“The Milwaukee Protocol and beyond: Is rabies really a death sentence?”

Stuart Mather

Within the discipline of virology, rabies is pretty unanimously regarded as the world’s deadliest human virus. Most commonly transmitted from the bite of an infected dog, the virus begins to spread to the central nervous system (CNS), originally causing pain, fever, headache and a tingling sensation (known as paraesthesia), before leading in some ases to paralysis and coma, whilst in others developing the characteristic rage, hyperactivity and hydrophobia associated with the disease. In either instance, the result is almost certainly death – statistically, the case-fatality rate of symptomatic rabies infection is 100%.

1Fortunately, rabies is as preventable as it is fatal. Through human and canine vaccination, the number of cases of the virus has significantly decreased in many countries. Furthermore, the administration of post-exposure prophylaxis – or PEP – following suspected occurrences of infection is estimated to avoid hundreds of thousands of rabies-attributed deaths every year.

Nevertheless, rabies still circulates on every continent other than Antarctica, is endemic in 150 countries worldwide, with roughly 60,000 individuals succumbing to the disease annually. Why is this? One o2f the main obstacles to further reducing the public health burden of rabies is poor accessibility to the most resource-deprived areas of the world, typically in Africa and Asia. It is not straightforward to roll out mass vaccination schemes in these regions, and many potential rabies transmission events, such as dog or wild animal bites, are not promptly reported to local medical services. And once the virus fully manifests itself within a host and reaches the CNS, there are no licensed medical treatments available to prescribe.

So, is there any way to combat rabies when it’s in the full swing of infection? This blog post explores some of the evidence to suggest that being diagnosed with rabies is not necessarily always a death sentence.

First of all, it is important to acknowledge that rabies is probably one of the oldest infectious diseases known to man. Reports of the virus date back to as far as 2300 BC, where Babylonian dog owners in the ancient city of Eshnunna were severely fined for deaths caused by bites from their dogs. Rabies was then consistently documented in Ancient Greece by the philosophers Democritus and Aristotle, as well as being alluded to in Homer’s The Iliad. They even dedicated two Gods to the prevention and healing of rabies – Arisaeus and Artemis, respectively. Mesopotamian and Roman physicians detailed4 the symptoms of rabid dogs and developed a cleaning regimen for management of bite wounds. In the following 1500 years, the infection steadily spread throughout Arabia and Europe, causing notable outbreaks in Germany (13th century) and Spain (15th century) before wreaking havoc in Paris and finally reaching the shores of England by the 1730s. At a similar time, undoubtedly due to the emergence of the global empires, the growing merchant shipping industry and the slave trade, rabies emerged in the West Indies, Barbados and Mexico, before spreading in both directions throughout North and South America, on its way to becoming the globally ubiquitous virus we see today.

Although the literature throughout history clearly focuses on the death and devastation caused by rabies, it is highly likely that, on rare occasions, some individuals may survive the infection, whether that be because of a very strong and rapid immune response in the patient or exposure to a particularly weak strain of the virus. Certainly nowadays, researchers are well aware that some wild animals conquer rabies alone, without vaccination or medical intervention. After all, viruses must hijack host cellular machinery to replicate themselves and flourish, so a virus that decimates every single host it infects is not necessarily a successful virus, with respect to its own self-preservation and evolution. And rabies can definitely be described as ‘successful’!

Speculation aside, the5 first reported instance of a human surviving the full force of rabies (perhaps contrary to popular belief) is that of Matthew Winkler, a 6-year-old boy from Ohio, USA, during the Autumn of 1970. One night, a bat managed to get into Matthew’s bedroom through a hole in the attic and firmly bit his thumb. The father managed to catch the bat after hearing his son screaming and upon sampling it a few days later, public health officials declared the animal rabid, prompting paediatrician Dr John Stechschulte to initiate a course of rabies vaccine for the boy over a fortnight. However, in the following weeks, Matthew developed a fever, stiffness of the neck and left side, and slipped into a semi-comatose state. The vaccine had failed and rabies had taken hold. Rather than resign themselves to the fact that the patient would soon die, they opted to fight the disease based on the assumption that death may be brought about as a result of the ailment’s symptoms, as opposed to the presence of the virus itself. So if, for instance, the physicians could perform a tracheotomy when Matthew’s throat contracted, or prescribe anti-convulsants to prevent hyperactive twitching and spasming, then they may be able to stave off death long enough to give his immune system time to mount a response against the rabies virus, altering the outcome for the boy. Three months after being admitted, Matthew had recovered enough to be released from hospital on his 7th birthday, and has since gone on to live a life relatively unhindered by neurological complications.

Definitely the most famous and well-documented case of rabies survival is that of Jeanna Giese, the first person to have overcome rabies with no vaccination or PEP whatsoever prior to symptom development. Jeanna was 15 years old when she attended a regular church Mass in September 2004. During the service, a bat was circling overhead, getting increasingly near to the attendants before finally being knocked to the ground by a church usher. Out of compassion and a love of animals, Jeanna decided to pick the bat up and take it outside, sustaining a small bite to her index finger in the process. After cleaning and dressing the wound, her family thought nothing more of the incident. A few weeks later, Jeanna started complaining of double vision and tingling in her limbs; suffering from fatigue, nausea and fever. When her arms started to stiffen and jerk involuntarily and her speech slurred, she was hospitalised and tested for a number of neurological diseases. Every result came back negative. In desperation, Jeanna’s mother mentioned the recent bat bite, which was an important step in achieving a rabies diagnosis, and soon after Jeanna was transferred to the Children’s Hospital of Wisconsin, where she was referred to Dr Rodney Willoughby, an infectious diseases consultant.

Despite his expertise in the discipline, Dr Willoughby had never encountered a patient with rabies before, and as neither licensed treatments nor promising but unpublished approaches were available, the plan of action for combatting the infection was completely unclear. So with Jeanna’s condition rapidly declining, Rodney went back to basics and pored over old case files and publications, trying to find clues about how the disease’s progression could be halted. One point, highlighted several times in the literature, caught the doctor’s eye –rabies pathology does not primarily function by physically destroying neuronal cells or causing lesions in the brain an6d CNS, but rather by disrupting the controlled release of neurotransmitters, such as acetylcholine and serotonin. Dr Willoughby and his colleagues therefore decided to place Jeanna into an induced coma, which could suppress her neuronal activity and delay the progression of rabies symptoms, effectively buying time for her adaptive immune system to produce enough antibodies directed against the virus o overcome, or neutralise, the infection. While comatose, Jeanna was also prescribed ketamine and midazolam to further dampen brain function, as well as the antivirals ribavirin and amantadine. After six days, Jeanna displayed protective antibody levels against rabies and was brought out of the coma to begin her gradual recovery. She had to re-learn how to stand and walk, then regain fine motor skills and so on. A decade on, Jeanna has undergone a pretty complete recovery, now only unable to run and speak at full speed. She graduated from college in 2011 with a degree in Biology and got married in 2014.

Dr Willoughby’s innovative treatment approach was subsequently dubbed the ‘Milwaukee Protocol’. Despite this initial success story, the protocol is a controversial and divisive subject for medical professionals and scientists in the field. Since 2004, the treatment has been attempted approximately 35 times, with only 5 resulting in patient survival. It is also unsure whether these successes can be attributed to the protocol itself, or rather exposure to a low-pathogenic variant of the rabies virus coupled with a robust immune response from the patient. Furthermore, the location of the bite wound may play an influential role in the propensity for the patient to overcome the infection. Both Matthew Winkler and Jeanna Giese were bitten on a finger or thumb, meaning that the rabies virus would have to travel further along nerve cell axons before reaching the CNS (at a rate of 1-2cm per day), allowing a longer timespan for patient immune responses to develop.

More recently, in 2012, one study published in the American Journal of Tropical Medicine and Hygiene detailed new evidence suggesting that rabies infections in humans may not be as lethal as first thought, potentially revolutionising the way the virus is regarded clinically. Dr Amy T Gilbert of the Centers for Disease Control and Prevention led a serosurveillance study in two communities at risk of vampire bat bites in the Peruvian Amazon – this involved taking blood samples from a number of community members and assessing levels of rabies virus neutralising antibodies in their serum. Over half claimed to have previously been bitten by bats and remarkably, 11% of those tested carried rabies antibodies at levels sufficient to protect them from subsequent infection. Out of these seven seropositive individuals, only one had received the rabies vaccine, indicating that the remaining six people had been naturally exposed to the virus, with a non-fatal outcome. Potential alternative explanations for these findings could be that these people were infected with a virus highly related to rabies, which can induce the production of cross-reactive antibodies but which is not fatal to humans; or that they were exposed to a large enough dose of rabies to virus to elicit an immune response, but that viral replication did not occur. In any instance, if these individuals possess some inherent genetic resistance to rabies, being able to understand why may lead to novel treatment strategies.

Other interesting approaches to rabies therapy have also been studied. It seems logical to try and identify antiviral drugs for the treatment of rabies, and the two agents known to have activity against the virus are ribavirin and interferon-α. These have both shown promise as treatments in in vitro and animal model studies, but have failed to display beneficial effects when administered to human patients in early stages of clinical rabies. A major limitation to the use of these antivirals is that they often have to penetrate the blood-brain barrier to reach the primary sites of infection, meaning they can’t reach many of the rabies virions.

Another approach that seems more experimental is deliberate hypothermia. Body cooling has previously proven effective in trials involving cardiac arrest patients, and works by reducing metabolism, oxidative stress and inflammation in the brain. These effects could also be beneficial in the treatment of rabies, but have not undergone clinical trials at any phase as of yet.

The cases discussed in this blog prove that rabies can be survived, albeit very rarely, and offer hope that more successful treatment strategies may be developed in the future. For now, it retains its place on top of the list of deadliest human viruses, so the best plan of action to survive rabies is… don’t get rabies!

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