History
Identify the following in any suspected case of rabies virus exposure:
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The nature of the interaction with the animal (Recall that "provocation" is not an indication of rabies risk, since humans may not understand what is provocative to a wild animal.)
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Strange animal behavior (eg, nocturnal animal out during the daytime)
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Vaccination status of the animal for rabies [18]
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Availability of the animal for testing
Incubation period
The rabies virus is segregated from the immune system during this period, and no antibody response is observed. The infected individual remains asymptomatic during this period. The average duration of incubation is 20-90 days. In more than 90% of cases, incubation is less than 1 year. A person whose inoculum occurs with a scratch on the hand may take longer to develop symptoms of rabies than a person who receives a bite to the head. The incubation period is less than 50 days if the patient is bitten on the head or neck or if a heavy inoculum is transferred through multiple bites, deep wounds, or large wounds. Infected patients may not recall exposure because of the prolonged incubation period.
Rarely, incubation has been reported many years following exposure. In cases of salivary exposure, incubation has been estimated based on molecular, phylogenetic, and epidemiologic evidence to be greater than 6-8 years. [28, 29, 30, 31] A suspected prolonged incubation of 25 years was reported in India with no identifiable risk factors other than a dog bite occurring in a time frame and location coincident with the likelihood of rabies in local dogs. [12]
Prodromal period
The virus enters the CNS. The duration of this period is 2-10 days. Nonspecific symptoms and signs develop, including fevers and flulike illness. Paresthesia, pain, or intense itching at the inoculation site is pathognomonic for rabies and occurs in 30% of canine-associated rabies cases and 70% of bat-associated rabies cases during this phase; this may be the individual’s only presenting sign. Symptoms may include the following:
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Malaise
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Anorexia
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Headaches
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Fever
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Chills
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Pharyngitis
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Nausea
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Emesis
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Diarrhea
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Anxiety
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Agitation
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Insomnia
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Depression
Acute neurologic period
This period is associated with objective signs of developing CNS disease; however, consciousness remains unaffected until the onset of coma. The duration is 2-7 days. Symptoms include muscle fasciculations, priapism, and focal or generalized convulsions. Patients may die immediately or may progress to paralysis, which may be present only in the bitten limb at first but usually becomes diffuse.
Two thirds of human rabies cases acquired from dogs manifest as "furious rabies." Patients develop agitation, hyperactivity, restlessness, thrashing, biting, confusion, or hallucinations. After several hours to days, this becomes episodic and interspersed with calm, cooperative, lucid periods. Furious episodes last less than 5 minutes. Episodes may be triggered by visual, auditory, or tactile stimuli or may be spontaneous. Seizures may occur. This phase may end in cardiorespiratory arrest or may progress to paralysis.
The remaining one-third of patients with rabies develop paralytic rabies, also known as dumb rabies or apathetic rabies, because the patient is relatively quiet compared with a person with the furious form. Paralysis occurs from the outset, and fever and headache are prominent. Paralytic rabies may initially mimic Guillain-Barré syndrome (GBS) with ascending lower–motor-neuron weakness unpreceded by classic "mad" signs, and rabies should be considered in the differential diagnosis of GBS. [32]
Bat-associated rabies often manifests with more atypical findings.
Coma
This begins within 10 days of onset, and the duration varies. Without intensive supportive care, respiratory depression, arrest, and death occur shortly after coma.
Physical Examination
Neurologic period
With furious rabies, patients present with episodic delirium, psychosis, restlessness, thrashing, muscular fasciculations, seizures, and aphasia. Hydrophobia and aerophobia are pathognomonic for rabies and occur in 50% of patients. Attempting to drink or having air blown in the face produces severe laryngeal or diaphragmatic spasms and a sensation of asphyxia. This may be related to a violent response of the airway irritant mechanisms. Even the suggestion of drinking may induce hydrophobic spasm.
Autonomic instability is observed with furious rabies, with symptoms that include the following:
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Fever
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Tachycardia
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Hypertension
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Hyperventilation
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Anisocoria, fixed pupillary dilation (“blown pupil”), optic neuritis (may falsely suggest brain death)
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Facial palsy
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Mydriasis
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Lacrimation
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Excessive salivation
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Perspiration
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Postural hypotension
In patients with paralytic rabies, fever and nuchal rigidity may occur. Paralysis is symmetrical and may be either generalized or ascending and may be mistaken for Guillain-Barré syndrome. The sensory system is usually spared. Calm clarity gradually progresses to delirium, stupor, and then coma.
Coma
Respiratory failure occurs within 1 week of neurologic symptoms. Hypoventilation and metabolic acidosis predominate. Acute respiratory distress syndrome is common. Wide variations in blood pressure, cardiac arrhythmias, and hypothermia ensue. Bradycardia and cardiac arrest occur. With intensive support, life may be extended for 3 or 4 months; however, death usually is the outcome.
Death
It is important to determine brain death by brain biopsy or absence of cerebral arterial flow, because some of the neurologic signs may falsely suggest brain death (see above).
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Hematoxylin and eosin stain of Negri body in a rabies-infected neuron. Courtesy of the US Centers for Disease Control and Prevention.
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Distribution of the 5 strains of rabies virus and the associated wildlife in the United States.
Tables
Category |
Nature of exposure | Target Population |
Relevant biogeography | Immunization Regimen |
Serologic Testing |
1. Elevated risk for unrecognized and recognized exposures including unusual or high-risk exposures |
High concentration exposure is possible, might be recognized or unrecognized, or might be unusual (eg, aerosolized virus) | Rabies research laboratory workers, vaccine production workers, or diagnostic laboratory workers who may work with live rabies virus |
Laboratories | Primary series: IM rabies vaccine on days 0 and 7 |
Rapid Fluorescent Foci Inhibition Test (RFFIT) titer every 6 months; booster if titer < 0.5 IU/mL |
2. Elevated risk for unrecognized and recognized exposures |
Exposure typically recognized but could be unrecognized; unusual exposures are unlikely | Persons who frequently 1) handle bats, 2) have contact with bats, 3) enter high-density bat environments, or 4) perform animal necropsies (eg, biologists who frequently enter bat roosts or who collect suspected rabies samples). |
All geographic regions where any rabies reservoir is present, US domestic and international | Primary series: IM rabies vaccine on days 0 and 7 |
RFFIT titer every 2 years; booster if titer < 0.5 IU/mL |
3. Elevated risk for recognized exposures, sustained risk |
Exposure nearly always recognized; risk for recognized exposures higher than that for the general population and duration exceeds 3 years after the primary vaccination | Persons who interact with animals that could be rabid; occupational or recreational activities that typically involve contact with animals include 1) veterinarians, technicians, animal control officers, and their students or trainees; 2) persons who handle wildlife reservoir species (eg, wildlife biologists, rehabilitators, and trappers); and 3) spelunkers |
All US domestic and international geographic regions where any rabies reservoir is present | Primary series: IM rabies vaccine on days 0 and 7 |
1) One-time RRFIT titer at years 1–3 after primary series; booster if titer < 0.5 IU/mL, OR 2) Booster at at point between day 21 and year 3 after primary series |
4. Elevated risk for recognized exposures, but not sustained or continuous |
Exposure nearly always recognized; risk for exposure higher than for general population but expected to be time-limited (≤3 years from the 2-dose primary vaccination series) | Same as for risk category 3, but risk duration ≤3 years (eg, short-term volunteer providing hands-on animal care or infrequent traveler with no expected high-risk travel >3 years after PrEP administration) |
Same as for risk category 3 | IM rabies vaccine on days 0 and 7 |
None |
| 5. Low risk for exposure | Uncommon exposure. | Typical person living in the United States. General population. | None | None | None |
