Abstract
BackgroundHuman rabies infection continues to be a significant public health burden globally, and is occasionally imported to high income settings where the Milwaukee Protocol for intensive care management has recently been employed, with limited success in improving survival. Access to molecular diagnostics, pre- and post-mortem, and documentation of pathophysiological responses while using the Milwaukee protocol, can add useful insights for the future of rabies management.Case presentationA 58-year-old British Asian woman was referred to a regional general hospital in the UK with hydrophobia, anxiety and confusion nine weeks after receiving a dog bite in North West India. Nuchal skin biopsy, saliva, and a skin biopsy from the site of the dog bite wound, taken on the day of admission, all demonstrated the presence of rabies virus RNA. Within 48 hours sequence analysis of viral RNA confirmed the diagnosis and demonstrated that the virus was a strain closely related to canine rabies viruses circulating in South Asia. Her condition deteriorated rapidly with increased agitation and autonomic dysfunction. She was heavily sedated and intubated on the day after admission, treated according to a modified Milwaukee protocol, and remained stable until she developed heart block and profound acidosis and died on the eighth day. Analysis of autopsy samples showed a complete absence of rabies neutralizing antibody in cerebrospinal fluid and serum, and corresponding high levels of virus antigen and nucleic acid in brain and cerebrospinal fluid. Quantitative PCR showed virus was also distributed widely in peripheral tissues despite mild or undetectable histopathological changes. Vagus nerve branches in the heart showed neuritis, a probable Negri body but no demonstrable rabies antigen.ConclusionRapid molecular diagnosis and strain typing is helpful in the management of human rabies infection. Post-mortem findings such as vagal neuritis highlight clinically important effects on the cardiovascular system which are typical for the clinical course of rabies in humans. Management guided by the Milwaukee protocol is feasible within well-resourced intensive care units, but its role in improving outcome for canine-derived rabies remains theoretical.
Highlights
Human rabies infection continues to be a significant public health burden globally, and is occasionally imported to high income settings where the Milwaukee Protocol for intensive care management has recently been employed, with limited success in improving survival
Rapid molecular diagnosis and strain typing is helpful in the management of human rabies infection
Post-mortem findings such as vagal neuritis highlight clinically important effects on the cardiovascular system which are typical for the clinical course of rabies in humans
Summary
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. It was recommended initially (prior to disease confirmation) as part of the standardized postexposure 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. 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 [51]; 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 [52].
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