Dr. Rodney Willoughby, a specialist in pediatric infectious disease at the Children’s Hospital of Wisconsin, in Milwaukee, was dubious when he heard that a possible case of rabies was being transferred to his care. “I was skeptical she had rabies,” he recalls. “Because that never happens.”
It was October 2004. The patient was a high-school athlete, a fifteen-year-old girl who was suffering from fatigue, vomiting, vision disturbances, confusion, and loss of coordination. Willoughby considered some other brain infection or various autoimmune diseases as more likely causes for her condition. But he made sure that the samples necessary to rule out rabies were collected and sent to the Centers for Disease Control and Prevention (CDC) in Atlanta within hours of the girl’s arrival. In the meantime, she was put in strict isolation to protect hospital personnel from possible exposure. Her condition quickly deteriorated; she began to salivate excessively and developed an involuntary jerking in her left arm. Soon, Willoughby had to sedate her and insert a breathing tube. As hours ticked by, he began to prepare for the possibility of a positive test result.
The girl’s name was Jeanna Giese, and her troubles had begun a month beforehand, during a Sunday Mass at St. Patrick’s Church in her hometown of Fond du Lac, Wisconsin. As she sat beside her mother, Giese observed the small silhouette of a silver-haired bat flitting against the sanctuary’s tall stained-glass windows. When the bat fluttered down toward the back of the room, barely above the heads of the worshipping congregation, an attending usher batted the creature to the ground. Giese decided she would take it outside. With her mother’s permission, she slipped quietly from her seat and walked back to where the bat lay prone. As she picked the bat up by the tips of its wings, it shrieked, but still she continued with it toward the door. Just as she nudged her way out into the open air, the bat reared its head around and bit its Good Samaritan on her left index finger.
Later, Giese showed the tiny wound to her mother, who ensured that it was thoroughly cleaned. No one in the family thought to seek postexposure treatment for rabies. But after symptoms set in four weeks later and Giese was admitted to a local hospital, her mother mentioned the bat bite to the pediatrician. Arrangements were immediately made for Giese’s transfer to the Children’s Hospital and into Dr. Willoughby’s care.
Like the vast majority of American physicians, Willoughby had never seen a case of clinical rabies before. He telephoned the CDC to ask if there was any treatment for rabies somewhere in the research pipeline—some promising new therapy, perhaps, that had been attempted in a case or two but not yet published in any medical journal. The CDC could offer no such hope. Not one person had ever been shown to survive rabies without receiving at least partial vaccination against it prior to the onset of symptoms. All the treatments tried to date had failed. No consensus existed for what therapy should be attempted next. Aside from palliative care, standard practice was to use intensive therapy but in a purely reactive way, trying to control the dangerous complications of rabies as they arose. But this had never saved a single patient in Giese’s predicament.
Willoughby attacked the problem with quick but deliberate reading. With less than a day to formulate a plan, he started out by searching for any recent papers that hinted at a possible treatment. None turned up. “I did a couple hours of diligence and figured out that nothing was new,” he recalls.
So he decided he would use his limited time to review the basic neuroscience of rabies. His understanding—though the science is still far from settled on this subject—was that rabies did not cause inflammation in the brain, nor did it destroy the brain’s slow-growing, densely networked cells. Instead, it seemed to interfere with how they communicated with one another, ultimately disabling the brain from performing crucial functions such as controlling cardiovascular activities and breathing.
Willoughby was struck with a novel idea for how to assist a patient through a rabies infection. The solution, he says, looking back, “was hiding in plain sight.” He sat down at his computer and searched the scientific literature for the terms “rabies neurotransmitters” and “rabies neuroprotection” and then quickly tried to absorb the fifty or so papers his query returned. As he read on, he began to permit himself to hope that even if Giese was confirmed to have rabies, there might be a way to help her survive. “With a little more reading,” he says, “it seemed to me like there was a real opportunity.”
Willoughby had started thinking about becoming a physician when he was still in high school. His mother’s father was a doctor, and Willoughby liked science, so it seemed a natural fit. He picked up the prerequisite courses as a Princeton undergraduate while still considering other possibilities; when none proved compelling, he enrolled in medical school at Johns Hopkins.
He most certainly did not become a doctor because of any burning desire to solve the human rabies problem. Not that he was unaware of the dreadful nature of the disease. During much of his childhood, Willoughby’s large Catholic family lived in Peru, where his father worked for an American oil company. There, his younger sister was bitten by a guard dog that was defending the home of a family friend. The bite itself was not terribly serious, and if the dog had been observed to remain in good health over the next week or two, no further action might have been necessary. However, just after this incident, in the course of a burglary, someone threw poisoned meat over the broken-glass-topped concrete wall that surrounded the friend’s property, killing the dog. Given the prevalence of canine rabies in Peru at the time, the Willoughby family did the prudent thing and started the girl on Pasteur’s vaccine.
Willoughby himself would often accompany his sister to the clinic for her inoculations. It was clear that those fourteen shots, delivered into the sensitive muscles of her abdominal wall, were tremendously painful. But the injections were made much more frightening by the brutal manner of the German nurse who dispensed them. “Frau Nurse would tell her to toughen up, and then would slam the shot into her belly,” he says. “The nurse was scarier than the shots were.”
By the time Willoughby graduated from Johns Hopkins in 1977, human rabies had become vanishingly rare in the United States. “For the boards,” he recalls, “you only needed to know one thing about rabies: it was 100 percent fatal.” Willoughby committed this fact to memory, passed his boards, and didn’t think much about the disease again for many years—even as he continued his training, first at the University of California at San Diego and then back at Johns Hopkins. “It’s so rare in this country, only a few cases per year. So I figured I’d go pretty much forever without seeing one.”
Willoughby would become a specialist in pediatric infectious disease, with a strong emphasis on clinical research. His work would center on diseases with importance in the developing world, such as rotavirus (a common and often fatal diarrheal infection in children) and cerebral palsy (which sometimes can be triggered by brain infection in young children). Along the way, his training exposed him to many talented clinicians and researchers. He was particularly impressed by Richard Moxon, now chair of pediatrics at Oxford, for the way he engaged in collaborative, open scientific discourse—to the point of being willing to share laboriously obtained DNA extracts from his laboratory with rival researchers. “That kind of openness to move the field forward, even if it doesn’t benefit you personally, has always been inspirational,” Willoughby says.
He had been practicing at the Children’s Hospital of Wisconsin for only five months when Jeanna Giese came under his care. The night she arrived was just his second night on call. Treatment of Wisconsin’s first human rabies patient in several years would turn out to be a great way to get to know his new colleagues and to reach out across the pediatric disciplines. With the help of his new boss, Michael “Joe” Chusid, Willoughby assembled a diverse team of talented clinicians. There were two neurologists, two criticalists, another infectious disease person, and an anesthesiologist—“a bunch of smart people,” says Willoughby, each bringing a different but relevant area of expertise to his fast-moving conundrum.
At 4:30 p.m. on Giese’s second day of hospitalization in Milwaukee, her test results came back from the CDC laboratory. She was positive for rabies, based on the presence of rabies antibodies in her blood and cerebrospinal fluid. None of the rabies virus itself could be recovered from her tissues, but based on her history and clinical signs, and in the absence of another likely cause for her symptoms, the positive antibody test was clinically adequate proof of rabies infection. An hour later, at 5:30, her physicians met at the hospital to discuss her treatment.
Willoughby brought to the meeting his idea for a new rabies treatment. He had developed it on the basis of two published assertions about the disease. The first was that rabies seemed—though this is somewhat controversial—to kill patients without causing any significant damage to their neuronal cells. The second was that the immune system does mount a response to rabies that could, in principle, fight off the infection. Willoughby had come to subscribe to the theory that rabies was a disease primarily affecting neurotransmission, or the electrochemical communication that takes place between the cells in the central nervous system. By disrupting signal transmission through the brain, so the theory went, rabies interrupted its ability to orchestrate such essential functions as breathing, blood pressure, and cardiac rhythm. These key roles are performed by what is called the autonomic nervous system—the unconscious, primitive seat of the brain. It is by disrupting the autonomic nervous system that rabies kills the patient, often through circulatory collapse or simple suffocation.
On Willoughby’s theory, the battle against rabies was primarily a battle for time. Rabies wasn’t killing the brain directly, but it was directing the brain to kill the body before the body had time to fight it off. Willoughby put a question to his colleagues at the Children’s Hospital of Wisconsin: What if they induced a coma in Giese? By suppressing her brain activity, and by controlling her respiration and circulation—the functions of that autonomic nervous system—they would try to give her immune system the time it needed to mount its own response.
He gave his colleagues an opportunity to raise objections. “I set it up so that any of them could blackball it,” Willoughby recalls. “If we had one blackball, then we wouldn’t do it—because it was such a simple idea it had to be wrong. It was just too obvious. Someone had to have tried it before. So if anybody could see a reason why it would clearly cause harm, they could object and we would drop the plan. Instead, thirty minutes later, we didn’t have an objection to it.”
Later that evening, Willoughby met with Giese’s shaken parents, Ann and John, to inform them of the test results and to discuss their daughter’s grim prognosis. “We brought the parents in and gave them the bad news,” recalls Willoughby. “The Giese parents, I think, especially John, still really didn’t fully understand that this was irrevocable.” He gave them three treatment options for their daughter: hospice care, which would allow their daughter a comfortable death at home; the standard critical care regimen, which so far had never been successful in saving an unvaccinated victim of rabies; or the experimental plan that Willoughby and his colleagues had laid out. The Gieses chose the third option without hesitation. They pointed out to Willoughby that even if their daughter didn’t survive her infection, the knowledge gained might help some future child with rabies. But even as they said this, their hopes were fastening themselves securely to the idea of a miracle. (John Giese would later tell a reporter from the Milwaukee Journal Sentinel about the desperate optimism that helped him through this terrible moment. “Somebody has to be the first person to walk away from this,” he recalls thinking. “Jeanna’s going to be it.”)
In the tense days that followed, the girl lay motionless in a hospital room, animated only by monitors and by the rhythmic whoosh of the mechanical ventilator. An infusion of ketamine, a dissociative anesthetic, maintained her state of unconsciousness. Willoughby chose ketamine for a particular reason: not only would it keep the patient in a state of coma, but it had been shown in a 1992 study on rats to have an antiviral effect against rabies. The effect of the ketamine was broadened by the addition of amantadine, an antiviral with a similar molecular mechanism of action but with an affinity for a different part of the brain. Midazolam, a sedative similar to Valium, was administered to smooth out the effects of the ketamine and to help maintain unconsciousness; this was supplemented occasionally with barbiturates, to keep the girl perfectly calm. On the second day, under counsel from the CDC, Willoughby added ribavirin, a broad-spectrum antiviral agent often used in treating hepatitis C. Nothing remotely resembling this regime, with its high-stakes induction of coma, had ever been administered to a rabies patient before. Tension pervaded the ward of the Children’s Hospital of Wisconsin where Jeanna Giese slept unperturbed, busy nurses hovering above her.
Onto the wall above Giese in the pediatric ICU, Willoughby had tacked up a blurry black-and-white photograph. It showed the bright gaze of a six-year-old boy in another hospital bed, far from Milwaukee in both space and time. The boy’s name was Matthew Winkler, and the photograph had been published with the report, in 1972, announcing his own recovery from rabies—the first scientifically supported case of survivorship ever published.
At 10:00 p.m. on the evening of October 10, 1970, six-year-old Matthew Winkler’s sleep had been interrupted by a terrible pain in his left thumb. The boy awoke to find a brown bat fiercely clinging to his digit with its tiny jaws. The resulting clamor startled awake the entire Willshire, Ohio, farmhouse, bringing Winkler’s father quickly to his bedside. The bat was wrenched free from Winkler’s thumb, leaving two bleeding puncture wounds that the family cleaned thoroughly. The next day, the Winklers sent the bat off to the Ohio Department of Health, which identified rabies lesions in a cut section of its brain. The test results were reported back on October 14, and that same day Winkler’s family physician initiated a fourteen-day course of duck-embryo vaccine. He did not, however, use immunoglobulin therapy—which by then was a common supplement to vaccination, providing a local immune response against the virus before the effects of the vaccine kick in. On October 30, two days after completing his inoculations, the boy began to complain to his parents of neck pain. Fever, loss of appetite, vomiting, and dizziness followed over the next few days, despite several doses of oral tetracycline initiated by the family doctor. Winkler was referred to pediatricians in Lima, Ohio, who admitted him to St. Rita’s Hospital on November 4.
Over the next few days, Winkler’s condition deteriorated precipitously. The normally studious and well-behaved first grader became uncoordinated, obstinate, unable to walk or write, then altogether mute. The left side of his body was markedly weak, and his bitten thumb tightened into a stiff flexion across his palm. Increased pressure in his skull necessitated the placement of a drainage catheter in the lateral ventricle of his brain. He developed frightening cardiac irregularities, as well as respiratory distress that could be relieved only with a tracheotomy and oxygen supplementation. Small seizures afflicted the left side of his body, and a rash appeared on his arms and torso. Winkler had slipped into a coma, however, and so was now mercifully unaware of the violent ordeal his body was undergoing.
Although no virus was isolated from Winkler’s skin or saliva, or even on his brain biopsy, abundant rabies antibody was present in his blood serum—much more than would be expected in response to vaccination alone. Antibodies were also present in his cerebrospinal fluid, which is expected to contain antibody only in the presence of natural infection. Tests for alternative diagnoses, infectious and noninfectious, were all negative. A diagnosis of rabies was thus established, and hope for the boy’s survival seemed bleak.
After days spent motionless in a coma, Winkler gradually began to show signs of improvement. First, he became able to sit up with assistance. By November 30 he was sitting up on his own and making squeaking sounds in an effort to speak. More improvements followed rapidly. On December 1, he said his first recognizable word, and by December 7 he could take a few steps on his own, although his left side was still notably impaired. After weeks of physical and speech therapy, Winkler’s doctors declared him normal in both voice and intellect. He was discharged from the hospital on January 21, 1971—his seventh birthday. At a recheck in May, he was found to have no lingering neurological abnormalities.
In their 1972 report in the Annals of Internal Medicine, Winkler’s clinicians—led by Dr. Michael A. Hattwick—tentatively attributed the boy’s survival to one of three possible factors. The first was the vaccinations received prior to onset of clinical infection, though the authors noted that no prior victims of vaccine failure were known to have survived. The second was the possibility that Winkler had been infected with a relatively low-virulence strain of bat rabies—though the authors also acknowledged that a test performed at the Ohio Department of Health indicated a high degree of virulence in the infecting strain. The third was the advanced critical care measures employed at St. Rita’s Hospital, including the intraventricular catheter, tracheostomy tube, antiseizure medications, and intensive nursing care. “Since no specific antiviral agent is known to be effective once symptoms have developed,” the report concluded, “the treatment of clinical rabies must rely on aggressive supportive care. We now know that such care can cure.”
Another, similar case of purported survivorship took place two years after Winkler’s. On August 8, 1972, a forty-five-year-old Argentinean woman was bitten by her suddenly furious dog; within a few days, the dog succumbed to its illness. At first, her doctor treated the deep wounds in her arm with cleaning, suturing, and a dose of tetanus antitoxin. She did eventually begin postexposure vaccine treatment for rabies, ten days after the attack. But less than two weeks later, before she had even completed the fourteen-day course, she began to feel tingling in her left arm. On September 8, she was admitted to the hospital with headaches and depression. She was found to be feverish and weak, with neuromuscular spasms, particularly on her left side. A clinical diagnosis of rabies was made, confirmed by positive antibody titers in her blood and cerebrospinal fluid. But over the next few months, despite setbacks, her condition generally improved under intensive care. By September 1973, her doctors described her recovery as “nearly complete.”
Since then, three additional “partial” recoveries from rabies in vaccinated patients have been described in medical case reports. One was a New York laboratory worker who inhaled rabies virus in the course of vaccine research. The second, a nine-year-old boy in Mexico, was bitten on the forehead and face by a dog that had already attacked twenty-five other dogs in the neighborhood. The third case, in India, resembled the second: a six-year-old girl bitten by a street dog. But in these three cases, the patients wound up with permanent handicaps after their infections, ranging from blindness and quadriplegia to severe brain damage.
All five survivors documented between 1972 and 2002 shared one important characteristic at the moment of developing their first symptoms: they had all received at least part of a course of vaccine against rabies. For each case like these, though, many more would perish despite having received some treatment before developing signs of illness. And for those who had never received vaccine when their illness set in, there was still no precedent of survival.
After Jeanna Giese had spent seven days in a coma, samples were taken of her blood and cerebrospinal fluid, which demonstrated a marked increase in the number of rabies virus antibodies compared with samples obtained on the first day of hospitalization. Her body was on the attack, striking back at the viral invasion. Giese’s immune system had mounted a robust defense against the rabies virus and delivered it to the embattled central nervous system. With this welcome piece of news, her doctors began gradually to withdraw the anesthetics. The girl’s return to consciousness was observed anxiously by Willoughby, who could not be sure what to expect. The medical literature had described survivorship among unvaccinated animals, he wryly notes—but in animal studies, “every time you get a survivor, you euthanize it.”
Although the electroencephalographic findings improved after the withdrawal of ketamine, the only immediate change on Giese’s physical exam was that her pupils became responsive to light. No other reflexes were apparent. Her limbs lay flaccid on the bed. Willoughby worried silently to himself. “Oh God, I created a lock-in,” he thought—meaning someone who is conscious but unable to communicate or respond in any physical way. “It’s, like, the worst thing you can do.”
The idea that Giese might survive rabies only to be left severely disabled was a constant source of worry during the days and weeks that followed. But her steady, slow improvements kept Willoughby’s worst-case scenarios at bay. Three days after the anesthesia was withdrawn, Giese’s lower leg resumed kicking in response to the reflex hammer. Two days later, she regained eye movement. In two more days, she was raising her eyebrows in response to speech; then, a few days after that, she began to wiggle her toes, and to squeeze people’s hands in response to commands. “Every day was something new, and it was just miraculous,” recalls Willoughby with a slow shake of his head.
Giese was clearly responding to her environment, but doctor and family both craved more definitive evidence of her return. At that point, to test the girl’s ability to recognize a familiar face, Dr. Willoughby and Ann Giese removed their protective face shields and stood side by side next to Jeanna’s bed. Her eyes, held open by Willoughby, flickered between them briefly and then fixed on her mother. Clearly she was in there, after all.
From there, Giese’s recovery took weeks of incremental improvement. She had to regain her alertness and her attention span, as well as her ability to communicate her thoughts and feelings. Only very gradually did she regain governance of her five-foot-ten frame: gesture, movement, expression, swallowing, and speech all had to be relearned. After a total of one month in medical isolation, Giese was transferred for intensive inpatient rehabilitation that lasted several more weeks.
On January 1, 2005, Giese finally left the hospital for her home in Fond du Lac, triumphantly crossing the threshold in a wheelchair pushed by her father, accompanied by her mother and three brothers. In the local TV news footage of her release, the towering teenage athlete appears diminished—a slumped and childlike figure clutching a floppy yellow stuffed dog in her lap. Facing her were nearly two years of intensive physiotherapy, during which she had to relearn all the basic skills of being human. She had to learn to crawl, then to stand, then to walk. In a video made by her doctors several weeks after her release, her obstacles were vividly apparent: despite an engaged, giggling demeanor, Giese is shown to be struggling to enunciate simple words and to be coping with limbs, particularly her left arm, that seem to have a mind of their own—spontaneously jerking, dancing, saluting.
But by the time a second video was made, a little more than a year later, Giese’s dedication to her rehabilitation had clearly paid off. She already appeared much more physically self-possessed; only a subtle slurring and a rare stumble in her speech remained apparent. While her gait had not returned to the easy athletic lope of a three-sport student athlete, at both the walk and the run she appeared comfortable, if not quite fully coordinated. And her improvements have continued over the years. In the spring of 2011, Giese graduated from Lakeland College with a degree in biology; her final project focused on a fungal disease afflicting North American bats. As the world’s first unvaccinated survivor of rabies, she sees herself as a public figure who can make a difference in the global antirabies effort. On her YouTube channel, she has posted numerous homemade videos to “demonstrate the importance of being rabies-aware,” and she maintains a Facebook account—“Jeanna Rabies-survivor Giese.”
How could Jeanna Giese have possibly survived? In an article in the New England Journal of Medicine, published a year after her release from the hospital, Willoughby (together with seven collaborators) spelled out various unique features of Giese’s case that may have aided her survival—such as her youth, her athleticism, and the fact that her exposure to rabies consisted of only a small, superficial puncture on an extremity of her body. They also acknowledged that since viral antigen had never been recovered from her tissues or from the attacking bat, it was possible that Giese was infected with a weak or variant strain of rabies. Nevertheless, the report caused a stir within the small community of rabies experts, who greeted the news of Giese’s cure with a mixture of hope and skepticism.
Beyond the rarefied academic laboratories and clinics of the world’s top rabies scientists—for whom the apparent benefits of Willoughby’s therapy pose an unresolved but largely theoretical question—embattled clinicians, laboring in hospitals big and small, wealthy and poor, are occasionally faced with the question of how to help the patient who arrives already dying of this seemingly indomitable disease. Just as Willoughby discovered during the stressful hours leading up to Giese’s diagnosis, treatment options available for rabies are limited to the failed and the unproven. And so, over the past five years, various physicians have begun to attempt Willoughby’s controversial method. Now called the Milwaukee protocol, the induction of coma in a rabies sufferer has great appeal when there are no other even anecdotally successful therapies to try.
Unlike in Pasteur’s day, when collaboration among doctors usually had to take place under the same roof, today’s medical innovators can use technology to share their insights at a distance. On a Web site hosted by the Medical College of Wisconsin, clinicians can download the detailed protocol along with an itemized checklist to guide treatment of a patient with rabies. They also can register the outcome of a case that they treated with the protocol. Willoughby declares that he interprets the data reported here in what he sees as the most conservative way possible, using the principle of “intention to treat.” That is, when he tallies the number of times that the Milwaukee protocol has been employed, he includes all of the cases—even those in which the protocol wasn’t followed closely (as when a hospital didn’t have on hand a drug or monitoring tool essential to the protocol), was interrupted (as when a family removed their relative from care due to concerns about expense), or was applied to patients without normally functioning immune systems (as when immunosuppressed transplant recipients were infected through donated organs).
By this metric, the Milwaukee protocol has been attempted some thirty-five times to date and counts six survivors, including Jeanna. Four of them have not recovered nearly so well as she did: one died of pneumonia before regaining her faculties, and three more are living with profound neurological disabilities. But the most recent (as of this writing, at least) has achieved the best outcome of all. In 2011, Precious Reynolds—an eight-year-old Wiyot Native American from Willow Creek, a small mountain community in far northern California—was diagnosed with an ordinary bout of flu by her local hospital. But soon her grandmother Shirlee Roby got suspicious about her unusual symptoms. “This ain’t no damn flu,” she exclaimed, and Reynolds was flown more than two hundred miles to UC Davis Children’s Hospital. It turned out that several weeks before her mysterious neurological symptoms appeared, Reynolds (who has been pinning boys to the mat in competitive wrestling ever since the age of four) had tussled with a feral cat outside her elementary school. Based on positive antibody titers of Reynolds’s serum and cerebrospinal fluid, rabies was diagnosed, and Willoughby’s latest version of the protocol was initiated.
Reynolds remained in a coma for a little over a week, during which time her grandmother stayed by her bedside encouraging her. “I told her she had to put [rabies] on the mat and put him in a half nelson and pin him,” Roby said to reporters. “And by golly if she didn’t do it.” Reynolds left UC Davis Children’s Hospital after just fifty-three days of hospitalization, most of them spent in rehabilitation. At her discharge in June 2011, she limped only slightly, supported on her right ankle by a slender brace decorated with butterflies. By summertime, she was playing and swimming with her siblings and cousins; that August, she won twenty-three dollars for her third-place finish in a “mutton bustin’” contest, which involves clinging to the bare back of a sheep as it scampers wildly around a ring.
Back at UC Davis for a checkup in early 2012, Reynolds bounced merrily along the corridors of the pediatric ICU, her butterfly-bedecked brace the only visible remnant of her brush with rabies. She remembers very little of the critical phase of her illness but seems to relish hearing about it from others. She is particularly delighted to hear doctors and nurses confess that they thought she would never survive. As far as Precious is concerned, everything is the same as it was before she got rabies: she still plays soccer, and wrestles, and does generally well at school. She still is fond of animals—most of them, that is. “I don’t like cats,” she says.
That six out of thirty-five cases have survived after receiving some version of the Milwaukee protocol represents an impressive success rate, at least when compared with the 100 percent fatality rate historically attributed to rabies. Nevertheless, the medical establishment remains largely skeptical. At the time of his original publication, Willoughby declared his intention to set up animal studies to test some of his claims. In particular, the idea that rabies causes mortal complications by way of brain “excitotoxicity”—meaning that the virus overactivates the neurons, disrupting the brain’s functions without killing its cells—has yet to be scientifically explored. Six and a half years later, these studies have yet to materialize. The basic reason is financial: Willoughby has not received enough funding to undertake the research himself, and meanwhile no other rabies researcher has made such efforts a priority. Around the world, most of the rabies-treatment research dollars—of which there are very few, given the concentration of the disease in resource-poor areas—are in the hands of scientists who disagree with Willoughby about the underlying biology of rabies infection. Until there is a better understanding of how the rabies virus interacts with the brain on a subcellular level, and of precisely how the various treatments instituted by Willoughby work within the central nervous system, there will be no consensus on the value of the protocol.
Of the Milwaukee protocol’s six successful cases, none besides Jeanna’s has yet been published in the medical literature. Willoughby has declined to pursue publication of them himself, feeling that the supervising clinicians should be allowed to publish their own observations if they so desire. Meanwhile, in at least two cases where the protocol failed, the physicians have published the results—sometimes with scathing commentary. One such case involved a thirty-three-year-old man treated at the King Chulalongkorn Memorial Hospital in Bangkok, Thailand, home to some of the best-known rabies scientists in the world. The primary clinician on that case, Thiravat Hemachudha, was a vocal skeptic of the protocol before he even tried using it. And in a subsequent paper, he and his colleagues went out of their way to declare that they thought no one should be testing the protocol at all. “There is no credible scientific basis,” they write, “for the use of therapeutic coma in rabies, and the risks of this therapy are substantial.”
Perhaps the preeminent critic of the Milwaukee protocol is the rabies expert Alan Jackson, who teaches at Queen’s University in Kingston, Ontario. Jackson has been a doubter from the very beginning. In the very same issue of the New England Journal of Medicine that published the report on Jeanna, Jackson penned a dissenting editorial that cautioned against Willoughby’s interpretation of the case. “Induction of coma is not known to have beneficial therapeutic effects in rabies or in other infections of the central nervous system,” Jackson averred, adding pointedly: “In the future, induction of coma will probably not be shown to be an effective therapeutic approach to the management of rabies.” Even as more apparent successes have emerged, he remains unconvinced, and for an intriguing reason. His central observation about all the survivors, including Jeanna Giese, is that they had significant virus-neutralizing antibodies detectable at the time of diagnosis. This fact points to a robust native immune response, he believes, that might predispose them to survival—regardless of the specific treatments received.
Jackson’s argument raises the tantalizing possibility, only hinted at in the margins of the medical literature before Pasteur, that a rare few rabies victims might survive without any intervention at all. We know that this is occasionally true in animals: Pasteur himself recorded the case of a dog that was inoculated with rabies virus, developed neurological symptoms, and then recovered. And since that time, recovery from rabies has been documented in several other animal species, including donkeys, foxes, bats, rats, mice, and guinea pigs.
Giese’s survival raises the question of whether this might sometimes happen in humans, too. For more than a hundred years, medical journals have contained occasional case reports that allege survival of rabies. One early nineteenth-century physician claimed in the Lancet to have cured rabies by injecting water into a patient’s veins; in the middle of the twentieth century, a handful of doctors reported recovery from rabies after they transfused serum from people who were recently vaccinated. A 1972 paper tallied nine cases of reported recovery between 1875 and 1968. A survey for serum rabies antibodies in a population of unvaccinated veterinary personnel yielded some positives, as did a similar study of cave explorers. But because most reports of human rabies survival were made before modern tests for rabies were in routine use, there has been considerable room for doubt as to whether these patients actually suffered from rabies instead of some other malady, real or imagined.
As recently as February 2010, the CDC’s Morbidity and Mortality Weekly Report published a case report that detailed an apparently unvaccinated survivor of rabies who did not receive the Milwaukee protocol or any intensive care at all. In February 2009, a seventeen-year-old girl appeared at a Texas community hospital complaining of severe headaches, extreme sensitivity to light, vomiting, dizziness, and tingling in the face and arms. When doctors examined her, they found her feverish and disoriented, with a stiff neck typical of nervous-system inflammation. A scan of her brain detected no abnormalities, but a tap of her cerebrospinal fluid showed an increased presence of inflammatory cells. After three days in the hospital, the girl’s symptoms had resolved, and she was sent home.
At home, the girl’s headaches resumed and intensified. On March 6, she went to another local hospital seeking relief from her headaches and photophobia, which now were occurring alongside muscle aches and pains, particularly in her neck and back. This time her brain imaging and cerebrospinal fluid tap were even more strongly indicative of central nervous system inflammation, and she was transferred to a tertiary-care children’s hospital the same day. There, the girl was found to have a variety of signs and symptoms consistent with infectious encephalitis. A flurry of tests ensued to determine a cause. Meanwhile, the girl was treated aggressively for several possible infectious causes of encephalitis: she received antiviral, antibiotic, and antituberculosis drugs.
Despite an extensive workup, no infectious or noninfectious cause for the girl’s neurological inflammation was apparent. Then, on March 10, prompted by her doctors, the girl recalled having recently had an encounter with bats. Two months previously, she had entered a cave while on a camping trip and, there, in the dark, had felt the percussive blows of flying bats colliding with her body. She had not noticed any bites or scratches, and she told the doctors that she had never received any rabies vaccine. But the next day, the CDC ran tests and found antibodies against rabies in the girl’s blood and cerebrospinal fluid—persuasive evidence of a rabies infection.
On March 14, the girl received a dose of rabies vaccine and immunoglobulin therapy. She remained in the hospital until March 22, receiving only basic supportive care during that time. She made two follow-up visits to the emergency department after her discharge, complaining each time of a recurrence of headaches. On her final visit, she reported relief following a spinal tap. This was the last contact between the girl and her doctors: they record her as being “lost to follow-up.” One hopes that medical science will eventually reconnect with this potentially historic case of rabies survivorship.
Is Willoughby correct in his belief that the Milwaukee protocol, refined over time through repeated use, could eventually serve as a reliable treatment—one that transforms rabies from a death sentence into a frequently survivable disease? Or is Alan Jackson correct in his conviction that a very few, fortunate individuals are just naturally predisposed to fight off the disease? Only years of further experimentation can answer these questions definitively. In the meantime, though, we can agree with the assessment of Dr. Rupprecht, back in 2008, when he cautioned both supporters and detractors of the protocol that “we need to focus more on prevention.” The protocol provides hope for patients already infected, he observed, but “the odds of coming out without neurological deficits are remote, even with the best care.” Three years later, despite the exciting success of Reynolds, this assessment still stands. It’s impossible to imagine that developing-world countries would ever have the resources to deploy controlled-coma therapy on more than a tiny fraction of the more than fifty thousand people who currently die of rabies each year. By contrast, it’s surprisingly cost-effective for those countries to prevent rabies, through the mass vaccination of dogs.
In our next and final chapter, we consider the ins and outs of canine vaccination but in the dramatic context of a real-world crisis: an outbreak on the Indonesian tourist island of Bali, which until 2008 had been entirely rabies-free.