“The microscope or the telescope, which of the two has the grander view?”.
—Victor Hugo, Les Misérables (1862)
13.1 History of Rabies
Rabies, which was known as hydrophobia (“fear of water”) in the 1800s, is a terrifying disease. It affects the CNS, causing delirium, hydrophobia, and aggression or stupor. The French scientist Louis Pasteur (1822–1895) was a trained chemist who made numerous contributions to the field of microbiology. He challenged and disproved the theory of spontaneous generation in 1862 through a series of experiments using a goose-necked flask, demonstrating that life does not arise from non-living materials. Pasteur also isolated and identified the microorganisms responsible for the fermentation of wine, beer, and vinegar. He then went on to develop methods to destroy microbes to prevent them from contaminating wine and beer by applying heat. His partial sterilization procedure became known as pasteurization.
Pasteur’s 1878 germ theory of disease causation postulated that infectious diseases are caused by germs or microbes. The germ theory of disease became a cornerstone of modern medicine. Pasteur went on to develop a vaccine to prevent chicken cholera caused by Pasteurella multocida in 1879 and anthrax caused by Bacillus anthracis in 1881.
While developing the anthrax vaccine, in 1880 Pasteur and his colleague Emile Roux began to focus their efforts on conquering rabies. They knew that a rabies vaccine would be a significant contribution to science and a great achievement for public health. Roux determined that the rabies agent was found in the brain of a dog that died from rabies. If a hole was drilled into the skull of a healthy dog (this is called trephination) and brain material from the rabid dog was inoculated into the trephined skull, the inoculated dog would display rabies symptoms within 21 days of the infection.
Further experimentation by Roux and Pasteur determined that the rabies agent existed in the spinal cord of rabid animals. They began to make an inactivated vaccine by drying strips of spinal cord that were removed from rabid rabbits. Over the next few years, Pasteur worked on methods to serial passage the rabies virus using infected brain material inoculated into different animal species, from dogs to monkeys, in order to attenuate the rabies agent. As their experiments continued, Pasteur and Roux developed a vaccine that consisted of dried spinal cord tissues injected under the skin of dogs to induce immunity. In 1885, Pasteur and Roux vaccinated 50 dogs and intentionally infected the dogs by inoculating them. All of the dogs survived. Pasteur was cautious in using the rabies vaccine on humans and insisted that additional years of research were needed before the treatment could be applied to humans. The press had picked up quickly on his successful vaccination of dogs, though, and on July 6, 1885, Pasteur’s first human subject arrived at his laboratory.
Two days earlier, 9-year-old Joseph Meister had been mauled and bitten 14 times on his hands, legs, and hips by a rabid dog. Meister’s mother appealed to Pasteur for the rabies treatment. After consulting his colleagues, Pasteur treated the boy, inoculating him 13 times over a 15-day period with a dried spinal cord suspension created from rabid rabbits. Meister survived and remained in fine health. Months later, another victim, 15-year-old shepherd Jean-Baptiste Jupille showed up at Pasteur’s research laboratory. Jupille was with a group of six shepherd boys who were attacked by a rabid dog. One of Pasteur’s many biographers, Rene Vallery-Radot, describes the event in his book La vie de Pasteur (Hachette et Cie, Paris, France, 1900):
“The children ran away shrieking, but the eldest of them, Jupille, bravely turned back in order to protect the flight of his comrades. Armed with his whip, he confronted the infuriated animal which flew at him and seized his left arm. Jupille wrestled the dog to the ground and succeeded in kneeling on him, forcing his jaws open in order that he might disengage his left hand, and in so doing, his right hand was seriously bitten in its turn; finally, having been able to get hold of the animal by the neck, Jupille called his little brother to pick up his whip which had fallen in the struggle and secured the animal’s jaws with the whip. He then took his wooden shoe, with which he battered the dog’s head.”
Jupille was brought to Pasteur for treatment 6 days after being bitten, in contrast to the Meister boy who was brought 2 days after being bitten. Pasteur was reluctant to treat Jupille because of the additional time that had elapsed since his attack. Nevertheless, Pasteur again put his reputation on the line and injected Jupille with the vaccine. Jupille did not develop rabies, and the boy’s act of bravery was commemorated with an impressive statue depicting the struggle between a boy and a rabid dog that stands today on the grounds of the Pasteur Institute (FIGURE 13-1A).
Pasteur’s success made him a hero and a legend. In 1887, the Pasteur Institute was founded to treat rabies victims. Today, it is widely respected for its role in research in the field of microbiology. More recent discoveries at the Pasteur Institute include the discovery of human immunodeficiency virus types 1 (HIV-1 in 1983) and 2 (HIV-2 in 1985); a vaccine against Helicobacter pylori (the cause of many peptic ulcers and gastric cancers; 1991); the complete genome sequence of Mycobacterium tuberculosis (the causative agent of tuberculosis; 1998); and the discovery of the nicotine receptor responsible for the pain-relieving activity of nicotine (1999). The Pasteur Institute’s website is available at http://www.pasteur.fr/en.
13.2 Epidemiology of Rabies
Rabies is one of the oldest known viral diseases. The word rabies originated in 3000 BC in Sanskrit, the official language of India. Rabhas (“rabies”) means “to do violence.” In Latin, the word rabies was derived from rabere, which means “to rave.” In 1546, the Italian scholar Girolamo Fracastoro (1478–1553) first described rabies, about 350 years before Louis Pasteur and Emile Roux developed the rabies vaccine. His description of classic rabies symptoms was as follows:
“The patient can neither stand nor lie down, like a mad man he flings himself hither and thither, tears his flesh with his hands, and feels intolerable thirst. This is the most distressing symptom, for he so shrinks from water and all liquids that he would rather die than drink or be brought near to water. It is then they bite other persons, foam at the mouth, their eyes look twisted, and finally they are exhausted and painfully breathe their last.”
In the 19th century, canine or street rabies was a scourge everywhere, especially in Europe. Rabies victims killed themselves or were killed by other people after a rabid dog bite. Sufferers in the late stages of the disease became extremely agitated and hypersalivated. During a frenzy, a victim might commit uncontrollable violent acts before succumbing to paralysis and eventually death. The appearance of these horrific symptoms caused overreactions, prompting some to take the lives of rabies victims in order to prevent them from further harming others. The image of the mad dog symbolized man’s fear of rabies for centuries (FIGURE 13-1B). Even though vaccines are available today, rabies remains a significant wildlife management and public health challenge. Continued education about rabies prevention is needed. World Rabies Day is September 28. It is a global health observance day that raises awareness about rabies and seeks to promote prevention and control efforts. The Global Alliance for Rabies Control (GARC) is the leading organization working for global prevention of rabies (https://rabiesalliance.org).
Rabies epidemiology is extremely complex and differs greatly from one continent to another. Surveillance programs are used to address the following questions:
What animals have rabies, and in what regions of the country are they found?
How many people get rabies, and from what animals did they contract it?
What are the best strategies to prevent rabies in humans and animals?
Rabies in the Wild
Rabies is a disease of mammals. In the United States, rabies is primarily a disease that affects wildlife populations. Worldwide, it is usually a disease in wild dogs, coyotes, foxes, raccoons, skunks, mongooses, and bats. The disease occurs less frequently in domesticated dogs, cats, cows, horses, pigs, sheep, and goats. FIGURE 13-2 is a composite world map showing locations of countries categorized by the World Health Organization (WHO) by human risk for contracting rabies. Pre-exposure vaccination is recommended for travelers and for individuals in medium- and high-risk areas who may have contact with dogs and other rabies vectors. Pre-exposure vaccination is only recommended for people in low-risk areas if they may have contact with bats. High-risk areas include Mexico and parts of South America, Africa, Asia, and Russia. Medium-risk countries include Greenland and countries in South America, the Middle East, and Asia. The United States, Australia, Iceland, Japan, and countries in Western Europe and Scandinavia are categorized as being at low risk of human exposure to rabid animals, including bats.
Rabies has been extensively studied in Thailand. Researchers have determined that unvaccinated dogs account for 95% of rabies cases; cats for 3% of cases; and rats, rabbits, civet cats, monkeys, tigers, squirrels, and other animals for the remaining 2% of cases—evidence that rabies virus is highly infectious among mammals. Control of canine (dog) rabies in Asia, Africa, parts of South America, and Mexico has proved difficult.
FIGURE 13-1 (a) Statue of Jean-Baptiste Jupille at the Pasteur Institute in Paris. Jupille was attacked by a rabid dog while attempting to protect younger children from the animal. He was the second person to receive the vaccine. (b) This 1826 cartoon depicts citizens equipped with weapons to protect themselves and to remove a rabid dog roaming the streets of London, England. A street peddler falls to avoid the dog while men hide behind a wall and a woman runs into a building.
FIGURE 13-2 Countries in which humans have a high risk for contracting rabies from rabid animals, including bats, in the wild. High-risk areas include Mexico and parts of South America, Africa, Asia, and Russia. The United States, Australia, Iceland, Japan, and countries in Western Europe and Scandinavia present a low risk of human exposure to rabid animals, including bats.
Foxes are an important rabies vector in Europe, Canada, Alaska, and Russia. Before 1992, Ontario, Canada, was known as the rabies capital of North America. Since the implementation of rabies control programs, though, the number of wildlife rabies cases has been reduced by 95%. The programs focused on the vaccination of arctic foxes and mid-Atlantic raccoons, in addition to an educational focus regarding various bats.
The raccoon dog, which is native from Siberia to Japan and in northern India, is an important rabies reservoir in Europe. Raccoon dogs were introduced into Europe because of the commercial value of their long, thick fur and spread throughout the continent. In 1877, the Indian mongoose was introduced into Puerto Rico from Jamaica for rat control on sugar plantations. The mongoose has become an important reservoir and vector of rabies virus in the Caribbean (FIGURE 13-3). The vampire bat presents a rabies threat to cattle and humans in Mexico and parts of South America. Recent human rabies deaths in North America have been associated with bites from rabid silver-haired bats.
The distribution of wild animal rabies in the United States and Puerto Rico from 2009 to 2012 is shown in FIGURE 13-4A. A graph comparing raccoon, fox, skunk, and bat rabies cases from 1984 to 2012 is provided in FIGURE 13-4B. The most commonly infected wildlife in the United States are raccoons, skunks, foxes, coyotes, and bats. The peak number of reported rabies cases in wild skunks and raccoons is seasonal, occurring between March and April. TABLE 13-1 displays the breakdown of wildlife and domestic animal rabies reporting and testing in the United States and Puerto Rico from 2008 to 2012. Consistently, raccoon cases were reported most frequently in the United States, but the most frequently submitted wildlife for rabies diagnostic testing were bats (n = 24,152) followed by raccoons (n = 11,680; data not shown).
Rabies Diagnostic Testing in Animals
In the United States, direct fluorescent antibody (dFA) testing is the gold standard for rabies diagnosis in animals. Animals that are behaving abnormally or that show signs consistent with rabies should be tested when human or animal exposures have occurred. The test is performed postmortem.
Rabies virus is present in nervous tissues. The brain of the suspected animal is the ideal test tissue (not blood, as is the case with many other viruses). Two or three areas of the animal’s brain are tested: the brain stem (medulla), which merges with the spinal cord, and the cerebellum or the hippocampus. A piece of tissue from each area is removed and placed on an impression slide. The tissues are air dried and fixed in acetone before being incubated with labeled antibodies (antirabies N protein that is labeled with a fluorescent dye [fluorescein-isothiocynate, or FITC]). After incubation, the slides are washed and viewed with a fluorescence microscope in a dark room. dFA testing is rapid (30 minutes to less than 4 hours). The results may save a patient from the unnecessary physical, emotional, and financial burdens if the animal is not rabid.
FIGURE 13-3 Common animal reservoirs of rabies virus in wildlife in the United States are (a) skunks, (b) raccoons, (c) and foxes. (d) Mongooses are the largest wildlife reservoir for rabies virus in the Caribbean Islands.
Rabies Management Programs in the United States
Vaccination and other rabies-control programs in the United States were implemented during the 1940s and 1950s. The rabies prevention strategy resulted in a significant reduction in the number of domestic rabies cases, but by the 1960s it still had not succeeded in eliminating rabies virus in wild dogs. Programs were initiated to interrupt rabies in wild dogs. The programs continued through the 1970s and 1980s and did substantially reduce the spread of dog rabies.
A small but increasing number of human rabies cases transmitted by rabid bats continue to occur. It is difficult to target and control bat rabies by conventional methods. Rabies in bats is widely distributed in the United States. Rabid bats were reported by all contiguous U.S. states in 2013. No rabid bats were reported in Alaska, Hawaii, or Puerto Rico (FIGURE 13-5).
The Wildlife Services (WS) program, which is part of the U.S. Department of Agriculture (USDA), is responsible for providing federal assistance in wildlife disease management through its regional and state offices and field stations (FIGURE 13-6A). Since 1995, WS has been working cooperatively with local, state, and federal governments and other partners by distributing Raboral V-RG oral rabies vaccine baits in targeted areas. In 2004, 15 states distributed the Raboral V-RG oral rabies vaccine for raccoons; Texas distributed baits for gray foxes and coyotes as well. Raboral V-RG is combined with an outer bait matrix that is composed of fishmeal (for raccoons and coyotes) or dog food (for gray foxes). The rabies vaccine is inserted inside of a small packet and waxed into the bait (FIGURE 13-6B). The packet is punctured when the animal bites the bait, releasing 1.5 mL of the oral rabies vaccine. Animals mount an immune response against the rabies virus in 2–3 weeks.
FIGURE 13-4 (a) Distribution of rabies animal reservoirs in wildlife in the United States and northeastern Caribbean (Puerto Rico) from 2009 to 2012. (b) Cases of rabies in wildlife in the United States by year and species. The most frequently reported rabid wildlife were raccoons, followed by skunks, bats, and foxes.
Table 13-1 Domestic and Wild Animal Rabies in the United States: 2008–2012
| Number of Animals Reported Rabid | Percentage of Samples with Positive Results | |
|---|---|---|
| Domestic Animals | ||
| Cats | 291 | 1% |
| Cattle | 77 | 6% |
| Dogs | 76 | 0% |
| Horses and mules | 40 | 5% |
| Sheep and goats | 10 | 2% |
| Wildlife | ||
| Raccoons | 2,181 | 15% |
| Bats | 1,585 | 6% |
| Skunks | 1,561 | 30% |
| Foxes | 431 | 23% |
Information from Dyer, J. L., et al. 2014. “Rabies surveillance in the United States during 2013.” J Am Vet Med Assoc 245:1111–1123. | ||
Baits are distributed by hand in urban and suburban areas, but in rural areas planes are the most effective means for distributing baits over large vaccination zones. During flight, oral rabies vaccine for wildlife is dispensed from a bait dispenser chute that is located under the plane’s wing. The dispenser is turned off when flying over a house or crossing a road to avoid human contact with the bait. In 2003, more than 10 million baits were distributed in the United States and Canada. An oral rabies vaccine blister pack bait, ONRAB, used in Canada to control rabies in raccoons, skunks, and foxes, underwent field testing in the United States in 2011. The blister packs were coated with a sweet attractant of vegetable-based fats, wax, icing sugar, vegetable oil, vanilla flavor, and dark green food color dye (FIGURE 13-7). Field testing results were promising, and distribution of the baits in targeted areas by dropping ONRAB baits by plane or by bait dispenser stations continued in 2014.
FIGURE 13-5 Reported cases of bat rabies in the United States, by county, in 2012. Rabid bats were reported in all of the contiguous United States. No rabid bats were reported in Alaska, Hawaii, or Puerto Rico.
13.3 Human Rabies
Human rabies has been reported in all parts of the world except Australia and Antarctica. Dogs are the global reservoir of rabies, and as a result the majority of human rabies cases outside of Canada and the United States occur in countries where dog rabies is not well controlled by vaccination. The WHO estimates that over 10 million humans receive postexposure prophylaxis (PEP; see Section 13.4) annually. More than 55,000 rabies-related human deaths occur each year, or 150 individuals each day.
FIGURE 13-6 (a) Biologists collect blood and other biological samples to evaluate the effectiveness of the oral rabies vaccine before releasing the animals back into the wild at the site of capture. (b) Raboral V-RG rabies vaccine bait. The bait consists of a fishmeal polymer cube that is hollow. A plastic packet containing the vaccine is inserted into the hollow area of the bait and sealed with wax. Planes are the most effective means for distributing baits over large-scale oral rabies vaccine zones. During flight, oral rabies vaccine for wildlife is dispensed from a chute located under the aircraft’s wing.
FIGURE 13-7 (a) Blister pack containing ONRAB used to vaccinate raccoons, foxes, and skunks in the wild. The baits are dropped by plane, on the ground by hand or using bait dispenser stations. (b) Rabies bait dispenser station used to dispense oral rabies vaccine. The dispenser costs about $15 to make. (c) A raccoon takes the bait from a rabies bait station dispenser. The raccoon eats the bait and is vaccinated against rabies virus. Visitation rates by raccoons to bait stations in Florida have been documented to be greater than 50%.
Rabies is a significant public health problem in China. China is a high-risk environment, with the number of human rabies deaths ranking only second to India’s. Unvaccinated dogs that contract rabies are the main reservoir of rabies virus in China and India, putting humans at risk for rabies virus infection. In China, rabies is among the top three causes of human death caused by infectious diseases. In 2007, more than 3,300 human cases of rabies were reported in China (FIGURE 13-8A). Chinese authorities have identified rabies as a priority and recognize the need to control rabies virus infections in dogs.
In the United States, the highest incidence of PEP occurs among boys in rural areas, primarily during the summer months. Many baby boomers will recall the 1957 Disney movie Old Yeller, which was based on a novel by Fredrick B. Gipson. The story takes place in Texas in 1869. Two boys, Travis and Arliss Coates, live on a remote homestead with their mother. The boys befriend a stray yellow mongrel dog they name “Old Yeller.” The dog proves his loyalty by saving Mrs. Coates from a rabid wolf but contracts rabies itself. The viewers watch the terrifying, raving transformation of the boys’ beloved pet. In the end, Travis is forced to shoot his dog (traumatizing several generations of movie-watching children). Today, about 80–100 dogs and a little more than 300 cats are diagnosed with rabies each year in the United States. In most cases these are domesticated pets that have not been vaccinated by their owners and that then have interactions with other rabies reservoir species. Americans coming into contact with wild animals that are suspected of having rabies results in 30,000–60,000 Americans receiving PEP to prevent rabies each year.
On average, only one to three cases of human rabies are reported annually in the United States. Thirty-four cases of human rabies have been diagnosed in the United States since 2003. Ten of these cases occurred in U.S. territories (e.g., Puerto Rico) or were initially contracted outside of the United States (e.g., travelers to Mexico, the Philippines, and countries in South America). Rabies vaccination programs have eliminated domestic dogs (pets) as reservoirs of rabies in the United States.
FIGURE 13-8 (a) Human rabies cases reported in China, 2007–2012. Map shows locations of provinces. Guizhou, Hunan, Guangxi, and Guangdong reported the highest number of cases. (b) Here are two rabid dogs showing symptoms of paralytic rabies, manifested as depression, and an attempt at self-imposed isolation. Domesticated animals suffering from paralytic rabies may become increasingly depressed and try to hide in isolated places, whereas wild animals seem to lose their fear of human beings, often appearing unusually friendly.
In 1990, over 92% of human rabies cases in the United States were associated with bat bites. Human-to-human transmission through biting is extremely rare. Besides bat bites, a few cases have been associated with direct implantation of infected organs during human transplant surgery (i.e., corneal transplants). Infection by aerosol has been suspected in caves heavily contaminated with bat guano.
Clinical Signs and Symptoms of Rabies
About 75% of humans contracting rabies experience symptoms of encephalitis (see Refresher: What Is Encephalitis) within the first 20–60 days of exposure. The incubation period of the virus ranges from 5 days to several years. However, it is usually 2–3 months and is rarely more than 1 year, depending on the number of rabies viruses present in the inoculum and the proximity of rabies virus entry to the CNS.
Human rabies can manifest in two forms: furious (encephalitic) or paralytic (dumb). Neither is correlated with a specific anatomical location of rabies virus in the CNS. The impairment of neuronal functioning helps to explain coma. With either form, the average course of the disease is 2–14 days before coma supervenes. Death occurs an average of 18 days after onset of symptoms. Symptoms during the primary period, or prodromal period, of rabies are nonspecific and are similar to those of other viral infections:
Headache
Malaise
Fever
Anorexia
Nausea
Vomiting
Secondary symptoms of furious rabies in humans include:
Hydrophobia (fear of water)
Difficulty swallowing
Agitation
Anxiety
Hallucinations
Hypersalivation
Bizarre behavior
Biting
Jerky and violent contractions of the diaphragm
Secondary symptoms of paralytic rabies in humans include:
Lack of hydrophobia
Lack of hyperactivity
Lack of seizures
Weakness and ascending paralysis
In addition to the symptoms mentioned earlier in humans, furious rabies in animals is marked by excitation and aggressiveness, notably biting of objects, other animals, humans, or even oneself. Dumb rabies in animals is characterized by reclusive behavior, drooling, anorexia, a startle response to sudden noise or light exposure, and irritation around the site of the bite, resulting in frequent licking and biting of the area. Salivation is profuse (causing the animal to choke to death), and there is usually a change in voice. Wildlife often seem to lose their fear of people, and nocturnal and crepuscular creatures may be out during daylight hours. They may appear “tame” (do not touch them!), and they may aggressively attack humans and other animals when approached. Infected bats may act strangely (e.g., crawling around, hissing) and tend to be weak, unable to fly, and suffer from hind leg paralysis. A general observation is that animals that are predators show signs of furious rabies, whereas nonpredators display paralytic rabies symptoms (FIGURE 13-8B).
Rabies Diagnosis in Humans
All individuals involved in rabies testing are required to receive pre-exposure immunization followed by regular serologic tests and booster immunizations, when necessary. In addition, all laboratory workers must participate in national rabies proficiency testing, available through the Wisconsin State Laboratory of Hygiene in Madison, Wisconsin.
The WHO defines a clinical case of rabies as “a subject presenting with an acute neurological syndrome (i.e., encephalitis) dominated by forms of hyperactivity (i.e., furious rabies) or paralytic syndromes (i.e., dumb rabies) progressing towards coma and death, usually by cardiac or respiratory failure, typically within 7–10 days after the first sign, if no intensive care is instituted.”
Laboratory tests for rabies are rarely conducted in developing countries. However, several routine tests are performed in the United States on humans antemortem (before the death of the patient). Saliva, tears, and cerebrospinal fluid (CSF) samples are used for rabies virus isolation in tissue culture, or reverse transcriptase-polymerase chain reaction (RT-PCR) is used to detect rabies virus genomic RNA. Serum and CSF are immediately tested for antibodies toward rabies virus in unvaccinated patients. Rabies antibodies usually appear during the second week of the illness. Skin punch biopsies at the nape of the neck are examined for rabies virus antigen that may be present in the cutaneous nerves at the base of the hair follicles.
Postmortem dFA tests are performed on the brain of the victim. Long-needle biopsies on two or more samples of the brain (e.g., the brain stem and cerebellum) are tested by RT-PCR, rabies virus isolation in cell culture, or suckling-mouse inoculation. Further histologic, immunocytochemistry, and transmission electron microscopic (FIGURE 13-9) examination of autopsy tissues may also be performed.
Rabies Survivors
Only nine well-documented reports exist of rabies survivors who received pre- or postexposure rabies prophylaxis (see Section 13.4 on PEP). TABLE 13-2 lists those individuals who recovered from rabies encephalitis. Half of the survivors had severe, permanent neurological disorders. Despite efforts to treat patients with steroids, interferon, and other antivirals, there is no therapy of proven value. Heavy sedation and pain medication are used to relieve the patient of agonizing symptoms. Supportive care has prolonged life, but there is no expectation of survival in unvaccinated patients (FIGURE 13-10).
The first individual who survived furious rabies without receiving PEP was a 15-year-old female in Fond du Lac, Wisconsin, in 2004. She was treated with ketamine, midazolam, and phenobarbital to induce coma and two antivirals (ribavirin and amantadine). The treatment became known as the Milwaukee protocol (VIRUS FILE 13-1).
FIGURE 13-9 Transmission electron micrograph of neurons infected by rabies virus. Two hallmarks of rabies virus infection are seen: (1) there is minimal damage to the structure of infected neurons even though the extent of the infection is dramatic and (2) large numbers of bullet-shaped rabies virions accumulate as a result of budding on the endoplasmic reticulum membranes of the host cells. Magnification approximately 25,000×.
Table 13-2 Human Rabies Survivors
| Year | Age (years) | Gender/Country | Exposure | Prophylaxis | Incubation Period | Symptoms | Recovery |
| 1970 | 6 | Male/Ohio, USA | Left thumb bite by rabid bat | Duck embryo vaccine the next day and 13 additional doses | 20 days | Encephalitis, seizures, paralysis, coma | Complete recovery in 6 months |
| 1972 | 45 | Female/Argentina | Bite by rabid dog | Suckling-mouse brain rabies vaccine 10 days after bite | 21 days | Headache, loss of motor strength, tremors, cerebellar dysfunction | Complete recovery 13 months after onset of rabies symptoms; relapsed twice after vaccine boosters |
| 1977 | 32 | Male/New York, USA | Inhaled aerosol of laboratory strain of rabies virus (SAD strain) | Pre-exposure duck embryo rabies vaccine* | 14 days | Fever, nausea, encephalitis, respiratory arrest | Partial recovery; dementia, personality disorder |
| 1985 | 10 | Male/India | Stray dog bite, lower left leg | Semple’s vaccine (phenol-inactivated nerve tissue) | 120 days | Fever, pain, hydrophobia, anxiety, photophobia, aerophobia | Complete recovery; case was severe, required 16 days of respiratory support |
| 1986 | 18 | Male/India | Stray dog bite, lower left leg | Semple’s vaccine (phenol-inactivated nerve tissue) | 60 days | Fever, pain, hydrophobia, anxiety, photophobia, aerophobia, alternating drowsiness with violent behavior | Complete recovery; patient also had cardiac irregularities and needed oxygen for 3 days |
| 1992 | 9 | Male/Mexico | Bite on forehead, nose, and left cheek, by rabid dog | Vero-cell vaccine the next day and at days 3, 7, 14, and 30 | 15 days | Encephalitis, fever, convulsions, coma, paralysis | Partial recovery; blind and deaf, neurological dysfunction, died 34 months later |
| 2000 | 6 | Female/India | Bites on hand and face by rabid dog | Three doses of purified chick embryo at days 0, 3, and 7; no wound treatment; 1 dose of human diploid cell vaccine on day 2 after hospital admission during symptoms | 16 days | Encephalitis, fever, difficulty swallowing, photophobia, visual hallucinations, hypersalivation, frothing at the mouth, profuse sweating | Partial recovery; child was comatose for 3 months; responding to simple verbal commands and oral feeding at the end of 5 months; rigidity and tremors of limbs; discharge after 6 months with follow-ups every 3 months, which indicated little improvement |
| 2004 | 15 | Female/Wisconsin, USA | Bite by rabid bat | No vaccine or immunoglobulin; instead patient was given ketamine, midazolam, ribavirin, and amantadine after onset of symptoms | 21 days | Double vision, fatigue, tingling and numbness of left hand, nausea and vomiting, blurred vision, nerve palsy, muscular twitching, tremors, fever, hypersalivation | Partial recovery; was able to return to school. Some long-term effects |
| 2008 | 9 | Female/SW rural area of Colombia, South America | Bite by unvaccinated cat | None | 28 days | Fever, headache, myalgia, vomiting, trouble swallowing, agitation, encephalitis | Partial recovery; but patient died 76 days after hospitalization |
*Six months prior to this episode, the individual had a neutralizing antibody titer of 1:32.  Stay updated, free articles. Join our Telegram channel
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