Rabies is a rapidly progressive, acute infectious disease of the central nervous system (CNS) in humans and animals that is caused by infection with rabies virus. The infection is normally transmitted from animal vectors. Rabies has encephalitic and paralytic forms that progress to death.
Rabies virus is a member of the family Rhabdoviridae. Two genera in this family, Lyssavirus and Vesiculovirus, contain species that cause human disease. Rabies virus is a lyssavirus that infects a broad range of animals and causes serious neurologic disease when transmitted to humans. This single-strand RNA virus has a nonsegmented, negative-sense (antisense) genome that consists of 11,932 nucleotides and encodes 5 proteins: nucleocapsid protein, phosphoprotein, matrix protein, glycoprotein, and a large polymerase protein. Rabies virus variants, which can be characterized by distinctive nucleotide sequences, are associated with specific animal reservoirs. Six other non–rabies virus species in the Lyssavirus genus have been reported to cause a clinical picture similar to rabies. Vesicular stomatitis virus, a vesiculovirus, causes vesiculation and ulceration in cattle, horses, and other animals and causes a self-limited, mild, systemic illness in humans (see “Other Rhabdoviruses,” below).
Rabies is a zoonotic infection that occurs in a variety of mammals throughout the world except in Antarctica and on some islands. Rabies virus is usually transmitted to humans by the bite of an infected animal. Worldwide, endemic canine rabies is estimated to cause 55,000 human deaths annually. Most of these deaths occur in Asia and Africa, with rural populations and children most frequently affected. Thus, in many resource-poor and resource-limited countries, canine rabies continues to be a threat to humans. However, in Latin America, rabies control efforts in dogs have been quite successful in recent years. Endemic canine rabies has been eliminated from the United States and most other resource-rich countries. Rabies is endemic in wildlife species, and a variety of animal reservoirs have been identified in different countries. Surveillance data from 2012 identified 6162 confirmed animal cases of rabies in the United States (including Puerto Rico). Only 8% of these cases were in domestic animals, including 257 cases in cats, 84 in dogs, and 115 in cattle. In North American wildlife reservoirs, including bats, raccoons, skunks, and foxes, the infection is endemic, with involvement of one or more rabies virus variants in each reservoir species (Fig. 105-1). “Spillover” of rabies to other wildlife species and to domestic animals occurs. Bat rabies virus variants are present in every state except Hawaii and are responsible for most indigenously acquired human rabies cases in the United States. Raccoon rabies is endemic along the entire eastern coast of the United States. Skunk rabies is present in the midwestern states, with another focus in California. Rabies in foxes occurs in Texas, New Mexico, Arizona, and Alaska.
Distribution of the major rabies virus variants among wild terrestrial reservoirs in the United States and Puerto Rico, 2008–2012. *Potential host-shift event. (From JL Dyer et al: J Am Vet Med Assoc 243:805, 2013.)
In Canada and Europe, epizootics of rabies in red foxes have been well controlled with the use of baits containing rabies vaccine. A similar approach is used in Canada to control raccoon rabies.
Rabies virus variants isolated from humans or other mammalian species can be identified by reverse-transcription polymerase chain reaction (RT-PCR) amplification and sequencing or by characterization with monoclonal antibodies. These techniques are helpful in human cases with no known history of exposure. Worldwide, most human rabies is transmitted from dogs in countries with endemic canine rabies and dog-to-dog transmission, and human cases can be imported by travelers returning from these regions. In North America, human disease is usually associated with transmission from bats; there may be no known history of bat bite or other bat exposure in these cases. Most human cases are due to a bat rabies virus variant associated with silver-haired and tricolored bats. These are small bats whose bite may not be recognized, and the virus has adapted for replication at skin temperature and in cell types that are present in the skin.
Transmission from nonbite exposures is relatively uncommon. Aerosols generated in the laboratory or in caves containing millions of Brazilian free-tail bats have rarely caused human rabies. Transmission has resulted from corneal transplantation and also from solid organ transplantation and a vascular conduit (for a liver transplant) from undiagnosed donors with rabies in Texas, Florida, and Germany. Human-to-human transmission is extremely rare, although hypothetical concern about transmission to health care workers has prompted the implementation of barrier techniques to prevent exposures.
The incubation period of rabies (defined as the interval between exposure and the onset of clinical disease) is usually 20–90 days but in rare cases is as short as a few days or >1 year. During most of the incubation period, rabies virus is thought to be present at or close to the site of inoculation (Fig. 105-2). In muscles, the virus is known to bind to nicotinic acetylcholine receptors on postsynaptic membranes at neuromuscular junctions, but the exact details of viral entry into the skin and SC tissues have not yet been clarified. Rabies virus spreads centripetally along peripheral nerves toward the CNS at a rate of up to ~250 mm/d via retrograde fast axonal transport to the spinal cord or brainstem. Once the virus enters the CNS, it rapidly disseminates to other regions of the CNS via fast axonal transport along neuroanatomic connections. Neurons are prominently infected in rabies; infection of astrocytes is unusual. After CNS infection becomes established, there is centrifugal spread along sensory and autonomic nerves to other tissues, including the salivary glands, heart, adrenal glands, and skin. Rabies virus replicates in acinar cells of the salivary glands and is secreted in the saliva of rabid animals that serve as vectors of the disease. There is no well-documented evidence for hematogenous spread of rabies virus.
Schematic representation of the pathogenetic events following peripheral inoculation of rabies virus by an animal bite. (Adapted from Jackson AC: Human disease, in Rabies: scientific basis of the disease and its management, 3rd ed., AC Jackson [ed], Oxford, UK, Elsevier Academic Press, 2013, pp 269–298; with permission.)
Pathologic studies show mild inflammatory changes in the CNS in rabies, with mononuclear inflammatory infiltration in the leptomeninges, perivascular regions, and parenchyma, including microglial nodules called Babes nodules. Degenerative neuronal changes usually are not prominent, and there is little evidence of neuronal death; neuronophagia is observed occasionally. The pathologic changes are surprisingly mild in light of the clinical severity and fatal outcome of the disease. The most characteristic pathologic finding in rabies is the Negri body (Fig. 105-3). Negri bodies are eosinophilic cytoplasmic inclusions in brain neurons that are composed of rabies virus proteins and viral RNA. These inclusions occur in a minority of infected neurons, are commonly observed in Purkinje cells of the cerebellum and in pyramidal neurons of the hippocampus, and are less frequently seen in cortical and brainstem neurons. Negri bodies are not observed in all cases of rabies. The lack of prominent degenerative neuronal changes has led to the concept that neuronal dysfunction—rather than neuronal death—is responsible for clinical disease in rabies. The basis for behavioral changes, including the aggressive behavior of rabid animals, is not well understood.
Three large Negri bodies in the cytoplasm of a cerebellar Purkinje cell from an 8-year-old boy who died of rabies after being bitten by a rabid dog in Mexico. (From AC Jackson, E Lopez-Corella: N Engl J Med 335:568, 1996. © Massachusetts Medical Society.)
In rabies, the emphasis must be on postexposure prophylaxis (PEP) initiated before any symptoms or signs develop. Rabies should usually be suspected on the basis of the clinical presentation. The disease usually presents as atypical encephalitis with relative preservation of consciousness. Rabies may be difficult to recognize late in the clinical course when progression to coma has occurred. A minority of patients present with acute flaccid paralysis. There are prodromal, acute neurologic, and comatose phases that usually progress to death despite aggressive therapy (Table 105-1).
TABLE 105-1CLINICAL STAGES OF RABIES ||Download (.pdf) TABLE 105-1 CLINICAL STAGES OF RABIES
|PHASE ||TYPICAL DURATION ||SYMPTOMS AND SIGNS |
|Incubation period ||20–90 days ||None |
|Prodrome ||2–10 days ||Fever, malaise, anorexia, nausea, vomiting; paresthesias, pain, or pruritus at the wound site |
|Acute neurologic disease |
|Encephalitic (80%) ||2–7 days ||Anxiety, agitation, hyperactivity, bizarre behavior, hallucinations, autonomic dysfunction, hydrophobia |
| Paralytic (20%) ||2–10 days ||Flaccid paralysis in limb(s) progressing to quadriparesis with facial paralysis |
|Coma, deatha ||0–14 days || |
The clinical features of rabies begin with nonspecific prodromal manifestations, including fever, malaise, headache, nausea, and vomiting. Anxiety or agitation may also occur. The earliest specific neurologic symptoms of rabies include paresthesias, pain, or pruritus near the site of the exposure, one or more of which occur in 50–80% of patients and strongly suggest rabies. The wound has usually healed by this point, and these symptoms probably reflect infection with associated inflammatory changes in local dorsal root or cranial sensory ganglia.
Two acute neurologic forms of rabies are seen in humans: encephalitic (furious) in 80% and paralytic in 20%. Some of the manifestations of encephalitic rabies, including fever, confusion, hallucinations, combativeness, and seizures, may be seen in other viral encephalitides as well. Autonomic dysfunction is common and may result in hypersalivation, gooseflesh, cardiac arrhythmia, and priapism. In encephalitic rabies, episodes of hyperexcitability are typically followed by periods of complete lucidity that become shorter as the disease progresses. Rabies encephalitis is distinguished by early brainstem involvement, which results in the classic features of hydrophobia (involuntary, painful contraction of the diaphragm and accessory respiratory, laryngeal, and pharyngeal muscles in response to swallowing liquids) and aerophobia (the same features caused by stimulation from a draft of air). These symptoms are probably due to dysfunction of infected brainstem neurons that normally inhibit inspiratory neurons near the nucleus ambiguus, resulting in exaggerated defense reflexes that protect the respiratory tract. The combination of hypersalivation and pharyngeal dysfunction is also responsible for the classic appearance of “foaming at the mouth” (Fig. 105-4). Brainstem dysfunction progresses rapidly, and coma—followed within days by death—is the rule unless the course is prolonged by supportive measures. With such measures, late complications can include cardiac and/or respiratory failure, disturbances of water balance (syndrome of inappropriate antidiuretic hormone secretion or diabetes insipidus), noncardiogenic pulmonary edema, and gastrointestinal hemorrhage. Cardiac arrhythmias may be due to dysfunction affecting vital centers in the brainstem or to myocarditis. Multiple-organ failure is common in patients treated aggressively in critical care units.
Hydrophobic spasm of inspiratory muscles associated with terror in a patient with encephalitic (furious) rabies who is attempting to swallow water. (Copyright DA Warrell, Oxford, UK; with permission.)
About 20% of patients have paralytic rabies in which muscle weakness predominates and cardinal features of encephalitic rabies (hyperexcitability, hydrophobia, and aerophobia) are lacking. There is early and prominent flaccid muscle weakness, often beginning in the bitten extremity and spreading to produce quadriparesis and facial weakness. Sphincter involvement is common, sensory involvement is usually mild, and these cases are commonly misdiagnosed as Guillain-Barré syndrome. Patients with paralytic rabies generally survive a few days longer than those with encephalitic rabies, but multiple-organ failure nevertheless ensues.
Most routine laboratory tests in rabies yield normal results or show nonspecific abnormalities. Complete blood counts are usually normal. Examination of cerebrospinal fluid (CSF) often reveals mild mononuclear cell pleocytosis with a mildly elevated protein level. Severe pleocytosis (>1000 white cells/μL) is unusual and should prompt a search for an alternative diagnosis. CT head scans are usually normal in rabies. MRI brain scans may show signal abnormalities in the brainstem or other gray-matter areas, but these findings are variable and nonspecific. Electroencephalograms show only nonspecific abnormalities. Of course, important tests in suspected cases of rabies include those that may identify an alternative, potentially treatable diagnosis (see “Differential Diagnosis,” below).
In North America, a diagnosis of rabies often is not considered until relatively late in the clinical course, even with a typical clinical presentation. This diagnosis should be considered in patients presenting with acute atypical encephalitis or acute flaccid paralysis, including those in whom Guillain-Barré syndrome is suspected. The absence of an animal-bite history is common in North America. The lack of hydrophobia is not unusual in rabies. Once rabies is suspected, rabies-specific laboratory tests should be performed to confirm the diagnosis. Diagnostically useful specimens include serum, CSF, fresh saliva, skin biopsy samples from the neck, and brain tissue (rarely obtained before death). Because skin biopsy relies on the demonstration of rabies virus antigen in cutaneous nerves at the base of hair follicles, samples are usually taken from hairy skin at the nape of the neck. Corneal impression smears are of low diagnostic yield and are generally not performed. Negative antemortem rabies-specific laboratory tests never exclude a diagnosis of rabies, and tests may need to be repeated after an interval for diagnostic confirmation.
Rabies virus–specific antibodies
In a previously unimmunized patient, serum neutralizing antibodies to rabies virus are diagnostic. However, because rabies virus infects immunologically privileged neuronal tissues, serum antibodies may not develop until late in the disease. Antibodies may be detected within a few days after the onset of symptoms, but some patients die without detectable antibodies. The presence of rabies virus–specific antibodies in the CSF suggests rabies encephalitis, regardless of immunization status. A diagnosis of rabies is questionable in patients who recover from rabies without developing serum neutralizing antibodies to rabies virus.
Detection of rabies virus RNA by RT-PCR is highly sensitive and specific. This technique can detect virus in fresh saliva samples, skin, CSF, and brain tissues. In addition, RT-PCR with genetic sequencing can distinguish among rabies virus variants, permitting identification of the probable source of an infection.
Direct fluorescent antibody testing
Direct fluorescent antibody (DFA) testing with rabies virus antibodies conjugated to fluorescent dyes is highly sensitive and specific and can be performed quickly and applied to skin biopsies and brain tissue. In skin biopsies, rabies virus antigen may be detected in cutaneous nerves at the base of hair follicles.
The diagnosis of rabies may be difficult without a history of animal exposure, and no exposure to an animal (e.g., a bat) may be recalled. The presentation of rabies is usually quite different from that of acute viral encephalitis due to most other causes, including herpes simplex encephalitis and arboviral (e.g., West Nile) encephalitis. Early neurologic symptoms may occur at the site of the bite, and there may be early features of brainstem involvement with preservation of consciousness. Anti-N-methyl-d-aspartate receptor (anti-NMDA) encephalitis occurs in young patients (especially females) and is characterized by behavioral changes, autonomic instability, hypoventilation, and seizures. Postinfectious (immune-mediated) encephalomyelitis may follow influenza, measles, mumps, and other infections; it may also occur as a sequela of immunization with rabies vaccine derived from neural tissues, which are used only in resource-limited and resource-poor countries. Rabies may present with unusual neuropsychiatric symptoms and may be misdiagnosed as a psychiatric disorder. Rabies hysteria may occur as a psychological response to the fear of rabies and is often characterized by a shorter incubation period than rabies, aggressive behavior, inability to communicate, and a long course with recovery.
As previously mentioned, paralytic rabies may mimic Guillain-Barré syndrome. In these cases, fever, bladder dysfunction, a normal sensory examination, and CSF pleocytosis favor a diagnosis of rabies. Conversely, Guillain-Barré syndrome may occur as a complication of rabies vaccination with a neural tissue–derived product (e.g., suckling mouse brain vaccine) and may be mistaken for paralytic rabies (i.e., vaccine failure).
There is no established treatment for rabies. There have been many recent treatment failures with the combination of antiviral drugs, ketamine, and therapeutic (induced) coma—measures that were used in a healthy survivor in whom antibodies to rabies virus were detected at presentation. Expert opinion should be sought before a course of experimental therapy is embarked upon. A palliative approach may be appropriate for some patients.
Rabies is an almost uniformly fatal disease but is nearly always preventable with appropriate postexposure therapy during the early incubation period (see below). There are seven well-documented cases of survival from rabies. All but one of these patients had received rabies vaccine before disease onset. The single survivor who had not received vaccine had neutralizing antibodies to rabies virus in serum and CSF at clinical presentation. Most patients with rabies die within several days of the onset of illness, despite aggressive care in a critical care unit.
Since there is no effective therapy for rabies, it is extremely important to prevent the disease after an animal exposure. Figure 105-5 shows the steps involved in making decisions about PEP. On the basis of the history of the exposure and local epidemiologic information, the physician must decide whether initiation of PEP is warranted. Healthy dogs, cats, or ferrets may be confined and observed for 10 days. PEP is not necessary if the animal remains healthy. If the animal develops signs of rabies during the observation period, it should be euthanized immediately; the head should be transported to the laboratory under refrigeration, rabies virus should be sought by DFA testing, and viral isolation should be attempted by cell culture and/or mouse inoculation. Any animal other than a dog, cat, or ferret should be euthanized immediately and the head submitted for laboratory examination. In high-risk exposures and in areas where canine rabies is endemic, rabies prophylaxis should be initiated without waiting for laboratory results. If the laboratory results prove to be negative, it may safely be concluded that the animal’s saliva did not contain rabies virus, and immunization should be discontinued. If an animal escapes after an exposure, it must be considered rabid, and PEP must be initiated unless information from public health officials indicates otherwise (i.e., there is no endemic rabies in the area). Although controversial, the use of PEP may be warranted when a person (e.g., a small child or a sleeping adult) has been present in the same space as a bat and an unrecognized bite cannot be reliably excluded.
Algorithm for rabies postexposure prophylaxis. RIG, rabies immune globulin. (From L Corey, in Harrison’s Principles of Internal Medicine, 15th ed. E Braunwald et al [eds]: New York, McGraw-Hill, 2001; adapted with permission.)
PEP includes local wound care and both active and passive immunization. Local wound care is essential and may greatly decrease the risk of rabies virus infection. Wound care should not be delayed, even if the initiation of immunization is postponed pending the results of the 10-day observation period. All bite wounds and scratches should be washed thoroughly with soap and water. Devitalized tissues should be debrided, tetanus prophylaxis given, and antibiotic treatment initiated whenever indicated.
All previously unvaccinated persons (but not those who have previously been immunized) should be passively immunized with rabies immune globulin (RIG). If RIG is not immediately available, it should be administered no later than 7 days after the first vaccine dose. After day 7, endogenous antibodies are being produced, and passive immunization may actually be counterproductive. If anatomically feasible, the entire dose of RIG (20 IU/kg) should be infiltrated at the site of the bite; otherwise, any RIG remaining after infiltration of the bite site should be administered IM at a distant site. With multiple or large wounds, the RIG preparation may need to be diluted in order to obtain a sufficient volume for adequate infiltration of all wound sites. If the exposure involves a mucous membrane, the entire dose should be administered IM. Rabies vaccine and RIG should never be administered at the same site or with the same syringe. Commercially available RIG in the United States is purified from the serum of hyperimmunized human donors. These human RIG preparations are much better tolerated than are the equine-derived preparations still in use in some countries (see below). Serious adverse effects of human RIG are uncommon. Local pain and low-grade fever may occur.
Two purified inactivated rabies vaccines are available for rabies PEP in the United States. They are highly immunogenic and remarkably safe compared with earlier vaccines. Four 1-mL doses of rabies vaccine should be given IM in the deltoid area. (The anterolateral aspect of the thigh also is acceptable in children.) Gluteal injections, which may not always reach muscle, should not be given and have been associated with rare vaccine failures. Ideally, the first dose should be given as soon as possible after exposure; failing that, it should be given without further delay. The three additional doses should be given on days 3, 7, and 14; a fifth dose on day 28 is no longer recommended. Pregnancy is not a contraindication for immunization. Glucocorticoids and other immunosuppressive medications may interfere with the development of active immunity and should not be administered during PEP unless they are essential. Routine measurement of serum neutralizing antibody titers is not required, but titers should be measured 2–4 weeks after immunization in immunocompromised persons. Local reactions (pain, erythema, edema, and pruritus) and mild systemic reactions (fever, myalgias, headache, and nausea) are common; anti-inflammatory and antipyretic medications may be used, but immunization should not be discontinued. Systemic allergic reactions are uncommon, but anaphylaxis does occur rarely and can be treated with epinephrine and antihistamines. The risk of rabies development should be carefully considered before the decision is made to discontinue vaccination because of an adverse reaction.
Most of the burden of rabies PEP is borne by persons with the fewest resources. In addition to the rabies vaccines discussed above, vaccines grown in either primary cell lines (hamster or dog kidney) or continuous cell lines (Vero cells) are satisfactory and are available in many countries outside the United States. Less expensive vaccines derived from neural tissues are still used in a diminishing number of developing countries; however, these vaccines are associated with serious neuroparalytic complications, including postinfectious encephalomyelitis and Guillain-Barré syndrome. The use of these vaccines should be discontinued as soon as possible, and progress has been made in this regard. Worldwide, >10 million individuals receive postexposure rabies vaccine each year.
If human RIG is unavailable, purified equine RIG can be used in the same manner at a dose of 40 IU/kg. Before the administration of equine RIG, hypersensitivity should be assessed by intradermal testing with a 1:10 dilution. The incidence of anaphylactic reactions and serum sickness has been low with recent equine RIG products.
Preexposure rabies vaccination
Preexposure rabies prophylaxis should be considered for people with an occupational or recreational risk of rabies exposures, including certain travelers to rabies-endemic areas. The primary schedule consists of three doses of rabies vaccine given on days 0, 7, and 21 or 28. Serum neutralizing antibody tests help determine the need for subsequent booster doses. When a previously immunized individual is exposed to rabies, two booster doses of vaccine should be administered on days 0 and 3. Wound care remains essential. As stated above, RIG should not be administered to previously vaccinated persons.