Peggy Sue Weintrub
Rabies is an acute encephalomyelitis with an extremely high fatality rate. It is primarily a viral infection of nonhuman carnivores.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
The etiologic agent is the rabies virus, a 100-nm to 150-nm RNA virus classified as a rhabdovirus. Infection is relatively rare in humans, and when it occurs, it is usually the result of an animal bite that introduces infectious saliva; it is not known to be introduced through intact skin.
The virus probably binds initially to the acetylcholine receptor and then travels centripetally, via the peripheral nerves, toward the central nervous system. After infection of the brain, virus travels via the sensory and autonomic nervous system to the eyes, salivary glands, skin, and viscera. The principal pathologic changes are confined to the central nervous system; they consist of neuronal necrosis and nonsuppurative encephalitis. Changes are most pronounced in the thalamus, hypothalamus, substantia nigra, pons, and medulla. The most distinctive histologic feature of rabies infection is the presence of the pathognomonic Negri bodies, acidophilic inclusion bodies found most commonly in the hippocampus.
The vast majority of animal rabies in the United States occurs in wildlife, not pets. Bats, skunks, wolves, coyotes, foxes, raccoons, and many other species are implicated; for purposes of prophylaxis, bats and skunks should be considered to be rabid unless proven otherwise. Rabies is not endemic in rodents or lagomorphs. Dog-associated rabies is relatively uncommon in the United States but remains a problem in many parts of Mexico, Latin America, Asia, and Africa. Dog bites continue to be a predominant reason for postexposure prophylaxis. In the United States, approximately 40,000 individuals receive postexposure prophylaxis per year.1
The World Heath Organization estimates that annually there are 55,000 deaths secondary to rabies worldwide; the majority occur in Asia, Africa, and the Middle East.2 The incidence of rabies infection is highest in children, probably because of their friendliness toward animals and their inability to defend themselves. In the United States since 1990, there have been approximately 50 reported cases.3,4 Of these, close to 20% were associated with dog bites occurring in travelers outside of the United States; the remaining cases followed exposure to indigenous reservoirs, most commonly insectivorous bats. In many cases, there is exposure to bats without a recognized bite.3,4 Rare cases are reported after organ transplantation or graft.5,6
The attack rate in persons bitten by rabid animals is difficult to estimate, and it depends on the location of the wound, the depth of the bite, the presence of saliva infected with virus, and the protection afforded by clothing. Administration of both active and passive immunization dramatically reduces the risk of disease in persons bitten by rabid animals.
CLINICAL MANIFESTATIONS
The average incubation period is 18 to 60 days; the interval, however, can be extremely variable, as short as 5 days and as long as 6 years.7 The illness begins with a prodrome characterized by apprehension, anxiety, insomnia, malaise, and headache. It then proceeds through an excitation phase, with fever, apprehension, delirium, meningismus, and convulsion, as well as spasms of the pharynx or larynx. The prodromal phase lasts 2 to 7 days and is usually followed by the onset of neurologic symptoms, initially an excitation phase, also known as “furious” rabies. The excitation phase appears rapidly; there is much apprehension and even terror. Twitching, delirium, meningismus, and mild convulsive movements are seen. When the patient attempts to swallow food or liquid, painful, violent spasms of the larynx and pharynx may occur. Later, just the sound, smell, or sight of liquid may precipitate these spasms. During these periods, cyanosis may be present, and choking and aspiration are quite common. The temperature is elevated (39.5°C/103.1°F to 40.5°C/104.9°F), and generalized convulsions may occur. Maniacal behavior, such as tearing of clothes and bedding, often occurs. Intermittent periods of relative calm ensue, during which the patient is often quite lucid.
The paralytic phase appears next, with progressive paralysis, cessation of spasms, and coma, with death shortly thereafter. A great many complications develop, including ascending paralysis, respiratory depression, hypoventilation, arrhythmias, and hypotension. Until recently, the disease was reported to be uniformly fatal except in rare cases of individuals who contracted the disease despite postexposure prophylaxis. In 2004, a 15-year-old female, who did not receive postexposure prophylaxis, survived rabies after treatment with the induction of coma and aggressive supportive care.8 Five months after onset, she was able to interact and participate in activities of daily living but had residual movement disorders.9
DIAGNOSIS AND TREATMENT
When classic symptoms are present and there is a history of an animal bite, the differential diagnosis is not difficult. It is important to consider the diagnosis even without an obvious exposure, because most patients have had no known contact with rabid animals. Other viral etiologies and tetanus should be considered in the differential diagnosis.
Isolation of virus from the saliva, cerebrospinal fluid, lacrimal secretions, nasal secretions, and urine should be attempted, although negative results do not exclude the diagnosis. Fluorescent antibody examination of brain tissue, skin, or corneal scrapings is fast, reliable, and accurate if done properly.10 Specimens for biopsy may be obtained from the skin at the back of the neck, which has a heavy concentration of nerve fibers, where it is particularly accessible and useful for immunofluorescence. Polymerase chain reaction tests of saliva or brain has been shown to be sensitive and specific and should be attempted where the test is available.11
Treatment consists of intensive supportive care, concentrating particularly on support of ventilation and circulation. Induction of coma may improve outcome, though this has been documented only once.8Evolving approaches to management including use of tetrahydrobiopterin (BH4), and deep sedation with ketamine and midzolam is detailed at the Web site: http://www.mcw.edu/File Library/Groups/Pediatrics/InfectiousDiseases/Checklist_MP3.1.pdf. Healthcare providers will be protected by following current infection control practices for contact with secretions. There is no known role for rabies immune globulin in rabies disease, nor is there any established antiviral therapy.
PREVENTION
Prevention of human infection includes general public health measures such as mandatory vaccination of dogs, quarantine for traveling pets, preexposure immunization (for veterinarians, animal handlers, and any other individuals who are likely to be exposed), and importantly, postexposure prophylaxis for those who have been bitten by animals. Wildlife rabies is a serious problem not subject to control at the present time.
The most common issue involving rabies confronting the physician is whether prophylaxis should be recommended after potential exposure. Many factors influence that decision; these include the species and vaccination status of the biting animal, the nature of the exposure, and the local epidemiology.6 An unprovoked attack is more likely to occur with a rabid animal, as contrasted to the provoked attack that may ensue when children tease or bother pets while they are feeding. The decision regarding prophylaxis is aided by knowing whether rabies exists in the region and in what animal species. This information can usually be provided by local public health officials.
Table 321-1. Rabies Postexposure Prophylaxis
Animals whose owners can produce vaccination certificates are considered safe. If vaccination status is unknown, the animal should be considered potentially infectious. Postexposure prophylaxis is assessed depending on the type of animal; recommendations are summarized in Table 321-1. Healthy-appearing domestic dogs and cats that bite human beings should be confined and observed by a veterinarian for 10 days. If an animal must be killed to be captured, it should be done in such a way as not to traumatize the head. Likewise, if the animal dies, the head should be shipped under refrigeration to a competent laboratory for diagnosis. For wildlife under suspicion, the animal should be killed and its head submitted for laboratory examination. The public health laboratory will perform an examination of the brain using the fluorescent antibody technique. If that examination is negative, one can assume that no rabies was present in the animal’s saliva.
Carnivorous animals, such as skunks, foxes, coyotes, wolves, raccoons, dogs, cats, and ferrets are most likely to be infectious; bats are highly suspect. Nonverbal individuals (eg, infants, those sleeping, or with altered mental status) in the same room with a bat should be given prophylaxis. Farm animals, squirrels, opossums, weasels, muskrats, woodchucks, and mongooses may occasionally be infectious. Bites of rodents, lagomorphs, birds, and reptiles seldom require treatment.
Open wounds or abrasions can be contaminated with infected saliva by licking. Inhalation of aerosolized rabies virus can occur in laboratory workers and spelunkers.
WOUND MANAGEMENT, HYPERIMMUNE RABIES GLOBULIN, AND RABIES VACCINE
Immediate and thorough local treatment of all bite wounds and scratches is a most important means of preventing rabies. At present, thorough washing with soap and water and irrigation of the wound with a virucidal agent is recommended.
When the decision is made to initiate postexposure prophylaxis, the current recommendations are that both passive and active immunization be used in all instances.2,6,12,13 Passive immunization with rabies immune globulin is prepared from the blood of patients with high levels of antibody to rabies. The recommended dose of rabies immune globulin is 20 IU/kg. If possible, the full dose of rabies immune globulin should be infiltrated around the wound; any remaining rabies immune globulin should be given intramuscularly. Equine antirabies serum should be used only if rabies immune globulin is not available. When the equine antiserum is used, the usual precautions for giving equine serum are mandatory, namely a careful history of allergy, skin, and eye tests for hyper-sensitivity, and careful administration with a view to prompt handling of possible anaphylaxis. The dose of this material is 40 IU/kg, and it is also given partially around the wound, with the balance intramuscularly.
Postexposure prophylaxis is also recommended for persons who report a possibly infectious exposure (bite, scratch, an open wound or mucous membrane contaminated with saliva or other infectious material) to a human with rabies, although human-to-human transmission has not been documented.
Two rabies vaccines are currently available in the United States: human diploid cell vaccine and purified chick embryo cell vaccine. Five doses are recommended, as soon as possible after exposure and again 3, 7, 24, and 28 days after the first dose. Reactions following vaccine are generally mild: nausea, abdominal pain, muscle aches, and dizziness. Persons who need to be vaccinated in other countries may find a variety of vaccines in use. In Southeast Asia this may include products made with attenuated virus in desiccated nerve tissue, which have a risk of causing allergic encephalomyelitis.14 Persons taking chloroquine at the time of vaccination with any product should receive the vaccine via the IM route as they may have reduced response rates after intradermal injection.15