OVERVIEW: What every practitioner needs to know

Are you sure your patient has rabies? What should you expect to find?

The symptoms found in a patient with rabies infection depend on 1) the form and 2) the stage of the disease. There are two classic forms of rabies: encephalitic and paralytic. A third, much less common form is discussed later. Each of these forms evolve through five general stages: incubation, prodromal, acute neurological, coma, and death.

Apart from the initial pain and inflammation from tissue destruction at the site of the bite, the incubation stage is largely asymptomatic, regardless of the form that the disease possesses.

In the prodromal stage the patient may subjectively experience systemic, nonspecific flu-like symptoms including low-grade fever, malaise, nausea, vomiting, anorexia, irritability, and sore throat. Also, during the prodromal period the patient may experience focal symptoms at the portal of innoculation including pain, parasthesias, and pruritus. In the paralytic form of rabies the prodromal period may present with choreiform movements of the bitten limb.

Following the prodromal stage is the acute neurological syndrome in which the patient experiences a variety of symptoms that depend on the clinical form that the rabies infection has undertaken.

Encephalitic rabies. In the encephalitic form of rabies the acute neurological syndrome classically includes painful pharyngeal spasms after exposure to a gust of air (aerophobia) or a drink of water (hydrophobia). The patient may also experience fever, hypersalivation, hyperactivity, fluctuating consciousness, and seizures.
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Paralytic rabies. In the paralytic form of rabies the acute neurological syndrome may present with generalized weakness and quadriparesis, thereby making it difficult to distinguish from Guillain–Barré syndrome. Distinguishing symptoms in paralytic rabies may include a lack of sensation disturbances (with the exception at the bite site), the presence of bladder dysfunction, and persistent fever coinciding with limb weakness. Cerebral involvement may not appear until late in the course making the diagnosis difficult.

During the coma stage the patient may become nonresponsive, and in addition experience worsening hydrophobia, prolonged apnea, and generalized flaccid paralysis which leads to respiratory and cardiovascular collapse. The ultimate end point in the natural history of an untreated rabies infection is death.

Key physical findings:

myoclonus

focal brain stem signs

hemiparesis

hemisensory loss

ataxia

Horner syndrome

convulsive/nonconvulsive seizures

fever

fluctuating consciousness that changes between normal, agitation, confusion, depression, and coma

hyperactive gag reflex

phobic or inspiratory spasms

autonomic dysfunction including hypersalivation, fixed pupils, piloerection, excessive sweating, priapism, spontaneous ejaculations

local reaction at site of bite

excoriation secondary to pruritus

weakness (paralytic rabies)

percussion myodema (paralytic rabies)

bladder dysfunction (paralytic rabies)

How did the patient develop rabies? What was the primary source from which the infection spread?

On a global scale, rabies infection transmitted from a canine vector represents the overwhelming majority of cases. However, in developed countries domestic animals (dogs, cats, and cattle) only account for 10% of human exposures, while wild animals (skunks, foxes, raccoons, bats, and coyotes) account for the other 90%. In the United States, bats represent the most common source of clinical rabies infection.

Rabies is usually transmitted from infected animal bites, but may also be transmitted by scratches, secretions that contaminate mucous membranes, aerosolized virus that enters the respiratory tract, and corneal transplants.

Which individuals are of greater risk of developing rabies?

In developed countries, individuals at high risk for exposure to rabies virus includes: veterinarians, animal handlers, laboratory personnel who handle infected specimens, diagnosticians, cave explorers where the virus is common, and travelers to areas with endemic canine rabies. These individuals would benefit from preexposure prophylaxis.

While all bites should be treated with the same urgency, individuals who have sustained bites on the head, face, neck, and hand, particularly with bleeding, carry the highest risk of developing clinical rabies and are generally associated with shorter incubation periods.

Beware: there are other diseases that can mimic rabies:

Diseases that can mimic encephalitic rabies:

viral encephalitis (i.e. Japanese, eastern equine, West Nile)

delirium tremens

acute substance intoxication (i.e. cocaine, amphetamines)

acute psychoses

bacterial meningitis

cerebral malaria

post-rabies vaccination encephalopathy

bite of an elapid snake (i.e., cobra)

tetanus

Diseases that can mimic paralytic rabies:

polio

Guillain–Barré syndrome

botulism

diphtheria

bite of an elapid snake (i.e., cobra)

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Most routine laboratory tests are nondiagnostic, however hyponatremia is often present, and routine cerebrospinal fluid (CSF) chemistries often show a moderate lymphocytosis (5 to 30 white cells/μL) , normal glucose, and a moderate increase in protein (usually <100mg/dL).

Results that confirm the diagnosis

Saliva: Diagnostic laboratory tests include detection of virus ribonucleic acid (RNA) (by reverse transcriptase polymerase chain reaction, RT/PCR) and isolation of infectious virus in cell culture.

Skin biopsy: A section of full thickness skin 5 to 6mm in diameter should be taken from the posterior region of the neck at the hairline. The sample should contain a minimum of approximately ten hair follicles and include the cutaneous nerves at the base of the follicle. Laboratory tests to be performed include RT/PCR and immunofluorescence staining for viral antigen.

Serum and CSF: Due to intermittent shedding of virus, serum antibodies to rabies virus may not be present until several days after the onset of clinical signs and may appear even later in the CSF, therefore serial testing is often needed. If no vaccine or rabies immune serum has been given, the presence of antibody to rabies virus in serum is diagnostic of infection. If the patient has been immunized, a second specimen should be obtained a few days later to see if antibody titers are rising. Antibody to virus in CSF, regardless of the immunization history, suggests virus infection. Laboratory tests include indirect immunofluorescence and virus neutralization.

What imaging studies will be helpful in making or excluding the diagnosis of rabies?

Head imaging can neither definitively diagnose nor exclude rabies. However, certain findings in head magnetic resonance imaging scans may be suggestive or consistent with rabies, including hypersignaling in the brainstem, hippocampus, or hypothalamus. Gadolinium enhancement is only found in the late stages of the disease.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has rabies, what therapies should you initiate immediately?

Key principles of therapy:

Unless vaccine is administered prior to the onset of symptoms, rabies infection is nearly always fatal. Symptomatic rabies treatment is largely supportive. Therefore, the cornerstone in management of rabies infection is 1) exposure prevention, 2) pre-exposure prophylaxis, and 3) postexposure prophylaxis.

Other key principles in rabies therapy:

The US Centers for Disease Control and Prevention recommends postexposure prophylaxis for anyone who has contact with a bat, even if there is no evidence of a bite. This is because the bite mark of a bat can be extremely small, the virus can be transmitted via aersolization, and the bite may have occurred in an individual unable to communicate or who is unaware of the incident. Possible examples include when a bat is found in the room of any person who awakens from sleep, young infants, intoxicated individuals, and mentally incapacitated individuals.

The animal responsible for exposure should be captured and undergo testing for rabies. Postexposure prophylaxis should be discontinued if the animal in question is found to have a negative rabies test.

Anti-infective agents:

Pre-exposure prophylaxis: Administered to individuals who are at high risk for coming in contact with rabies virus.

Three 1mL intramuscular injections of either human diploid cell vaccine (HDCV, trade name Imovax) or purified chick embryo cell vaccine (PCECV, trade name RabAvert) administered on days 0, 7, and 21 or 28.

Postexposure prophylaxis: The precise course of postexposure prophylaxis is dependent on the vaccination status of the individual who has been infected. The decision to initiate postexposure prophylaxis should occur swiftly, as delays may increase an individual’s risk for developing clinical rabies. When used appropriately, postexposure prophylaxis is nearly 100% effective.

The first step is always thorough wound cleansing with soap and water for a minimum duration of 15 minutes. Virucidal antiseptics such as povidone iodine and ethanol may also be used. Closure of bite and scratch wounds should be avoided.

Protocol from here depends on the vaccination status of the infected patient. For patients not previously vaccinated, who were vaccinated more than 2 years earlier, or whose titers have decreased below 0.5IU/mL.

Either rabies vaccine (HDCV or PCECV) should be administered immediately (day 0) and subsequently administered on day 3, 7, and 14. Vaccine should be administered at a site distant from administration of human rabies immune globulin (HRIG), as HRIG can interfere with the immune action of the vaccine. If the patient is immunosuppressed than an additional dose of vaccine should be given on day 28.

HRIG (tradename HyperRAB S/D or Imogam Rabies HT) 20IU/kg should be immediately administered directly into the wound, or if no wound is apparent, intramuscularly in the upper arm or lateral thigh muscle. If HRIG is not given on the same day the first vaccination is given (day 0) it can be given up to day 7 of the vaccination series. After day 7 an immune response should have occurred so use of HRIG is no longer warranted.

For patients who have received vaccination within the previous 2 years:

HDCV or PCECV should be administered immediately (day 0). A second dose should be administered on day 3.

No HRIG is warranted as passive antibody administration may interfere with innate antibody production.

If I am not sure what pathogen is causing the infection what anti-infective should I order?

If rabies exposure is suspected, the postexposure prophylaxis per above should be swiftly initiated. Summary of prophylaxis recommendations are show in Table I.

Table I.

Type of prophylaxis	Product	Regimen
Pre-exposure prophylaxis	Rabies vaccine	1mL on days 0, 7, and 21 or 28
Postexposure prophylaxis in patients not previously vaccinated, were vaccinated >2 years earlier, or whose titers have decreased to <0.5IU/mL	Rabies vaccineHuman rabies immune globulin	1mL on days 0, 3, 7, and 1420IU/kg (0.133mL/kg) on days 0–7
Postexposure prophylaxis in patients vaccinated within previous 2 years	Rabies vaccine	1mL on days 0 and 3

2. Other key therapeutic modalities

Symptomatic rabies in the absence of prophylaxis has been shown to be nearly uniformly fatal. Therefore, the cornerstone of human rabies management remains prophylaxis.

Treatment of symptomatic rabies is usually palliative, and focuses mostly on nutrition, pain control, sedation, and appropriate quarantine measures.

The Milwaukee Protocol was developed after the survival of a young patient in Wisconsin diagnosed with symptomatic rabies. To date, she remains the only documented survivor of symptomatic rabies infection in a patient who did not receive some form of prophylaxis. The protocol consists of induction into a therapeutic coma with ketamine—which has been shown to inhibit rabies virus replication in vitro—and benzodiazepines with subsequent administration of amantadine and ribavirin. Subsequent uses of the Milwaukee Protocol or variants of the protocol have not resulted in patient survival.

What complications could arise as a consequence of rabies?

What should you tell the family about the patient's prognosis?

Prognosis in patients with potential rabies virus exposure but who receive timely prophylaxis remains excellent from both a morbidity and mortality standpoint.

Rabies is associated with the highest case fatality of any infectious disease. Ergo, prognosis in patients with symptomatic rabies infection remains exceedingly poor. It should be stressed that family members of patients with symptomatic rabies that elect to undergo aggressive treatment protocols such as the Milwaukee Protocol must be informed about the high likelihood of mortality, and that even if mortality is averted that there is a high likelihood that the patient will experience permanent neurologic sequelae.

What-if scenarios:

Factors that may be associated with better outcomes in symptomatic rabid patients are younger age, vaccination before the onset of symptoms, relatively few or no comorbidities, and early presentation at the time of treatment initiation.

How do you contract rabies and how frequent is this disease?

Each year approximately 55,000 people worldwide die of rabies, with 95% of victims reported residing in Asia or Africa. Only 61 cases of human rabies were diagnosed in the United States from 1980 through 2006, an average of approximately two per year. In developing countries, the overwhelming majority of rabies transmission happens from dogs. In the United States, where there are strict canine vaccination policies in place, rabies vectors are primarily sylvatic and include bats, raccoons, skunks, foxes, and coyotes. The majority of clinical rabies cases in humans within the United States have been attributed to bat-associated rabies, and in particular silver-haired bats (Lasionycteris noctivagans) and eastern pipestrelle bats (Pipistrellus subflavus).

Although the incidence of human rabies is very low in the United States, approximately 16,000 to 39,000 cases with contact to potentially rabid animals receive rabies postexposure prophylaxis annually.

While on a global scale the vast majority of rabies cases are found in Asia and Africa, rabies is endemic to the continental United States, Canada, Europe, Latin America, and Australia as well. Hawaii remains rabies free, as do several other islands, including the British Isles, New Zealand, Japan, Taiwan, and many of the Caribbean islands.

What pathogens are responsible for this disease?

Rabies is caused by infection from a negative-stranded, RNA virus with the following classification:

Order: Mononegavirales

Family: Rhabdoviridae

Genus: Lyssavirus

There are seven recognized genotypes. The genotypes responsible for causing human rabies are types 1 (which is found in terrestrial animals), and 3 to 7.

How do these pathogens cause rabies?

Generally, rabies is transmitted by saliva from infected animal bites, but may also be transmitted by scratches, secretions that contaminate mucous membranes, aersolized virus that enters the respiratory tract, and corneal transplants.

In canine rabies virus, the viral glycoprotein may bind to nicotinic acetylcholine receptors on the muscle, whereas in some bat lyssaviruses the virus may bind to unknown receptors in the dermis or epidermis.

After budding from the plasma membrane of the muscle cells, the virus is taken up into unmyelinated nerve endings at neuromusclar junctions or at the muscle spindles, and is transported to the central nervous system via retrograde axoplasmic flow. Travel from the peripheral nerves to the central nervous system (CNS) occurs at a rate of anywhere between 8 to 100mm/day.

Once the virus reaches the dorsal-root ganglia and anterior-horn cells it replicates again. At the dorsal-root ganglia, viral replication may be recognized and attacked by the immune system, resulting in ganglioneuronitis which clinically manifests itself as prodromal neuropathic pain at the bite site. This is clinically significant because once the patient is experiencing prodromal symptoms, prophylaxis with vaccine and HRIG has not been shown to be able to prevent death.

Once the virus reaches the CNS rapid dissemination occurs, with preferential localization to the brainstem, thalamus, basal ganglia, and spinal cord. From there, the virus centrifugally spreads from the CNS throughout the rest of the peripheral nervous system and the organs they innervate, especially to highly innervated areas such as salivary glands. This causes the classic presentation of hypersalivation and spasms of the pharyngeal muscles at the sound, sight, or taste of water. All major neural and nonneural organs may contain significant viral load.

Eventually the systemic viral burden manifests itself as encephalomyelitis, generalized nervous system failure, and death.

What other clinical manifestations may help me to diagnose and manage rabies?

Apart from the more common encephalitc and paralytic form of rabies, there is a third, atypical form that is seen less often.

Patients who have bat-associated rabies are at higher risk for developing the atypical form of rabies.

In the atypical form of rabies the acute neurological syndrome consists mostly of neuropathic and even radicular pain, convulsive and nonconvulsive seizures, hallucinations, hemiparesis, hemisensory loss, ataxia, vertigo, and facial and bulbar weakness with preserved arm strength or bilateral arm weakness.

What other additional laboratory findings may be ordered?

Brain biopsy: This test is not usually done antemortem, however virus isolation RT/PCR and immunofluorescence staining for viral antigen can be diagnostic for rabies infection.

How can rabies be prevented?

Prevention is the cornerstone in rabies management. Apart from the specific measures required in preexposure and postexposure prophylaxis (please see section on “Anti-infective agents” above), exposure prevention is a vital component in rabies prevention.

A society that creates and enforces strict animal vaccination policies is a key preventative measure. Pets should be supervised so they do not come into contact with wild animals. Communities should maintain animal-control agencies to remove stray or wild animals. Wild animals that are a natural reservoir of rabies virus, such as coyotes, raccoons, skunks, foxes, and bats should be enjoyed at a distance but not adopted or handled by nonprofessionals. At-risk homes can be bat-proofed by covering ventilation openings with screens.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Manning, SE, Rupprecht, CE, Fishbein, D. “Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices”. MMWR Recomm Rep. vol. 57. 2008. pp. 1-28. (The Advisory Committee on Immunization Practices periodically updates the recommendations on a variety of communicable diseases, including rabies.)

“Bats and rabies: a public health guide, 2008”. 18 May 2011. (The Centers for Disease Control provides common sense guidelines and facts pertaining to rabies on their public website.)

Finnegan, CJ, Brookes, SM, Johnson, N. “Rabies in North America and Europe”. J R Soc Med. vol. 95. 2002. pp. 9-13. (A brief summary on the state of rabies in North America and Europe, including vaccine use, and prevalence.)

Fishbein, D, Robinson, L. “Rabies”. N Engl J Med. vol. 329. 1993. pp. 1632-8. (An early paper describing the epidemiology, pathology, and prevention of rabies.)

Hankins, D, Rosekrans, J. “Overview, prevention, and treatment of rabies”. Mayo Clin Proc. vol. 79. 2004. pp. 671-6. (A paper describing the overview, prevention, and treatment of rabies.)

Hemachudha, T, Laothamatas, J, Rupprecht, C. “Human rabies: a disease of complex neuropathogenic mechanisms and diagnostic challenges”. Lancet Neurol. vol. 1. 2002. pp. 101-9. (A paper describing the neuropathogenic mechanisms and diagnostic challenges in rabies.)

Jackson, A. “Rabies”. Can J Neurol Sci. vol. 27. 2000. pp. 278-83. (A broad paper on the epidemiology, pathology, and prevention of rabies.)

“The Milwaukee protocol”. 18 May 2011. (The formal proposal for a seminal treatment protocol for rabies.)

Meslin, FX. “Rabies as a traveler's risk, especially in high-endemicity areas”. J Travel Med. vol. 12. 2005. pp. S30-40. (A paper expounding on the level of risk of acquiring rabies depending on endemicity of the geographic area.)

Nigg, AJ, Walker, PL. “Overview, prevention, and treatment of rabies”. Pharmacotherapy. vol. 29. 2009. pp. 1182-95. (A paper expounding on the overview, prevention, and treatment of rabies.)

Takayama, N. “Rabies: a preventable but incurable disease”. J Infect Chemother. vol. 14. 2008. pp. 8-14. (A paper describing the limitations experienced by the medical community in curing rabies, but expounds on the preventability of the disease.)

“WHO expert consultation on rabies”. (The World Health Organization provides a comprehensive overview on the state of the global rabies situation.)

Wunner, WH, Briggs, DJ. “Rabies in the 21st Century”. PLoS Negl Trop Dis. vol. 4. 2010. pp. e591(An opinion piece on the state of rabies in modern times, and a proposed way forward.)

DRG CODES and expected length of stay

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