RABIES

RABIES

Current Diagnosis

• A history of animal bite or exposure is often absent in North America.

• Pain, paresthesias, and pruritus are early neurologic symptoms of rabies, probably reflecting infection in local sensory ganglia.

•   Autonomic features are common.

•   Hydrophobia is a highly specific feature of rabies.

• Paralytic features may be prominent, and the clinical presentation can resemble that of Guillain-Barré syndrome.

• Saliva samples for reverse transcription polymerase chain reaction (RT-PCR) and a skin biopsy should be obtained to detect rabies virus antigen in order to make a laboratory diagnosis of rabies.

Current Therapy

• Details of an exposure determine whether postexposure rabies prophylaxis should be initiated.

•   Wound cleansing is important after potential rabies exposure.

• Active immunization with a schedule of four doses of rabies vaccine (RabAvert or Imovax) at intervals is recommended. Four doses is a new Centers for Disease Control and Prevention (CDC) recommendation and is not yet reflected in the package insert, which calls for five doses.

• Passive immunization (if previously the patient was not immunized) consists of infiltrating human rabies immune globulin (HyperRAB, Imogam Rabies) into the wound, with the remainder of the 20 IU/kg dosage given intramuscularly.

Rabies is an acute infection of the nervous system caused by rabies virus, which is a member of the family Rhabdoviridae in the genus Lyssavirus. Other lyssaviruses have only very rarely caused rabies in locations outside of the Americas.

Pathogenesis

Rabies virus is usually transmitted by bites from rabid animals. Transmission has rarely occurred through an aerosol route (in a laboratory accident or bat cave containing millions of bats) or by transplantation of infected organs or tissues (e.g., corneas). The virus is in the saliva of the rabid animal and is inoculated into subcutaneous tissues or muscles via a bite.

During most of the long incubation period (lasting 20–90 days or longer), the virus is close to the site of inoculation. The virus binds to the nicotinic acetylcholine receptor at the postsynaptic neuromuscular junction and travels toward the central nervous system (CNS) in peripheral nerves by retrograde fast axonal transport. There is rapid dissemination throughout the CNS by fast axonal transport. Under natural conditions, degenerative neuronal changes are not prominent, and it is thought that the rabies virus induces neuronal dysfunction by mechanisms that are not well understood. In rabies vectors, the encephalitis is associated with behavioral changes that lead to transmission by biting. After the CNS infection is established, the virus spreads by autonomic and sensory nerves to multiple organs, including the salivary glands of rabies vectors in which the virus is secreted in saliva.

Clinical Features

In North America, where the bat is the most common rabies vector, a history of an animal bite is usually absent, and there may be no known contact with animals. The incubation period is usually between 20 and 90 days, but it occasionally lasts 1 year or longer.

Prodromal features are nonspecific and include malaise, headache, and fever, and patients can also have anxiety or agitation.

Approximately half of patients experience pain, paresthesias, or pruritus at the site of the wound, which has often healed, and these symptoms likely reflect infection and inflammation involving local sensory ganglia. Approximately 80% of patients with rabies have encephalitic rabies; approximately 20% have paralytic rabies.

In encephalitic rabies, there are characteristic periods of generalized arousal or hyperexcitability separated by lucid periods. Autonomic dysfunction is common and includes hypersalivation, gooseflesh, cardiac arrhythmias, and priapism. Hydrophobia is the most characteristic feature of rabies and occurs in 50% to 80% of patients; contractions of the diaphragm and other inspiratory muscles occur on swallowing. This can become a conditioned reflex, and even the sight or thought of water can precipitate the muscle contractions.

Hydrophobia is thought to be caused by inhibition of inspiratory neurons near the nucleus ambiguus.

In paralytic rabies, prominent muscle weakness usually begins in the bitten extremity and progresses to quadriparesis; typically there is sphincter involvement. Patients have a longer clinical course than in encephalitic rabies. Paralytic rabies is often misdiagnosed as Guillain- Barré syndrome.

Coma subsequently develops in both clinical forms. With aggressive medical therapy, a variety of medical complications develop, and multiple organ failure is common. Survival is very rare and has usually occurred in the context of incomplete postexposure rabies prophylaxis that included administration of one or more doses of rabies vaccine.

Epidemiology

Worldwide about 60,000 human deaths per year are attributed to rabies. The impact is particularly significant in terms of years of life lost because children are commonly the victims. Most human rabies cases occur through transmission from dogs in developing countries with endemic dog rabies, particularly in Asia and Africa. In the United States and Canada, transmission of rabies virus occurs most commonly in human cases from insect-eating bats, and often there is no known history of a bat bite or exposure to bats. A bat bite might not be recognized. The rabies virus variant responsible for most human cases is found in silver-haired bats and tricolored bats. These are small bats not often in contact with humans. Other rabies vectors in North American wildlife include skunks, raccoons, and foxes, but these species are rarely responsible for transmission to humans. This is likely because of effective postexposure rabies prophylaxis.

Diagnosis

Most cases of rabies can be diagnosed clinically or the diagnosis will be strongly suspected, which is particularly important so that appropriate barrier nursing techniques can be initiated in order to prevent exposures of many health care workers. Some patients are candidates for an aggressive therapeutic approach. A serum- neutralizing titer can be useful for diagnosis in a previously unimmunized person, but a positive titer might not develop until the second week of clinical illness, and the result of the test might not be readily available. Detection of rabies virus antigen in a skin biopsy obtained from the nape of the neck using a fluorescent antibody technique is a useful diagnostic test. Detection of rabies virus ribonucleic acid (RNA) in saliva or in skin biopsies using RT-PCR amplification is an important recent advance for rapid rabies diagnosis. Rabies virus antigen can be detected in brain tissue obtained by brain biopsy or postmortem.

Prevention

After a rabies exposure is recognized, rabies can be prevented with initiation of appropriate steps, including wound cleansing and active and passive immunization. After a human is bitten by a dog, cat, or ferret, the animal should be captured, confined, and observed for a period of at least 10 days; initiation of postexposure rabies prophylaxis is not necessary if the animal remains healthy. The animal should also be examined by a veterinarian prior to its release. If the animal is a stray, unwanted, shows signs of rabies, or develops signs of rabies during the observation period, the animal should be killed immediately, and its head should be transported under refrigeration for a laboratory examination. The brain should be examined via an antigen-detection method using the fluorescent antibody technique and viral isolation using cell culture or mouse inoculation.

The incubation period for animals other than dogs, cats, and ferrets is uncertain; these animals should be killed immediately after an exposure, and the head should be submitted for examination. If the result is negative, one may safely conclude that the animal’s saliva did not contain rabies virus; if immunization has been initiated, it should be discontinued. If an animal escapes after an exposure, it should be considered rabid unless information from public health officials indicates this is unlikely, and rabies prophylaxis should be initiated.

The physical presence of a bat might warrant postexposure prophylaxis when a person (such as a small child or sleeping adult) is unable to reliably report contact that could have resulted in a bite.

Local wound care should be given as soon as possible after all exposures, even if immunization is delayed, pending the results of an observation period. All bite wounds and scratches should be washed thoroughly with soap and water. Devitalized tissues should be débrided.

Purified chick embryo cell culture vaccine (RabAvert) and human diploid cell vaccine (Imovax) are licensed rabies vaccines in the United States and Canada. Other vaccines grown in either primary cell lines (hamster or dog kidney) or continuous cell lines (Vero cells) are also satisfactory and available in other countries. A regimen of four 1-mL doses of rabies vaccine should be given IM in the deltoid area (anterolateral aspect of the thigh is also acceptable in children). Four doses is a recent CDC recommendation and is an update from the five doses recommended in the current package insert. Ideally, the first dose should be given as soon as possible after exposure, but failing that, it should be given regardless of the length of a delay.

Three additional doses should be given on days 3, 7, and 14. Pregnancy is not a contraindication for immunization. Live vaccines should not be given for 1 month after rabies immunization.

Local and mild systemic reactions are common. Systemic allergic reactions are uncommon, and anaphylactic reactions may be treated with epinephrine and antihistamines. Corticosteroids can interfere with the development of active immunity. Immunosuppressive medications should not be administered during postexposure therapy unless they are essential. The risk of developing rabies should be carefully considered before deciding to discontinue vaccination because of an adverse reaction. A serum-neutralizing antibody determination is necessary only after immunization of immunocompromised patients. Less-expensive vaccines derived from neural tissues are still used in some developing countries; these vaccines are associated with serious neuroparalytic complications.

Human rabies immune globulin (Imogam Rabies or HyperRAB) should also be administered as passive immunization for protection before the development of immunity from the vaccine. It should be given at the same time as the first dose of vaccine and no later than 7 days after the first dose. Rabies vaccine and human rabies immune globulin should never be administered at the same site or in the same syringe. The recommended dose of human rabies immune globulin is 20 IU/kg; larger doses should not be given because they can suppress active immunity from the vaccine. After wounds are washed, they should be infiltrated with human rabies immune globulin (if anatomically feasible), and the remainder of the dose should be given IM in the gluteal area. If the exposure involves a mucous membrane, the entire dose should be administered IM. With multiple or large wounds, the human rabies immune globulin might need to be diluted for adequate infiltration of all of the wounds. Adverse effects of human rabies immune globulin include local pain and low-grade fever.

After an exposure, a previously immunized patient should receive two 1-mL doses of rabies vaccine on days 0 and 3, but the patient should not receive human rabies immune globulin.

Management of Human Rabies

Only 15 people have survived rabies, and 14 received rabies vaccine prior to the onset of their disease. The possibilities for an aggressive approach were reviewed (see Jackson et al., 2003). There was one survivor in Wisconsin in 2004 who did not receive rabies vaccine. It is now doubtful whether the therapy she received played a significant role in her favorable outcome because a similar approach has failed in many cases (see Jackson, 2013). Palliation is an alternative approach and may be appropriate for many patients who develop rabies.

References

1.     Fooks A.R., Banyard A.C., Horton D.L., et al. Current status of rabies and prospects for elimination. Lancet. 2014;384:1389– 1399.

2.    Jackson A.C. Human disease. In: Jackson A.C., ed. Rabies: scientific basis of the disease and its management. 3rd ed. Oxford, UK: Elsevier Academic Press; 2013:269–298.

3.     Jackson A.C. Human rabies: a 2016 update. Curr Infect Dis Rep. 2016;18:38.

4.    Jackson A.C. Current and future approaches to the therapy of human rabies. Antiviral Res. 2013;99:61–67.

5.     Jackson A.C., Warrell M.J., Rupprecht C.E., et al. Management of rabies in humans. Clin Infect Dis. 2003;36:60–63.

6.      Jackson A.C. Rabies: scientific basis of the disease and its management. 3rd ed. Oxford, UK: Elsevier Academic Press; 2013.

7.    Manning S.E., Rupprecht C.E., Fishbein D., et al. Human rabies prevention—United States, 2008: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2008;57(RR-3):1–28.

8.    World Health Organization. WHO expert consultation on rabies. Second report, WHO Technical Report Series 982. Geneva: WHO; 2013.

9.       Zeiler F.A., Jackson A.C. Critical appraisal of the Milwaukee protocol for rabies: this failed approach should be abandoned. Can J Neurol Sci. 2016;43:44–51.

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