Chapter VI.26. Rabies
Kornkanok Saringkarisate, MD, MPH
May 2022

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition Dr. Grant Chen. This current third edition chapter is a revision and update of the original author’s work.

An 8-year-old male presents to the emergency department (ED) with headache, temperature of 39.5, chills, and vomiting. His mother reports that he had experienced worsening headache over the past 2 days. Meningitis is a concern, so a lumbar puncture is performed which shows 20 RBCs and 0 WBCs per mm3, a mildly elevated protein, and normal glucose. Since meningitis is ruled out, he is discharged home. Two days later, he returns to the ED with worsening mental status. A lumbar puncture is repeated. Opening pressure is 28 cmH2O, clear, 0 RBC and 6 WBCs per mm3 (84% lymphocytes), glucose 92 mg/dL and an elevated protein. There are no focal deficits on neurological examination, but since he is agitated and combative, he is sedated and intubated because of deteriorating mental status. Acyclovir is added to his therapy for the possibility of encephalitis. He is admitted to the pediatric intensive care unit (PICU).

He is a recent immigrant from the Philippines. His parents deny a history of animal bites, but there is an interesting history of contact with bats that were caught by his grandparents to be used as pets. Based on this history, immunofluorescence of a skin biopsy and a saliva sample for RT- PCR (reverse transcriptase polymerase chain reaction) are sent for testing.

Two days later, his fever resolves, and he becomes alert at times, but he is still agitated. His skin biopsy is positive for rabies antigen and his saliva RT-PCR is positive for rhabdovirus.

The family is notified of the diagnosis and he continues to progressively deteriorate, passing away 10 days after admission despite aggressive attempts at support and treatment. Postmortem autopsy of cerebellar tissue reveals the presence of basophilic inclusion bodies. The brain is soft and edematous. RT-PCR analysis of the tissue done at the Center for Disease Control and Prevention (CDC) implicates a strain of the rabies virus associated with the Philippines.

Once neurological symptoms appear, rabies is a nearly inevitably fatal acute progressive encephalitis, accounting for approximately 59,000 deaths globally per year, 40% of which occur in children living in Asia and Africa (1). Rabies is also associated with an estimated cost of $8.6 billion per year (2). Rabies is categorized as one of the Neglected Tropical Diseases (NTD) primarily affecting poor and vulnerable populations in remote areas. In 2018, the World Health Organization (WHO) launched a global strategic plan (named: Zero by 30) to end human deaths from dog-mediated rabies by 2030 (1).

Rabies virus is a single-stranded RNA virus that belongs to the Rhabdoviridae family. Globally, in most cases rabies occurs secondary to a rabid dog bite. In the U.S., rabies among dogs has been eradicated but still persist among wildlife, mainly bats, raccoons, skunks, foxes, coyotes, bobcats and mongoose. From 2000 to 2014, there were only 44 cases of human rabies reported in the U.S; 31 were acquired domestically and of them, 27 were associated with bats (3). Animal rabies cases have been reported in all states except Hawaii, which continues to be rabies-free.

Transmission of rabies occurs following direct contact with an infected animal's saliva or tissue to human mucosa (eyes, nose, or mouth) or fresh skin wounds (2,4). Petting a rabid animal or having contact with the blood, urine, or feces of the rabid animal is by itself not considered exposure to rabies. Contraction through aerosolization or transplantation of infected organs has been described but is extremely rare. Theoretically, direct human-to-human transmission is possible but has never been documented (4), except via tissue transplantation. The virus becomes noninfectious when it dries and is exposed to sunlight. In the U.S., bats are the primary source of infection through aerosolization of bat secretions and direct contact. Bats, raccoons, skunks, foxes, coyotes, bobcats, and mongooses are also considered important potential sources of rabies infection in the United States (3).

After a bite from a rabid animal, the rabies virus from the animal's saliva enters the wound and travels through the nerves and spinal cord, eventually reaching the brain. One of the known receptors of the rabies virus, the nicotinic acetylcholine receptor (nAchR), is restricted to muscle cells. It is believed that the rabies virus enters primary motor neurons first before neuroinvasion. During this initial phase, the bitten animal shows no symptoms. In humans, the incubation period is usually between 1 to 3 months but can range from days to years. Once the virus reaches the brain, it then multiplies rapidly before moving to the salivary glands and saliva. Almost all infected animals will start showing the first signs of the disease after this multiplication phase and usually die within seven days of symptoms appearance. Many factors, including site of the exposure, type of rabies virus and immunity of the animal or person who got bitten contribute to the variation in the incubation period (4).

There are two presentations of rabies: a furious, and a paralytic (dumb) form. Both forms are invariably fatal, with the furious form causing death within a week and the paralytic form causing death within two weeks. Furious rabies is characterized by high fever, hyperactivity, excitable behavior, hydrophobia, hypersexuality, priapism lasting for several days, autonomic dysfunction, piloerection, and pupillary abnormalities (2). The autonomic dysfunction leads to excess salivation, which can produce the foaming at the mouth that is often associated with rabies. The paralytic form progresses in a less dramatic manner with a longer course, which is often misdiagnosed. The patient then gradually develops muscle paralysis, starting from the site of the bite or scratch, before entering a coma state and death (2).

Bat rabies differs from canine rabies not only in the method of inoculation but also in presentation. Patients with bat rabies have a high incidence of focal brainstem signs and myoclonus and may display hemiparesis, hemisensory deficits, ataxia, chorea, or Horner syndrome (myosis, ptosis, and anhidrosis of one eye). In contrast, victims of canine bite rabies display only focal weakness, usually in the limb that was bitten.

The histopathologic hallmark of rabies is the presence of Negri bodies. These are inclusion granules found in cells of the central nervous system, most often within the pyramidal cells of Ammon's horn or the Purkinje cells in the cerebellum. They are described in the literature as either eosinophilic or basophilic and are cytoplasmic inclusion bodies containing viral nucleoprotein. The presence of Negri bodies is variable, as non-rabid tissues have displayed inclusions that are indistinguishable from Negri bodies, while rabid tissue from animals shows Negri bodies in only 50% of samples taken. Consequently, searching for Negri bodies is not considered a suitable diagnostic assessment given its low sensitivity (3).

The direct fluorescent antibody (DFA) test for rabies is normally performed post-mortem brain tissue, usually to test rabid animals. For humans, multiple tests are required. Tests for virus in saliva by RT-PCR or testing of the blood, serum, or spinal fluid for antibodies to the rabies virus can be obtained. Skin biopsy specimens may also show rabies antigen in cutaneous nerves (4). The small number of rabies cases in the U.S. contributes to the unfamiliarity and lack of clinical suspicion by many practitioners. Still, it is important to consider the possibility of rabies in any patient presenting with encephalopathy of unknown cause, even in the absence of known exposure to the virus through animal bites. Given that animal bites are one of the leading causes of accidents in children and that 40% of rabies cases worldwide occur in children, it is important to heighten clinical suspicion among practitioners.

There is no specific treatment for rabies. Historically, the Milwaukee protocol, which included the induction of therapeutic coma and a combination of several drugs, worked for one patient who had not received postexposure prophylaxis; however, many subsequent cases using the same protocol were not successful, questioning the efficacy of the protocol (3).

Since rabies is an almost uniformly fatal disease once the symptomatic stage of the disease has developed, the only opportunity to intervene is to provide postexposure prophylaxis after the animal bite/contact. Frequently, the animal is not available for testing and even if it is available, observation and/or testing of the animal is very slow. For dogs, cats, and ferrets, if the animal is available, the animal can be held and observed for 10 days (3). But if the animal is not available and/or the risk or rabies exposure is high, post-exposure prophylaxis must be initiated immediately once a suspicious animal bite or bat exposure occurs. A bite from a pet dog or cat which is known to have completed rabies vaccine is of very low risk. Bites from squirrels, hamsters, guinea pigs, gerbils, chipmunks, mice, rats, rabbits, hares, and pikas rarely require rabies prophylaxis (3). Bites from other animals have varying degrees of risk and these risks must be assessed to determine the need to initiate rabies prophylaxis.

Since bats can expose humans to rabies without a bite, a bat exposure could warrant rabies prophylaxis. A commonly described scenario is a bat that has flown into an open bedroom window. Bats have natural high frequency sound navigation capabilities, thus flying into a bedroom window is suspected to occur only if the bat is ill, which could increase the aerosolization of bat secretions, and this illness could be rabies. Additionally, if the person sleeping in the room is a young child or someone who has difficulty with communication or recall, it might not be possible to determine if a bite or scratch has occurred. Thus, such close contact with bats could warrant rabies prophylaxis as well (3).

The origins of modern rabies treatment lie in Louis Pasteur's work with live attenuated rabies virus in the 19th century. Following Pasteur's work, the rabies duck embryo vaccine (DEV) was produced in 1955 and was used for prophylaxis for more than 25 years, proving effective when combined with equine rabies immunoglobulin (ERIG). This regimen had significant drawbacks in that the duck embryo vaccine caused allergic reactions in response to the avian antigens, required 21 to 23 painful doses, and sometimes resulted in serum sickness due to the equine origin of ERIG.

Modern rabies immunization consists of two products: active immunization with an active rabies vaccines such as human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV), plus human rabies immune globulin (HRIG). HRIG is derived from the plasma of hyperimmunized human donors, thus eliminating the equine antigens present in ERIG. HRIG induces a rapid, passive immunity with a half-life of approximately 21 days, while, the rabies vaccine induces an active immune response that takes 7 to 10 days to develop and lasts for two or more years.

Preexposure vaccinations are recommended for select high-risk situations, such as people who work with or have a planned activity that will involve contact with wild or domestic animals, visit remote areas, or stays longer than one month in an area where dog rabies is endemic, and medical care is scarce. For them, previous recommendation for 3 IM (deltoid muscle) 1 mL doses on days 0, 7, and 21 or 28 (5), has recently being modified to 2 doses on days 0 and 7 (6). Booster doses of the vaccine may be given every 6 months to 2 years to individuals at elevated risk if the antibody titers decrease, and the risk of exposure remains. (6) The rate of systemic allergic reaction to the rabies vaccine is approximately 11 per 10,000 vaccinations, which has resulted in a few hospitalizations, but no deaths. In those who have received preexposure prophylaxis, in case of subsequent exposure to a potentially rabid animal, 2 extra doses of a rabies vaccine are recommended on day 0 and 3. Preexposure prophylaxis does not obviate the need for vaccination in case of exposure, but reduces the number of doses needed and, more importantly, obviates the need for HRIG (or ERIG), which may not be widely available, especially in countries outside the U.S.

Most persons do not qualify and do not receive preexposure prophylaxis. Thus, for most patients who sustain a bite or exposure from a potential rabid animal, wound care should be promptly administered with extensive wound washing for a minimum of 15 minutes, preferably with povidone-iodine or at least with soap and water (2). In addition, postexposure prophylaxis should be initiated with rabies vaccine and rabies immunoglobulin. Rabies vaccine should be administered as 4 doses, 1 ml IM each, on days 0, 3, 7, and 14 (5,7). If available, rabies immunoglobulin (RIG) should also be administered. The preferred product (and the one used in the U.S.) is HRIG, administered as 20 IU/kg of body weight. If feasible, the full dose should be administered (infiltrated) around the wound(s). If there is any remaining volume, it should be administered IM at a site distant from the vaccine administration site. HRIG should not be administered in the same syringe as the rabies vaccine, as it may suppress the formation of an antibody. In low-resource countries, where HRIG may not available, ERIG may be used instead, but at a double dose (40 IU/kg). Administration of ERIG poses a higher risk of serum sickness or anaphylaxis when compared to HRIG; however, this complication remains rare with the current purified ERIG. Skin testing for sensitivity to ERIG is not recommended since it is unreliable. Immunosuppressed individuals should be treated in the same manner, and titers should be checked to confirm the development of rabies antibodies (6).

Given scarce resources in some areas of the world, where rabies exposure may be particularly common, the World Health Organization, recommends basing the use of postexposure prophylaxis to the severity of contact to the suspect or known rabid animal (1,2), as shown in Table 1 below.

Table 1: World Health Organization recommendations for rabies prophylaxis in areas of the world where HRIG and rabies vaccine are in short supply.
Categories of contact with suspect rabid animalPostexposure prophylaxis measures
Category I: Touching or feeding animals, animal licks on intact skin (no exposureWashing of exposed skin surfaces, no vaccine or RIG indicated
Category II: Nibbling of uncovered skin, minor scratches or abrasions without bleeding (exposure)Wound washing and immediate vaccination
Category III: Single or multiple transdermal bites or scratches, contamination of mucous membrane of broken skin with saliva from animal licks, exposures due to direct contact with bats (severe exposure)Wound washing, immediate vaccination and administration of RIG

More than 29 million people worldwide receive postexposure vaccination, estimated to prevent several thousand deaths per year. (2). The efficacy of the regimen is evidenced by the fact that of the millions of doses administered worldwide, there have been only 13 reported failures, and all of them have been associated with deviation from the recommended protocol. However, the cost of postexposure prophylaxis can be prohibitive for some communities.

Far more effective than medical prophylaxis, are measures that encourage prevention and awareness. The CDC has a multilevel set of recommendations to prevent rabies and rabies exposure (4), to include:

For pets: 1) Visit veterinarians regularly and keep rabies vaccination up-to-date; 2) Maintain control of pets by keeping them indoors or under direct supervision; 3) Spay or neuter pets to help reduce the number of unwanted or stray pets and animals; 4) Call animal control to remove stray animals.

For people: 1) Leave all wildlife alone; 2) Know the risk, avoid contact with bats and consider preexposure or postexposure prophylaxis as recommended; 3) Wash animal bites or scratches immediately with soap and water; 4) Discuss with a healthcare providers, the risk and the possibility of postexposure prophylaxis if bitten, scratched, or unsure; 5) Vaccinate your pets.

As Hawaii remains the only rabies-free state in the United States, all dogs and cats, regardless of age or purpose, must follow Hawaii's import requirements. If qualified, they might be able to enter through the 5-Day-Or-Less quarantine program. Dogs and cats that do not meet all the program requirements, though, need to be quarantined for up to 120 days upon arrival in Hawaii. (8).

1. The following animals are most frequently reported rabid in the United States? (select all true answers)
   a. Squirrels
   b. Raccoons
   c. Rabbits
   d. Hamsters
   e. Skunks

2. Which of the following would provide the best method for ante-mortem diagnosis of rabies in a human?
   a. Identification of clinical symptoms.
   b. Direct fluorescent antibody testing of brain tissue.
   c. Identification of Negri bodies.
   d. Observation of the animal in question to be rabid.
   e. PCR of isolate from the saliva of the victim.

3. True/False: Petting a rabid animal is likely to lead to rabies

4. In which of the following cases would postexposure rabies prophylaxis be appropriate (select all appropriate):
   a. A tour group observes a large colony of bats emerge from a cave.
   b. While cleaning out the attic, a man gets some scratches and then removes a dead bat without using gloves.
   c. A child is bitten by his pet dog in Hawaii.
   d. A dead bat is removed from the crib of a child.

5. The most common animal associated with rabies in the United States is?
   a. Bat
   b. Raccoon
   c. Skunk
   d. Coyote
   e. Cat

1. World Health Organization. Zero by 30: The global strategic plan to end human deaths from dog-mediated rabies by 2030. Available at Retrieved April 30, 2022
2. World Health Organization. Rabies. (May 17, 2021). Available at Retrieved April 30, 2022
3. Rabies. In: Kimberlin DW, Barnett ED, Lynfield R, Swyeer MH (eds). Red Book: 2021 Report of the Committee on Infectious Diseases. 2021. American Academy of Pediatrics, Itasca, IL. pp: 619-627.
4. Centers for Disease Control and Prevention. Rabies. Available at Retrieved April 30, 2022
5. Manning SE, Rupprecht CE, Fishbein D, et al Human rabies prevention--United States, 2008: Recommendations of the Advisory Committee on Immunization Practices. MMWR. Morb Mortal Wkly Rep 2008; 7(RR-3):1–28.
6. Rao AK, Briggs D, Moore SM, et al. Use of a Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human rabies: Recommendations of the Advisory Committee on Immunization Practices – United States, 2022. MMWR Morb Mortal Wkly Rep 2022;71(18):619-627
7. Rupprecht CE, Briggs D, Brown CM, et al. Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices. MMWR. Morb Mortal Wkly Rep 2010;59(RR-2):1–8.
8. State of Hawai’i Animal Industry Division. Animal Quarantine Information Page (Updated). Available at Retrieved April 30, 2022.

Answers to questions
1.b,e, 2.e, 3.False, 4.b,d, 5.a

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