Why does the prognosis remain so poor in human rabies?

Human rabies has been a problem since antiquity. Although rabies may be effectively prevented after a recognized exposure, medical management once the clinical disease develops has almost universally proved to be ineffective, resulting in a fatal outcome. Worldwide, there are at least 55,000 human cases of rabies each year, largely owing to transmission related to endemic dog rabies in developing countries in Asia and Africa [1]. In North America, most human cases of rabies are caused by bat rabies variants, and there may be no history of a bat exposure in these cases.

Recovery from rabies is dependent on an immune response with viral clearance. Pathogenic strains of rabies virus have selected immunosubversive strategies to escape the host immune response; there is viral-mediated immune suppression with loss of cellular-mediated immunity [2]. In addition, viral clearance of rabies virus infection from the brain is difficult because immune effectors do not penetrate the blood–brain barrier or the brain very well. Studies by Hooper and colleagues have recently shown the importance of this barrier in rabies [3–5], and in the future therapeutic approaches aimed at enhancing permeability may prove to be fruitful.

In 2003, a group of physicians with expertise in rabies and rabies researchers published an article giving recommendations on therapies that could be considered for an aggressive approach [6]. It was believed that in young and previously healthy patients with an early clinical diagnosis of rabies (prior to laboratory confirmation), prompt initiation of therapy should offer the best opportunity for a favorable outcome [6]. Therapies suggested for potential consideration include rabies vaccine, human rabies immunoglobulin, monoclonal antibodies (in the future), ribavirin, IFN-a and ketamine. The recommendation for therapy with ketamine was based on animal work that was performed at the Institut Pasteur in Paris, France, in the early 1990s [7]. Like current therapies for cancer, HIV infection and chronic hepatitis C infection, it was felt that a combination of therapies might be effective where specific therapies had failed in the past.

In 2004, a patient survived from rabies who had not received the rabies vaccine prior to the onset of clinical disease [8]. This 15-year-old female was bitten by a bat on her finger and did not receive post-exposure prophylaxis therapy for rabies. Approximately 1 month after the bite, she developed clinical features of rabies encephalitis. A magnetic resonance brain scan was normal. On her fourth day of illness, her cerebrospinal fluid showed a pleocytosis and mildly elevated protein. The history of the bat bite was not obtained until this time. Five days after the onset of neurologic symptoms, the patient was transferred to a tertiary care hospital in Milwaukee, WA, USA. Neutralizing anti-rabies virus antibodies were detected in sera and cerebrospinal fluid (initially 1:32). Nuchal skin biopsies were negative for rabies virus antigen, rabies virus RNA was not detected in the skin biopsies or in saliva by reverse transcriptase-PCR, and viral isolation on saliva was negative. The patient was intubated and put into a drug-induced coma, which included the noncompetitive N-methyl-D-aspartate antagonist ketamine at 48 mg/kg/day as a continuous infusion and intravenous midazolam for 7 days. A burst–suppression pattern on her electroencephalogram was deliberately maintained and supplemental phenobarbital was required in order to maintain this pattern. She also received antiviral therapy including intravenous ribavirin and amantadine 200 mg/day administered enterally. She improved and was discharged from hospital with neurologic deficits and she subsequently demonstrated further progressive neurologic improvement [9]. This is the first documented survivor who did not receive the rabies vaccine prior to the onset of clinical rabies. As discussed in an accompanying editorial, it is unknown if therapy with one or more specific agents played an important role in the favorable outcome of this case [10]. However, since that time there have been 20 or more cases in which the main components of this approach (the ‘Milwaukee Protocol’) have been used and fatal outcomes have resulted [11], but it is likely that there have been other unsuccessful attempts of the therapy. The induction of coma per se has not been shown to be useful in the management of infectious diseases of the nervous system, and to date there is no evidence supporting this approach in rabies or other viral encephalitides. Therapeutic coma should not become a routine therapy for the management of rabies. There is no established experimental evidence supporting excitotoxicity in rabies and there is recent evidence in an animal model that argues against this hypothesis and the evidence includes the lack of efficacy of ketamine therapy both in vitro and in vivo[12]. Even where there is strong experimental evidence of excitotoxicity in animal models, multiple clinical trials in humans have shown a lack of efficacy of neuroprotective agents in stroke [13]. Hence, a neuroprotective effect of a therapy given to a single patient without a credible scientific rationale is very doubtful. It is much more likely that this patient would have recovered with only supportive therapy and probably received an additional ‘insult’ of therapeutic coma without benefit.

The presence of neutralizing anti-rabies virus antibodies early in a patient’s clinical course, probably occurring in less than 20% of all patients with rabies, is likely an important factor contributing to a favorable outcome. Neutralizing anti-rabies virus antibodies are a marker of an active adaptive immune response that is essential for viral clearance [2]. There have been six survivors of rabies who received the rabies vaccine prior to the onset of their disease (and only one without vaccine). This supports the idea that an early immune response is associated with a positive outcome. Bat rabies viruses may be less neurovirulent than canine or other variants that are responsible for most human cases of rabies [14], and rabies due to canine rabies virus variants may have a less favorable outcome than cases caused by bat rabies variants. A previous survivor of rabies, who received the rabies vaccine prior to the onset of disease and had a good neurological recovery, was also infected with a bat rabies virus [15]. It is unknown if the causative bat rabies virus variant in the Milwaukee case was, in some way, attenuated and different from previously isolated strains because viral isolation was not successful. Finally, most survivors of rabies to date have shown neutralizing anti-rabies virus antibodies in sera and cerebrospinal fluid, but other diagnostic laboratory tests are usually negative for rabies virus antigen and RNA in fluids and tissues (brain tissues not tested). This may be because viral clearance was so effective that centrifugal spread of the infection to peripheral organ sites was reduced or very rapid clearance occurred through immune-mediated mechanisms.

A Canadian case of rabies was treated with the Milwaukee Protocol and, after therapy with therapeutic coma, remained in a brain death-like state for approximately 4 weeks. At autopsy there was complete loss of neurons in the cerebral cortex and positive staining for rabies virus antigen was observed in both brainstem and cerebellar neurons, indicating a failure of therapy to clear the viral infection from the brain or prevent neuronal injury and loss [16]. In Germany, lung and kidney/pancreas recipients from a rabies virus-infected donor developed rabies and were treated with major components of the Milwaukee Protocol, including intravenous midazolam, ketamine and phenobarbital (in one) [17]. One patient died within 2 days whereas the other survived 64 days after the onset of clinical rabies. At autopsy the two patients had 1.2–2.3 × 10⁹ RNA copies/mg of CNS tissue, again indicating ineffective viral clearance by the therapy. The patient who survived for longer did show viral clearance from systemic organs and peripheral nerves. Hence, Milwaukee Protocol therapy has proved ineffective in promoting viral clearance from the CNS in rabies. For reasons that are unclear, the girl from Milwaukee probably cleared the infection from her CNS with her own immune response and the administered therapies may not have played an important role in the outcome. The presence of neutralizing anti-rabies virus antibodies on clinical presentation is likely a favorable laboratory finding. Negative tests detecting rabies virus antigen or RNA are probably also favorable because they may reflect a blockade of centrifugal viral spread or effective viral clearance by the immune system.

Although rabies can be prevented after recognized exposures, effective therapy for human rabies is not yet available. It remains highly doubtful that the Milwaukee Protocol will prove to be useful in the management of human rabies. Unfortunately, promotion and repetition of this flawed therapeutic approach may continue to impede progress in developing new effective therapies for rabies. We need an improved understanding of the basic mechanisms underlying rabies pathogenesis in humans and animals to allow the development of novel therapeutic approaches for the management of human rabies.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.