Rabies

Introduction

Infectious agent

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

Transmission

The normal and most successful mode of rabies virus transmission is via the bite of a rabid animal. Rabies virus is neurotropic; it gains access to the nervous system through exposed peripheral nerve synapses after inoculation, most often through bite wounds. The virus travels from its point of entry within peripheral nerves to the central nervous system (CNS), where viral replication increases exponentially. Rabies virus then migrates from the CNS back to the peripheral nervous system (PNS) into, among other innervated tissues, the salivary glands. Rabies virus secreted in saliva allows the transmission cycle to repeat. Viral shedding typically occurs just days prior to onset of clinical signs in infected animals and humans; early clinical signs in the animal can be non-specific. In the context of foreign travel, any bite or scratch exposure from a mammal that is not available for observation and is consistent with the World Health Organization's (WHO's) case definition for a suspected rabid animal should lead to rabies post-exposure prophylaxis (Box 4.15.1). International health agencies have only established observation periods for dogs, cats, and ferrets. In those animals, an animal that stays healthy for 10 days after the exposure event is considered not to have been infectious for rabies at the time of the exposure. Observation is rarely an option in the context of foreign travel, and it is common that post-exposure prophylaxis (PEP) is administered out of an abundance of caution.

Exposure of highly innervated tissues (e.g., those in the face and hands) can increase the risk for successful infection, and exposures occurring closer to the CNS (e.g., head, neck) can potentially shorten the incubation period. In addition to saliva, rabies virus can be found in CNS and PNS tissue, and in tears. Infection from non-bite exposures (e.g., organ and innervated tissue transplantation from infected humans) has occurred, but human-to-human transmission generally does not occur.

All mammals are believed to be susceptible to rabies virus infection. Bats are capable of transmitting rabies in any destination. Dogs are the main reservoir in many low- and middle-income countries. Controversy exists as to the risk of bites from rodents. Rabies has been documented in rats in Thailand that have bitten humans. In general, rodents are thought to not transmit rabies because of the feeling that if a rodent were bitten by a large carnivore, it would likely die from its wound. Bites from rodents, while traveling, would require individual assessment as to whether rabies PEP is required.

Box 4.15.1

Notes

Adapted from: World Health Organization. (2018). WHO Expert Consultation on Rabies: Third Report. https://www.who.int/iris/handle/10665/272364.

Epidemiology

Lyssaviruses, the causative agents for 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 genetic differentiations, geographic extent, and the reservoir species in which they circulate. Regionally, different viral variants are adapted to various mammalian hosts and perpetuate in dogs and wildlife (e.g., bats, foxes, jackals, mongooses, raccoons, skunks).

Dog-maintained rabies virus variants remain enzootic in many areas of the world, including Africa, parts of Central and South America, and Asia. In addition to rabies virus, the Lyssavirus genus includes 16 other viruses that cause rabies disease. Non-rabies lyssaviruses are found in Africa, Asia, Australia, and Europe; while several non-rabies lyssaviruses have caused human deaths, these viruses contribute relatively little to the global rabies burden compared to rabies virus.

Timely and specific information about the global occurrence of rabies is often difficult to find. Surveillance levels vary, and reporting status can change suddenly because of disease reintroduction, emergence, or disruptions in surveillance operations. The rate of rabies exposures in travelers is an estimate, at best, and might range from 16 to 200 exposures per 100,000 travelers. Reported deaths from rabies in travelers average about 2 travelers per year worldwide.

Clinical presentation

After viral invasion of the PNS and then CNS, clinical illness in humans culminates in an acute, fatal encephalitis. After infection, the asymptomatic incubation period is variable, but signs and symptoms most commonly develop within several weeks to 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 prodromal phase (fever and non-specific symptoms) to a neurologic phase characterized by anxiety, paralysis, paresis, and other signs of encephalitis. Swallowing muscle spasm can be stimulated by the sight, sound, or perception of water (hydrophobia). Early clinical signs often present as autonomic dysfunction, resulting from infection of the autonomic nervous system. At least 1 traveler underwent cardiac catheterization because a cardiac etiology rather than rabies was initially suspected. Delirium and convulsions can develop, followed soon thereafter by coma and death.

Most rabies cases detected by healthcare systems are in people with classic encephalitic disease in which fever, hydrophobia, hyperactivity, or spasms eventually progress to paralysis and coma; this progression corresponds to "furious" rabies in animals. Paralytic rabies is less commonly diagnosed, and patients typically present with paralysis at the site of exposure, which then progresses as an ascending paralysis, ultimately leading to coma; this is the equivalent of paralytic or "dumb" rabies in animals. Once clinical signs appear, patients die quickly in the absence of intensive supportive care.

Diagnosis

Diagnosis can be made in a patient with a compatible exposure history and a classic clinical presentation (Box 4.15.2). Clinical suspicion and prioritization of differential diagnoses can be complicated by variations in clinical presentation and a lack of exposure history. Because several weeks to months could have elapsed since exposure, and an accurate exposure history can be difficult to elicit in a patient exhibiting signs of rabies, patients might not reveal potential rabies virus exposures, and healthcare professionals might not initially consider the possibility. As a result, rabies diagnosis in the United States is almost always missed at the first clinical encounter.

Definitive antemortem diagnosis requires use of specialized diagnostic methods on multiple specimens, including cerebrospinal fluid (CSF), saliva, serum, and skin biopsies taken from the nape of the neck. Because the probability of virus and antibody detection varies over the course of illness, sequential sample collection is indicated if initial testing is negative but clinical suspicion remains high. Finding rabies virus antigen or nucleic acid in any antemortem sample confirms the diagnosis. Finding rabies virus antibody in CSF also confirms the diagnosis, whereas antibody in serum could indicate either infection, previous vaccination, or recent administration of rabies antibody-containing products (e.g., RIG [rabies immune globulin], intravenous immunoglobulin [IVIG]).

A thorough review of all medical care provided to patients prior to sample collection is necessary to correctly interpret some diagnostic test results. Recent reports, for example, have described how human-derived products (e.g., IVIG) administered to patients can be a passive source of high concentrations of donor-derived rabies lyssavirus-antibodies (RLAs); in the absence of an accurate history of recent IVIG administration, finding RLAs in serum can incorrectly suggest a diagnosis of rabies. In unvaccinated encephalitic patients, however, the presence of rabies virus antibodies (particularly in CSF samples) confirms the diagnosis (see more information on diagnostic testing).

Rabies is a nationally notifiable disease. The Centers for Disease Control and Prevention (CDC) is designated as the national rabies reference laboratory for the United States, along with the WHO Collaborating Center for Rabies and the World Organisation for Animal Health Rabies Reference Laboratory. In this capacity, CDC performs public health testing for domestic and international health agencies, for both human and animal rabies diagnoses. Healthcare professionals submitting samples to CDC for rabies testing must first consult with program staff, obtain approval, and complete the requisite paperwork (see step-by-step instructions).

Box 4.15.2

Notes

Adapted from: World Health Organization. (2018). WHO Expert Consultation on Rabies: Third Report. https://www.who.int/iris/handle/10665/272364.

Treatment

No evidence-based approach to treating rabies patients is available. Most cases are managed with symptomatic and palliative supportive care. Survival after the clinical phase of rabies virus infection is incredibly rare, but case reports continue to provide insight into potential therapeutic options, and experimental treatment regimens continue to be investigated. To date, early and robust production of rabies virus-neutralizing antibodies has been the primary factor associated with rare reports of survival. Rabies is still considered universally fatal for practical purposes; avoiding rabies virus exposures remains the most important prevention measure. For those who are (or who suspect they might have been) exposed to a rabid animal, urgently taking the other prevention measures described below is the only way to optimize survival.

Prevention

Travelers can best prevent rabies by learning about infection risks and the need to avoid bites and scratches from mammals, especially high-risk rabies reservoir species; consulting with travel health professionals to determine whether pre-exposure vaccination is recommended; knowing how to prevent rabies after a bite; and knowing how to obtain PEP, which might involve urgent importation of rabies biologics or travel to somewhere PEP is available. If infected, not seeking PEP or receiving inadequate care likely will result in death from rabies.

Avoid animal exposures

Avoiding bites is truly the best prevention measure for rabies. Traumatic bites that deeply puncture skin are the greatest risk for rabies transmission; however, even low-trauma events such as "nips" from young animals or bites from bats can lead to rabies deaths. While scratches are a lower risk for transmission compared to bites, scratches that break skin can be contaminated by rabies-laden saliva and are a potential route for rabies transmission. Although rabies can be completely prevented by appropriate post-exposure care, obtaining that care and worrying about its effectiveness can be nerve-wracking for patients. Warn travelers going to rabies-enzootic countries about the risks for rabies exposure. Counsel them to stay away from unfamiliar mammals, including puppies and kittens, and to avoid contact with bats and other wildlife.

Children are at greater 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 a child's stature, the more likely they are to experience severe bites to high-risk areas (e.g., the head and face). Also contributing to the higher risk for children is their attraction to animals and the possibility that they might not report an exposure.

Bats and other wildlife

Besides rabies virus, other bat-associated pathogens include Histoplasma spp., coronaviruses, and viral hemorrhagic fever viruses (see Zoonotic Exposures: Bites, Scratches, and Other Hazards chapter). Educate travelers to avoid handling bats or other wildlife and to consider using personal protective equipment before entering caves where bats are found. Many bats have tiny teeth, and the wounds they inflict might not be readily apparent. If a bat has had contact with bare skin or has gotten caught up in one's hair, a potential bite should be suspected. Failure to find the tiny bite wound has led to rabies deaths in a few people. Warn travelers that any contact with a bat on bare skin or in the hair should be grounds for seeking PEP.

Dogs

In many low- and middle-income countries, dogs roam freely; encourage travelers to remain vigilant of unfamiliar dogs and to avoid physical contact, when possible. Inadvertently approaching puppies when the mother is near, stepping on sleeping dogs, walking into dogs, or getting too close to dogs fighting or protecting food sources can provoke biting behavior. Travelers that encounter an unfamiliar dog that is showing aggression should avoid direct eye contact, attempt to remain still, and slowly back away; shouting, erratic movements, or reciprocal aggression is likely to provoke a bite from the dog.

Travelers bitten by a dog once are almost never bitten a second time, validating the observation that with proper awareness, bites can be avoided. Scanning for dogs on the street can become second nature for experienced travelers and expatriates. Knowledgeable travelers (even those never bitten) can travel for decades without ever having a dog bite.

Cats

While cats are not a reservoir for rabies virus, rabid cats are often reported from rabies-enzootic countries. Due to ecological and behavioral traits, cats have an increased risk of interacting with rabid wildlife (particularly bats) and dogs. Like dogs, cats commonly roam freely and can become aggressive if approached. An increasing, yet small, number of human rabies deaths due to cat bites and scratches have been reported in recent years. Bites and scratches from unfamiliar cats should be reported to a medical professional for a rabies assessment.

Non-human primates

Although non-human primates (NHPs) are rarely rabid, they are a common source of bites, mainly in Asia, and often are associated with tourist attractions. In most instances, wild NHPs cannot be followed up for rabies assessments, and PEP is recommended for bite victims. Awareness of this risk and simple prevention are particularly effective: advise travelers not to approach or otherwise interact with NHPs or carry food while NHPs are near, especially those that have become habituated to tourists. B virus infection is another risk from NHP bites and is discussed in the Zoonotic Exposures: Bites, Scratches, and Other Hazards chapter.

Pre-exposure prophylaxis

Pre-exposure prophylaxis (PrEP) does not eliminate the need for additional medical attention after a rabies exposure, but it simplifies PEP (see Post-Exposure Prophylaxis later in this chapter). PrEP might also provide some protection when an exposure to rabies virus goes unrecognized or PEP is otherwise delayed. Travelers who complete a recognized PrEP immunization series (see Revised Vaccine Schedule later in this chapter) or who receive 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 do not otherwise fall into the frequent or continuous risk categories and have no immunodeficiencies (Table 4.15.1).

Table 4.15.1: Rabies pre-exposure prophylaxis recommendations—United States, 2022¹

Recommended traveler categories

Recommendations for pre-exposure rabies vaccination can be made for certain international traveler categories based on multiple factors: the occurrence of animal rabies in the destination country; the availability of anti-rabies biologics; the traveler's intended activities, especially in remote areas; and the traveler's duration of stay. A decision to receive pre-exposure rabies immunization might also be based on the likelihood of repeat travel to at-risk destinations or long-term travel to a high-risk destination. Consider PrEP for animal handlers, field biologists, cavers, missionaries, veterinarians, and some laboratory workers. Table 4.15.1 provides criteria for PrEP. Regardless of whether PrEP is administered, encourage travelers to purchase medical evacuation insurance if they are going to areas where the risk for rabies is high (see Travel Insurance, Travel Health Insurance, and Medical Evacuation Insurance chapter).

Revised vaccine schedule

In the United States, PrEP previously consisted of a series of 3 intramuscular (deltoid) injections of human diploid cell rabies vaccine (HDCV) or purified chick embryo cell (PCEC) vaccine given on days 0, 7, and 21 or 28. Based on recent changes in WHO recommendations and the availability of empirical studies, the U.S. Advisory Committee on Immunization Practices (ACIP) reviewed its own recommendations for PrEP and approved a 2-dose pre-exposure regimen, given on days 0 and 7 (Table 4.15.2).

The advantages of the revised ACIP schedule are that it is less expensive and easier to complete prior to travel. Data strongly support a 3-year duration of immunity for this 2-dose series; however, longer durations of immunity are still being evaluated. Because of this uncertainty, travelers with a sustained risk for rabies exposure should either have a titer drawn 1–3 years after the 2-dose primary series or receive a third dose of vaccine no sooner than day 21 and no later than year 3 after the 2-dose primary series. Travelers unlikely to visit an at-risk destination after 3 years require no further titers or boosters unless they have a subsequent exposure or resume travel to at-risk destinations. Under current guidelines, which may change as more long-term data become available, a person with a rabies exposure more than 3 years after their initial 2 immunizations, without an intervening titer or booster, would need to undergo full PEP with RIG. A traveler who has had 3 pre-exposure immunizations, or an adequate titer 1–3 years after their initial series, is considered to be pre-immunized for life, assuming they remain immunologically healthy. Persons considered pre-exposure vaccinated are still recommended to receive 2 doses of rabies vaccine on days 0 and 3 to ensure a robust immune response in the face of an exposure.

Table 4.15.2: Pre-exposure immunization for rabies¹

Vaccine safety and adverse reactions

Advise travelers that they might experience local reactions after vaccination (e.g., erythema, itching at the injection site, pain, swelling) or mild systemic reactions (e.g., abdominal pain, dizziness, headache, muscle aches, nausea). Approximately 6% of people receiving booster vaccinations with HDCV experience systemic hypersensitivity reactions characterized by malaise, pruritis, or urticaria. The likelihood of these reactions is less with PCEC vaccine.

Wound management

Travelers should clean all animal bites and scratches with copious amounts of soap and water, povidone iodine, or other products with virucidal activity. Inform travelers that cleaning bite wounds immediately (or as soon as possible) substantially reduces the risk for rabies virus infection, especially when followed by timely administration of PEP. For unvaccinated patients, delay suturing any wounds for a few days. If suturing is necessary to control bleeding or for functional or cosmetic reasons, inject RIG into all exposed tissues before closing the wound. Use of local anesthetics is not contraindicated in wound management.

Post-exposure prophylaxis

Travelers who received pre-exposure prophylaxis

For previously vaccinated people, PEP consists of 2 doses of modern cell culture vaccine given 3 days apart (days 0 and 3), ideally initiated shortly after the exposure. The booster doses do not have to be the same brand as the one used for the original pre-exposure immunization series. RIG should not be administered to people who were previously vaccinated, because it can lead to a diminished immune response to vaccine and provides no benefit to the recipient.

Travelers who did not receive pre-exposure prophylaxis

Rabies immune globulin plus rabies vaccine

For unvaccinated people, PEP consists of RIG administration (20 IU/kg for human RIG [HRIG] or 40 IU/kg for equine RIG) and a series of 4 injections of rabies vaccine over 14 days; immunocompromised patients should receive 5 doses over a 1-month period (Table 4.15.3). After cleaning the wound, inject as much of the dose-appropriate volume of RIG (Table 4.15.3) as is anatomically feasible at wound sites. The intent is to put RIG anywhere saliva might have contaminated the wounded tissue. Avoid administering RIG into the same anatomical site as the vaccine because the 2 products neutralize each other. Likewise, RIG should never be administered in the same syringe as the first vaccine dose.

Once initiated, rabies PEP should not be interrupted or discontinued because of local or mild systemic reactions to the vaccine. If an adverse event occurs with one of the vaccine types, consider switching to the alternative cell culture vaccine for the remainder of the series. Antihistamines or nonsteroidal anti-inflammatory medications taken before vaccination can help reduce mild adverse reactions in people with a history of such reactions.

Table 4.15.3: Post-exposure prophylaxis for rabies¹

Rabies immune globulin: availability and timing

HRIG is manufactured by plasmapheresis of blood from hyperimmunized volunteers. The total quantity of commercially produced HRIG falls short of worldwide demand, and it is not available in many low- and middle-income countries. Equine RIG, purified fractions of equine RIG, and rabies monoclonal antibody products might be available in some countries where HRIG is not. Such products are preferable to no RIG.

If access to RIG is delayed but modern cell culture vaccine is available, start the vaccine series as soon as possible, and add RIG to the regimen ≤7 days after the first dose of vaccine was administered. After day 7 (e.g., 3 doses of vaccine), RIG is unlikely to provide benefit because antibodies from the patient's own vaccine-derived immune response should be present. If a patient experiences deviations in the vaccination schedule, including HRIG deviations, expert consultation should be sought.

Because rabies virus can persist in tissue for a long time before invading a peripheral nerve, a previously unimmunized traveler who sustained a bite 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 the area.

Rabies immune globulin: dilution

If the wound is small and on a distal extremity (e.g., a finger, toe), use clinical judgment to decide how much RIG to inject to avoid complications (e.g., ischemia) due to local distention of the digit or digits. Administer any remaining dose intramuscularly at a site distant from the site of vaccine administration. If wounds are extensive, do not exceed the dose-appropriate volume of RIG. If the indicated volume is inadequate to inject all wounds, dilute the RIG with normal saline to ensure sufficient volume to inject all wounds. The one exception is the newer more concentrated version of HRIG (HyperRAb 300 i.u./ml), which requires using dextrose 5% in water (D5W) as the diluent. RIG dilution is particularly important in children whose body weight might be small in relation to the size and number of wounds.

Historically, HRIG has consisted of a product with 150 IU per mL. In recent years, new products with 300 IU per mL have entered the market. This requires the healthcare professional to ascertain which product is available in their clinic or hospital to make sure they do not exceed the total calculated dose of HRIG.

Rabies immune globulin: safety and adverse events

The incidence of adverse events after the use of modern equine-derived RIG is low (0.8%–6.0%), and most reactions are minor. Because such products are not regulated by the U.S. Food and Drug Administration, however, their use cannot be recommended unequivocally. In addition, unpurified anti-rabies serum of equine origin might still be used in some countries where neither human nor equine RIG is available.

Contraindications and precautions

Pregnancy is not a contraindication to receiving PEP. In infants and children, the dose of HDCV or PCEC for PrEP or PEP is the same as that recommended for adults. The PEP RIG dose is based on body weight (Table 4.15.3).

Rabies vaccines were once manufactured from viruses grown in animal brains; some of these vaccines are still in use in low- and middle-income countries. Typically, travelers can identify brain-derived vaccines, also known as nerve tissue vaccines, if they are offered a daily large-volume injection (5 mL) for approximately 14–21 days. Because of variability in the potency in these preparations, which might limit their effectiveness, and the risk for severe adverse reactions, advise travelers to decline these vaccines and to travel to a location where acceptable vaccines and RIG are available.

Variations in post-exposure prophylaxis

Different PEP schedules, alternative routes of administration, or other rabies vaccines besides HDCV and PCEC might be used abroad. For example, commercially available purified Vero cell rabies vaccine is an acceptable alternative, if available. Other rabies vaccines or PEP regimens could require additional prophylaxis or confirmation of adequate rabies virus-neutralizing antibody titers. Encourage travelers to take photos of the rabies PEP products they receive and to be conscious of the vaccine storage conditions and corresponding administration schedule. This information is necessary for healthcare professionals to determine whether additional vaccines or titers are indicated. Healthcare professionals can obtain assistance managing complicated PEP scenarios from experienced travel medicine professionals, health departments, or CDC (rabies@cdc.gov).

Healthcare professionals are justifiably concerned about getting everything right when trying to prevent a disease that is virtually 100% fatal, leading to overconcern about small variations in the administration of rabies vaccines. Modern-day cell culture rabies vaccines are highly immunogenic, however, and post-exposure rabies vaccine schedules have been developed to provide the quickest onset of endogenous antibodies, which is why these vaccines are given on such a short schedule.

Make every effort to adhere to a recognized ACIP or WHO schedule. Variations of days to weeks are unlikely to diminish the immune response to vaccination but could delay the onset of protection. Numerous schedules and routes of administration have been recognized by international health authorities and have been shown to be highly effective at preventing rabies.

Acknowledgements

The following authors contributed to the previous version of this chapter: Brett W. Petersen.