Rabies is a fatal, acute, progressive encephalomyelitis caused by neurotropic viruses in the family Rhabdoviridae, genus Lyssavirus. Numerous, diverse lyssavirus variants are found in various animal 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.
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 in bite wounds. The virus travels from its point of entry along 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 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 can be nonspecific, however, and public health professionals should conduct a thorough risk assessment to determine if medical care is indicated.
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 transplantation from infected humans) has occurred, but human-to-human transmission generally does not occur otherwise.
All mammals are believed to be susceptible to rabies virus infection, but terrestrial mesocarnivores and bats are major rabies virus reservoirs. Dogs are the main reservoir in many low- and middle-income countries, and the epidemiology of the disease differs between regions and countries. All patients with mammal bites should be medically evaluated to ascertain if rabies postexposure prophylaxis is indicated.
Bat exposure anywhere in the world is a cause for concern and an indication to consider rabies postexposure prophylaxis.
Lyssaviruses, the causative agent 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 and on 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).
Canine rabies remains 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 14 other viruses that all cause rabies disease. Non–rabies lyssaviruses are found in Africa, Asia, Australia, and Europe; although 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 16–200 per 100,000 travelers.
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 nonspecific, vague 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). Delirium and convulsions can develop, followed soon thereafter by coma and death.
Approximately 80% of people with rabies will manifest with classic encephalitic disease in which fever, hydrophobia, hyperactivity, and spasms eventually progress to paralysis and coma; this progression corresponds to “furious” rabies in animals. Another 20% of people can present with paralytic rabies, in which paralysis often first involves the bitten extremity and 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 can be made in a patient with a compatible exposure history and a classic clinical presentation (Box 5-05). Clinical suspicion and prioritization of differential diagnoses can be complicated by variations in clinical presentation and a lack of exposure history, however. Because several weeks to months could have elapsed since exposure, and an accurate exposure history can be difficult to elicit, patients might not discuss potential rabies virus exposures with friends or family, and clinicians 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.
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., intravenous immune globulin [IVIG]) administered to patients can be a passive source of high concentrations of donor-derived Rabies lyssavirus–neutralizing antibodies (RLNAs); in the absence of an accurate history of prior, recent IVIG administration, finding RLNAs in serum can incorrectly suggest a diagnosis of rabies. In unvaccinated encephalitic patients, however, the presence of rabies virus–neutralizing 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 World Health Organization (WHO) Collaborating Center for Rabies and World Organisation for Animal Health (OIE) Rabies Reference Laboratory. In this capacity, CDC performs public health testing for domestic and international health agencies, for both human and animal rabies diagnoses. Clinicians 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.
A person presenting with an acute neurologic syndrome (encephalitis) dominated by forms of hyperactivity (furious rabies) or paralytic syndromes (paralytic rabies) progressing toward coma and death, usually by cardiac or respiratory failure, typically within 7–10 days after the first symptom if no intensive care is instituted.
Symptoms include any of the following: aerophobia, dysphagia, hydrophobia, nausea or vomiting, paresthesia or localized pain, localized weakness.
A case compatible with the clinical case definition.
A suspected case plus a reliable history of contact with a suspected, probable, or confirmed rabid animal.
A suspected or probable case confirmed in the laboratory.
No evidence-based “best practices” 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; not getting bitten in the first place is therefore the most important prevention measure. For those who are (or who suspect they might have been) bitten by a rabid animal, urgently taking the other prevention measures described next is the only way to optimize survival.
Travelers can best prevent rabies by learning about infection risks and the need to avoid bites from mammals, especially high-risk rabies reservoir species; consulting with travel health professionals to determine whether preexposure vaccination is recommended; knowing how to prevent rabies after a bite; and knowing how to obtain postexposure prophylaxis (PEP), which might involve urgent importation of rabies biologics or travel to somewhere PEP is available. Not seeking PEP or receiving inadequate care likely will result in death from rabies. See a list of pretravel rabies precautions.
Avoiding bites is truly the best prevention measure for rabies. Although rabies can be completely prevented by appropriate postexposure care, obtaining that care and worrying about its effectiveness can be nerve-racking for patients. Warn travelers going to rabies-enzootic countries about the risks for rabies exposure. Counsel them to stay away from all free-roaming 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.
Besides rabies virus, other bat-associated pathogens include Histoplasma spp., coronaviruses, and viral hemorrhagic fever viruses (see Sec. 4, Ch. 7, Zoonotic Exposures: Bites, Stings, Scratches & Other Hazards). Educate travelers to avoid handling bats or other wildlife and to consider using personal protective equipment (PPE) before entering caves where bats are found. Many bats have tiny teeth, and the wounds they inflict might not be readily apparent. Warn travelers that any suspected or documented bite or wound from a bat should be grounds for seeking PEP.
In many low- and middle-income countries, dogs stray freely in cities; encourage travelers to remain vigilant. 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 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.
Although nonhuman primates (NHPs) are rarely rabid, they are a common source of bites, mainly on the Indian subcontinent. 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 (see Sec. 4, Ch. 7, Zoonotic Exposures: Bites, Stings, Scratches & Other Hazards).
Preexposure prophylaxis (PrEP) does not eliminate the need for additional medical attention after a rabies exposure, but it simplifies PEP (see Postexposure 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 (Table 5-17).