Rabid

by Monica Murphy

  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 communicati
on 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 nurs
ing 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.