Elsevier

Antiviral Research

Volume 99, Issue 1, July 2013, Pages 61-67
Antiviral Research

Current and future approaches to the therapy of human rabies

https://doi.org/10.1016/j.antiviral.2013.01.003Get rights and content

Abstract

Human rabies has traditionally been considered a uniformly fatal disease. However, recent decades have seen several instances in which individuals have developed clinical signs of rabies, but survived, usually with permanent neurologic sequelae. Most of these patients had received prophylactic rabies vaccine before the onset of illness. The best outcomes have been seen in patients infected with bat viruses, which appear to be less virulent for humans than strains associated with other rabies vectors. In 2003, an article by rabies experts suggested that survival might be improved through a combination of vaccine, anti-rabies immunoglobulin, antiviral drugs and the anesthetic ketamine, which had shown benefit in an animal model. One year later, a girl in Milwaukee who developed rabies after bat exposure was treated with some of these measures, plus a drug-induced (therapeutic) coma, and survived her illness with mild neurologic sequelae. Although the positive outcome in this case has been attributed to the treatment regimen, it more likely reflects the patient’s own brisk immune response, as anti-rabies virus antibodies were detected at the time of hospital admission, even though she had not been vaccinated. This conclusion is supported by the failure of the “Milwaukee Protocol” to prevent death in numerous subsequent cases. Use of this protocol should therefore be discontinued. Future research should focus on the use of animal models to improve understanding of the pathogenesis of rabies and for the development of new therapeutic approaches.

Highlights

► Rabies can be effectively prevented after recognized exposures. ► Human rabies is virtually always fatal. ► There is no known effective therapy for rabies. ► The Milwaukee Protocol lacks scientific rationale and efficacy for rabies therapy. ► A better understanding of rabies pathogenesis is needed to develop novel therapies.

Introduction

Rabies is the most severe acute viral infection of humans, with a case fatality rate of almost 100%. Although the prompt administration of rabies vaccine and rabies immune globulin after a dog bite or other recognized exposure can reliably prevent the disease, no effective measures have been identified to rescue a patient who has developed signs of illness. The past decade has seen intense interest in the treatment of rabies, in large part because of the survival of a young patient who was treated with a combination of drugs, including the induction of “therapeutic coma” (Willoughby et al., 2005). Unfortunately, numerous subsequent applications of this approach have failed to achieve success. This paper reviews the current status of rabies therapy and identifies promising directions for future research.

Section snippets

Rabies virus and the disease

Rabies is usually caused by infection with rabies virus, a single-stranded, negative-sense RNA virus in the genus Lyssavirus, family Rhabdoviridae; only very rarely is rabies caused by other non-rabies virus lyssaviruses (e.g., Duvenhage virus). Rabies is an acute viral infection of the central nervous system (CNS) that is transmitted by biting animals. Worldwide, most cases of human rabies occur in Africa and Asia as a result of exposure to dogs in rabies-endemic areas. In contrast, most cases

How does postexposure prophylaxis prevent rabies?

Rabies can be effectively prevented after a recognized exposure through postexposure prophylaxis (PEP), providing current recommendations are followed closely (Manning et al., 2008, World Health Organization, 2005). PEP consists of immediate wound cleansing, active immunization with multiple doses of rabies vaccine, and passive immunization with human rabies immune globulin, injected into and around the wound and intramuscularly. The objective of PEP is to prevent rabies virus from gaining

Why is the prognosis so poor in human rabies?

In contrast to rabies, acute encephalomyelitis caused by West Nile virus, Japanese encephalitis virus and other arboviruses has a lower case fatality rate, though survivors often have severe neurological sequelae (Jackson, 2013b). Because viral clearance from the CNS is essential for recovery, immunocompromised patients tend to develop more severe disease. Neutralizing anti-rabies virus antibodies are thought to be the critical mediator of the immune response in rabies, and there is evidence

Approaches to the therapy of rabies: the “Milwaukee protocol”

In 2003, a group of physicians and researchers with expertise in rabies published an article describing a variety of potential therapies, including rabies vaccination, rabies immune globulin, ribavirin, interferon-α and ketamine (Jackson et al., 2003). Because combination therapies have shown success in the treatment of cancer and a variety of infectious diseases, including human immunodeficiency virus infection and chronic hepatitis C, the authors suggested a similar approach to rabies. The

The way forward

There is an obvious need to re-assess clinical approaches to the treatment of rabies. First, it must be recognized that any aggressive approach to rabies therapy will require the full resources of a critical care unit, with access to medical specialists, and that it will have a high probability of failure. The following should be considered “favorable” factors for initiating aggressive therapy:

  • •

    administration of rabies vaccine prior to the onset of illness;

  • •

    young age, good baseline health and

The role of antiviral therapy

Antiviral drugs, which aim to inhibit viral replication and spread, are a logical component of combination therapy for rabies. However, ribavirin and interferon-α are the main currently available agents with known activity against rabies virus, and studies of their efficacy have been very limited (Jackson et al., 2003). Ribavirin inhibited rabies virus in vitro (Bussereau et al., 1983, Bussereau and Ermine, 1983), but it was not effective in laboratory animals (Bussereau et al., 1988), and a

The role of neuroprotective therapies

Treatments are needed to prevent neuronal damage in human rabies, but effective therapies to reduce neuronal injury for acute neurological diseases are currently very limited. A “trial and error” approach to finding an effective treatment is unlikely to succeed. In the case of acute stroke, numerous clinical trials have shown a lack of efficacy of candidate neuroprotective drugs, despite promising studies in animal models (Sutherland et al., 2012).

One approach that has proven effective in

Challenges of studying rabies therapy in laboratory animals and humans

The evaluation of potential therapies for human rabies in laboratory animals is expected to be very challenging. Even the best animal model cannot replicate the management of critically ill patients, which require a variety of resources, including the expertise of multiple specialists, readily available diagnostic investigations, therapies for a wide range of potential systemic complications, and around-the-clock care. A veterinary critical care setting would be the most appropriate setting for

Conclusion

New approaches are needed for the treatment of rabies, which may combine hypothermia, antiviral drugs, and other therapeutic agents. Much work is needed to identify new therapies, which will require a better understanding of basic mechanisms involved in the pathogenesis of rabies.

References (87)

  • M. Lafon

    Bat rabies – the Achilles heel of a viral killer?

    Lancet

    (2005)
  • M. Lafon

    Immunology

  • P. Leyssen et al.

    Molecular strategies to inhibit the replication of RNA viruses

    Antiviral Res.

    (2008)
  • S.N. Madhusudana et al.

    Partial recovery from rabies in a six-year-old girl (Letter)

    Int. J. Infect. Dis.

    (2002)
  • B. Oberg

    Rational design of polymerase inhibitors as antiviral drugs

    Antiviral Res.

    (2006)
  • K.B. Spurgers et al.

    Oligonucleotide antiviral therapeutics: antisense and RNA interference for highly pathogenic RNA viruses

    Antiviral Res.

    (2008)
  • L. Alvarez et al.

    Partial recovery from rabies in a nine-year-old boy

    Pediatr. Infect. Dis. J.

    (1994)
  • A. Aramburo et al.

    Failure of the Milwaukee protocol in a child with rabies

    Clin. Infect. Dis.

    (2011)
  • R. Badillo et al.

    Human rabies encephalitis by a vampire bat bite in an urban area of Colombia (Spanish)

    Biomédica

    (2009)
  • S. Bagchi

    Coma Therapy

    (2005)
  • S.A. Bernard et al.

    Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia

    N. Engl. J. Med.

    (2002)
  • D. Black et al.

    Survey of raccoon hunters for rabies antibody titers: pilot study

    J. Fla Med. Assoc.

    (1986)
  • J.D. Blanton et al.

    Rabies surveillance in the United States during 2009

    J. Am. Vet. Med. Assoc.

    (2010)
  • H. Branswell

    Testing Suggests Toronto Rabies Case Infected in Dominican Republic

    (2012)
  • F. Bussereau et al.

    Treatment of rabies in mice and foxes with antiviral compounds

    Acta Virol.

    (1988)
  • M. Castren et al.

    Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness)

    Circulation

    (2010)
  • J.C. Christenson et al.

    Human rabies–Indiana and California, 2006

    MMWR

    (2007)
  • E. Christian et al.

    A review of selective hypothermia in the management of traumatic brain injury

    Neurosurg. Focus

    (2008)
  • J. Claassen et al.

    Emergency neurological life support: status epilepticus

    Neurocrit. Care

    (2012)
  • B. Dietzschold et al.

    Delineation of putative mechanisms involved in antibody-mediated clearance of rabies virus from the central nervous system

    Proc. Natl. Acad. Sci. USA

    (1992)
  • Drosten, C., 2007. Rabies – Germany (Hamburg) ex Morocco. ProMED-mail 20070419.1287. Available from:...
  • A.T. Gilbert et al.

    Evidence of rabies virus exposure among humans in the Peruvian Amazon

    Am. J. Trop. Med. Hyg.

    (2012)
  • D.M. Greer et al.

    Case records of the Massachusetts general hospital: Case 1–2013: a 63-year-old man with paresthesias and difficulty swallowing

    N. Engl. J. Med.

    (2013)
  • M.A.W. Hattwick et al.

    Recovery from rabies: a case report

    Ann. Intern. Med.

    (1972)
  • T. Hemachudha et al.

    Failure of therapeutic coma and ketamine for therapy of human rabies

    J. Neurovirol.

    (2006)
  • G. Holzmann-Pazgal et al.

    Presumptive abortive human rabies – Texas, 2009

    MMWR

    (2010)
  • Houston Chronicle, 2006. Rabies, human – USA (Texas). ProMED-mail 20060513.1360. Available from:...
  • W.T. Hu et al.

    Long-term follow-up after treatment of rabies by induction of coma (Letter)

    N. Engl. J. Med.

    (2007)
  • M. Hunter et al.

    Immunovirological correlates in human rabies treated with therapeutic coma

    J. Med. Virol.

    (2010)
  • IAfrica.com, 2012. Rabies – South Africa (03): (Kwazulu-Natal), human ex Mozambique. ProMED-mail 20120608.1160328....
  • A.C. Jackson

    Recovery from rabies (Editorial)

    N. Engl. J. Med.

    (2005)
  • A.C. Jackson

    Therapy of Human Rabies

  • Jackson, A. C., 2013b. Viral infections of the human nervous system. Basel, Springer Basel. Birkhäuser Advances in...

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