ESSENTIALS OF DIAGNOSIS
History of animal bite.
Paresthesias, hydrophobia, rage alternating with calm.
Convulsions, paralysis, thick tenacious saliva.
Rabies is a viral (rhabdovirus) encephalitis transmitted by infected saliva that enters the body by an animal bite or an open wound. Worldwide, over 17 million cases of animal bites are reported every year, and it is estimated that about 59,000 deaths annually are attributable to rabies. Rabies is endemic in over 150 countries; on the basis of interviews, it is estimated that over 40% of the world’s population lives in areas without rabies surveillance. Most cases of rabies occur in rural areas of Africa and Asia. India has the highest incidence, accounting for 36% of global deaths (http://www.who.int/rabies/epidemiology/en/). In developing countries, more than 90% of human cases and 99% of human deaths from rabies are secondary to bites from infected dogs. Rabies among travelers to rabies-endemic areas is usually associated with animal injuries (including dogs in North Africa and India, cats in the Middle East, and nonhuman primates in sub-Saharan Africa and Asia), with most travel-associated cases occurring within 10 days of arrival. Rare but related viruses are the Australian lyssavirus, transmitted by bats including one referred to as the black flying fox, and which has caused three deaths over the last 20 years, and the European lyssavirus, with cases from Germany and the United Kingdom. Rabies-free areas include much of Western Europe, Australia, New Zealand, Japan, and the state of Hawaii in the United States. A map outlining these areas is available with Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Rabies_Free_Countries_and_Territories.svg).
In the United States, domestically acquired rabies cases are rare (approximately 92% of cases are associated with wildlife) but probably underreported. Reports largely from the East Coast show an increase in rabies among cats, with about 1% of tested cats showing rabies seropositivity. The annual caseload in the United States is 1–3 cases (https://www.cdc.gov/rabies/location/usa/surveillance/human_rabies.html). Between 1960 and 2018, a total of 125 human rabies cases were reported in the United States. These included 36 cases (28%) with a history of dog bites during international travel. The remaining 89 cases (72%) were acquired in the United States, most often by bats.
Surveillance for animal rabies in 2017 showed 4454 animal and 2 human cases occurring in 49 states and Puerto Rico. Wild animals accounted for 91% of cases, and among wild animals, bats were the most common animal (31.2%). Wildlife reservoirs, with each species having its own rabies variant(s), follow a unique geographic distribution in the United States: raccoons on the East Coast; skunks in the Midwest, Southwest, and California; and foxes in the Southwest and in Alaska (eFigure 32–2). However, some areas have all three wildlife reservoirs (eg, the hill country of Texas) https://www.cdc.gov/rabies/location/usa/surveillance/wild_animals.html.
Distribution of major rabies virus variants (RVVs) among mesocarnivores in the United States and Puerto Rico. The areas indicated by black diagonal stripes represents the distribution of Arizona gray fox RVV. The solid-colored areas represent RVV distributions for 2014 through 2018; dashed borders represent the previous 5-year distributions for 2013 through 2017. (Reproduced, with permission, from Ma X et al. Public Veterinary Medicine: Public Health: Rabies surveillance in the United States during 2018. J Am Vet Med Assoc. 2020 Jan 15;256(2):195–208. https://avmajournals.avma.org/action/showPopup?citid=citart1&id=figure1&doi=10.2460%2Fjavma.256.2.195)
Raccoons, bats, and skunks in 2017 accounted for 82% of the rabid animals found in the United States; other rabid animals include foxes, cats, cattle, and dogs. Rodents and lagomorphs (eg, rabbits) are unlikely to spread rabies because they cannot survive the disease long enough to transmit it (woodchucks and groundhogs are exceptions). Wildlife epizootics present a constant public health threat in addition to the danger of reintroducing rabies to domestic animals. Vaccination is the key to controlling rabies in small animals and preventing rabies transmission to human beings.
The virus enters the salivary glands of dogs 5–7 days before their death from rabies, thus limiting their period of infectivity. Less common routes of transmission include contamination of mucous membranes with saliva or brain tissue, aerosol transmission, and corneal transplantation. Recognized mutations in rabies virus proteins can subvert the host immune system. Transmission through solid organ and vascular segment transplantation from donors with unrecognized infection is also reported. A number of transplantation-associated cases are reported, including two clusters in the United States. Postexposure prophylaxis can be administered in these patients and may prevent development of disease.
The incubation period may range from 10 days to many years but is usually 3–7 weeks depending in part on the distance of the wound from the CNS. The virus travels in the nerves to the brain, multiplies there, and then migrates along the efferent nerves to the salivary glands. Rabies virus infection forms cytoplasmic inclusion bodies similar to Negri bodies. These Negri bodies are thought to be the sites of viral transcription and replication.
While there is usually a history of animal bite, bat bites may not be recognized. The prodromal syndrome consists of pain at the site of the bite in association with fever, malaise, headache, nausea, and vomiting. The skin is sensitive to changes of temperature, especially air currents (aerophobia). Percussion myoedema (a mounding of muscles after a light pressure stimulus) can be present and persist throughout the disease. Abnormal sexual behavior is also a recognized presenting symptom of rabies and such behavior includes priapism and frequent ejaculation in males and hypersexuality in females.
The CNS stage begins about 10 days after the prodrome and may be either encephalitic (“furious”) or paralytic (“dumb”). The encephalitic form (about 80% of the cases) produces the classic rabies manifestations of delirium alternating with periods of calm, extremely painful laryngeal spasms on attempting drinking (hydrophobia), autonomic stimulation (hypersalivation), and seizures. In the less common paralytic form, an acute ascending paralysis resembling Guillain-Barré syndrome predominates with relative sparing of higher cortical functions initially. Both forms progress relentlessly to coma, autonomic nervous system dysfunction, and death.
Biting animals that appear well should be quarantined and observed for 10 days. Sick or dead animals should be tested for rabies. A wild animal, if captured, should be sacrificed and the head shipped on ice to the nearest laboratory qualified to examine the brain for evidence of rabies virus. When the animal cannot be examined, raccoons, skunks, bats, and foxes should be presumed to be rabid.
Direct fluorescent antibody testing of skin biopsy material from the posterior neck of the potentially infected animal (where hair follicles are highly innervated) has a sensitivity of 60–80%.
Quantitative RT-PCR, nucleic acid sequence-based amplification, direct rapid immunohistochemical test, and viral isolation from the patient’s CSF or saliva are advocated as definitive diagnostic assays. Antibodies can be detected in the serum and the CSF. Pathologic specimens often demonstrate round or oval eosinophilic inclusion bodies (Negri bodies) in the cytoplasm of neuronal cells, but the finding is neither sensitive nor specific. MRI signs are diffuse and nonspecific.
Management requires intensive care with attention to the airway, maintenance of oxygenation, and control of seizures. Universal precautions are essential. The induction of coma by ketamine, midazolam, and supplemental barbiturates along with the use of amantadine and ribavirin (the Milwaukee protocol) was reportedly helpful in one case but failed to reproduce success in 26 subsequent cases. Corticosteroids are of no use. Survival is rare, and data are insufficient to provide estimate of success.
If postexposure prophylaxis (discussed below) is given expediently, before clinical signs develop, it is nearly 100% successful in prevention of disease. Once the symptoms have appeared, death almost inevitably occurs after 7 days, usually from respiratory failure. Most deaths occur in persons with unrecognized disease who do not seek medical care or in individuals who do not receive postexposure prophylaxis. The very rare cases in which patients recover without intensive care are referred to as “abortive rabies.”
Immunization of household dogs and cats and active immunization of persons with significant animal exposure (eg, veterinarians) are important. The most important decisions, however, concern animal bites. Animals that are frequent sources of infection to travelers are dogs, cats, and nonhuman primates.
In the developing world, education, surveillance, and animal (particularly dog) vaccination programs (at recurrent intervals) are preferred over mass destruction of dogs, which is followed typically by invasion of susceptible feral animals into urban areas. In some Western European countries, campaigns of oral vaccination of wild animals led to the elimination of rabies in wildlife.
A. Local Treatment of Animal Bites and Scratches
Thorough cleansing, debridement, and repeated flushing of wounds with soap and water are important. Rabies immune globulin or antiserum should be given as stated below. Wounds caused by animal bites should not be sutured.
B. Postexposure Immunization
The decision to treat should be based on the circumstances of the bite, including the extent and location of the wound, the biting animal, the history of prior vaccination, and the local epidemiology of rabies. Any contact or suspect contact with a bat, skunk, or raccoon is usually deemed a sufficient indication to warrant prophylaxis. Consultation with state and local health departments is recommended. Postexposure treatment including both immune globulin and vaccination should be administered as promptly as possible when indicated.
For patients who had not received rabies vaccination prior to possible exposure, the optimal form of passive immunization is human rabies immune globulin (HRIG; 20 international units/kg), administered once. As much as possible of the full dose should be infiltrated around the wound, with any remaining injected intramuscularly at a site distant from the wound. Finger spaces can be safely injected without development of a compartment syndrome. If HRIG is not available and appropriate tests for horse serum sensitivity are done, equine rabies antiserum (40 international units/kg) can be used.
Two vaccines containing inactivated rabies viruses are licensed for active immunization and available for use in humans in the United States: a human diploid cell vaccine (Immovax) and a purified chick embryo cell vaccine (RabAvert). There are several postexposure prophylaxis strategies. The most commonly used one is the “abbreviated Essen” strategy, where either of the current vaccines is given as four intramuscular injections of 1 mL in the deltoid or, in small children, into the anterolateral thigh muscles on days 0, 3, 7, and 14 after exposure. (The fifth dose at 28 days after exposure is no longer recommended except among immunosuppressed patients.) The vaccine should not be given in the gluteal area due to suboptimal response. An alternative intramuscular vaccination strategy that takes only 1 week, with injections on days 0, 3, and 7 after exposure with a Vero cell vaccine (Verorab) is reportedly successful in achieving adequate neutralizing titers at days 14 and 28 in a study from Thailand; this vaccine is not currently available in the United States. A new rabies vaccine with a similarly short schedule is currently in phase II clinical trials. It is an inactivated rabies vaccine paired with a PIKA adjuvant (synthetic analog of a dsRNA and a refined form of polyinosinic-polycytidylic acid stabilized with kanamycin and calcium) that is given as two doses on days 0 and 3, and then one final dose on day 7. To date, this new vaccine has been well-tolerated with noninferior immunogenicity compared to the classic regimen using the commercially available vaccine in healthy adults.
The WHO supports an intradermal vaccination strategy using Verorab and the inactivated rabies virus vaccine Rabipur (an alternative formulation of the purified chick embryo cell) (0.1 mL per intradermal injection) for regions of the world where vaccine is in short supply; either vaccine can be given at two sites on days 0, 3, 7, and 28.
Rabies vaccines and HRIG should never be given in the same syringe or at the same site. Allergic reactions to the vaccine are rare and include a report of sudden unilateral sensorineural hearing loss and immune thrombocytopenic purpura, although local reactions (pruritus, erythema, tenderness) occur in about 25% and mild systemic reactions (headaches, myalgias, nausea) in about 20% of recipients. Rare cases of post-immunization encephalitis have been reported. Intradermal vaccines appear to be better tolerated than intramuscular vaccines, especially among young children (while titers achieved with intramuscular vaccinations are higher, the titers achieved with intradermal vaccination are deemed sufficient for protection against clinical rabies). The vaccines are commercially available or can be obtained through health departments. Adverse reactions to HRIG seem to be more frequent in women and rare in young children.
In patients with history of past vaccination, the need for HRIG is eliminated (HRIG is in short supply worldwide), but postexposure vaccination is still required. The vaccine should be given 1 mL in the deltoid twice (on days 0 and 3). Neither the passive nor the active form of postexposure prophylaxis is associated with fetal abnormalities and thus pregnancy is not considered a contraindication to vaccination. Peripartum rabies transmission occurs but is rare. Neonates may also receive both forms of postexposure prophylaxis at birth.
The WHO has a program to eliminate dog-transmitted human rabies by 2030.
C. Preexposure Immunization
Preexposure prophylaxis with three injections of human diploid cell (Immovax) vaccine intramuscularly (1 mL on days 0, 7, and 21 or 28) is recommended for persons at high risk for exposure: veterinarians (who should have rabies antibody titers checked every 2 years and be boosted with 1 mL intramuscularly); animal handlers; laboratory workers; Peace Corps workers; and travelers with stays over 1 month to remote areas in endemic countries in Africa, Asia, and Latin America. An intradermal route is also available (0.1 mL on days 0, 7, and 21 over the deltoid) but not in the United States. A prophylactic mRNA-based vaccine encoding rabies virus glycoprotein (CV7201) is currently under development and showed success in a phase I clinical trial given as three doses with a needle-free device. Immunosuppressive illnesses and agents including corticosteroids as well as antimalarials—in particular chloroquine—may diminish the antibody response. A single-dose booster at 10 years after initial immunization increases the level of antibody titers. Unfortunately, data from travel services indicate that only a small proportion of travelers with anticipated lengthy stays in rabies-impacted areas receive the vaccine as recommended.
Suspicion of rabies requires contact with public health personnel to initiate appropriate passive and active prophylaxis and observation of suspect cases.
Respiratory, neuromuscular, or CNS dysfunction consistent with rabies.
Patients with suspect rabies require initiation of therapy until the disease is ruled out in suspect animals, and this requires coordination of care based on likelihood of patient compliance, availability of inpatient and outpatient facilities, and response of local public health teams.
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