Rabies

The fatal madness of rabies has been described throughout recorded history, and its association with rabid canines is well known. For centuries, dog bites were treated prophylactically with cautery, with predictable and unfortunate results. In the 19th century, Pasteur developed a vaccine that successfully prevented rabies after inoculation and launched a new era of hope in the management of this uniformly fatal disease. (See Treatment and Medications.)

Rabies is a viral disease that affects the central nervous system (CNS). The genus Lyssavirus contains more than 80 viruses. Classic rabies, the focus of this article, is the prototypical human Lyssavirus pathogen.[1] (See Etiology.)

There are 10 viruses in the rabies serogroup, most of which only rarely cause human disease. The genus Lyssavirus, rabies serogroup, includes the classic rabies virus, Mokola virus, Duvenhage virus, Obodhiang virus, Kotonkan virus, Rochambeau virus, European bat Lyssavirus types 1 and 2, and Australian bat Lyssavirus.[1] (See Etiology.) Five antigenic variants of rabies strains are recognized in the United States.

The rabies virus is a bullet-shaped virion with a single-stranded ribonucleic acid (RNA) nucleocapsid core and lipoprotein envelope. Its nucleocapsid material consists of Negri bodies, which are observed in the cytoplasm of infected neurons. The virus is transmitted in saliva or in aerosolized secretions from infected animals, typically via a bite. The virus is not hardy and is quickly inactivated by drying, ultraviolet rays, x-rays, trypsin, detergents, and ether. (See Etiology.)

Rabies is a highly neurotropic virus that evades immune surveillance by its sequestration in the nervous system. Upon inoculation, it enters the peripheral nerves. A prolonged incubation follows, the length of which depends on the size of the inoculum and its proximity to the CNS. Amplification occurs until bare nucleocapsids spill into the myoneural junction and enter motor and sensory axons. At this point, prophylactic therapy becomes futile, and rabies can be expected to follow its fatal course, with a mortality rate of 100%.

The rabies virus travels along these axons at a rate of 12-24 mm/d to enter the spinal ganglion. Its multiplication in the ganglion is heralded by the onset of pain or paresthesia at the site of the inoculum, which is the first clinical symptom and a hallmark finding. From here, the rabies virus spreads quickly, at a rate of 200-400 mm (7-15 inches) per day, into the CNS, and spread is marked by rapidly progressive encephalitis. Thereafter, the virus spreads to the periphery and salivary glands, where it may be transmitted to others.

From the standpoint of diagnosis and therapeutic opportunities, it is important to understand that rabies does not damage neurons. Neuronal morphology and lifespan is normal throughout the course of the disease. Death occurs from global neurotransmitter blockade and widespread neurologic dysfunction. The virion acts in the synaptic space, where homology in amino acid sequences between neurotransmitter receptors for acetylcholine, GABA, and glycine may afford a mechanism for viral binding of these receptors. Thus, its action is neurotoxic, rather than cytotoxic.

Ironically, as disease progresses, virus may no longer be viable or replicating in tissue, although Negri bodies are present.

If the virus could be contained or the binding action reversed, complete recovery indeed might be possible. 

United States

Rabies is recognized as global zoonosis yet remains remarkably neglected, despite unmatched lethality. It remains a threat underappreciated by healthcare practitioners in many endemic areas, often owing to lack of rapid diagnostic tools, postmortem evaluation, and public health reporting. Further, few resources have been devoted to its mechanisms of disease and potential therapeutic targets; the therapeutic approach remains a crude guess at best, based on anecdotal experiences shared across the globe. Most attention has focused on preventive strategies, which are fortunately highly effective where implemented.

The prevalence of rabies varies by location depending on animal-control effectiveness and immunization programs. The largest number of human deaths annually was recorded during the first half of the 20th century, with an average of 50 documented cases per year. Most were related to rabid-dog exposure. After 1940, when canine rabies vaccination programs began, the average number of documented cases declined to two per year. From 2001-2005, 15 cases of human rabies were reported in the United States.

Human rabies reflects the prevalence of animal infection and the extent of contact this population has with humans. Less than 5% of cases in developed nations occur in domesticated dogs; however, unvaccinated dogs serve as the main reservoir worldwide. Undomesticated canines, such as coyotes, wolves, jackals, and foxes, are most prone to rabies and serve as reservoirs.[5] These reservoirs allow rabies to remain an indefinite public health concern, and ongoing public health measures are critical to its control. Animal-control and vaccination strategies currently supersede postexposure prophylaxis in preventing the spread of rabies. Through such programs, rabies has been eliminated in some parts of the United States, as well as several nations.

In the United States, rabies is most common in raccoons on the eastern coast and in skunks, foxes, coyotes, and dogs on the Texas-Mexico border, Bats, however, account for the highest number of rabies deaths in the United States, because these exposures are more likely to go unrecognized[5] ; inoculation with infected saliva may occur via tiny bites or scratches, mucosal contact (eyes, mouth), or theoretically, aerosolized saliva. Canine rabies, and to a lesser extent, bat rabies are significant problems in Mexico and around the world. (Opossums are rarely infected and are not considered a likely risk for exposure.)

The only rodent in the United States that can carry rabies long enough to transmit it to humans is the groundhog. Other small rodents (eg, squirrels, chipmunks, rats, mice) and lagomorphs (eg, rabbits, hares) usually die before being able to transmit rabies virus to humans, and human disease has not been documented from these mammals.

Domestic animals usually succumb to the virus strain predominant in their geographic region. Other cases have been associated with dog or animal bites in travelers returning from abroad, especially in countries where wild canine rabies is endemic. In other countries, canines are the most common source of rabies. Other animals, such as mongooses, jackals, ferrets, and domestic farm animals, may be common sources. Human-to-human transmission has only occurred with corneal and other organ transplants.[6, 7] Transmission of virus in saliva through mucous membranes, open wounds, or scratches is possible but rarely documented.

Rabies continues to adapt to new hosts and evolve transmissibility in previously “dead-end” hosts. In Arizona 2001, a mutated bat strain was confirmed to have developed both pathogenicity and transmissibility in both foxes and skunks, which previously were not seriously affected or contagious upon infection. Human encroachments into natural areas, as in suburban development, have been associated with the spread of rabies strains in the past.[13]

In addition, changes in epidemiology are expected to follow global climate change and are most likely to be detected in areas of climate extremes. This is being illustrated in Alaska, as increased viral transmission shifts from red fox to arctic fox populations following warming trends. Increased surveillance is needed to improve predictive models of epidemiology and human risk.[14]

Bats

Bat (avian) rabies appears to be widespread in the 49 continental states, and since 1980, most endemic rabies cases in humans in the United States have been associated with bat strains.[15]

Bat bites, if noticed by the patient, are generally thought to be trivial injuries because of the small size of most temperate-zone species (eg, silver-haired bats, eastern pipistrelles). In addition, bat bites can go completely unrecognized by the patient; consequently, appropriate postexposure prophylaxis is not administered.

One third of rabies cases occur in children, and most have no known exposure to a rabid animal. Because children may not be able to recall contact with a bat, if a bat is found in a room where a child has been sleeping, the bat should be captured and submitted for examination to the county or state health authorities. In 60% of cases, testing of the bat can avoid the need for rabies immunization.[16]

At least 30 of the more than 39 species of bats in the United States have been reported as rabid at some time.

Raccoons

Raccoons have been recognized a reservoir for rabies in the southeastern United States since the 1950s.[17]  The risk for raccoon transmission exists in all of the eastern coastal states and Alabama, Pennsylvania, Vermont, West Virginia, and Ohio.

Skunks

Three areas are associated with skunk-borne rabies: the north-central United States, the south-central United States, and California. As recently as 2001, a new skunk-borne variant arose from a bat strain and since has been quickly spreading.

Dogs and cats

Cats are the most common domestic animals reported by US health departments as being rabid, owing to unvaccinated strays with possible contacts with bats and other mammals.[18, 19]

Dogs and cats along the Mexican border

Limited resources and minimal public health infrastructure in the bordering communities have hindered efforts to maintain animal control through dog-vaccination programs. Viral studies of human cases reported from US border states implicate an urban canine rabies strain and a link to coyote rabies in southern Texas.[20]

Lower-risk animal species in the United States

Any mammal is potentially at risk for rabies, some more than others. Lower-risk animal species in the United States include dogs, cats, and ferrets in areas not near a border. No person in the United States has ever contracted rabies from a dog, cat, or ferret held in quarantine for 10 days.

American opossums are especially at low risk, because the species’ low body temperature hinders replication.

Animal rabies vaccine

The vaccinia-rabies glycoprotein virus used in rabies vaccine–laden baits for wild animals is a self-replicating agent. This oral animal vaccine may cause adverse effects in some humans exposed to it through animal bites, particularly in hosts with altered immunocompetence and persons in whom smallpox vaccination is contraindicated (eg, pregnant women, patients with an exfoliative skin condition).[21, 22]

Transplantation patients

The innate state of immunosuppression in this population often provides a favorable environment for viral replication. Recipients of neurally derived tissues are at highest risk; however, any tissue poses a risk. In 2004, kidneys and liver were inadvertently transplanted from a donor from Texas with undiagnosed rabies; the recipients developed clinical rabies within 30 days, resulting in 100% mortality.[23]

International

Rabies is more prevalent in the developing world than in industrialized countries. The World Health Organization (WHO) estimates that rabies is responsible for 35,000 to 50,000 deaths annually worldwide and that gross underreporting is likely. An estimated 10 million people receive postexposure prophylaxis each year after being exposed to animals with suspected rabies. Unvaccinated dogs are the major reservoir for rabies.

Global reservoirs of rabies virus are as follows[24, 25] :

• Europe - Foxes, bats

• Middle East - Wolves, dogs

• Asia - Dogs 

• Africa - Dogs, mongooses, antelopes

• North America - Foxes, skunks, raccoons, insectivorous bats

• South America - Dogs, vampire bats

Gender or sex-related demographics

Encounters with rabid animal vectors may be increased in males, who may have greater contact in certain geographic areas. Evidence to support this is found in data on dog bites, which are observed more frequently in males than in females.

Rabies virus infection is remarkable for the lack of evident pathology despite dramatic neurologic symptoms. Minimal inflammation and neuronal cytopathy may be observed even postmortem. Similarly, viremia does not occur or play a role in spread to the CNS.

Pathophysiology has been best characterized in canine rabies variants. Canine rabies in humans requires deep-muscle inoculation. Endogenous muscle micro-RNA bind to viral transcripts and limit both replication and viral protein production, such that the virus is able to evade detection by antigen-presenting cells. Once enough virus replicates (or with a high-level inoculum or direct nerve injury), it binds motor neuron junctions at postsynaptic nicotinic acetylcholine receptors, which initiates uptake into the motor endplate. From here, the virus rapidly propagates across motor axons and chemical synapses in retrograde fashion toward the ganglia and nerve roots, at which point the prodromal symptoms of neuralgia and hypoesthesia may begin, in addition to fever and flulike illness.

Once reaching the CNS, it spreads throughout via the more ubiquitous nicotinic acetylcholine receptors of the brain. Of note, anterograde spread of rabies virus may then occur via sensory and autonomic pathways from the CNS to viscera, explaining many of the symptoms of progressive disease. Throughout propagation of the virus along motor pathways, the virus elicits little inflammation, and the motor neurons continue their otherwise normal functions of neurotransmission. Increasing signs of inflammation develop as CNS and visceral spread occurs, although a significant paucity of findings remains, other than mild nonspecific MRI T2 enhancements. Spinal fluid remains largely acellular, even in the presence of detectable rabies virus.

Propagation to the CNS via peripheral sensory or autonomic synapses does not seem to occur with canine variants, and only about 30% of cases result in peripheral sensory neuralgia. However, 70% of cases with bat variants result in neuropathic pain in the region of inoculation, as well as Horner syndrome and other findings; thus, these alternate pathways may occur in bat rabies variants.[26, 27]

Despite aggressive and intensive care management, the prognosis of rabies remains exceedingly poor. The very few cases of survival have involved bat variants.

The general public should be aware of the risk for rabies with wild and feral domestic canine breeds, cats, raccoons, and, in particular, bats, which often appear to be innocuous or produce small injuries that may be dismissed. Bats found in a room with a sleeping child or incapacitated individual should prompt rabies prophylaxis. Animals with rabies may act unusually docile or be found out and about in daylight when otherwise nocturnal, or the animal may be unusually aggressive. Thus, the concept of "unprovoked" versus "provoked" injury is not useful in determining rabies risk.[5] Children should be taught not to pet or handle wild animals. A bat on the ground or easily caught should be considered rabid.

Prompt washing of potentially rabies-exposed wounds or mucosa with soap and water is important and may significantly reduce viral inoculum.

Travelers to areas endemic for rabies and who may participate in activities that may increase the exposure risk (eg, exploring caves or ruins, exposure to wild or feral animals) should seek rabies preexposure prophylaxis or be aware of sites to access reliable postexposure prophylaxis in the area. CDC Travel offers comprehensive guidance based on type of travel, region, and activity for the public and healthcare professionals.

Identify the following in any suspected case of rabies virus exposure:

• The nature of the interaction with the animal (Recall that "provocation" is not an indication of rabies risk, since humans may not understand what is provocative to a wild animal.)

• Strange animal behavior (eg, nocturnal animal out during the daytime)

• Vaccination status of the animal for rabies[18]

• Availability of the animal for testing

Incubation period

The rabies virus is segregated from the immune system during this period, and no antibody response is observed. The infected individual remains asymptomatic during this period. The average duration of incubation is 20-90 days. In more than 90% of cases, incubation is less than 1 year. A person whose inoculum occurs with a scratch on the hand may take longer to develop symptoms of rabies than a person who receives a bite to the head. The incubation period is less than 50 days if the patient is bitten on the head or neck or if a heavy inoculum is transferred through multiple bites, deep wounds, or large wounds. Infected patients may not recall exposure because of the prolonged incubation period.

Rarely, incubation has been reported many years following exposure. In cases of salivary exposure, incubation has been estimated based on molecular, phylogenetic, and epidemiologic evidence to be greater than 6-8 years.[28, 29, 30, 31] A suspected prolonged incubation of 25 years was reported in India with no identifiable risk factors other than a dog bite occurring in a time frame and location coincident with the likelihood of rabies in local dogs.[12]

Prodromal period

The virus enters the CNS. The duration of this period is 2-10 days. Nonspecific symptoms and signs develop, including fevers and flulike illness. Paresthesia, pain, or intense itching at the inoculation site is pathognomonic for rabies and occurs in 30% of canine-associated rabies cases and 70% of bat-associated rabies cases during this phase; this may be the individual’s only presenting sign. Symptoms may include the following:

• Malaise
• Anorexia
• Headaches
• Fever
• Chills
• Pharyngitis
• Nausea
• Emesis
• Diarrhea
• Anxiety
• Agitation
• Insomnia
• Depression

Acute neurologic period

This period is associated with objective signs of developing CNS disease; however, consciousness remains unaffected until the onset of coma. The duration is 2-7 days. Symptoms include muscle fasciculations, priapism, and focal or generalized convulsions. Patients may die immediately or may progress to paralysis, which may be present only in the bitten limb at first but usually becomes diffuse.

Two thirds of human rabies cases acquired from dogs manifest as "furious rabies." Patients develop agitation, hyperactivity, restlessness, thrashing, biting, confusion, or hallucinations. After several hours to days, this becomes episodic and interspersed with calm, cooperative, lucid periods. Furious episodes last less than 5 minutes. Episodes may be triggered by visual, auditory, or tactile stimuli or may be spontaneous. Seizures may occur. This phase may end in cardiorespiratory arrest or may progress to paralysis.

The remaining one-third of patients with rabies develop paralytic rabies, also known as dumb rabies or apathetic rabies, because the patient is relatively quiet compared with a person with the furious form. Paralysis occurs from the outset, and fever and headache are prominent. Paralytic rabies may initially mimic Guillain-Barré syndrome (GBS) with ascending lower–motor-neuron weakness unpreceded by classic "mad" signs, and rabies should be considered in the differential diagnosis of GBS.[32]

Bat-associated rabies often manifests with more atypical findings.

Coma

This begins within 10 days of onset, and the duration varies. Without intensive supportive care, respiratory depression, arrest, and death occur shortly after coma.

Neurologic period

With furious rabies, patients present with episodic delirium, psychosis, restlessness, thrashing, muscular fasciculations, seizures, and aphasia. Hydrophobia and aerophobia are pathognomonic for rabies and occur in 50% of patients. Attempting to drink or having air blown in the face produces severe laryngeal or diaphragmatic spasms and a sensation of asphyxia. This may be related to a violent response of the airway irritant mechanisms. Even the suggestion of drinking may induce hydrophobic spasm.

Autonomic instability is observed with furious rabies, with symptoms that include the following:

• Fever

• Tachycardia

• Hypertension

• Hyperventilation

• Anisocoria, fixed pupillary dilation (“blown pupil”), optic neuritis (may falsely suggest brain death)

• Facial palsy

• Mydriasis

• Lacrimation

• Excessive salivation

• Perspiration

• Postural hypotension

In patients with paralytic rabies, fever and nuchal rigidity may occur. Paralysis is symmetrical and may be either generalized or ascending and may be mistaken for Guillain-Barré syndrome. The sensory system is usually spared. Calm clarity gradually progresses to delirium, stupor, and then coma.

Coma

Respiratory failure occurs within 1 week of neurologic symptoms. Hypoventilation and metabolic acidosis predominate. Acute respiratory distress syndrome is common. Wide variations in blood pressure, cardiac arrhythmias, and hypothermia ensue. Bradycardia and cardiac arrest occur. With intensive support, life may be extended for 3 or 4 months; however, death usually is the outcome.

Death

It is important to determine brain death by brain biopsy or absence of cerebral arterial flow, because some of the neurologic signs may falsely suggest brain death (see above).

If the patient presents after an acute or recent bite

When the patient presents with a bite, the wound should be cleansed immediately with soap and water, flushing it thoroughly to remove saliva. Debridement and careful exploration for foreign body (eg, broken tooth) are essential; this should take at least 10 minutes. Generally, leave wounds to heal by secondary intention to permit drainage of wound fluids and prevent infection.[33, 34]

If the animal to which the patient was exposed has been captured, it should be delivered to a veterinarian for further evaluation or euthanasia; state health departments can then test the unfixed brain tissue.[35]

Consult immediately with public health authorities regarding need for prophylaxis.

If the patient presents with encephalitis and suspected rabies

Skin biopsy from the nape of the neck

Rabies antigen can be detected in cutaneous nerves by direct fluorescent antibody. Consult with public health authorities, as these require specialized laboratories and shipping.

Corneal touch impression

Less preferably, scraping of corneal epithelia, or corneal touch impression, for direct fluorescence antibody can be used. This requires topical ocular anesthetic and is best performed by an ophthalmologist, under public health authority guidance on specimen preparation and transport. Corneal impression is obtained by pressing the surface of sterile glass slide gently but firmly onto the cornea. Corneal scrapings should be performed by an ophthalmologist unless none is available; epithelial cells are gently collected using a sterile loop or spatula and smeared carefully on a glass slide.

Viral cultures and polymerase chain reaction (PCR) assay

Consult with public health authorities, as these require specialized laboratories and shipping. The following may be used:

• Saliva - Results of saliva culture for rabies virus are positive in low yield within 2 weeks of illness onset

• Cerebrospinal fluid - After the first week of illness, 80% monocytosis may be observed; protein levels may be elevated, and glucose test results are normal. However, spinal fluid may also be normal.

• Brain tissue - Often postmortem; staining with immunohistochemical or florescent antibody staining is definitive. Negri bodies are pathognomonic (cytoplasmic inclusion bodies reflective of accumulated virions within rabies-infected neurons). They are found in the horn of Ammon of the hippocampus and cerebral cortex

Blood gas analysis

Respiratory alkalosis resulting from hyperventilation develops in the prodromal and early acute neurologic phases of rabies; this is followed by respiratory acidosis as respiratory depression progresses

Hematology studies

Results of the white blood cell (WBC) count range from normal to elevated, with 6-8% atypical monocytes

Imaging studies

As the neurologic phase of rabies progresses, chest radiographs may reveal infiltrates due to aspiration, nosocomial pneumonia, acute respiratory distress syndrome, or congestive heart failure.

Findings from magnetic resonance imaging (MRI) and computed tomography (CT) scanning of the brain often indicate that no abnormalities are present. MRI may demonstrate increasing nonspecific low-level T2 enhancement early along the nerve plexus and nerve root ganglia early in illness. Later, moderate gadolinium enhancement may appear in the thalamus, substantia nigra, brainstem, deep gray matter, and cranial nerves.[26]

Electroencephalography

Electroencephalography (EEG) findings include encephalopathic changes. Due to generalized vasospasm of cerebral arteries during the first week of illness, EEG amplitude may drop precipitously and mimic brain death. This may be further suggested by papillary reflex abnormalities such as anisocoria or fixed pupils due to dysautonomia. These findings may reverse with return of blood flow. A more reliable means of determining brain death in the case of rabies may therefore be cerebral arterial flow scanning that demonstrates absent flow. Brain biopsy is another option.[36, 37, 38, 39]

Cardiac monitoring

Supraventricular tachycardia may be observed during cardiac monitoring. Eventually, bradycardia and cardiac arrest occur.

Future tests

The nucleic acid sequence ̶ based amplification (NASBA) technique on urine samples may be used in the future.[40, 41] The NASBA technique on saliva and CSF can be used for rapid diagnosis as early as 2 days after symptom onset.

Serum rapid fluorescent focus inhibition test (RFFIT) titer results are positive in 50% of rabies cases. Results of the CSF RFFIT are antibody-positive (2-25% of serum titer) after the first week of illness.

Detection of viral RNA from saliva using PCR assay and viral antigen from brain biopsy specimens yields 100% specificity. Viral antigen assessment involving nuchal skin that contains hair follicles and corneal touch impressions have sensitivities of 67% and 25%, respectively.

Rabies virus RNA may be detected via PCR in saliva, nuchal skin containing hair follicles, CSF, and urine.[26]

In true rabies cases, however, the rise in specific neutralizing antibodies is often not documented through an RFFIT, because the victims succumb to the disease prior to mounting a response. Serologic testing is more useful to ascertain serostatus in immunized animals and humans.[33]

Nuchal skin biopsy is the most reliable test of rabies infection during the first week. Results from nuchal skin punch biopsy for immunofluorescent antibody staining are 50% positive within the first week.

Obtain a full-thickness punch biopsy from the nape of the neck and include hair follicles. Place the specimen in a sterile container with saline-soaked sterile gauze, store it at -70°C, and obtain shipping instructions for a laboratory that performs the examination.

General findings on pathology include cerebral congestion and inflammation typical of encephalitis. Neuronal cell death is uncommon histopathologically.

Immunohistochemical or fluorescent antibody staining of nervous tissue, usually of unfixed brain or skin biopsy specimens with sensory nerve endings, reveals deposition of virion in the cytoplasm.

Negri bodies, seen in the image below, are observed in neurons on light microscopy and represent round cytoplasmic inclusions of assembling nucleocapsid. Only 70% of brain biopsy tissue exhibits this finding in human rabies encephalitis. Electron microscopy is more sensitive than light microscopy and reveals the characteristic bullet-shaped virion.

When the patient presents with a bite, the wound should be cleansed immediately with soap and water, flushing it thoroughly to remove saliva. Debridement and careful exploration for foreign body (eg, broken tooth) are essential; this should take at least 10 minutes. Generally, leave wounds to heal by secondary intention to permit drainage of wound fluids and prevent infection.[33, 34]

Inpatient care

Inpatient care of patients with rabies may be needed if wounds are extensive or are on the face and hands, if surgical repair or replacement of blood loss is required, or if infection occurs.

Transfer

For a patient with an illness consistent with rabies, transfer to a tertiary care center with intensive care support and capability of providing timely diagnostic workup is essential.

Follow-up

Coordinate follow-up evaluations of patients with the primary caregiver, the local health department, and, if applicable, the veterinarian who quarantined the animal.

Preexposure, active prophylaxis or immunization is recommended for individuals who are exposed to rabies virus or who handle specimens considered high risk for rabies and persons who visit countries where rabies is a significant problem. The US Advisory Committee on Immunization Practices (ACIP) updated recommended risk categories and preexposure prophylaxis based on evolving rabies epidemiology, availability and logistics of rabies vaccine administration (especially prior to planned travel), and optimized cost-to-benefit ratio. (See Table 1, below, with detailed review and examples available at https://read.qxmd.com/doi/10.15585/mmwr.mm7118a2)

Table 1. Risk Categories for Active Preexposure Immunization and Rabies Titer Monitoring, ACIP 2022   (Open Table in a new window)

 

In the United States, the CDC recommends rabies postexposure prophylaxis only with intramuscular (IM) cell-cultured vaccines; intradermal (ID) formulations are not approved by the US Food and Drug Administration (FDA) for use in the United States.

Outside the United States, in areas where cost and vaccine supply are limiting factors, alternatives to the IM regimens may be more feasible. In addition, rabies vaccination may be the norm in some countries where rabies is endemic, and anamnestic response may permit effective alternative dosing. In 1998, the World Health Organization (WHO) released guidelines for ID use of human diploid cell vaccine (HDCV), purified chick embryo cell vaccine, and purified duck embryo cell vaccine.[42] The WHO published updated postexposure prophylaxis guidelines that included ID regimens often used outside the United States.[43]

A Rapid Fluorescent Foci Inhibition Test (RFFIT) titer greater than or equal to 0.5 IU/mL (or complete neutralization at a serum dilution of 1:5) is considered an acceptable antibody response for protection against rabies.

Booster immunization is indicated for individuals at continuous or frequent risk for rabies, who should undergo periodic rabies antibody testing as per the ACIP guidance above (Table 1).

Passive immunization consists of the administration of human rabies immunoglobulin (HRIG) pooled from the sera of immunized human donors.

As previously stated, washing and wound debridement at the time of a bite is essential, along with careful cleaning of the wound for longer than 10 minutes. Generally, leave wounds to heal by secondary intention.[33, 34] Antibiotic prophylaxis should be considered.[34, 44]

Administer HRIG to any person not previously vaccinated against rabies, at a dose of 20 IU/kg (for adults and children). Apply as much of the dose as possible at the injury site and the remainder as an IM injection at a site distant from vaccine administration. HRIG may be administered as long as 7 days after the first dose of vaccine if it is not immediately available when the patient presents for evaluation.[18, 33]

Equine rabies immunoglobulin may be available in other countries. Minimal adverse effects occur if it is in the purified form. If unpurified, however it may cause serum sickness and anaphylaxis. Recombinant monoclonal rabies antibody has been developed and licensed outside the United States, with the advantages of greater neutralizing activity, greater specificity for the viral target, a more standardized product, and lower side effect profile. [45]

Two different inactivated rabies vaccines are licensed and produced in the United States, as follows:

• Human diploid cell vaccine (HDCV; Imovax) - Usual dosing for postexposure prophylaxis to be administered as IM injection

• Purified chick embryo cell vaccine (PCEC; RabAvert) - Licensed in the United States in 1997 for IM use only

Doses of all the vaccines for postexposure prophylaxis are 1 mL IM in the deltoid or in the upper outer thigh in infants.

Mild local and systemic adverse reactions to these vaccines and immunoglobulin may occur but are usually treatable with supportive care, antihistamines, and anti-inflammatory medications. Local pain, erythema, headache, nausea, and abdominal pain may occur. If prophylaxis is warranted, do not postpone or discontinue treatment because of mild adverse effects.

Before the onset of rabies symptoms, optimal results require immediate, vigorous wound cleansing; passive immunization with immunoglobulin; and active immunization with rabies vaccine.[25] Children are prone to extensive wounds on the face, upper body, and hands because of their short stature.[46] These wounds may require extensive debridement and inpatient management.

Do not administer immunoglobulin and vaccine with the same syringe or in the same site. Do not administer vaccine in the gluteus, as antibody response may be reduced.

Passive immunoglobulin provides protection for 1-2 weeks until the vaccine elicits protective antibody.

If the patient has had no prior rabies vaccination, if they are of unknown status, or if more than 5 years have passed since their last vaccination, rabies vaccine and immunoglobulin should be administered as follows (these dosages being applicable to products available in the United States):

• Rabies vaccine IM (deltoid) - 1 mL on Days 0, 3, 7, and 14
• In the immunocompromised individual, antibody response to vaccination may be inadequate. Perform RFFIT at least 1 week after last dose and/or consider an additional dose on day 28. ^{[47, 48, 49]}
• Rabies immunoglobulin - 20 IU/kg infiltrated as much as feasible around and under the bite wound; if any is left over, it "should be injected IM at a site distant from vaccine administration."  ^[47]
• The pediatric dose of HRIG, calculated by body weight, may be of insufficient volume to infiltrate all of the wounds. The immunoglobulin may be diluted with sterile saline so that more volume can be used without exceeding the total recommended dose. ^[50]

If the patient has had prior rabies vaccination, rabies vaccine should be administered IM (deltoid) 1 mL on Days 0 and 3 (this dosage again being applicable to US vaccine).

The World Health Organization (WHO) has revised PEP guidance for previously unimmunized individuals in order to reduce cost and spare vaccine doses without reducing effectiveness. Currently recommended guidance for rabies PEP outside the United States, in order of preference, includes the following[25, 51] :

• Two-site intradermal (ID) vaccine administration on Days 0, 3, and 7
• One-site IM vaccine administration on Days 0, 3, 7 and the fourth dose between Days 14 and 28
• Two-site IM vaccine administration on Day 0 and one-site IM administration on Days 7 and 21

Empiric treatment for rabies should be guided by local public health recommendations, whenever feasible, taking into account whether viral shedding periods are known for the species, the animal's history and risk for rabies exposure, and local epidemiology. Some countries and limited areas in US territories are considered rabies-free, and no prophylaxis is administered. 

High-risk wild or feral animals implicated in exposures will be captured, if possible, and euthanized for both humane reasons and for examination of brain tissue. Because of the exceedingly low prevalence of rabies in domestic animals in the United States, healthy, unvaccinated domestic dogs, cats, and ferrets are often observed for 10 days for signs of illness. If the animal remains healthy, no treatment is administered. Vaccinated animals in the United States have not transmitted rabies; outside the United States, rare instances of transmission occur. Note that an assessment of whether a bite was provoked is subjective and does not significantly affect the chances that the animal is rabid. Therefore, this is not helpful in determining the need for prophylactic treatment.[5]

In most settings where rabies is a risk, prophylaxis should be initiated regardless of whether or not the animal is in custody and being observed.  Prophylaxis may be discontinued if the animal does not develop rabies within 10 days or is found to be free of rabies upon sacrifice.The median duration of rabies illness in dogs, cats, and ferrets is less than 10 days, and viral shedding in saliva occurs within a few days of onset of illness and death.

Pregnancy is not a contraindication to postexposure prophylaxis against rabies, which is warranted to protect the life of the fetus and mother. No adverse pregnancy outcomes have been documented with postexposure prophylaxis. No mother-to-fetus transmission has been described, and spread of the virus is not hematogenous; thus, neither rabies exposure nor diagnosis in the mother is an indication for pregnancy termination.[52, 53]

Intradermal (ID) regimens have not been approved by the US Food and Drug Administration (FDA) or recommended by the CDC for use in the United States. WHO recommends ID regimens for use outside the United States when IM vaccine is unavailable or its use is not feasible.

In previously vaccinated individuals, studies have shown that single-visit, 4-site ID booster regimens offer satisfactory anamnestic response. A retrospective study at The Queen Saovabha Memorial Institute (QSMI) investigated booster regimens in more than 5000 previously immunized individuals who presented with rabies exposures. The study found that the single-visit, 4-site ID booster regimen using cell-cultured vaccine demonstrated superior anamnestic response, more rapid rise in Nab levels, and more persistently high Nab levels 1 year after prophylaxis than did the standard WHO 2-visit booster regimen.[54] Advantages of the single-visit booster also included reduced time and reduced costs from loss of work or from delayed travel, along with enhanced compliance.

Inpatient care

Symptomatic rabies cannot be managed in the outpatient setting. Intensive cardiopulmonary supportive care is the only treatment available for patients with symptomatic rabies. Rabies vaccination and administration of HRIG is ineffective at this point, since the CNS does not possess humoral immune mechanisms to mount antibodies and inflammation is insufficient to allow B lymphocytes to cross the blood-brain barrier and mount a defense. In animal studies, rabies immunoglobulin has been associated with “early death”; it has been suggested that HRIG may also pose a risk for early death in humans and should be avoided.[55]  However, there is animal data supporting the use of human monoclonal antibody to reverse rabies, albeit by concomitant administration intramuscularly and via cerebroventricular infusion.[56] Treatment in the United States would require at minimum an emergent Investigational New Drug application on a compassionate use basis.[57]

However, it must be noted that there is no current scientific consensus on the management of rabies, and management is symptomatic. Therapeutic coma is no longer recommended, and sedation should be limited to that required for comfort and management of spasms. Nimodipine may be used for cerebrovascular spasm but may cause severe hypotension.[26]

Regardless of treatment, symptomatic rabies is almost invariably fatal, with autonomic dysfunction leading to cardiac arrhythmia and hypotension. Some role for combination treatments including ribavirin, interferon, ketamine, and immunomodulatory therapies has been proposed and may be considered in future cases under investigational protocols.

The survival of a teenaged girl from Wisconsin received substantial attention in October 2004 as the first reported case of human survival of rabies in the absence of preceding vaccination or postexposure prophylaxis.[58] Notably, she received an investigational regimen of ribavirin, amantadine, and a ketamine-midazolam–induced coma. However, this therapy has not been validated and has not been reproducible in several subsequent cases. It is no longer recommended, and the University of Wisconsin no longer maintains the Rabies Registry website. Furthermore, the bat rabies virus isolated in this case may be less neurovirulent than canine or other variants that are responsible for most human cases of rabies.[26, 59]

The rarity of human rabies hinders timely testing of therapies. Immunomodulatory therapies such as rabies immunoglobulin, rabies vaccine, and interferon have not altered outcomes in trials.

Steroids, which usually are indicated in the treatment of local vaccine reactions or cerebral edema, are contraindicated because of increased mortality noted in animal studies and because they reduce the response to the vaccine.

Transfer

For a patient with an illness consistent with rabies, timely diagnostic workup is essential. Transfer to a tertiary care center with high-level intensive care support and clinicians knowledgeable in managing rabies is optimal whenever feasible.

In the community

Patient education

The need for adherence to local public health recommendations regarding the control and vaccination of domestic animals and the vaccination of individuals who may be exposed to rabies in their occupation cannot be stressed enough. The case of the Wisconsin survivor, who did not seek medical attention after being bitten, underscores the need for ongoing public education about preventing this almost uniformly fatal infection.

Counsel patients regarding the subjective nature of provocative behavior toward animals. Especially stress avoiding contact with unfamiliar or wild animals. Wild animals seen in areas or at times of day that seem unusual are reason to suspect rabid behavior. Wild animals that are rabid may seem unusually docile or fearless. Hypersalivation, or “foaming at the mouth,” is pathognomonic for rabies but is often absent.

Prompt, vigorous cleansing of any injury or bite from any animal is critical and may reduce the risk of rabies transmission. Provide extensive reassurance after any injury that may be related to rabies transmission. Fear of rabies is primal and is known to induce hysterical reactions that mimic the disease manifestations.

Promote educational efforts at home and at schools teaching children about safety procedures and precautions regarding pets and wild animals. Many communities have programs through camps, schools, and public libraries, as well as information through local health department Web sites.[60] Veterinarians and public health officials are excellent resources for concerns regarding animal rabies prevention.[18, 61]

In addition, the public should be advised to do the following:

• Teach children at an early age not to handle stray animals or wildlife, especially bats found on the ground

• Report any animals that are sick or acting strange to local public health authorities

• Consult public health authorities if a bat is seen in the home at night, even if a bite is not suspected

• Keep pets indoors at night and fenced in or on a leash when outdoors

• Keep pet food and water dishes indoors

• Have professional animal trappers remove bat colonies from homes and barns

• Handle sick or dead animals with heavy gloves and shovels

• Keep trash container lids tight and maintain compost piles away from dwellings

• Wash hands with soap and water after contact with wildlife

• If an animal scratch or bite occurs, especially if due to a bat, fox, raccoon, skunk, or unvaccinated dog or cat, (1) immediately wash the areas vigorously with soap and water and (2) immediately seek care at an emergency department. Aside from rabies, bites may become infected, and preventive care is available if sought.

For patient education information, see the Infections Center, as well as Rabies.

Healthcare workers

Universal precautions and respiratory precautions during respiratory therapy are indicated for healthcare providers. Rabies postexposure prophylaxis of health care workers is indicated only for high-risk exposures as determined with the assistance of local infection control and public health authorities.

Organ transplant recipients

Pretransplantation screening for potential rabies infection or exposure should be performed on organ donors.[18] Recipients of corneal and neurally derived tissues are at highest risk for rapid development of rabies; however, solid organ transplant recipients have also become infected.

Clinical screening of potential organ donors should include a history of animal bites, presence of clinical features of rabies, and a travel history (within a period of months) to areas where rabies is endemic; preexposure rabies immunization of potential organ recipients is being evaluated as an alternative approach to prevent transmission associated with organ transplantation.[23]

Control of rabies in the animal population

Because rabies is a zoonosis, primary prevention requires control of rabies in the animal population. In 1997, approximately 100,000 animal brains were tested for rabies virus antigen using a direct fluorescent assay. Of these specimens, 8509 (8.5%) had positive results.

Mass control and mandatory vaccination of domesticated dogs and cats are effective in controlling rabies in the United States; however, developing nations have found cost to be a barrier to such campaigns.

Live viral vaccines containing modified live rabies or recombinant vaccinia-rabies glycoprotein virus, placed in a bait, are used for disease control in Europe and North America.[21] In the United States, more than 22 million doses of vaccinia-rabies glycoprotein vaccine were distributed between 1990 and 2000. The baits were mainly used to control rabies in raccoons in the eastern United States and in foxes and coyotes in Texas. People will inevitably find vaccine-laden baits. Dogs are frequently attracted to the baits and bring them to their owners. Luckily, adverse events are rare.[21]

Consultation with infectious disease specialists, neurologists, and neurosurgeons may be necessary to assist in diagnosis and management of patients with rabies or patients exposed to rabies.

Consultation with public health authorities is appropriate to assist in management of bite wound prophylaxis and animal epidemiology.[62]

The Centers for Disease Control and Prevention maintains a 24/7 Emergency Operations Center for consultation at 770-488-7100.

Also, consult with animal control officers and veterinarians for the management, disposal, and testing of animals that have attacked and injured a human.

Before the onset of rabies symptoms, passive and active immunizations are effective in preventing progression to full-blown rabies.

If the patient has had no prior rabies vaccination, if they are of unknown status, rabies vaccine and immunoglobulin should be administered as follows (these dosages being applicable to products available in the United States):

• Rabies vaccine IM (deltoid) - 1 mL on Days 0, 3, 7, and 14 (if immunocompromised, add an additional dose: 1 mL IM deltoid on days 0, 3, 7, 14, and 28)

• Rabies immunoglobulin - 20 IU/kg infiltrated as much as feasible around and under the bite wound; if any is left over, give IM at a site distant from vaccine administration

If the patient has had prior rabies vaccination, vaccine should be administered as follows (this dosage again being applicable to US vaccine): Rabies vaccine IM (deltoid) 1 mL on Days 0 and 3.

Class Summary

Rabies immunoglobulin is recommended as part of the rabies postexposure regimen for persons not previously immunized against rabies. Vaccine and antiserum should never be mixed or injected in the same limb.

In the United States, passive immunization consists of administration of HRIG pooled from the sera of immunized human donors. In developing countries, equine rabies immunoglobulin (ERIG) is sometimes used but has a higher incidence of adverse effects. ERIG is no longer produced by large pharmaceutical companies. When produced by smaller pharmaceutical firms, its quality cannot be assured. New-generation purified ERIG preparations are under investigation.

Human rabies virus–specific monoclonal antibody preparations are in development, theoretically to decrease the possibility of anaphylaxis.[63, 64, 65]

Because of cost, ERIG and HRIG are not readily available throughout much of the developing world, areas in which rabies is more common than in the United States. If HRIG is available only after more than a week after vaccination has started, then it is probably unnecessary, because an active antibody response has already begun.

Rabies immune globulin, human (RIG) (HyperRAB S/D, KedRab, Imogam Rabies-HT)

HRIG has been licensed since 1975, and unlike its predecessor, ERIG, it is not associated with significant adverse reactions, anaphylaxis, or serum sickness. Purified ERIG is still used in some developing nations because of cost or availability and is associated with an adverse effect rate of 0.8-6%, which usually involves minor reactions. HRIG is not associated with transmission of viral hepatitis or HIV. Experimentally, infiltration of HRIG at the site of exposure is more protective than IM administration. The current recommendation is that the entire dose be infiltrated, if possible, in and around the site, with any remaining solution administered IM at a site distant from vaccine administration.

Heat-treated and cold alcohol–fractionated immunoglobulin is derived from pooled human plasma from individuals immunized with human diploid cell rabies vaccine.

A stabilized, ready-to-use solution for injection (KedRab) is also available.

Class Summary

These agents promote immunity by inducing an active immune response. Two types of rabies vaccines have been produced: cell-cultured vaccines and nerve tissue vaccines.

In developing countries worldwide, nerve tissue vaccines have been the most widely used type for prophylaxis of rabies. They are dangerous because they may induce autoimmune CNS disease and may produce neurologic reactions; they also require multiple injections and are not always effective. WHO has advised discontinuation of nerve tissue rabies vaccines.[3]

Two types of nerve tissue vaccine exist: the Semple type (STV) and the suckling mouse brain vaccine (SMBV). STV is obtained from inactivated virus prepared on adult animal nerve tissue. It is inexpensive and relatively easy to produce. In India, 3 million people receive postexposure courses of STV each year. STV may produce neurologic reactions, including postvaccination encephalomyelitis, in up to 1 in 220 courses, with a 3% mortality rate.

SMBV is cultured on immature mouse brain tissue, which contains little myelin. It is the most widely used rabies postexposure vaccine in Vietnam. Rare neurologic reactions occur, with complications in 1 in 27,000 treated people, with a 22% mortality rate.

Because SMBV and STV are widely used throughout the developing world, they are the vaccines that are administered to US travelers exposed to animal bites in some countries. It is advisable that US travelers to endemic areas receive pretravel rabies immunization with a cell-cultured vaccine if the itinerary suggests sufficient risk.

Cell-cultured rabies vaccines benefit from efficacy demonstrated in trials and a high level of immunogenicity; this permits a rational dosing schedule, and cell-cultured vaccines are considered the reference standard. The disadvantage of these vaccines is the cost of production.

In the United States, the CDC recommends rabies postexposure prophylaxis only with IM cell-cultured vaccines; intradermal (ID) formulations are not FDA approved for use in the United States.

Outside the United States, in areas where cost and vaccine supply are limiting factors, alternatives to the IM regimens may be more feasible. In addition, rabies vaccination may be the norm in some countries where rabies is endemic, and anamnestic response may permit effective alternative dosing.

In 1998, WHO released guidelines for ID use of HDCV, purified chick embryo cell vaccine, and purified duck embryo cell vaccine.[42] WHO published updated postexposure prophylaxis guidelines that included ID regimens often used outside the United States.[43]

In previously vaccinated individuals, studies have shown that single-visit, 4-site ID booster regimens offer satisfactory anamnestic response. A retrospective study at The Queen Saovabha Memorial Institute (QSMI) investigated booster regimens in more than 5000 previously immunized individuals who presented with rabies exposures. The study found that the single-visit, 4-site ID booster regimen using cell-cultured vaccine demonstrated superior anamnestic response, more rapid rise in Nab levels, and more persistently high Nab levels 1 year after prophylaxis than did the standard WHO 2-visit booster regimen.[54] Advantages of the single-visit booster also included reduced time and reduced costs from loss of work or from delayed travel, along with enhanced compliance.

Booster immunization is indicated for individuals at continuous or frequent risk of rabies, who should undergo periodic rabies antibody testing and who have serum rabies titer of less than 1:5 dilution based on RFFIT results.

Rabies vaccine (HDCV, Imovax Rabies, Rabies vaccine human diploid cell culture)

Indicated for preexposure and postexposure. Grown in human diploid cell culture. Contains the inactivated virus that promotes immunity by inducing an active immune response. For IM use only.

Rabies vaccine chick embryo cell derived (RabAvert)

Indicated for preexposure or postexposure. Contains the inactivated virus that promotes immunity by inducing an active immune response. For IM injection.