An 8 year old male presents to the ER with headache, temperature of 39.5 C, chills, and vomiting. His mother reports that he had experienced worsening headache over the past 2 days. Meningitis is a concern, so an LP is performed which shows 20 RBCs, 0 WBC, a mildly elevated protein and normal glucose. Therapy is started with broad spectrum antibiotics, and he is admitted to the floor. Two days later, his mental status worsens in spite of therapy, so a repeat LP is performed. The repeat reveals: opening pressure of 28 cm water, clear fluid, 6 WBC, (84% lymphs), 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. Acyclovir is added to his therapy for the possibility of encephalitis.
Two days later, his fever drops, and he became alert at times, but he is still agitated. Further history from the mother reveals that the family had recently moved from the Philippines. The mother denies a history of dog bites, but notes that the child would occasionally play with bats that were caught by his grandparents for him to be used as pets. She denies bat bites, but states that there may have been skin to bat contact when the bat would land on the child. Based on this history, his saliva is sampled, along with a skin biopsy from his neck. Immunofluorescent staining of the skin reveals the presence of rabies antigen, and rhabdovirus is present in his saliva after reverse transcription and PCR testing. The family is notified of the diagnosis and he continues to progressively deteriorate, passing away 10 days after admission. Postmortem autopsy of cerebellar tissue reveals the presence of basophilic inclusion bodies. The brain is soft and edematous. PCR analysis of the tissue at the CDC implicates a strain of the rabies virus associated with the Philippines.
Rabies is a disease whose presence has been noted throughout recorded history. Rabies in inevitably fatal by the time that significant symptoms appear, which is why prophylaxis must be started before symptoms appear. It causes a highly fatal acute encephalitis, causing approximately 35,000 deaths each year worldwide. Rabies virus belongs to the Rhabdoviridae family. Animal cases of rabies have been reported in all states with the exception of Hawaii, which continues to be rabies free. Human acquisition of rabies in the United States is a relatively rare occurrence, as only 32 cases of rabies were recorded between 1980 and 1996, occurring in 20 states (1). However, the yearly mortality rate in the Philippines is approximately 340, and in India, more than 25,000 people fall victim to rabies each year.
The normal mode of transmission of this disease has been by direct contact between animal and man. The animal implicated most frequently has been the dog, but other common zoonotic reservoirs of the disease include raccoons, bats and skunks. It is estimated in the Philippines that 10,000 dogs are infected each year (3). The primary wild reservoir of rabies in the United States is the raccoon. The rabies virus reproduces in both human and animal reservoirs, and is found in not only nervous tissue, but also in saliva, which provides the primary method for transmission of the virus. It is notable that the titer of rabies virus is much higher in skunks than other animals (5). Also, cats, while less frequently infected, have sharper teeth that cause deeper puncture wounds. In the case of transmission from bats, it is believed that transmission may occur through inhalation of aerosolized bat feces (highest risk in caves with high bat populations), and also through direct skin-to-skin contact. Non-animal associated transmission of rabies is extremely rare, and has occurred by means of corneal transplantation from an unknowingly infected donor who died from rabies (diagnosed after the corneal transplant recipients were diagnosed with rabies at post-mortem).
Rabies spreads centripetally from the bite wound (usually an extremity) into the CNS, moving at an estimated rate of 1-2 cm/day (8). The period between the inoculation of the virus into the victim and its invasion of the CNS is the incubation period. The median incubation period is 85 days (range 53-150 days) (1), although molecular biological analysis reveals that the incubatory stage can last up to 7 years (5). It is not known what mechanism modulates the rate of rabies virus travel from the periphery to the central nervous system. It is believed that the primary factor involved in determining whether or not the bitten individual is inoculated with the virus is whether or not the virus makes contact with muscle. Prior to the invasion of the nervous system, the virus reproduces in the muscle tissue, subsequently invading the motor neurons. Bat rabies, unlike canine rabies, possesses the ability to replicate in skin and connective tissue, explaining why non-bite inoculation is prevalent in bat exposures (8).
The first signs and symptoms of rabies are often nonspecific, including fever, sore throat, chills, malaise, anorexia, headache, nausea, vomiting, dyspnea, cough, and weakness. A characteristic symptom is the presence of paresthesia in the area local to the bite. This is thought to be early ganglionic invasion of the virus.
There are two presentations of canine rabies, a "furious" (encephalitic) or "dumb" (paralytic) form. Both forms are invariably fatal, with the furious form causing death within a week, and the dumb form causing death within 2 weeks. Characteristic of furious rabies is high fever, hyperactivity, hypersexuality, including an increase in sexual appetite and priapism of several days, along with autonomic dysfunction, piloerection, and pupillary abnormality (1,5,6,8). The autonomic dysfunction also includes excess salivation, which can produce the "foaming at the mouth" that is often said to accompany rabies. The dumb form progresses from the peripheral weakness to a generalized craniospinal weakness (1,6,8). The late features of dumb rabies are typically encephalitic.
Bat rabies differs from canine rabies not only in 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's syndrome (1,8). In contrast, victims of canine bite rabies display only focal weakness, usually in the limb that was bitten.
In addition to the clinical findings of rabies, a histopathologic finding is the presence of Negri bodies. These are inclusion granules found in cells of the CNS, 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 inclusions, 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 have shown Negri bodies in only 50% of samples taken.
Thus, the most reliable test for rabies prior to the appearance of symptoms remains the direct fluorescent antibody test (DFA). However, the DFA requires brain tissue, and is therefore performed post-mortem. It is the test of choice for the testing of rabid animals. For humans, it is necessary to perform multiple tests to diagnose rabies before death. The two main tests are testing for the virus in saliva by PCR, or testing the blood serum or spinal fluid for antibodies to rabies virus. Additionally, skin biopsy specimens may display rabies antigen within cutaneous nerves (10). The small number of rabies cases in the United States undoubtedly contributes to the lack of clinical suspicion by the physician, but it is important to remember that any patient presenting with encephalopathy of unknown cause should be considered to potentially have rabies, even in the absence of known exposure to the virus through animal bites. The validity of this statement is further justified by noting that 12 of the 32 deaths (37.5%) in the US attributable to rabies were not diagnosed until after the death of the patients, and of these 12 cases, 6 were not diagnosed until several weeks after death (1). Additionally, while all 32 fatal rabies cases in the US between 1980 and 1996 were seen by their physicians on an outpatient basis prior to the onset of terminal symptoms, not one of them received a complete set of rabies prophylaxis post-exposure. As a further reminder of the importance of clinical suspicion for pediatricians, a 1990 study showed that animal bites were the fourth leading cause of accidents in children 9 years old or less.
As rabies is a uniformly fatal disease once the symptomatic stage of the disease has developed, it is important to provide pre-exposure, and if necessary, post-exposure prophylaxis for patients. The origins of modern rabies treatment lie in Louis Pasteur's work with live attenuated rabies virus in the 19th century. After discovering the transmissibility of rabies by nervous tissue inoculation, Pasteur determined that passage of the virus from dogs to monkeys attenuated the virus, while transmission from rabbit to rabbit increased the virulence of the strains. By utilizing his attenuated strain on 9 year old Joseph Meister, he was able to attain "the happy outcome" now known to all.
Following Pasteur's work, the duck embryo rabies vaccine was produced in 1955, and was used for prophylaxis for more than 25 years, proving effective when combined with equine rabies immunoglobulin (RIG). However, this therapy caused allergic reactions in response to the avian antigens, required 21-23 doses, was very painful, and the equine origin of the RIG could cause serum sickness (5).
Modern rabies immunization consists of two types of products: Active immunization with rabies vaccine (HDCV-human diploid cell vaccine, PCECV-purified chick embryo cell vaccine, or RVA-rabies vaccine adsorbed), and rabies immune globulin (RIG). The modern version of the RIG is derived from the plasma of hyperimmunized human donors, thus eliminating the equine antigens present in the previous version of the RIG. RIG produces a rapid, passive immunity with a half-life of approximately 21 days. On the other hand, rabies vaccine creates an active immune response that takes 7-10 days to produce, and lasts for 2 or more years. The recommended pre-exposure vaccination is three 1.0 ml injections of HDCV IM (deltoid) on days 0,7, and 21 or 28. Should immunosuppressed individuals become exposed to rabies, they should be treated as indicated, and titers should be taken to confirm development of rabies antibodies. Booster doses of the vaccine may be given every 2 years if the antibody titers in the patient are decreased. Should pre-vaccinated persons become exposed to rabies, they should NOT be given RIG, as an amnestic response will develop. Treatment of persons known to be exposed to rabies is threefold: First, there should be an immediate and thorough cleansing of the wound with soap and water. If virucidal agents such as povidone-iodine are available, they should be used for irrigation. Secondly, RIG should be administered, 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. To note, RIG should not be administered in the same syringe as the vaccine, and as it may suppress formation of antibody, it should not be administered in excess of the recommended dose. Lastly, HDCV should be administered in the same dosage as mentioned for pre-exposure prophylaxis.
The efficacy of the recommended prophylaxis is evidenced by the fact that of the millions of doses administered worldwide, there have been only 13 reported failures, and all of the failures have been associated with deviation from the recommended treatment protocol. 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. It is currently the recommendation of the Advisory Committee on Immunization Practices (ACIP) that persons in high risk groups, such as veterinarians, animal handlers, and certain lab workers be treated with pre-exposure vaccine. Additionally, rabies prophylaxis is recommended that persons traveling (for more than 30 days) into areas where rabies is endemic and medical care is limited.(2,8). It is also recommended that even immunosuppressed patients receive prophylaxis if exposed to rabies. While pre-exposure prophylaxis is recommended, it is important to note that it does not negate the need for post-exposure. Pre-exposure prophylaxis negates the need for RIG immunization after exposure, but does not alter the remainder of the post-exposure prophylaxis schedule.
Far more effective than medical prophylaxis are the recommendations of the national working group on prevention and control of rabies in the United States. Their recommendations include:
1. Vaccinate all dogs and cats against rabies. Do not keep wild animals as pets.
2. Do not feed or pet stray animals; avoid animals you do not know.
3. Report any animals that are acting sick or strange to local animal control authorities.
4. Keep pets indoors at night. Feed pets indoors.
5. Keep pets fenced in or leashed.
6. Do not handle dead, sick, or injured wild animals. If necessary, use sticks or shovels and wear heavy gloves.
7. Remove roosting bats from homes and barns.
8. Keep all trash container lids tightly closed. Keep compost piles away from buildings.
Since the prognosis for patients displaying symptoms of rabies infection is invariably fatal, it is of the greatest importance for all possible measures to be taken to avoid the transmission of rabies, both through the application of animal vaccination and public health awareness. It is also vital for physicians to recognize individuals at risk for rabies exposure and treat them with both pre and post-exposure prophylaxis.
1. Which 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.
. . . . . 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: Inoculation of rabies from animal to human requires a physical animal-human contact.
4. In which of the following cases would post-exposure 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 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. Which animal is most likely to transmit rabies to humans by mere contact (as opposed to a bite)?
. . . . . a. Bat
. . . . . b. Racoon
. . . . . c. Skunk
. . . . . d. Coyote
. . . . . e. Cat
1. Noah, DL, Drenzek, CL, Smith, JS, et al. Epidemiology of Human Rabies in the United States, 1980 to 1996. Ann Int Med 1998;128(1): 922-930.
2. Centers for Disease Control and Prevention. Human rabies prevention - United States, 1999: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999; 48(No. RR-1).
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4. Dutta JK, Dutta TK. Rabies in Endemic countries. Br Med J 1994;308(6927):488-489.
5. Fisher DJ. Resurgence of Rabies: A Historical Perspective on Rabies in Children. Arch Pediatr Adolesc Med 1995;149(3):306-312.
6. Gomez-Alonso J. Rabies: A possible explanation for the vampire legend. Neurology 1998;51(3):856-859.
7. Moran GJ, Talan DA, Mower W, et al. Appropriateness of Rabies Postexposure Prophylaxis Treatment for Animal Exposures. JAMA 2000;284(8):1001-1007.
8. Pleasure SJ, Fischbein NJ. Correlation of Clinical and Neuroimaging Findings In a Case of Rabies Encephalitis. Arch Neurol 2000;57(12):1765-1769.
9. Jackson AC, Lopez-Corella E. Rabies. New Engl J Med 1996;355(8):568-569.
11. Weber ED, Callahan ML. Infections from animal sources. In: Schillinger D, Harwood-Nuss A (eds). Infections in Emergency Medicine. 1990, New York, NY: Churchill Livingstone, Inc., pp. 287-361.
12. Geison GL. Pasteur, Roux and rabies: Scientific versus clinical mentalities. J Hist Med Allied Sci 1990;45:341-365.
13. Statement on Travelers and Rabies Vaccine. Can Med Assoc J 1995;152(8):1241-1242.
14. Hay E, Derazon H, Bukish N, et al. Postexposure Rabies Prophylaxis in a Patient with Lymphoma. JAMA 2001;285(2):166-167.
15. Gibbons RV, Rupprecht CE. Postexposure Rabies Prophylaxis in Immunosuppressed Patients. JAMA 2001;285(12):1574-1575.
16. Hanlon CA, Olson JG, Clark CJ, et al. Recommendations of a national working group on prevention and control of rabies in the United States. J Am Vet Med Ass 1999;215(9):1276-1281.
Answers to questions
1.b,e, 2.e, 3.False, 4.b,d, 5.a