Approach Considerations
If the patient presents after an acute or recent bite
When the patient presents with a bite, the wound should be cleansed immediately with soap and water, flushing it thoroughly to remove saliva. Debridement and careful exploration for foreign body (eg, broken tooth) are essential; this should take at least 10 minutes. Generally, leave wounds to heal by secondary intention to permit drainage of wound fluids and prevent infection. [33, 34]
If the animal to which the patient was exposed has been captured, it should be delivered to a veterinarian for further evaluation or euthanasia; state health departments can then test the unfixed brain tissue. [35]
Consult immediately with public health authorities regarding need for prophylaxis.
If the patient presents with encephalitis and suspected rabies
Skin biopsy from the nape of the neck
Rabies antigen can be detected in cutaneous nerves by direct fluorescent antibody. Consult with public health authorities, as these require specialized laboratories and shipping.
Corneal touch impression
Less preferably, scraping of corneal epithelia, or corneal touch impression, for direct fluorescence antibody can be used. This requires topical ocular anesthetic and is best performed by an ophthalmologist, under public health authority guidance on specimen preparation and transport. Corneal impression is obtained by pressing the surface of sterile glass slide gently but firmly onto the cornea. Corneal scrapings should be performed by an ophthalmologist unless none is available; epithelial cells are gently collected using a sterile loop or spatula and smeared carefully on a glass slide.
Viral cultures and polymerase chain reaction (PCR) assay
Consult with public health authorities, as these require specialized laboratories and shipping. The following may be used:
-
Saliva - Results of saliva culture for rabies virus are positive in low yield within 2 weeks of illness onset
-
Cerebrospinal fluid - After the first week of illness, 80% monocytosis may be observed; protein levels may be elevated, and glucose test results are normal. However, spinal fluid may also be normal.
-
Brain tissue - Often postmortem; staining with immunohistochemical or florescent antibody staining is definitive. Negri bodies are pathognomonic (cytoplasmic inclusion bodies reflective of accumulated virions within rabies-infected neurons). They are found in the horn of Ammon of the hippocampus and cerebral cortex
Blood gas analysis
Respiratory alkalosis resulting from hyperventilation develops in the prodromal and early acute neurologic phases of rabies; this is followed by respiratory acidosis as respiratory depression progresses
Hematology studies
Results of the white blood cell (WBC) count range from normal to elevated, with 6-8% atypical monocytes
Imaging studies
As the neurologic phase of rabies progresses, chest radiographs may reveal infiltrates due to aspiration, nosocomial pneumonia, acute respiratory distress syndrome, or congestive heart failure.
Findings from magnetic resonance imaging (MRI) and computed tomography (CT) scanning of the brain often indicate that no abnormalities are present. MRI may demonstrate increasing nonspecific low-level T2 enhancement early along the nerve plexus and nerve root ganglia early in illness. Later, moderate gadolinium enhancement may appear in the thalamus, substantia nigra, brainstem, deep gray matter, and cranial nerves. [26]
Electroencephalography
Electroencephalography (EEG) findings include encephalopathic changes. Due to generalized vasospasm of cerebral arteries during the first week of illness, EEG amplitude may drop precipitously and mimic brain death. This may be further suggested by papillary reflex abnormalities such as anisocoria or fixed pupils due to dysautonomia. These findings may reverse with return of blood flow. A more reliable means of determining brain death in the case of rabies may therefore be cerebral arterial flow scanning that demonstrates absent flow. Brain biopsy is another option. [36, 37, 38, 39]
Cardiac monitoring
Supraventricular tachycardia may be observed during cardiac monitoring. Eventually, bradycardia and cardiac arrest occur.
Future tests
The nucleic acid sequence ̶ based amplification (NASBA) technique on urine samples may be used in the future. [40, 41] The NASBA technique on saliva and CSF can be used for rapid diagnosis as early as 2 days after symptom onset.
Serology
Serum rapid fluorescent focus inhibition test (RFFIT) titer results are positive in 50% of rabies cases. Results of the CSF RFFIT are antibody-positive (2-25% of serum titer) after the first week of illness.
Detection of viral RNA from saliva using PCR assay and viral antigen from brain biopsy specimens yields 100% specificity. Viral antigen assessment involving nuchal skin that contains hair follicles and corneal touch impressions have sensitivities of 67% and 25%, respectively.
Rabies virus RNA may be detected via PCR in saliva, nuchal skin containing hair follicles, CSF, and urine. [26]
In true rabies cases, however, the rise in specific neutralizing antibodies is often not documented through an RFFIT, because the victims succumb to the disease prior to mounting a response. Serologic testing is more useful to ascertain serostatus in immunized animals and humans. [33]
Skin Biopsy
Nuchal skin biopsy is the most reliable test of rabies infection during the first week. Results from nuchal skin punch biopsy for immunofluorescent antibody staining are 50% positive within the first week.
Obtain a full-thickness punch biopsy from the nape of the neck and include hair follicles. Place the specimen in a sterile container with saline-soaked sterile gauze, store it at -70°C, and obtain shipping instructions for a laboratory that performs the examination.
Histologic Findings
General findings on pathology include cerebral congestion and inflammation typical of encephalitis. Neuronal cell death is uncommon histopathologically.
Immunohistochemical or fluorescent antibody staining of nervous tissue, usually of unfixed brain or skin biopsy specimens with sensory nerve endings, reveals deposition of virion in the cytoplasm.
Negri bodies, seen in the image below, are observed in neurons on light microscopy and represent round cytoplasmic inclusions of assembling nucleocapsid. Only 70% of brain biopsy tissue exhibits this finding in human rabies encephalitis. Electron microscopy is more sensitive than light microscopy and reveals the characteristic bullet-shaped virion.
Hematoxylin and eosin stain of Negri body in a rabies-infected neuron. Courtesy of the US Centers for Disease Control and Prevention.
-
Hematoxylin and eosin stain of Negri body in a rabies-infected neuron. Courtesy of the US Centers for Disease Control and Prevention.
-
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 |
