Harkess, G¹., Johnson, N¹., Marston, D¹., Goddard, T¹., Goharriz, H¹., Voller, K¹., Solomon, T²., Hunter, M³., Hedderwick, S³., McCaughey, C³., Willoughby, R⁴. and Fooks, A.R¹.

¹ Veterinary Laboratories Agency (VLA), Weybridge, UK
² University of Liverpool, UK
³ Royal Victoria Hospital, Belfast, UK
⁴ Medical College Wisconsin, USA

Rabies is endemic in many regions of the world and causes a fatal encephalomyelitis following infection of the central nervous system.  The causative agent, rabies virus, is a member of the genus lyssavirus, family Rhabdoviridae.  Many island states have actively excluded the disease (including the United Kingdom).  Others have taken action to control and eliminate rabies in dogs (North America) and terrestrial wildlife (Western Europe).  Across the developing world the burden of rabies continues to fall particularly heavily where dog rabies remains a notable public health problem.  It is estimated by the World Health Organisation that over 50,000 rabies deaths occur annually as a result of dog bites, although this figure is considered to be a conservative estimate. 

It is widely accepted that there is no proven effective treatment once clinical symptoms of rabies are observed.  However, a recent report has described a form of induced-coma that is suggested to have contributed to the survival of a teenager infected with rabies in Milwaukee, US, now commonly referred to as the “Milwaukee protocol”.  This was in a child infected with bat rabies, who unusually had anti-rabies antibodies at the time of presentation.  Although subsequent attempts to repeat this therapy have failed for a number of human presentations with rabies, there have been promising developments that have led to 3 survivors from approximately 30 attempts across the globe (2005, Wisconsin, USA), (2008, Brazil), (2009, Equatorial Guinea).  Whilst this sample size is limited, it does present an encouraging trend.  However, the absence of suitable animal models to develop this approach has limited investigation into its mode of action or refinement.

Here we report on a 37-year-old woman resident in Northern Ireland, who presented with a history of exposure to rabies virus whilst in South Africa.  The decision was taken to instigate the Milwaukee protocol once a diagnosis of rabies was confirmed and with the support of the patient’s relatives.  In this case therapy failed to prevent the death of the patient.  However, the patient was monitored extensively over time for virus expression in saliva and for seroconversion to rabies virus in both blood and cerebrospinal fluid.

The patient was initially admitted to hospital with progressive encephalitis.  Nuchal skin biopsy analysed using a Rabies TaqMan© PCR, demonstrated the presence of rabies virus RNA.  The patient had not received pre-or post-exposure prophylaxis.  Rabies virus was isolated from cerebral spinal fluid (CSF) and saliva, and rabies antibody was demonstrated in serum (from day 11 onwards) and CSF (day 13 onwards).  She died 35-days after being hospitalized.  Samples at autopsy demonstrated the presence of rabies antigen, viral RNA, and viable rabies virus in the central nervous system, displaying a heterogeneous distribution throughout the brain. Molecular methods of diagnosis demonstrated utility in terms of speed of diagnosis in this case. Rabies TaqMan provided a rapid, reliable method for detecting rabies in a range of samples. This re-affirms the use of RT-PCR for ante-mortem diagnosis of rabies. However, conventional virus isolation did detect virus in some samples that were PCR negative.
Analysis of the samples that were positive in this patient suggests that the ability to detect virus in ante-mortem samples is highly dependent on the immune status of the patient. Once peripheral seroconversion had occurred (day 11) only one further saliva sample (day 12) was positive by rabies TaqMan PCR. This suggests that there is a narrow window for ante-mortem diagnosis of disease based on detection of virus in accessible antemortem samples such as saliva, CSF, and skin biopsy.

This travel related human case highlights the importance of rabies vaccination. Vaccination against rabies should be considered for all persons who travel to a rabies endemic region for either recreational or occupational purposes bearing in mind that the majority of dog-bite exposures occur in urban and not rural regions. 

A full description of this case is available in: Hunter et al. (2010) Immunovirological correlates in human rabies treated with therapeutic coma. Journal of Medical Virology 82:1255–1265