Rabid
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 Three days after the anesthesia was withdrawn, Giese’s lower leg resumed kicking in response to the reflex hammer.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, an
tibiotic, 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.