Continuing Education Activity

Rabies causes viral encephalitis, which kills up to 70000 people/year worldwide. Infected animal saliva transmits viral encephalitis to humans. Rabies is one of the oldest known diseases, with cases dating back to 4000 years. For most of human history, a bite from a rabid animal was uniformly fatal. In the past, people were so scared of rabies that after being bitten by a potentially rabid animal, many would commit suicide. This activity describes the pathophysiology of rabies and stresses the importance of an interprofessional team in its management.

Objectives:

• Identify the etiology of rabies.

• Determine the pathophysiology of rabies.

• Differentiate the treatment and management options available for rabies.

• Communicate interprofessional team strategies for improving care and outcomes in patients with rabies.

Introduction

Rabies causes viral encephalitis, which kills up to 70,000 people per year worldwide. Infected animal saliva transmits viral encephalitis to humans. Rabies is 1 of the oldest known diseases, with cases dating back to 4000 years. For most of human history, a bite from a rabid animal was uniformly fatal. In the past, people were so scared of rabies that after being bitten by a potentially rabid animal, many would commit suicide. Pasteur's rabies vaccine from 1885 has led to such intense prophylaxis in developed countries that in the United States, for example, there have only been about 2 rabies deaths per year for the past 2 decades; less developed countries are not so lucky.[1][2][3]

Etiology

The Rhabdoviridae family of bullet-shaped viruses is composed of 2 parts that cause rabies. The first part is considered more structural and is a viral envelope, while the second part is more functional and contains the ribonucleocapsid core. The virus most commonly spreads through the bite of an infected mammal, including domestic and wild ones, but transmission can occur from saliva through broken skin or mucous membranes. Other routes of infection include inhalation of the virus in an aerosolized form, ingestion, transplacentally, and even through organ transplants.[4][5]

Epidemiology

Researchers estimate that 30,000 to  70,000 deaths are attributable to rabies each year, with less developed countries affected more. In the United States, few human cases are reported, though that may be due to the widespread use of post-exposure prophylaxis and the prevention programs in place. In developed countries, domesticated animals have only been responsible for about 10% of cases of rabies transmission. In contrast, wild animals such as skunks, raccoons, foxes, and bats are responsible for the rest of the cases. Any mammal may carry rabies, and so while small rodents and the rabbit family are usually considered safe as they are not expected to survive an inoculating wound from a rabid animal, there have been anecdotal reports of rabies caused by transmission from rats. As animal carriers vary by region, it is important to know your region’s carriers to help determine who may need prophylaxis.[6][7]

Pathophysiology

Following viral transmission, the rhabdovirus travels through the peripheral nervous system, targeting the central nerves and leading to encephalomyelitis. In humans, the first symptoms seem like any other nonspecific viral syndrome (fever, malaise, headache). These benign symptoms may then progress to anxiety, then to agitation, and then to frank delirium. One very consistent symptom after a rabid bite is tingling at the bite site within the first few days. Interestingly, after the virus has spread from peripheral nerves to the central nervous system (CNS), it travels back to the peripheral nervous system, particularly affecting highly innervated areas (eg, salivary glands). The "frothing," as portrayed in the movies Cujo and Old Yeller, is due to hypersalivation, and victims can suffer from intense pharyngeal muscle spasms at the mere sight, taste, or sound of water. This is called "hydrophobia." Eventually, the virus progresses to complete failure of the entire nervous system, which causes a quick death. While animals tend to die within 10 days, the incubation period following inoculation can last 2 weeks to 6 years, averaging a few months. Determining factors for the onset time include the viral load, location of exposure, and wound severity. The virus ultimately affects the central nervous system, usually severely affecting the brainstem. The toxic effects occur through an inflammatory response, with functional changes not completely understood. Ultimately, the virus is suspected to affect neurotransmission, and apoptosis may occur through virus-dependent and cell-dependent routes. Once clinical features are seen, rabies is universally fatal.[8]

Histopathology

Autopsy studies have revealed that the brain is usually swollen and congested and has an acute inflammatory process. Neuronal death is rare in most cases. Immunochemical staining reveals deposits of the virion in the nerve cytoplasm. Negri bodies are often seen on light microscopy but only in about two-thirds of cases.

History and Physical

The history of a rabies-infected patient may be straightforward, with a known bite from a rabid animal. Unfortunately, it may be challenging to obtain a history pointing towards rabies due to the potential for a long incubation period and multiple potential transmission methods. There are 5 stages of rabies following inoculation: incubation, prodrome, acute neurologic illness, coma, and death.

1. Incubation is the period defined as an inoculation to the first onset of symptoms and can range from days to years.
2. The prodrome phase includes nonspecific symptoms similar to flu-like illnesses, with gastrointestinal symptoms, myalgias, and fevers being some of the possible symptoms.
3. The third stage of rabies is when neurologic symptoms occur. These are classified into 1 of 3 categories: encephalitic (also considered "furious"), paralytic (also considered "dumb"), and a rare non-classic form.
   • The encephalitic form is most common and presents in approximately 85% of cases. These patients may exhibit hydrophobia or aerophobia when spasms develop due to stimuli such as swallowing liquids (hydrophobia). Agitation and changes in mentation can occur during the encephalitic form, with the potential for autonomic dysfunction, increased deep tendon reflexes, nuchal rigidity, and finding positive Babinski sign. Other examination findings outside the nervous system include tachycardia, tachypnea, and fever. This progresses rapidly to hyperactivity.
   • The paralytic form of rabies is less common and noted to occur less than 20% of the time. These patients may be confused with Guillain-Barre syndrome as the classically associated hydrophobia and irritability are not seen. Weakness is a hallmark, though patients may also have altered mentation, ongoing fevers, and bladder dysfunction.
   • The final form of rabies is considered non-classic and is rare, generally associated with seizures and more profound motor and sensory symptoms.
4. Stage 4 of rabies is the coma stage and usually begins within 10 days of stage 3. Patients may have ongoing hydrophobia, develop prolonged apnea periods, and have flaccid paralysis.
5. Following the onset of stage 4, without supportive care due to cardiopulmonary failure, most patients experience death within 2 to 3 days. Even with supportive therapy, virtually zero patients survive rabies.

Evaluation

Without a clear-cut rabid bite history, rabies is often a diagnosis of exclusion. In the early stages, it may manifest similar to influenza, Coxsackie, enterovirus, and herpes. In later stages, rabies may present similarly to delirium tremens, tetanus, botulism, diphtheria, tick-borne diseases, and Guillain Barre. It is common for physicians to check CBC, electrolytes, cultures, CT, chest x-ray, and MRI, but they still have no idea that rabies is the culprit. Unless isolated in a rabies-specific viral culture, detected by polymerase chain reaction (PCR) in saliva, found to have positive antibody titer, or isolated in cerebrospinal fluid (CSF), the diagnosis may continue to be elusive until too late.

Rabies can be diagnosed using CSF, blood, saliva, tears, and tissue biopsies (neck, immunofluorescent stain). CSF analysis can show pleocytosis and may allow the virus to be isolated. The Centers for Disease Control and Prevention notes that no single test is enough to rule in or out rabies. Ultimately, a high level of suspicion is required in developed countries due to the rarity of the disease.[9][10][11]

If the biting animal can be euthanized and tested, the need to administer post-exposure prophylaxis may be prevented. Public health may be able to facilitate the testing of the animal.

Treatment / Management

There is no effective treatment for rabies. Prevention is the mainstay of treatment, including domestic animal vaccination programs, education, and monitoring.[12][13][14] Wound care is the first step in treating any individual with a feared rabies exposure. Appropriate wound care alone is almost 100% effective if initiated within 3 hours of inoculation. Recommendations include scrubbing the wound and surrounding area with soap and water (solutions include a 20% soap solution, povidone, and alcohol solutions) and swabbing deeply for puncture wounds with irrigation. After cleaning the wound thoroughly, a virucidal agent such as benzalkonium chloride or povidone-iodine is recommended.

In the United States, when a bite is known to be from a bat, skunk, raccoon, or fox, it is treated immediately with rabies vaccine and rabies immune globulin. For all other bites, consult the public health department. Outside the United States, a dog bite should be treated immediately with a vaccine and rabies immune globulin.

Treatment is then initiated based on whether the patient was previously immunized. For patients with previous immunization, a typical treatment may be with a human diploid cell vaccine or purified chick embryo cell vaccine at a dose of 1 mL injected intramuscularly on the day it occurs (day 0) and on day 3.

Suppose the patient has not been previously immunized. In that case, the treatment still involves dosing with 1 of the 2 vaccines listed above, with 1 mL given intramuscularly on days 0, 3, 7, and 14 (and on days 28 if the individual is immunosuppressed). The dose of the vaccine should be given at a site distant from where the second part of treatment (human rabies immune globulin or HRIG) is given. These unimmunized patients are treated with human rabies immune globulin as well at a dose of 20 IU/kg, with a preference to infiltrate as much of that dose around the wound as possible. Any remaining dose of human rabies immune globulin not infiltrated into the wound is then given intramuscularly and, as mentioned above, is given at a site distant from the vaccine.

Recommendations have recently been updated in the United States. Since bats are the major source of rabies here, anyone who awakens from sleep and finds a bat in the room should be urgently immunized.

Differential Diagnosis

The differential diagnoses for rabies include the following:

• Psychosis
• Seizures
• Poisoning with belladonna alkaloids
• Stroke
• Jacob Creutzfeldt disease
• Brain tumor
• Encephalitis
• Tetanus

Complications

The complications that can manifest with rabies are as follows:

• Seizures
• Fasciculations
• Psychosis
• Aphasia
• Autonomic instability
• Paralysis
• Coma
• Death

Consultations

Consultations that are typically requested for patients with this condition include the following:

• Neurologist
• Infectious disease
• Neurosurgeon
• Public health

Enhancing Healthcare Team Outcomes

When rabies is diagnosed, an interprofessional team is necessary as the repercussions of this infection go way beyond the acute infection. Blood transfusions have not been documented to transmit rabies, though holding donations for 1 year after exposure prophylaxis has been suggested. If no exposure was noted but vaccination occurred, it is recommended to wait 4 weeks.

Since rabies is entrenched within the native animal population in the United States, human exposure to this fatal disease continues. Public health officials take a very active role in preventing rabies before and after possible exposure.

Animal control must be notified to determine if the domestic animals require vaccination. In addition, vaccination of workers who may be exposed to rabies may also be necessary.

Patients need to be educated on avoiding contact with wildlife, and if ever bitten, the area should be thoroughly washed to lower the risk of rabies transmission. All dead and sick animals should be handled with heavy gloves. If bitten by a wild animal, one should seek immediate medical assistance.[15][16][17]

Outcomes

For those who develop symptoms of rabies, survival is rare. Only a handful of survivors exist in the USA after acquiring rabies. For those without symptoms but with rabies vaccine prophylaxis, survival is assured. Individuals who have rabid animal bites need the rabies vaccine and immunoglobulin ASAP for survival- once the symptoms appear, death is inevitable.[18][19]