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