Rabies in humans usually results from a bite by a rabid animal or contamination of a wound by its saliva. It presents as an acute, fulminant, fatal encephalitis; human survivors have been reported only occasionally. The clinical stages of rabies infection are summarized in Table 17–1. After an average incubation period of 20 to 90 days (range 10 days to 1 year), the disease begins as a nonspecific flu-like illness marked by fever, headache, malaise, nausea, and vomiting known as prodrome stage. Abnormal sensations at or around the site of viral inoculation occur frequently and probably reflect local nerve involvement. In the acute neurologic stage, the onset of encephalitis is marked by periods of excess motor activity and agitation. Hallucinations, combativeness, muscle spasms, signs of meningeal irritation, seizures, and focal paralysis occur. Periods of mental dysfunction are interspersed with completely lucid periods; however, as the disease progresses, the patient lapses into coma. Autonomic nervous system involvement often results in increased salivation. Brainstem and cranial nerve dysfunction is characteristic, with double vision, facial palsies, and difficulty in swallowing. The combination of excess salivation and difficulty in swallowing produces the fearful picture of “foaming at the mouth.” Hydrophobia, the painful, violent involuntary contractions of the diaphragm and accessory respiratory, pharyngeal, and laryngeal muscles, initiated by swallowing liquids including water, is seen in about 50% of the cases. Involvement of the respiratory center produces respiratory paralysis, the major cause of death. Occasionally, rabies may appear as an ascending paralysis resembling Guillain-Barré syndrome. Once symptoms have developed, no drug or vaccine administration can improve survival. The median survival after onset of symptoms is 4 days, with a maximum of 20 days unless artificial supportive measures are instituted. Recovery is exceedingly rare.
TABLE 17–1Clinical Stages of Rabies Virus Infection ||Download (.pdf) TABLE 17–1 Clinical Stages of Rabies Virus Infection
|STAGES OF INFECTION ||TIME FRAME ||SYMPTOMS ||SITE OF VIRUS REPLICATION |
|Incubation period || |
Average: 20-90 days
|No symptoms ||Site of bite, muscle cells |
|Prodrome stage ||2-10 days ||Nonspecific symptoms, malaise, headache, fever, nausea, vomiting, upper respiratory distress, subtle mental changes (insomnia), pain, itching, tingling at the site of bite ||Virus replication in the CNS |
|Acute neurologic stage ||2-7 days || |
Furious or dumb presentation
Furious: Hyperactivity, excitement, disorientation, hallucination, bizarre behavior, hydrophobia, convulsions, aggressive
Dumb (paralytic phase): Lethargy, paralysis, (respiratory)
|Virus replication in brain and transported to other sites (salivary glands and other organs) |
|Coma ||0-14 days ||Patient in coma; respiratory paralysis, cardiac arrest, drop in blood pressure, secondary infections ||Virus replication in brain and transported to other organs |
|Death || ||Extremely rare survival || |
✺ Four phases of clinical manifestations: Incubation period, prodrome stage, acute neurologic stage, and coma
✺ Encephalitis common, sometimes with ascending paralysis
There are several tests that are performed from different sources, including saliva, neck biopsy, serum, and CSF in human ante mortem to rule out rabies. Viral RNA can be detected by RT-PCR in saliva, neck biopsy, and brain biopsy (if taken for other tests). Viral antigen can be detected by immunofluorescent staining in neck biopsy. Rabies antibody can be detected by immunofluorescence test in serum and CSF. Rabies antibody in the CSF regardless of immunization history suggests a rabies virus infection. Virus culture can also be performed from saliva sample. The CSF of a rabies patient shows minimal with some patients exhibiting a lymphocytic pleocytosis (5-30 cells/mm3), mainly monocytosis with normal glucose and protein. Laboratory diagnosis of rabies in animals or deceased patients is accomplished by demonstration of virus in brain tissue. Viral antigen can be demonstrated rapidly by immunofluorescence procedures. Intracerebral inoculation of infected brain tissue or secretions into suckling mice results in death in 3 to 10 days. Histologic examination of their brain tissue shows the Negri bodies in 80% of the cases; electron microscopy may demonstrate both the Negri bodies and rhabdovirus particles. Specific antibodies to rabies virus can be detected in serum, but generally only late in the disease.
Viral RNA, antigen and antibody are detected ante mortem in saliva, neck biopsy, serum and CSF, and brain biopsy (if available) to rule out rabies
Viral antigen detected in brain tissue of human postmortem or animals
The Negri bodies by histologic examinations
Prevention is the mainstay of controlling rabies in humans immediately after exposure by starting the rabies vaccination process. With symptomatic rabies, intensive supportive care has resulted in four or five long-term survivals; despite the best modern medical care, however, the mortality rate still exceeds 90%. In addition, because of the infrequency of the disease, many patients die without definitive diagnosis. Human hyperimmune antirabies globulin, interferon, and vaccine do not alter the disease once the symptoms have developed. Postexposure prophylaxis is considered as a treatment for rabies exposure to humans after bites from rabid or wild animals.
No specific treatment is available
✺ Vaccination immediately after animal bites to prevent rabies disease
How is rabies vaccine successful in treating and/or preventing rabies if given soon after exposure?
In a controversial experimental treatment strategy in 2004, known as the Wisconsin or Milwaukee protocol, a 15-year old patient with rabies symptoms was placed in a chemically induced coma to protect her brain from rabies virus and treated with antivirals (ribavirin and amantadine). The coma was reversed in the patient after 6 days when her immune system started making rabies antibodies. The patient became free of rabies virus and survived.
In the late 1800s, Pasteur, noting the long incubation period of rabies, suggested that a vaccine to induce an immune response before the development of disease might be useful in prevention. He apparently successfully vaccinated Joseph Meister, a boy severely bitten and exposed to rabies, with multiple injections of a crude vaccine made from dried spinal cord of rabies-infected rabbits. This treatment emerged as one of the best-known and most noteworthy accomplishments in the annals of medicine. It is now believed that vaccination induces antibody that is either neutralizing or inhibits cell-to-cell spread of virus. Natural infection does not lead to an early immune response and limitation of viral migration, because the virus is replicating in muscle or neural tissue and lymphocytes do not access these sites. Cytotoxic T lymphocytes are also induced by vaccine and appear to be directed against viral antigens.
Vaccine-induced antibody inhibits viral spread
Currently, the prevention of rabies is divided into preexposure prophylaxis (PreEP) and postexposure prophylaxis (PEP). There are currently two inactivated (killed) vaccines licensed in the United States: human diploid cell vaccine (an attenuated strain of rabies virus grown in human diploid cell culture and inactivated by β-propiolactone) and purified chick embryo cell vaccine (fixed rabies virus strain grown in primary cultures of chicken fibroblasts and inactivated by β-propiolactone). Rabies vaccine made by Novartis is called “RabAvert” and by Sanofi Pasteur “IMOVAX” used for PreEP and PEP.
Think ➮ Apply 17-2. Postexposure prophylaxis through rabies vaccine is both treatment and prevention if given soon after infections, including on Day 0, 3, 14, and 28. Because the incubation period of rabies is from 10 days to 1 year (average 20-90 days), it is sufficient to elicit neutralizing antibodies to prevent travel of the virus to the CNS.
Preexposure prophylaxis is recommended for individuals with high risk of contact with rabies virus, such as veterinarians, spelunkers, laboratory workers, and animal handlers. Preexposure prophylaxis consists of three doses of intramuscular injections (deltoid area) of vaccine on Days 0, 3, and 21 or 28. A booster dose is needed to maintain a neutralizing antibody titer of 1:5 in high-risk people (researchers working with rabies vaccine, veterinarians) after testing 6 months later.
High-risk individuals include veterinarians, spelunkers, laboratory workers, and animal handlers
Postexposure prophylaxis requires careful evaluation and judgment. Every year, more than 1 million people are bitten by animals in the United States, and approximately 25 000 receive postexposure rabies prophylaxis. Worldwide, more than 15 million people receive rabies vaccine after rabid animal bites (postexposure) that prevents thousands of deaths annually worldwide. The physician must consider (1) whether the individual came into physical contact with saliva or another substance likely to contain rabies virus; (2) whether there was significant wound or abrasion; (3) whether rabies is known or suspected in the animal species and area associated with the exposure; (4) whether the bite was provoked or unprovoked (ie, the circumstances surrounding the exposure); and (5) whether the animal is available for laboratory examination.
Any wild animal or ill, unvaccinated, or stray domestic animal involved in a possible rabies exposure, such as an unprovoked bite, should be captured and killed. The head should be sent immediately to an appropriate laboratory, usually at the state health department, to search for rabies antigen by immunofluorescence. If examination of the brain by this technique is negative for rabies virus, it can be assumed that the saliva contains no virus and that the exposed person requires no treatment. If the test is positive, the patient should be given postexposure prophylaxis. It should be noted that rodents and rabbits are not important vectors of rabies virus. There have been no rabies deaths in the United States when postexposure prophylaxis was given promptly after exposure.
Careful history and studies of biting animal are important in decision making
Postexposure prophylaxis is based on immediate, thorough washing of the wound with soap and water (to kill the virus around the wound); passive immunization with antirabies hyperimmune globulin, including a portion instilled around the wound site (to neutralize the virus); and active immunization with killed rabies vaccine on Days 0, 3, 7, and 14. For individuals who were previously immunized, the postexposure prophylaxis includes would cleansing with soap and water and rabies vaccination on Days 0 and 3 (hyperimmune globulin should not be given). Physicians should always seek the advice of the local health department when the question of rabies prophylaxis arises.
✺ Rabies immune globulin plus vaccine necessary in postexposure management