Rabies

Infectious Agents

Rabies is a fatal, acute, progressive encephalomyelitis caused by neurotropic viruses in the family Rhabdoviridae, genus Lyssavirus . Numerous and diverse variants of lyssaviruses are found in a wide variety of animal species throughout the world, all of which may cause fatal human rabies. Rabies virus is by far the most common lyssavirus infection of humans. Tens of millions of potential human exposures and tens of thousands of deaths from rabies virus occur each year.

Transmission

The normal and most successful mode of transmission is inoculation of saliva from the bite of a rabid animal. Clinical signs of rabies in an animal are not always obvious because of the broad spectrum of disease manifestations. Rabies virus is neurotropic and gains access to the peripheral nervous system by being taken up at a nerve synapse at the site of the bite. The virus travels through peripheral nerves to the central nervous system before traveling back out through the peripheral nervous system. After reaching the salivary glands, virus can be secreted allowing the transmission cycle to repeat. Exposure of rabies virus to highly innervated tissue may increase the risk of successful infection. In addition to saliva, rabies virus may also be found in nervous tissues (central and peripheral) and tears. Infection from nonbite exposures, such as organ transplantation from infected humans, does occur.

All mammals are believed to be susceptible to infection, but major rabies reservoirs are terrestrial carnivores and bats. Although dogs are the main reservoir in developing countries, the epidemiology of the disease differs from one region or country to another. All patients with mammal bites should be medically evaluated. Bat bites anywhere in the world are a cause of concern and an indication to consider prophylaxis.

Epidemiology

Lyssaviruses, the causative agent for the disease rabies, have been found on all continents except Antarctica. Rabies virus is classified into 2 major genetic lineages: canine and New World bat. These 2 lineages can be further classified into rabies virus variants based on the reservoir species in which they circulate. Regionally, different viral variants are adapted to various mammalian hosts and perpetuate in dogs and wildlife, such as bats, foxes, jackals, mongooses, raccoons, and skunks. Canine rabies remains enzootic in many areas of the world, including Africa, Asia, and parts of Central and South America.

Timely and specific information about the global occurrence of rabies is often difficult to find. Surveillance levels vary, and reporting status can change suddenly as a result of disease reintroduction or emergence. The rate of rabies exposures in travelers is at best an estimate and may range from 16 to 200 per 100,000 travelers.

Clinical Presentation

Clinical illness in humans begins following invasion of the peripheral and then central nervous system and culminates in acute fatal encephalitis. After infection the asymptomatic incubation period is variable, but signs and symptoms most commonly develop within several weeks to several months after exposure. Pain and paresthesia at the site of exposure are often the first symptoms of disease. The disease then progresses rapidly from a nonspecific, prodromal phase with fever and vague symptoms to an acute, progressive encephalitis. The neurologic phase may be characterized by anxiety, paresis, paralysis, and other signs of encephalitis; spasms of swallowing muscles can be stimulated by the sight, sound, or perception of water (hydrophobia); and delirium and convulsions can develop, followed rapidly by coma and death. Once clinical signs manifest, patients die quickly in the absence of intensive supportive care.

Diagnosis

The diagnosis may be relatively simple in a patient with a compatible history and a classic clinical presentation (Box 3-4). However, clinical suspicion and prioritization of differential diagnoses may be complicated by variations in clinical presentation and a lack of exposure history. The exposure history is difficult to elicit if the risk of exposure to rabies was not recognized, the exposure was not discussed with friends and family, and several weeks to months have elapsed since the exposure.

Definitive antemortem diagnosis requires high-complexity experimental test methods on multiple samples (such as serum, cerebrospinal fluid [CSF], saliva, and skin biopsy from the nape of the neck), which can be collected sequentially if initial testing is negative and clinical suspicion is high. Additional detailed information on diagnostic testing may be obtained from CDC (www.cdc.gov/rabies/specific_groups/doctors/ante_mortem.html). Rising levels of rabies virus–neutralizing antibodies, particularly in the CSF, is diagnostic in an unvaccinated, encephalitic patient. Rabies is a nationally notifiable disease.

Box 3-4. World Health Organization, human rabies case definition

Clinical case definition: a person presenting with an acute neurologic syndrome (encephalitis) dominated by forms of hyperactivity (furious rabies) or paralytic syndromes (dumb rabies) progressing towards coma and death, usually by respiratory failure, within 7–10 days after the first symptom if no intensive care is instituted.

Human rabies:

Suspected: A case that is compatible with the clinical case definition.

Probable: A suspected case plus history of contact with a suspected rabid animal.

Confirmed: A suspected case that is laboratory-confirmed.

Treatment

There is not yet an evidence-based “best practices” medical approach to treating patients with rabies; most patients are managed with symptomatic and palliative supportive care. An experimental approach, known as the Milwaukee protocol, involves inducing coma and treating with antiviral drugs, but it remains controversial. Rabies is still considered universally fatal for practical purposes, and preventive measures are the only way to optimize survival after a bite from a rabid animal.

Prevention

Rabies in travelers is best prevented by having a comprehensive strategy. This consists of (1) education about risks and the need to avoid bites from mammals, especially high-risk rabies reservoir species; (2) consultation with travel health professionals to determine if preexposure vaccination is recommended; (3) knowing how to prevent rabies after a bite; and (4) knowing how to obtain postexposure prophylaxis (PEP). The last may involve urgent importation of rabies biologics or international travel to where PEP is available. Travelers who have died of rabies either did not seek PEP or received inadequate care when they did.

Avoiding Animal Bites

Travelers to rabies-enzootic countries should be warned about the risk of rabies exposure and educated as to how to avoid animal bites. Travelers should avoid free-roaming mammals, avoid provoking domestic animals, and avoid contact with bats and other wildlife. Although nonhuman primates are rarely rabid, they are a common source of bites, mainly on the Indian subcontinent. In most instances these nonhuman primates cannot be followed up for rabies assessments, and the bite victims are recommended to receive PEP. Awareness of this risk and simple prevention is particularly effective. Travelers should be advised to not approach or otherwise interact with monkeys or carry food while monkeys are near, especially around monkeys that are habituated to tourists. Travelers should be educated to not handle bats or other wildlife and consider the need for personal protective equipment before entering caves where bats may be found, given the risk for exposures to rabies virus, histoplasmosis, Marburg virus (see Ebola Virus Disease and Marburg Virus Disease section this chapter), or other bat-associated pathogens. Many bats have tiny teeth, and wounds may not be readily apparent. Any suspected or documented bite or wound from a bat should be grounds for seeking PEP.

Children are at higher risk for rabies exposure and subsequent illness because of their inquisitive nature and inability to read behavioral cues from dogs and other animals. The smaller stature of children makes them more likely to experience severe bites to high-risk areas, such as the face and head. Also contributing to the higher risk is their attraction to animals and the possibility that they may not report an exposure.

Preexposure Vaccination

Preexposure rabies vaccination may be recommended for certain international travelers based on the occurrence of animal rabies in the country of destination; the availability of antirabies biologics; the intended activities of the traveler, especially in remote areas; and the traveler’s duration of stay. A decision to receive preexposure rabies immunization may also be based on the likelihood of repeat travel to at-risk destinations or long-term travel to a high-risk destination. Preexposure vaccination may be recommended for veterinarians, animal handlers, field biologists, cavers, missionaries, and certain laboratory workers. Table 3-15 provides criteria for preexposure vaccination. Regardless of whether preexposure vaccine is administered, travelers going to areas where the risk of rabies is high should be encouraged to purchase medical evacuation insurance (see Chapter 2, Travel Insurance, Travel Health Insurance, & Medical Evacuation Insurance).

Table 3-15. Criteria for preexposure immunization for rabies
Risk CategoryNature of RiskTypical PopulationsPreexposure Regimen
Continuous
  • Virus present continuously, often in high concentrations
  • Specific exposures likely to go unrecognized
  • Bite, nonbite, or aerosol exposure
Rabies research laboratory workers, 1 rabies biologics production workersPrimary course; serologic testing every 6 months; booster vaccination if antibody titer is below acceptable level 2
Frequent
  • Exposure usually episodic with source recognized, but exposure might also be unrecognized
  • Bite, nonbite, or aerosol exposure possible
Rabies diagnostic laboratory workers, 1 cavers, veterinarians and staff, and animal-control and wildlife workers in areas where rabies is enzootic. All people who frequently handle bats.Primary course; serologic testing every 2 years; booster vaccination if antibody titer is below acceptable level 2
Infrequent (greater than general population)
  • Exposure nearly always episodic with source recognized
  • Bite or nonbite exposure
Veterinarians and animal control staff working with terrestrial carnivores in areas where rabies is uncommon to rare; veterinary students; and travelers visiting areas where rabies is enzootic and immediate access to medical care, including biologics, is limitedPrimary course; no serologic testing or booster vaccination
Rare (general population)
  • Exposure always episodic, with source recognized
  • Bite or nonbite exposure
US population at large, including people in rabies-epizootic areasNo preexposure immunization necessary
1 Judgment of relative risk and extra monitoring of vaccination status of laboratory workers are the responsibility of the laboratory supervisor (see www.cdc.gov/biosafety/publications/bmbl5 for more information).
2 Preexposure booster immunization consists of 1 dose of human diploid cell (rabies) vaccine or purified chick embryo cell vaccine, 1.0-mL dose, intramuscular (deltoid area). Per Advisory Committee on Immunization Practices recommendations, minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test, which is equivalent to approximately 0.1 IU/mL. A booster dose should be administered if titer falls below this level in populations that remain at risk.

In the United States, preexposure vaccination consists of a series of 3 intramuscular injections given on days 0, 7, and 21 or 28 in the deltoid with human diploid cell rabies vaccine (HDCV) or purified chick embryo cell (PCEC) vaccine (Table 3-16). Travelers should receive all 3 preexposure immunizations before travel. If 3 doses of rabies vaccine cannot be completed before travel, the traveler should not start the series, as few data exist to guide PEP after a partial immunization series.

Preexposure vaccination does not eliminate the need for additional medical attention after a rabies exposure, but it simplifies PEP. Preexposure vaccination may also provide some protection when an exposure to rabies virus is unrecognized or PEP might be delayed. Travelers who have completed a 3-dose preexposure rabies immunization series or have received full PEP are considered previously vaccinated and do not require routine boosters. Routine testing for rabies virus–neutralizing antibody is not recommended for international travelers who are not otherwise in the frequent or continuous risk categories (Table 3-15).

Table 3-16. Preexposure immunization for rabies 1
VaccineDose (mL)Number of DosesSchedule (Days) 2Route
HDCV, Imovax (Sanofi)1.030, 7, and 21 or 28IM
PCEC, RabAvert (Novartis)1.030, 7, and 21 or 28IM
Abbreviations: HDCV, human diploid cell vaccine; IM, intramuscular; PCEC, purified chick embryo cell.
1 Patients who are immunosuppressed by disease or medications should postpone preexposure vaccinations and consider avoiding activities for which rabies preexposure prophylaxis is indicated during the period of expected immunosuppression. If this is not possible, immunosuppressed people who are at risk for rabies should have their antibody titers checked after vaccination.
2 Every attempt should be made to adhere to recommended schedules; however, for most minor deviations (delays of a few days for individual doses), vaccination can be resumed as though the traveler were on schedule. If 3 doses of rabies vaccine cannot be completed before travel, the traveler should not start the series, as few data exist to guide PEP after a partial immunization series.

Wound Management

Any animal bite or scratch should be thoroughly cleaned with copious amounts of soap and water, povidone iodine, or other substances with virucidal activity. All travelers should be informed that immediately cleaning bite wounds as soon as possible substantially reduces the risk of rabies virus infection, especially when followed by timely administration of PEP. For unvaccinated patients, wounds that might require suturing should have the suturing delayed for a few days. If suturing is necessary to control bleeding or for functional or cosmetic reasons, rabies immune globulin (RIG) should be injected into all wounded tissues before suturing. The use of local anesthetic is not contraindicated in wound management.

Postexposure Prophylaxis

In Travelers Who Received Preexposure Vaccination

PEP for someone previously vaccinated consists of 2 doses of modern cell culture vaccine given on days 0 and 3 after the exposure. The booster doses do not have to be the same brand as the one in the original preexposure immunization series.

In Travelers Who Did Not Receive Preexposure Vaccination

PEP for an unvaccinated patient consists of administration of RIG (20 IU/kg for human RIG and 40 IU/kg for equine RIG) and a series of 4 injections of rabies vaccine over 14 days, or 5 doses over a 1-month period in immunosuppressed patients (Table 3-17). After wound cleansing, as much of the dose-appropriate volume of RIG (Table 3-17) as is anatomically feasible should be injected at the wound site. The intent is to put the RIG in the areas where saliva may have contaminated wounded tissue. If the wound is small and on a distal extremity such as a finger or toe, the health care provider must use clinical judgment to decide how much RIG to inject to avoid local tissue compression and complications. Any remaining dose should be administered intramuscularly at a site distant from the site of vaccine administration. If the wounds are extensive, the dose-appropriate volume of RIG must not be exceeded. If the volume is inadequate to inject all the wounds, the RIG may be diluted with normal saline to ensure sufficient volume to inject in all of the wounds. This is a particular issue in children whose body weight may be small in relation to the size and number of wounds.

Table 3-17. Postexposure immunization for rabies 1
Immunization StatusVaccine/ProductDoseNumber of DosesSchedule (Days) 2Route
Not previously vaccinatedRIG plus20 IU/kg body weight10Infiltrated at bite site (if possible); remainder IM
Not previously vaccinatedHDCV or PCEC1.0 mL4 30, 3, 7, 14 (28 if immunocompromised 4)IM
Previously vaccinated 5, 6HDCV or PCEC1.0 mL20, 3IM
Abbreviations: RIG, rabies immune globulin; IM, intramuscular; HDCV, human diploid cell vaccine; PCEC, purified chick embryo cell.
1 All postexposure prophylaxis should begin with immediate, thorough cleansing of all wounds with soap and water, povidone iodine, or other substances with virucidal activity.
2 Every attempt should be made to adhere to recommended schedules; however, for most minor deviations (delays of a few days for individual doses), vaccination can be resumed as though the traveler were on schedule. When substantial deviations occur, immune status should be assessed by serologic testing 7–14 days after the final dose is administered.
3 Five vaccine doses for the immunosuppressed patient. The first 4 vaccine doses are given on the same schedule as for an immunocompetent patient, and the fifth dose is given on day 28; patient follow-up should include monitoring antibody response. See www.cdc.gov/mmwr/preview/mmwrhtml/rr5902a1.htm for more information.
4 CDC recommends 4 postexposure vaccine doses, on days 0, 3, 7, and 14, unless the patient is immunocompromised in some way, in which case a fifth dose is given at day 28.
5 Preexposure immunization with HDCV or PCEC, prior postexposure prophylaxis with HDCV or PCEC, or people previously vaccinated with any other type of rabies vaccine and a documented history of positive rabies virus neutralizing antibody response to the prior vaccination.
6 RIG is not recommended.

RIG is difficult to access in many countries. If modern cell culture vaccine is available but access to RIG is delayed, the vaccine series should be started as soon as possible, and RIG may be added to the regimen up to and including day 7. After day 7, RIG is unlikely to provide benefit, as antibodies would be expected to be present from the patient’s own vaccine-derived immune response.

Because rabies virus can persist in tissue for a long time before invading a peripheral nerve, a traveler who has sustained a bite that is suspicious for rabies should receive full PEP, including RIG, even if a considerable length of time has passed since the initial exposure. If there is a scar, or the patient remembers where the bite occurred, an appropriate amount of RIG should be injected in that area.

Human RIG is manufactured by plasmapheresis of blood from hyperimmunized volunteers. The total quantity of commercially produced human RIG falls short of worldwide demand, and it is not available in many developing countries. Equine RIG or purified fractions of equine RIG may be available in some developing countries where human RIG might not be available. Such products are preferable to no RIG.

The incidence of adverse events after the use of modern equine-derived RIG is low (0.8%–6.0%), and most reactions are minor. However, such products are not regulated by the Food and Drug Administration, and their use cannot be recommended unequivocally. In addition, unpurified antirabies serum of equine origin might still be used in some countries where neither human nor equine RIG is available. The use of this antirabies serum is associated with higher rates of serious adverse reactions, including anaphylaxis and serum sickness.

Different PEP schedules, alternative routes of administration, and other rabies vaccines besides HDCV and PCEC may be used abroad. For example, commercially available purified Vero cell rabies vaccine and purified duck embryo cell vaccine are acceptable alternatives if available. However, other rabies vaccines or PEP regimens might require additional prophylaxis or confirmation of adequate rabies virus neutralizing antibody titers. Assistance in managing complicated PEP scenarios can be obtained from experienced travel medicine professionals, health departments, and CDC.

Rabies vaccine was once manufactured from viruses grown in animal brains, and some of these vaccines are still in use in developing countries. Typically, the brain-derived vaccines, also known as nerve tissue vaccines, can be identified if the traveler is offered a large-volume injection (5 mL) daily for approximately 14–21 days. Because of variability of potency in these preparations, which may limit effectiveness, and the risk of adverse reactions, the traveler should not accept these vaccines but travel to a location where acceptable vaccines and RIG are available.

Rabies Vaccine

Vaccine Safety and Adverse Reactions

Travelers should be advised that they may experience local reactions after vaccination such as pain, erythema, swelling, or itching at the injection site, or mild systemic reactions such as headache, nausea, abdominal pain, muscle aches, and dizziness. Approximately 6% of people receiving booster vaccinations with HDCV may experience systemic hypersensitivity reactions characterized by urticaria, pruritus, and malaise. The likelihood of these reactions may be less with PCEC. Once initiated, rabies PEP should not be interrupted or discontinued because of local or mild systemic reactions to rabies vaccine. If an adverse event occurs with one of the vaccine types, consider switching to the alternative vaccine for the remainder of the series.

Precautions and Contraindications

Pregnancy is not a contraindication to PEP. In infants and children, the dose of HDCV or PCEC for preexposure or PEP is the same as that recommended for adults. The dose of RIG for PEP is based on body weight (Table 3-17).

CDC website: www.cdc.gov/rabies

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Authors

Brett W. Petersen, Ryan M. Wallace, David R. Shlim