, even the experts aren’t sure exactly how the virus typically causes death. “We don’t know the mechanism,” Pierre Rollin told me. He could point to liver failure, to kidney failure, to breathing difficulties, to diarrhea, and in the end it often seemed that multiple causes were converging in an unstoppable cascade. Karl Johnson voiced similar uncertainty, but mentioned that the virus “really goes after the immune system,” shutting down production of interferon, a class of proteins essential to immune response, so that “nothing stops the continued replication of the virus.”
This idea of immune suppression by ebolaviruses has also appeared lately in the literature, along with speculation that it might allow catastrophic overgrowth of a patient’s natural populations of bacteria, normally resident in the gut and elsewhere, as well as unhindered replication of the virus itself. Runaway bacterial growth might in turn put blood into the urine and feces, and even lead to “intestinal destruction,” according to one source.17 Maybe that’s what Preston had in mind when he wrote about liquefied organs and people dissolving in their beds. If so, he was blurring the distinction between what Ebola virus does and what garden-variety bacteria can do in the absence of a healthy immune system keeping them cropped. But, hey, don’t we all like a dramatic story better than a complicated one?
Still another aspect of the pathology of Ebola virus disease is a phenomenon called disseminated intravascular coagulation, familiar to the medical community as DIC. It’s also known as consumptive coagulopathy (if that helps you), because it involves consumption of too much of the blood’s coagulating capacity in a misdirected way. Billy Karesh had told me about DIC as we boated down the Mambili River after our gorilla stakeout. Disseminated intravascular coagulation, he explained, is a form of pathological blood sludge, in which the normal clotting factors (coagulation proteins and platelets) are pulled out to form tiny clots along the insides of blood vessels throughout the victim’s body, leaving little or no coagulation capacity to prevent leakage elsewhere. As a result, blood may seep from capillaries into a person’s skin, forming bruiselike purple marks (hematomas); it may dribble from a needle puncture that seems never to heal, or it may leak into the gastrointestinal tract or the urine. Still worse, the mass aggregation of small clots in the vessels may block blood flow to the kidneys or the liver, causing organ failure as often seen with Ebola.
At least that was the understanding of DIC’s role in Ebola virus disease at the time Karesh alerted me to it. More recently, Karl Johnson and others have begun questioning whether the immune-shutdown effect that the virus somehow achieves, and the consequent blossoms of bacteria, might better explain some of the damage formerly blamed on DIC. “When it was first discovered, DIC, da da da, was the key to everything in hemorrhagic fever,” Johnson told me, again cheerily dismissive of conventional wisdom. Now, he said, he was reading a hell of a lot less about DIC in the literature.
Ebola virus is still an inscrutable bug in more ways than one, and Ebola virus disease is still a mystifying affliction as well as a ghastly, incurable one—with or without DIC, with or without melting organs and bloody tears. “I mean, it’s awful,” Johnson stressed. “It really, really is.” He had seen it almost before anyone else, under especially mystifying conditions—in Zaire, 1976, before the virus even had a name. But the thing hasn’t changed, he said. “And frankly, everybody in the world is much too afraid of it, including the medical fraternity worldwide, to really want to try and study it.” To study its effect on a living, struggling human body, he meant. To do that, you would need the right combination of hospital facilities, BSL-4 facilities, dedicated and expert professionals, and circumstances. You couldn’t do it during the next outbreak at a mission clinic in an African village. You would need to bring Ebola virus into captivity—into a research situation, under highly controlled scrutiny—and not just in the form of frozen samples. You would need to study a raging infection inside somebody’s body.
That isn’t easy to arrange. He added: “We haven’t had an Ebola patient yet in the United States.” He was speaking in 2008. But for everything that happens, there is a first time. For the United States, it occurred in 2014, when two infected Americans were brought back from West Africa to an isolation suite at Emory University Hospital. And there were precursors.
10
ENGLAND HAD ITS first case of Ebola virus disease in 1976. Russia had its first case (that we know of) in 1996. Unlike the Swiss woman who did the chimp necropsy in Côte d’Ivoire, these two unfortunate people didn’t pick up their infections during African fieldwork and come home prostrate in an ambulance jet. Their exposure derived from laboratory accidents. Each of them suffered a small, fateful, self-inflicted injury while doing research.
The English accident occurred at Britain’s Microbiological Research Establishment, a discreetly expert institution within a high-security government compound known as Porton Down, not far from Stonehenge in the rolling green countryside southwest of London. Think of Los Alamos, but tucked into the boonies of pastoral England instead of the mountains of New Mexico, and with bacteria and viruses in place of uranium and plutonium as the strategic materials of interest. In its early years, beginning in 1916, Porton Down was an experiment station for the development of chemical weapons such as mustard gas; during World War II, its scientists worked also on biological weapons derived from anthrax and botulin bacteria. But eventually, at Porton Down as at USAMRIID, with changing political circumstances and government scruples, the emphasis shifted to defense—that is, research on countermeasures against biological and chemical weapons. That work involved high-containment facilities and techniques for studying dangerous new viruses, and therefore qualified Porton Down to offer assistance in 1976, when the WHO assembled a field team to investigate a mysterious disease outbreak in southwestern Sudan. Deep-frozen blood samples from desperately ill Sudanese patients arrived fo
r analysis—at about the same time, during that fretful autumn, as blood samples from Yambuku went to the CDC. The field people were asking the laboratory people to help answer a question: What is this thing? It hadn’t yet been given a name.
One of the lab people at Porton Down was Geoffrey S. Platt. On November 5, 1976, in the course of an experiment, Platt filled a syringe with homogenized liver from a guinea pig that had been infected with the Sudanese virus. Presumably he intended to inject that fluid into another test animal. Something went amiss, and instead he jabbed himself in the thumb.
Platt didn’t know exactly what pathogen he had just exposed himself to, but he knew it wasn’t good. The fatality rate from this unidentified virus, as he must have been aware, was upwards of 50 percent. Immediately he peeled off his glove, plunged his thumb into a hypochlorite solution (bleach-like stuff, which kills virus) and tried to squeeze out a drop or two of blood. None came. He couldn’t even see a puncture. That was a good sign if it meant there was no puncture, a bad sign if it meant a little hole sealed tight. The tininess of Platt’s wound, in light of subsequent events, testifies that even a minuscule dose of an ebolavirus is enough to cause infection, at least if that dose gets directly into a person’s bloodstream. Not every pathogen is so potent. Some require a more sizable foothold. Ebolaviruses have force but not reach. You can’t catch one by breathing shared air, but if a smidgen of the virus gets through a break in your skin (and there are always tiny breaks), God help you. In the terms used by the scientists: It’s not very contagious but it’s highly infectious. Six days after the needle prick, Geoffrey Platt got sick.
At the start he merely felt nauseous and exhausted, with abdominal pain. Given the circumstances, though, his malaise was taken very seriously. He was admitted to a special unit for infectious diseases at a hospital near London and, within that unit, put into a plastic-walled isolator tent under negative air pressure. The historical records don’t mention it but you can be sure his nurses and doctors wore masks. He was given injections of interferon, to help stimulate his immune system, and blood serum (flown up from Africa) that had been drawn from a recovered Ebola patient to supply some borrowed antibodies. On the fourth day, Platt’s temperature spiked and he vomited. This suggested the virus was thriving. For the next three days, his crisis period, he suffered more vomiting, plus diarrhea, and a spreading rash; his urine output was low; and a fungal growth in his throat hinted at immune failure. All these were gloomy signs. Meanwhile he was given more serum. Maybe it helped.
By the eighth day, Platt’s vomiting and diarrhea had ended. Two days later, the rash began to fade and the fungus was under control. He had been lucky, perhaps genetically, as well as privileged to receive optimal medical care. The virus disappeared from his blood, from his urine, and from his feces (though it lingered awhile in his semen; apparently he promised doctors that he wouldn’t make that a risk issue for anyone else). He was taken out of the isolator. Eventually he went home. He had lost weight, and during the long, slow convalescence much of his hair fell out. But like the Swiss woman, he survived.
The Russian researcher, in 1996, wasn’t so lucky. Her name, as given in one Russian news account (but unspoken in the western medical literature), was Nadezhda Alekseevna Makovetskaya. Employed at a virological institute under the Ministry of Defense, she had been working on an experimental therapy against Ebola virus disease, derived from the blood serum of horses. Horses aren’t highly susceptible to Ebola, which is why they are used to make antibodies. Testing the efficacy of this treatment required exposing additional horses. “It is difficult to describe working with a horse infected with Ebola,” according to the dry, cautious statement from Russia’s chief biowarfare man at the time, a lieutenant general named Valentin Yevstigneyev, in the Ministry of Defense.18 No doubt he was right about that. A horse can be nervous and jumpy, even if it’s not suffering convulsions. Who would want to get close with a needle? “Under normal conditions this animal is difficult to manage and we had to work in special protective gear,” said General Yevstigneyev. What he meant by “we” might be broadly interpreted. He was a high officer and military bureaucrat, not likely pulling the latex mitts onto his own hands. “One false step, one torn glove and the consequences would be grave.” Makovetskaya had evidently taken that false step. Or maybe it wasn’t her mistake so much as the twitch of a sensitive gelding. “She tore her protective gloves but concealed it from the leadership,” by General Yevstigneyev’s unsympathetic account, “since it happened just before the New Year holidays.” Was he implying that she hadn’t wanted to miss seasonal festivities while sitting in quarantine? He didn’t mention a needlestick, or a scratch, or an open cut beneath the torn glove, though some such misfortune must have been involved. “As a result, by the time she turned to a doctor for help it was too late.” The details of Makovetskaya’s symptoms and death remain secret.
Another Russian woman stuck herself with Ebola in May 2004, and about this case slightly more is known. Antonina Presnyakova was a forty-six-year-old technician working at a high-security viral research center called Vektor (which sounds like something from Ian Fleming) in southwestern Siberia. Presnyakova’s syringe carried blood from a guinea pig infected with Ebola virus. The needle went through two layers of gloves into her left palm. She immediately entered an isolation clinic, developed symptoms within a few days, and died at the end of two weeks.
These three cases reflect the inherent perils of doing laboratory research on such a lethal, infectious virus. They also suggest the context of concerns that surrounded America’s closest approach to a home-grown case of Ebola. This one occurred also in 2004, just months before the death of Antonina Presnyakova.
11
KELLY L. WARFIELD GREW up in a suburb of Frederick, Maryland, not many miles from Fort Detrick, the US Army base devoted to medical research and biodefense within which sits USAMRIID. She was a local girl, bright and curious, whose mother owned a convenience store just outside the Fort Detrick gate. Helping her mom since she was a middle-schooler, Kelly first saw and spoke with scientists from the disease-research institute when they stopped into the store to buy Diet Coke, quarts of milk, Nicorette gum, Tylenol … whatever it is that top-level, Army-affiliated virologists buy. Unlike your average young convenience-store clerk, Kelly herself had a strong early aptitude for science. During high-school summers she worked in a government institute of standards and measures. After her freshman year of college and each summer until graduation, she served as a laboratory assistant at the National Cancer Institute, which had a branch on the grounds of Fort Detrick. She finished a bachelor’s degree in molecular biology and considered her options for grad school. Around the same time she read The Hot Zone, which had recently been published.
“I’m a Hot Zone kid,” Warfield told me much later. She couldn’t vouch for the book’s scientific accuracy, she added, but its effect on her then was galvanic. She was inspired by one of the main characters, Nancy Jaax, an Army major and veterinary pathologist at USAMRIID, who had been part of the response team at the infected monkey house in Reston. Warfield herself hoped to return to Fort Detrick after graduate school and join USAMRIID as a scientist—if possible, to work on Ebola virus.
She looked for a doctoral program that would teach her virology and found a good one at Baylor College of Medicine, in Houston. An entire department at Baylor was devoted to viral research, with two dozen virologists, some of whom were quite eminent, though none dealt with such high-hazard pathogens as Ebola. Warfield found a place in the lab of a mentor there and began studying a group of gastrointestinal viruses, the rotaviruses, which cause diarrhea in humans. Her dissertation project looked at immune response against rotavirus infection in mice. That was intricate and significant work (rotaviruses kill a half million children around the world every year), though not especially dramatic. She got experience in using lab animals (especially mice) as models for human immune response to viral infections, and she learned a bit about making va
ccines. In particular, she gained expertise in a line of vaccine development using viruslike particles (VLPs), rather than the more conventional approach, which uses live virus attenuated by laboratory-induced evolution. VLPs are essentially the outer shells of viruses, capable of inducing antibody production (immune readiness) but empty of functional innards, and therefore incapable of replicating or causing disease. VLPs seem to hold high promise for vaccines against viruses, such as Ebola, that might be too dangerous for live-virus vaccination.
It took some time for Kelly to achieve her dream, but not much, and she wasted none. With the doctorate finished, twenty-six-year-old Dr. Warfield began work at USAMRIID in June 2002, just days after her graduation in Houston. The Army’s institute had hired her, in part, for her VLP skills. Immediately she enrolled in the Special Immunizations Program, a punishing series of shots and more shots required before a new person can be cleared to enter the BSL-3 labs. (BSL-3 comprises the laboratory suites in which researchers generally work on dangerous but curable diseases, many caused by bacteria, such as anthrax and plague. BSL-4 is reserved for work on pathogens such as Ebola, Marburg, the SARS virus, Machupo, and Nipah, for which there are neither vaccines nor treatments.) They vaccinated her against a whole list of unsavory things that she might or might not ever face in the lab—against Rift Valley fever, against Venezuelan equine encephalitis, against smallpox, and against anthrax—all within a year.
Some of these vaccines can make a person feel pretty sick. Anthrax, for Warfield, was a particular disfavorite. “Ooof, terrible!” she recalled, during our long conversation at her home, in a new suburb outside of Frederick. “That’s a terrible vaccine.” After all these challenges to her immune system, and possibly as a result, she suffered an attack of rheumatoid arthritis, which runs in her family. Rheumatoid arthritis is an immune dysfunction, and the medicine used to control it can potentially suppress normal immune responses. “So I wasn’t allowed to get any vaccines anymore.” Nonetheless, she was cleared to enter the BSL-3 suites, and then soon the BSL-4s. She began working with live Ebola virus.
Ebola: The Natural and Human History of a Deadly Virus Page 6
