This is the fifth case of rabies in the UK since 2000 and highlights the need for better education of travellers and clinicians on the risks of travel-related acquisition.
Rabies is a vaccine-preventable disease. UK imported rabies cases, acquired through animal contact in rabies endemic countries, have been uniformly fatal and were noted to have not received pre- or post-exposure prophylaxis (PEP) . Financial cost has been cited as a reason for declining pre-exposure immunization  and therefore, when appropriate, the advantages need to be clearly communicated to justify the cost to the patient. The basis for poor post-exposure prophylaxis remains unclear: a recent Geosentinel survey of 23,509 travellers found that 320 travellers sustained animal-related injuries (mainly in Asia involving dogs) yet only 66% received PEP .
This case illustrates the insidious and nonspecific symptoms that may precede rabies and reminds clinicians to consider the diagnosis. Lack of awareness of potential rabies exposure compounded with the nonspecific prodrome that may precede neurological signs mean that delayed clinical suspicion is frequent .
Phylogenetic analysis demonstrated that the virus isolated from this patient was from a canine lineage of viruses thought to have evolved 500 years ago from strains in Polar regions, and now a dominant strain in parts of Asia [24, 25]. The virus isolated here is very similar to previous imported cases from India ten years previously  and similar to cases in dogs in 1970s-1980s (Figure 1). This implies that current strains are very similar to those circulating in stable endemic independent cycles in the region for the past 30 years. An average of only 57 rabies cases have been reported in animals from the whole of India annually since 2005 , and there is therefore likely to be significant underreporting. This case illustrates the growing divide between countries where rabies is endemic and underreported, and those where rabies is extremely rare.
Until 2005, some form of prophylaxis was documented in the handful of patients who survived clinical rabies [27–31]. However, in 2004, in the absence of vaccination, a 15-year-old girl with rabies, diagnosed on the basis of a history of bat bite and anti-rabies antibodies in the CSF, survived after the use of the Milwaukee Protocol . The protocol comprised therapeutic bundles based on rebalancing an apparent rabies-induced tetrahyrobiopterin deficiency that leads to dopamine and serotonin deficiency and poor nitric oxidase activity  whilst the natural immune response clears the virus, as reported in animal models showing immune-mediated viral clearance from the central nervous system and T-cell mediated neuronal apoptosis [33–37].
The logistical complexities of adoption of the Milwaukee Protocol are substantial, and this report provides additional data on its lack of efficacy. Despite revisions to reduce adverse reactions to component drugs [13, 32, 38], patients treated by the Protocol and submitted on a central database  number 43, of which only five (excluding the first survivor) have been registered as survivors. Multiple failed attempts have been described [9, 11–13, 40–42] including the last UK imported case  but the potential for efficacy has been debated due to case by case protocol deviations. In the absence of animal trial data, the only evidence for the protocol has emerged from individual case review. Specific factors that appear relevant include: therapy with rabies vaccine prior to onset of symptoms, young age, lack of comorbidity, infection with bat rabies variant, early evolution of neutralizing antibodies in serum and CSF, and mild neurological disease [8, 13, 43–45]. Also relevant is the immune response, as asymptomatic seroconversion and abortive infection have been described [46–48]. In our case, the above positive prognostic factors were absent. Furthermore, our case was treated with vaccine and immune globulin prior to institution of the recommended protocol, which may have resulted in delay in generation of the host immune response. As in other cases, it was recommended initially (prior to disease confirmation) as part of the standardized post-exposure protocol. This patient had no serum antibody on presentation, and failed to develop detectable antibody levels in CSF by day 8, which supports previous evidence that lack of CSF antibody is a poor prognostic indicator. It is unknown whether the patient would have developed an effective immune response given sufficient time. We acknowledge that, in future suspected cases, post exposure prophylaxis should await results of diagnostic tests to give the protocol optimum chance.
The actual mode of this patient’s death appears to have been profound dysautonomia. Despite anticipating it, we were ultimately unable to control it. Perhaps an earlier and even more aggressive approach to dampen this autonomic dysfunction may have changed the outcome, but elements of the Milwaukee Protocol are at odds with this therapeutic strategy. Other elements were just not feasible on our ICU. Adoption of the Protocol remains contentious. It may be that individualization of care in future cases is possible with the identification of prognostic biomarkers, and recent metabolomic studies on the spinal fluid of 2 survivors versus 7 non-survivors have proposed several biomarkers .
Viral distribution studies in animal models, and through quantitative PCR in this case, demonstrate that virus can be widely distributed. There was no detectable RNA in the heart muscle, albeit from only one sampled region (data not shown), however. virus replication centres (Negri bodies) in the cardiac vagus nerve were detected histologically (Figure 3). Previously described autopsy studies of cardiac tissue have shown the presence of rabies viral antigen deposits in the ganglia of three cases, with concurrent ganglioneuritis and myocarditis seen in two and one of the cases respectively - from which it was inferred that centrifugal neuronal spread of the rabies virus occurred with subsequent spread to the myocardium . Similarly, clinical and autopsy data in this case support the spread of virus but do not conclusively prove presence of virus in the heart. The anterograde axonal spread of virus is not well understood: it is recognised that the virus will spread via the autonomic nervous system to a wide range of organs including the heart ; and that the latter is typical for the clinical course of rabies in humans and leads to myocardial dysfunction and death.
In this case, the autopsy demonstrated the previously documented conundrum that death with brain involvement occurs despite minimal encephalitis and neuronal >loss . However, the marked brainstem involvement recently described in studies of viral antigen distribution and magnetic resonance imaging (MRI) in rabies patients [53–55] and implicated as potentially relevant to centrally-mediated dysautonomia was not seen here.
Consensus regarding the Milwaukee Protocol in patients with canine rabies will evolve as more outcomes are published. In the interim, the emphasis of management is based on timely diagnosis to optimise supportive care. The prompt availability of the sequence and phylogenetic analysis of the virus also aided clarification of the source as this was not initially clear. Much can be learnt from the promptness of confirmation of diagnosis in this case, as well as the efficient and daily coordination of information between specialist and referring hospitals, public health authorities and national experts which was crucial in this patient’s care and minimization of onward transmission. This highlights the benefit of discussion on a daily basis by relevant experts and fully encompasses the ‘One Health’ agenda  for rare imported human infectious diseases.