Rabies

Etiology

The RABV and other rabies-like viruses are zoonotic, neurotropic, bullet-shaped RNA viruses belonging to the genus Lyssavirus, family Rhabdoviridae, and order Mononegavirales.[1] Enhanced surveillance and sequencing technologies demonstrate that Lyssaviruses are highly diverse and continuously evolving, with 14 species other than RABV known to cause rabies disease. Some lineages are well-known and widespread, whereas others comprise only a few known isolates.

The RABV most likely came from a bat ancestor and evolved through multiple host-switching events in dogs, bats, and other animals.[14][15][16] Seven main lineages of RABV exist worldwide, each with many variants associated with specific animals and geographies.[4][1] The most widespread lineage occurs in dogs and wildlife species such as foxes, jackals, and skunks in Europe, Africa, the Americas, and Asia. Many bat-associated lineages in Latin America continue to cause rabies in humans and domestic livestock. Continued genetic diversification of RABV and other Lyssaviruses raises concerns that the existing HRIG and rabies vaccines may cease to be effective for human rabies prevention.[4]

Epidemiology

Clinical Presentation 

Rabies is a zoonotic infection transmitted to humans through contact with the saliva of an infected animal's saliva via a bite, open wound, abrasion, conjunctiva, or mucous membranes, including genitalia.[17][1][8] Bite exposures carry a much higher risk of rabies transmission than nonbite exposures.[17] The incubation period of rabies can range from a few days to a few years, with an average of 20 to 90 days.[1][5] The incubation period is influenced by factors such as the density of nerve endings at the entry site, wound depth, inoculum, the type of mammal, and the host's immunocompetency.[1] The literature documents only a few dozen cases of survival after the onset of rabies symptoms, many with significant neurological deficits.[4]

Rabies Virus Distribution and Sources of Transmission

Rabies viruses are distributed worldwide except in Antarctica and can infect any mammal, including dogs, cats, livestock, and wildlife.[1] Chiropters, or bats, are the reservoir species for most Lyssaviruses. However, the most common reservoir species for the RABV are mesocarnivores—animals whose diet is 50% to 70% meat—such as dogs, raccoons, mongooses, and skunks.[1] Many rabies-free countries are endemic for other Lyssaviruses. The RABV contributes the vast majority of the rabies disease burden (CDC. CDC Yellow Book).

Although wild animals can transmit rabies to humans, domestic dogs are the source of transmission in more than 99% of human cases worldwide, mostly from unvaccinated domestic dogs.[17][18] In contrast, wildlife transmits more than 90% of RABV, resulting in human cases in the United States.[17] In 2022, the National Rabies Surveillance System reported 3579 total animal rabies cases, of which bats (34.0%), raccoons (28.3%), skunks (18.4%), and foxes (27.5%) were the most common.[19] Greater than 90% of reported domestic animal rabies occurred in cats (6.2%), cattle (1.2%), and dogs (1.4%); nearly all were unvaccinated. Most animal rabies cases occur in areas with enzoonotic raccoon variant RABV spilling over to other animal species.[1]

Small rodents, rabbits, and hares are generally not reservoirs of rabies worldwide, although infection can occur in rare circumstances.[9] Transmission to humans has never been documented in the United States (CDC. Clinical Overview of Rabies). Large rodents such as groundhogs (woodchucks) and beavers can serve as reservoirs. Rodents are a known transmitter of Lyssaviruses in some parts of Africa.[1]

Transmission through corneal, solid organ, or vascular transplantation or aerosolization of highly concentrated virus in caves or laboratories occurs rarely. Human-to-human transmission generally does not otherwise occur (CDC. CDC Yellow Book).

Morbidity and Mortality

A 2015 study estimates that canine rabies causes roughly 59,000 human deaths and more than 3.7 million disability-adjusted life years each year.[20] Rabies is considered a neglected tropical disease because it is more prevalent in endemic countries that have few resources to apply adequate preventative measures.[21] The majority of human rabies deaths occur in Africa (36.4%) and Asia (59.6%); less than 0.05% of cases occur in the Americas, where 70% of cases occur in Haiti.[20] India had the highest number of human rabies deaths, accounting for 35% of total global cases; however, the highest per-person death rates occur in the poorest countries of sub-Saharan Africa.[20] In low-socioeconomic countries, the age-standardized incidence and mortality of rabies follow an M shape with peaks in childhood and working age. Males are more commonly affected than females, and children are more commonly affected than older adults, as these populations carry a higher exposure risk to rabid animals.[20] Children are more likely to be bitten on the head, carrying a higher risk for infection and a short incubation period.[1][20]

Human rabies is extremely rare in the United States and other resource-rich countries due to the widespread use of PEP, mandatory domestic animal vaccination, adequate surveillance, and other large-scale preventive measures that decrease the incidence of rabies in domesticated animals, wildlife, and, subsequently, humans.[1][17] The United States, with national control programs since the 1940s, reports only a few human rabies cases annually; most of these cases are acquired domestically, and none of the affected individuals received pre- or post-exposure prophylaxis.[18][8] About 60,000 individuals in the United States receive PEP each year after exposure to potentially rabid animals (CDC. Clinical Overview of Rabies).

Despite timely PEP, an 84-year-old male died of rabies in Minnesota in 2021, 6 months after exposure to a bat, due to an unrecognized underlying immunocompromising condition. This case is the only documented PEP failure in the Western Hemisphere after the timely receipt of a modern cell culture–based vaccine.[8] The estimated rate of rabies exposure is 16 to 200 per 100,000 returning travelers (CDC. CDC Yellow Book).

Rabies Costs

A 2015 study estimates that canine rabies causes 8.6 billion USD in annual economic losses globally.[20] Healthcare expenses include the high cost of HRIg, vaccine storage equipment and transport, and surveillance systems. Patients also incur costs for travel, time away from work, and accommodation during the PEP treatment completion period. These factors decrease the ability of patients to complete treatment with more extended regimens.

Pathophysiology

Following viral transmission, RABV multiplies locally until it reaches a peripheral nerve synapse, typically neuromuscular. The nicotinic acetylcholine receptor, a neuronal cell adhesion molecule at the neuronal synapse, plays a key role in RABV cell entry.[1] Exposures in highly innervated tissues such as the face and hands increase the risk for successful transmission. (CDC. CDC Yellow Book).

Once peripheral neuroinvasion occurs, RABV travels proximally through retrograde axoplasmic flow.[1] RABV enters the dorsal root ganglia that correspond to the nerves at the entry site of the virus.[1] Pain or paresthesia at the bite site is an early symptom of rabies caused by local inflammation once the virus reaches the dorsal root ganglia (CDC. CDC Yellow Book).[1] Exposure in a proximal location, such as the head and neck, often results in a shorter incubation period (CDC. CDC Yellow Book).

Viral replication increases exponentially once reaching the CNS due to a failure of glial cells to produce adequate type I interferon, an inadequate immune response, and unhindered RABV replication.[1][22] The initial location of cerebral infection depends on which motor neurons innervate the RABV entry site. Centrifugal spread of RABV by anterograde axonal transport occurs following CNS invasion, leading to infection of various tissues. The salivary glands are the primary target, with invasion leading to sialorrhea, the classic frothing observed in clinical rabies.[23][24] Continued viral replication leads to encephalitis, nervous system failure, and death.

Histopathology

Autopsy studies reveal a varied picture of the brain when infected with RABV. Histologically, a picture of encephalitis predominates, which is difficult to distinguish from other viral encephalitis. Intracytoplasmic Negri bodies are pathognomonic for rabies but are only present in 20% to 60% of cases. Immunochemical staining reveals deposits of the virion in the nerve cytoplasm.[25]

History and Physical

Two clinical scenarios of potential rabies exposures and potential clinical rabies are addressed separately in this section—patients seeking assessment following a known or suspected rabies exposure and patients presenting with possible clinical rabies.

Rabies Exposure Risk Assessment

Patients frequently seek medical care after a known or suspected encounter with an animal known or suspected to be rabid. All injuries where teeth break the skin or where mammalian saliva or other potentially rabies-infected tissue comes into contact with the conjunctiva, mucous membranes, or open skin carry a potential risk for rabies. The CDC recommends that most potential rabies exposures require urgent but not emergent evaluation. However, immediate assessment is necessary for the following situations:

• Direct contact with bats, unless the person can rule out a bite or scratch
• Exposure to high-risk animals, such as bats, raccoons, skinks, foxes, and mongooses in the United States
• Severe exposures, such as multiple wounds or exposures to the head and neck
• Exposure in young children (CDC. Clinical Overview of Rabies)

The history and physical examination should evaluate the animal's characteristics, the circumstances of exposure, and the wound to determine the likelihood of rabies exposure and the need for rabies treatment.[9] There is no time limit for assessment; clinicians should perform a risk assessment even if a patient presents months or years following a possible exposure.

In most scenarios, clinicians assessing patients for possible rabies exposure should consult public health officials, according to local guidelines (CDC. Clinical Overview of Rabies). However, consultation is unnecessary if clinicians determine that no broken skin or mucous membrane contamination occurred and the animal was not a bat.

Medical history: Clinicians should obtain a history of previous rabies vaccination for PrEP or animal exposure. If a patient started rabies treatment in another jurisdiction, documentation should be requested, including details of wound treatment; tetanus vaccination; the dose; the route, such as intramuscular (IM) or intradermal (ID); the site; the number of rabies vaccines received; the dose and site of RIg administration; and the facility where care was provided, such as local clinic, national hospital, or certified travel clinic. Patients receiving treatment overseas may receive no or less than the recommended HRIg dose. Receipt of substandard vaccination products has led to rabies deaths.[9] Clinicians should generally accept a medical decision to start treatment abroad, as local physicians are more likely to know the local rabies epidemiology (CDC. Clinical Overview of Rabies). In addition, clinicians should ask the patient about immunocompromising conditions or medications, as these factors can change the PEP regimen.

Animal characteristics: In low-prevalence countries such as the United States, the source animal's geographic location, type, behavior, and vaccination status are all essential parts of the history. The clinician should ask whether the animal is available for observation (for domestic animals) or testing (for strays and wild animals).

Due to high vaccination rates, domestic animals are uncommon rabies transmitters in the United States and other countries with comprehensive rabies control programs. Transmission is more likely from recently imported, recently vaccinated, or unvaccinated dogs, cats, and ferrets or where vaccination schedules lapsed. Outdoor pets are more likely to carry rabies than indoor pets. The risk also varies regionally.

Wild animals such as bats, raccoons, skunks, and foxes are the most common rabies carriers in the United States. However, other species, such as otters and coyotes, pose risks in specific locations (CDC. Clinical Overview of Rabies). Clinicians should ask whether the animal appeared unhealthy and obtain a description of its behavior. Exposure to healthy-appearing, normal-behaving rabbits, hares, and small rodents rarely constitutes a risk requiring PEP (CDC. Clinical Overview of Rabies).[9]

All animals should be considered potentially rabid in endemic countries, regardless of species.[12] Dogs are the most common source of human rabies in most of the world; however, exposures to wild animals carry the highest risk. Animal (and human) vaccines may not have adequate quality control in some countries, so previous vaccination of a domestic animal cannot be relied upon as a sign of immunity.[12]

Exposure circumstances: Clinicians should assess when the potential exposure occurred, as patients may present days, weeks, or even years after exposure. Unprovoked attacks or aggressive behavior may be more likely to result in rabies transmission. Bites incurred while attempting to feed or handle wild animals are generally regarded as provoked.

Bat exposures merit special consideration. The ACIP states no prophylaxis is necessary if the patient can confidently confirm that no bite, scratch, or mucous membrane exposure occurred.[9] A challenging clinical scenario is finding a bat in a room with a child or a deeply sleeping, mentally disabled, or intoxicated adult. These scenarios typically constitute an exposure unless circumstances suggest exposure is unlikely, such as the presence of a bed net or an open window. Clinicians should discuss all such cases with state or local public health officials. Other jurisdictions may assess such exposures differently due to local epidemiology. 

Wound assessment: A thorough examination of wounds is essential for an accurate rabies risk assessment. The depth, number, and location of injuries influence the risk of transmission. Even where wounds are obvious, a full-body examination should be considered to identify possible minor injuries to other body parts that may otherwise be overlooked, particularly in children. For lick exposures, the affected area should be carefully inspected for open cuts or scrapes. Following bat exposure, clinicians may or may not find puncture marks or scratches, as these can be extremely small.

The WHO categorizes wounds into 3 exposure categories based on the likelihood of the RABV entering the bloodstream.[12]

• Category I: Touching or feeding animals, contact with blood, urine, or feces, licks on intact skin; these do NOT constitute an exposure.
• Category II: Nibbling of uncovered skin, minor scratches, or abrasions without bleeding; the skin is broken, constituting an exposure.
• Category III: Single or multiple transdermal bites or scratches, contamination of mucous membranes or broken skin with saliva from animal licks or neural tissue, or exposure due to direct contact with a bat; these constitute severe exposure.

Clinical Rabies

Clinical rabies is exceedingly rare in most industrialized nations; however, clinicians should consider it in the differential diagnosis of a wide variety of febrile or neurological clinical presentations. A detailed history, a thorough physical examination, and a high index of suspicion are essential for achieving a timely diagnosis. A known history of animal exposure facilitates the diagnosis; however, its absence does not exclude it due to the difficulty of accurate recall following a possibly long incubation period.

Nonspecific viral symptoms such as fever, malaise, myalgias, gastrointestinal symptoms, and headache, which are difficult to distinguish from other common viral illnesses, characterize the initial prodromal phase of rabies.[1][17] Within 2 weeks, the neurological phase begins with anxiety, agitation, and delirium (CDC. CDC Yellow Book). Prodromal and neurological symptoms may overlap.[8] Approximately 80% of patients develop encephalitis or furious rabies, with severe pharyngeal muscle spasms stimulated by the sight, sounds, or thought of water resulting in hydrophobia or aerophobia, hyperactivity, and spasms progressing to paralysis (CDC. CDC Yellow Book). The remaining 20% develop paralytic rabies (previously called dumb), with ascending, progressive paralysis initially affecting the exposed limb (CDC. CDC Yellow Book).[1] Atypical or non-classic presentations of rabies occur rarely. The factors determining clinical presentation remain ill-defined.[1]

The classic hydrophobia and irritability are not observed in patients with paralytic rabies. Weakness is a hallmark, although patients may also have altered mentation, ongoing fevers, and bladder dysfunction. Non-classic rabies is associated with seizures and more profound motor and sensory symptoms. The presentations may overlap with other neurological syndromes such as neuropathy, delirium tremens, tetanus, botulism, diphtheria, tick-borne diseases, or Guillain-Barré syndrome.

Agitation, mentation changes, and autonomic dysfunction can occur, with increased deep tendon reflexes, nuchal rigidity, and a positive Babinski sign. Examination findings outside the nervous system include tachycardia, tachypnea, and fever. With cardiac involvement, patients may have signs and symptoms related to myocarditis, heart block, ST-elevation syndrome, and heart failure, such as chest pains and arrhythmias.[26]

The coma stage of rabies typically begins within 10 days of the onset of neurological symptoms. Patients may have ongoing hydrophobia, prolonged apneic periods, and flaccid paralysis. Most patients die within 2 to 3 days of coma onset.[1]

A careful review of systems in the early stages may reveal ambiguous initial signs of neuropathy, such as tingling, pruritus, or discomfort at the injury site.[1] The diagnosis of more advanced rabies is primarily clinical when patients present with classic encephalitic symptoms. Atypical or paralytic may be challenging to diagnose. Rabies should always be considered in the differential diagnosis of any patient with acute, progressive viral encephalitis, even if the disease is uncommon in the region.

Evaluation

Rabies Exposure

Laboratory, radiographic, and other tests are not routinely required to assess a patient for possible rabies exposure unless the severity of the wound indicates otherwise. Healthy patients completing PEP or PrEP do not require routine virus-neutralizing antibody testing; however, the CDC recommends post-PEP and post-PrEP antibody testing for immunocompromised patients.[12] Antibody testing using rapid fluorescent focus inhibition testing (RFFIT) within 1 to 2 weeks of a patient receiving questionable rabies biologicals overseas can also be helpful to determine further treatment. The minimum acceptable antibody level is one that completely neutralizes a virus challenge at a serum dilution of 1:5, according to the CDC. The WHO recommends a titer of greater than 0.5 IU/mL.[9] State and local health departments can help find an appropriate lab for RFFIT.

Rabies Disease

As rabies is a rare disease with initial symptoms often similar to other neurological diseases, laboratory testing is crucial for early diagnosis. Routine laboratory evaluations include a complete blood count, electrolyte measurements, and cultures. Cerebrospinal fluid (CSF) analysis typically results in nonspecific findings typical of encephalitis, such as pleocytosis and elevated protein. An electrocardiogram or other cardiac testing may indicate myocarditis, heart block, ST-elevation syndrome, or heart failure.[26] Imaging, including neuroimaging, is typically normal in rabies cases but may rule out other diseases in the differential diagnosis. Obtaining neuroimaging can be challenging in agitated patients.

Distinguishing rabies from other viral encephalitis and confirming a rabies diagnosis requires specific testing of multiple samples.[25] For a definitive antemortem diagnosis, the CDC mandates 4 specimens—CSF, saliva, serum, and skin biopsies taken from the nape of the neck. The punch biopsy must be full thickness, containing at least 10 hair follicles and at least 1 cutaneous nerve at the follicle base. Samples must be stored without preservatives or additional fluid and sent immediately. Samples stored at −20 °C  or lower must be received at the CDC within 21 days; refrigerated samples must be received within 3 days. Turnaround time is typically 7 days but can be expedited to less than 3 days for human or animal species. Testing may also be available commercially, in state health departments, or at universities (CDC. Rabies Biologics).

The CDC performs the following confirmatory rabies-specific testing on antemortem specimens:

• Serum and CSF
  • Viral neutralizing antibodies using RFFIT 
  • Indirect fluorescent antibody test for immunoglobulin (Ig)G and IgM

•  Saliva
  • Reverse-transcription polymerase chain reaction (RT-PCR)

• Nuchal skin biopsy
  • Direct fluorescent antibody test (DFA)
  • RT-PCR

Other countries may use various combinations of DFA, RT-PCR, RFFIT, and other tests to diagnose rabies. For example, DFA detects antibodies in other tissues, serum, and CSF,[27] and RT-PCR detects RABV RNA in saliva, CSF, skin biopsies, brain tissue, or serum samples.[28] A correct interpretation of these tests can be challenging. For example, IgG antibodies to the RABV may be present in the blood or CSF with prior vaccination or rabies immunoglobulin (RIg) and not indicate rabies infection; a careful history of prior rabies PEP or PrEP is required.[29] 

The gold standard for postmortem confirmation is virus detection via DFA or RT-PCR in cerebellar and full cross-section brain stem samples. The CDC prefers fresh-frozen specimens, and submission of these samples requires pre-approval. The turnaround time for frozen specimens is 7 days. Tissue decomposition can hinder diagnosis if it occurs.

Animal Observation and Testing

Stray domestic or wild animals, including bats, implicated in a possible human rabies exposure should be safely captured, immediately euthanized, and submitted for rabies testing. Patients or families should not put themselves at risk of exposure to capture the animal. Animal control officers submit only the animal's intact head or brain, including the brainstem, to preserve anatomical features for examination. Very small animals, such as bats, are submitted whole. Specimens must be kept refrigerated.

Experts routinely recommend a 10-day observation period for cats, dogs, and ferrets, as the rabies incubation period for these species is well understood. A veterinarian may require a rabies antigen level and must examine any animal showing signs of illness, promptly reporting the case to public health authorities. Animals showing signs of rabies must be euthanized and submitted for diagnostic testing. State or local public health departments can assist with obtaining appropriate laboratory testing through the CDC or other state or university facilities. The CDC provides a 3-day turnaround time for submitted specimens.

Treatment / Management

This section begins with a brief overview of rabies biologicals and then discusses the following three clinical scenarios:

• The patient presents with a possible rabies exposure.
• The patient presents with clinical manifestations consistent with rabies.
• Public health management of confirmed or suspected cases of rabies.

Rabies Biologicals

Rabies vaccines: Rabies vaccines are extremely safe and well-tolerated. Given the high mortality rate of rabies, no contraindications exist for rabies vaccine use as PEP.[12] Experts worldwide consider the rabies vaccine safe during lactation and in pregnancy; limited data show no increase in fetal anomalies, premature births, or spontaneous abortions.[6][18][9](B3)

The United States Food and Drug Administration (FDA) approves 2 types of rabies vaccine—a human diploid cell vaccine (HDCV) (Imovax^®) and a purified chick embryo cell vaccine (PCECV) (RabAvert^®) (CDC. Rabies Biologicals).[9] Multiple rabies vaccines that are not FDA-approved and may or may not be WHO-recommended are available and in use worldwide.[9][12][9] Like the United States, the WHO recommends HDCV or PCECV.[12] The WHO advises against the production or use of any nerve-derived vaccines. Rabies vaccine adsorbed (RVA) is not recommended. Nerve-cell-derived and RVA vaccines are less effective and carry a higher risk of adverse effects.[12](B3)

HDCVs and PCECVs contain greater than 2.5 IU of rabies antigen diluted at the point of care in 1 mL of diluent. The United States and many other countries continue to recommend only IM vaccine administration, despite the WHO recommendation for time- and vaccine-sparing ID schedules.[12][13][12](B3)

Rabies immunoglobulin: RIg provides passive immunity for rabies PEP when the patient has no prior immunity to rabies. The United States licenses 3 HRIg products using plasma derived from hyperimmune individuals—HyperRab^TM S/D, HyperRab^TM, and Imogam^® Rabies-HT (CDC. Rabies Biologicals). All are administered IM in and around the wound.[18] HyperRab^TM is the only RIg with a concentration of 300 IU/mL (compared to 150 IU/mL for all others), thus requiring a lower volume for administration (CDC. Clinical Overview of Rabies). Care must be taken to ensure administration of the correct dose.

Other countries license multiple other HRIg formulations, all at 150 IU/L (except where a 300 IU/L product is available).[12] Some countries use equine rabies immunoglobulin (ERIg) due to better availability or lower cost. Clinicians must be ready to treat anaphylactic reactions. ERIg carries a 0.8% to 6% risk of adverse reactions, which are mostly minor but higher than for HRIg. India produces and licenses 2 effective rabies monoclonal antibody products,[30] and the WHO encourages monoclonal antibody use over RIg where available.[12]

Postexposure Prophylaxis

General principles

Treating a patient at risk of rabies transmission requires immediate wound care and rabies vaccination, with or without rabies immune globulin (RIg), administered as soon as possible after exposure.[12] Globally, recommended regimens vary based on the number and route of rabies vaccine administration and the wound categories requiring RIG, depending on risk tolerance, financial resources, and the local availability of rabies biologicals. The guidelines for treating potential bat exposure differ between Canada and the United States, highlighting the need for clinicians to adhere to local protocols. The CDC advises rabies PEP in all cases unless there is reason to believe no contact occurred (CDC. Clinical Overview of Rabies). In contrast, the Canadian Immunization Guide recommends PEP only if there is reason to believe contact with a bat occurred, such as if the person feels the contact, the bat is found on the bed, or a child awakens crying (Government of Canada. Rabies vaccines: Canadian Immunization Guide). This recommendation is based on the rarity of bat rabies in Canada, with an estimated 314,000 individuals requiring treatment to prevent one case of human rabies.

When determining the appropriate treatment, clinicians should consider the following:

• If a clinician determines no rabies exposure has occurred based on a careful risk assessment, the patient can be reassured and discharged after cleaning exposed skin surfaces.
• Some jurisdictions require clinicians to consult local or state public health authorities for all potential rabies exposures. Public health authorities should be contacted whenever uncertainty exists.
• Treatment received by returning travelers abroad may not meet home-country standards; clinicians in the home country may need to provide additional prophylaxis.
• Public health officials may recommend delayed PEP in cases where an animal is being observed or euthanized, and timely results are expected. If PEP has been started, it can be discontinued if the source animal tests negative for rabies using an appropriate diagnostic test, such as direct immunofluorescence antibody testing.[18][9][12]
• HRIg and vaccine are not indicated for patients with a repeat exposure within 3 months.[18][9][12] Treatment for repeat exposures lasting longer than this remains the same as for other previously vaccinated patients.
• The WHO and CDC recommend rabies PEP even years after exposure, as rabies can rarely develop after a prolonged period.[18][9][12]
(B3)

Wound care: Thorough, gentle cleaning is the first step in treating any wound caused by a bite or exposure to saliva or tissue, irrespective of the potential for rabies. Animal studies indicate that washing with soap and water for at least 15 minutes reduces the risk of rabies by 30%.[17] Care should be taken to avoid further tissue damage. If available, irrigation with a virucidal agent such as povidone-iodine should follow.[6][31] Adequate wound care is particularly crucial for individuals with immunocompromising conditions.(B3)

Please see StatPearls' companion resource, "Animal Bites," for further information.

Previous unvaccinated patient: Patients previously unvaccinated with the rabies vaccine require both the rabies vaccine and HRIg as PEP.

• Rabies vaccine
  • IM rabies vaccines should be administered in the deltoid for adults and the deltoid or anterolateral thigh for children. IM vaccines should never be administered in the buttocks or gluteal area. WHO-recommended ID vaccines may be given in the deltoid, anterolateral thigh, or suprascapular regions across all age groups.[12]
  • The CDC recommends administering the rabies vaccine on days 0, 3, 7, and 14 after exposure for patients with no prior rabies immunization.[32] Patients with immunocompromising conditions should receive a fifth dose on day 28.
  • The WHO recommends IM and ID vaccination regimens; ID regimens extend the vaccine supply and minimize disruption for patients who often travel long distances for treatment.[12] For multisite schedules, the vaccine should be administered in different sites and limbs. For patients with normal immune function, the regimens are as follows:
    • 2-site intradermal administered on days 0, 3, 7 [6][31]
    • 1-site IM on days 0, 3, 7, and 14-28 (Essen regimen, same as United States regimen)
    • 2-site IM on day 0 and 1-site IM on days 7 and 21 (Zagreb regimen)
(B3)

• Rabies immunoglobulin
  • The CDC and other communicable disease control centers in high-resource countries recommend RIg for all bite and nonbite rabies exposures, regardless of time since the exposure, except in patients presenting with clinical signs of rabies. The WHO recommends RIg only for category III wounds as rabies risk from nonbite exposures is very low, and global RIg supplies are often limited.[12] All immunocompromised patients with category II or III wounds require RIg, even if previously vaccinated.
  • If not administered immediately, HRIg may be provided up to day 7 after initiating the vaccine. Administration beyond 7 days provides no benefit and may interfere with the anamnestic antibody response.[18][9][12]
  • The dose of HRIg is 20 IU/kg (eRIg 40 IU/L) for all patients, regardless of weight or age.[12] Infiltrate the entire dose, or as much as anatomically possible, in and around the wound. Clinicians must avoid compartment syndrome and ischemia when infiltrating distal extremity wounds. The CDC recommends that any remaining RIg be provided by IM injection at a site distant from the vaccine administration site.[9] RIg should not be administered in the gluteal region.
  • HRIg may be diluted to provide sufficient volume for infiltration of large or multiple wounds, particularly for children, where the dose of HRIg may be small. Most HRIg formulations require dilution with normal saline; however, HyperRab^TM must be diluted with dextrose 5% in water.
(B3)

Previously immunized patient: Patients with prior rabies vaccination require only rabies vaccine after an exposure assessed to be at risk of rabies. These patients should not receive RIg as it may interfere with mounting an adequate antibody response. The CDC defines prior rabies vaccination as patients who previously received PrEP or PEP with HDCV, PCECV, or RVA, or a documented antibody response to prior vaccination with any other rabies vaccine.[9](B3)

The CDC recommends 2 doses of rabies vaccine given IM 3 days apart on days 0 and 3 (day 0 is the day the 1st shot is given). The WHO recommends either a 1-site intradermal vaccination on days 0 and 3 or a 4-site intradermal vaccination regimen administered on day 0.[6][31](B3)

The WHO recommends that immunocompromised patients receive the vaccine and RIg as PEP, even with prior vaccination. The WHO recommends a 3-visit IM or ID regimen on days 0 and 7, and between days 21 and 28. Serological testing may be conducted 2 to 4 weeks after the first vaccine to determine whether a third shot is required. The CDC recommends serological testing following routine PEP or PrEP to assess the patient's antibody response and determine future vaccination requirements.[32]

Avoiding common errors: Clinicians must be vigilant to prevent common errors in rabies PEP administration, including the following:

• Do not administer the vaccine into the gluteal area. 
• Do not administer the vaccine and HRIg in the same syringe or location.
• Do provide HRIg where indicated.
• Do infiltrate as much of the HRIg into the wound as possible.
• Do follow the recommended vaccine schedule. 

Rabies Clinical Treatment

Treatment for clinical rabies caused by RABV and related Lyssaviruses is largely supportive, focusing on minimizing patient suffering.[4] Management includes a quiet care setting that minimizes unnecessary stimulation and directed symptom management, which may include:

• Mouth care, provision of high-water-content foods, and intravenous fluids for hydrophobia
• Antipyretics, often administered rectally for fever
• Benzodiazepines for the management of agitation, anxiety, and seizures
• Anticholinergics for the management of hypersecretion and disordered swallowing
• Opioids for pain management

Some authors recommend the Starfish Palliative Care treatment protocol as the preferred treatment model.[4] This protocol recommends low-dose haloperidol (10-20 mg in 24h) over benzodiazepines to reduce anxiety and agitation, improving healthcare providers' capacity to provide physical and personal care. There is no role for HRIg or rabies vaccine in managing rabies, as clinical studies demonstrate that these do not alter the clinical course.[18]

Patient emotional, social, and spiritual care needs must also be addressed. Support from family members, if comforting, is encouraged. As with other carers, family caregivers must use appropriate personal protective equipment and be provided with PEP if needed.

Some authors suggest aggressive treatment may not be unreasonable in scarce situations despite the extremely high mortality and chance of neurological sequelae in case of survival.[4] A decision to treat aggressively must be made only after a thorough discussion between the clinician and family, carefully assessing and weighing the anticipated risks and benefits, especially if the patient is a child.

A higher likelihood of survival exists in cases with:

• Previous full or partial vaccination
• Infection with the American bat RABV
• Neutralizing anti-RABV antibodies at the time of presentation
• Younger age
• No comorbidities
• Early clinical disease presentation, such as sensory symptoms rather than fulminant encephalopathy
• No detectable CSF RABV antigen or RNA [4]

In these rare cases, therapy is based on supportive care, supplemented with antivirals and neuroprotective factors. This treatment is only possible in countries with specialized intensive care units. The details of treatment are beyond the scope of this article.

Public Health Management

All confirmed or suspected rabies cases must be reported urgently to the local or state public health department. Public health authorities identify and manage other possible exposures by developing a contact list, interviewing all identified contacts, assessing rabies exposure risk, and providing PEP as required.

Public health investigations can be extensive. For example, public health officials identified and assessed 332 contacts in the 2021 Minnesota case. As the risk of rabies exposure following human rabies cases is low, only 3 (0.9%) required PEP.[8](A1)

Please refer to the Deterrence and Patient Education and Enhancing Healthcare Team Outcomes sections for more information on rabies PrEP and primary prevention through dog vaccination and other public health measures, respectively. Please see StatPearls' companion resource, "Animal Bites," for further information.

Differential Diagnosis

The differential diagnoses for rabies include the following:

• Guillain–Barré syndrome
• Psychosis
• Seizures
• Poisoning with belladonna alkaloids
• Cerebral malaria
• Meningitis
• Acute encephalitis from any other infectious or noninfectious causes
• Poliomyelitis
• Poisoning
• Metabolic causes such as hypoglycemia and thiamine deficiency
• Cerebrovascular accident
• Creutzfeldt–Jakob disease
• Brain tumor
• Neurosyphilis
• Tetanus
• Autoimmune encephalitis

Prognosis

Rabies disease is almost universally fatal; however, rabies PEP is nearly 100% effective in preventing the disease. Treatment failure is primarily caused by delayed administration after exposure, errors in RIg or vaccine administration, and the use of low-quality, counterfeit, or unavailable rabies biologics. Once the virus enters the CNS, PEP treatment is ineffective.

Complications

Complications associated with rabies can include:

• Seizures
• Fasciculations
• Psychosis
• Aphasia
• Autonomic instability
• Paralysis
• Coma
• Death