Rabies and Other Rhabdovirus Infections

Chapter 214 | Part 5: Infectious Diseases

KEY CLINICAL POINTS

• Rabies is a zoonotic infection caused by the rabies virus, a single-stranded RNA lyssavirus, with near-universal fatality without postexposure prophylaxis (PEP).
• Postexposure prophylaxis (PEP) is critical for preventing rabies after exposure, with initiation based on exposure risk, animal behavior, and local epidemiology.
• Rabies presents in two clinical forms: encephalitic (furious) and paralytic, with distinct neurologic manifestations and outcomes.
• Diagnosis relies on clinical suspicion, RT-PCR, direct fluorescent antibody (DFA) testing, and CSF analysis, with no definitive antemortem test.
• Rabies vaccine and rabies immune globulin (RIG) are central to PEP, with RIG administered at the wound site and intramuscularly.

1. DEFINITION & OVERVIEW

Rabies is a rapidly progressive, acute infectious disease of the central nervous system (CNS) caused by rabies virus, a member of the Rhabdoviridae family. It is transmitted primarily via bites from infected mammals and causes severe neurologic disease in humans. The virus is a nonsegmented, negative-sense RNA virus with five structural proteins. Rabies is a zoonotic infection, with dogs and wildlife serving as primary reservoirs globally.

1.1 Transmission and Pathogenesis

Rabies is transmitted via bites or non-bite exposures (e.g., aerosols, organ transplants). The virus binds to nicotinic acetylcholine receptors at neuromuscular junctions, spreads via retrograde axonal transport to the CNS, and replicates in neurons. It then spreads centrifugally to peripheral nerves, salivary glands, and other tissues, leading to neurologic dysfunction and death.

2. EPIDEMIOLOGY

Rabies is endemic in mammals worldwide except Antarctica and some islands. Canine rabies causes ~59,000 human deaths annually, predominantly in Asia and Africa. In the U.S., 3,579 confirmed rabies cases were reported in 2021, with 9.6% in domestic animals. Wildlife reservoirs include bats, raccoons, skunks, and foxes. Human rabies is rare in resource-rich countries but remains a threat in resource-limited regions.

3. ETIOLOGY & PATHOPHYSIOLOGY

Rabies virus (genus Lyssavirus) is a single-stranded RNA virus with a nonsegmented, negative-sense genome. It infects mammals and causes neurologic disease. The incubation period is 20–9,000 days, with viral spread via peripheral nerves to the CNS. Pathogenesis involves retrograde axonal transport, CNS replication, and centrifugal spread to salivary glands and other tissues. Negri bodies (rabies virus inclusions) are pathognomonic but not always present.

3.1 Viral Variants and Reservoirs

Rabies virus variants are associated with specific animal reservoirs (e.g., bat, raccoon, skunk, fox). Six non-rabies Lyssavirus species (e.g., vesicular stomatitis virus) cause similar clinical presentations. Bat rabies variants are responsible for most human cases in the U.S., while raccoon and skunk variants are endemic in specific regions.

4. CLINICAL FEATURES

Rabies presents as atypical encephalitis with relative preservation of consciousness. Prodromal symptoms include fever, malaise, and paresthesias. Encephalitic rabies (80% of cases) features hyperexcitability, hydrophobia (involuntary swallowing-induced diaphragmatic spasm), and aerophobia. Paralytic rabies (20% of cases) presents with flaccid paralysis, often mimicking Guillain-Barré syndrome.

4.1 Differential Diagnosis

Rabies must be differentiated from herpes simplex encephalitis, West Nile virus encephalitis, anti-NMDA receptor encephalitis, and post-infectious encephalomyelitis. Paralytic rabies may mimic Guillain-Barré syndrome, while vaccine-induced encephalitis may mimic rabies.

5. DIFFERENTIAL DIAGNOSIS

Rabies must be distinguished from other viral encephalitides (e.g., herpes simplex, West Nile), autoimmune encephalitis (anti-NMDA receptor), post-infectious encephalomyelitis, and psychiatric disorders. Paralytic rabies may mimic Guillain-Barré syndrome, and vaccine-induced encephalitis may mimic rabies.

6. INVESTIGATIONS & DIAGNOSIS

Diagnosis is based on clinical suspicion and laboratory confirmation. Key tests include RT-PCR for viral RNA, DFA testing for antigen detection, and CSF analysis (pleocytosis, elevated protein). Antemortem tests are limited, and definitive diagnosis often requires postmortem examination.

Table 214-1: Clinical Stages of Rabies

STAGE	TYPICAL DURATION	SYMPTOMS AND SIGNS
Incubation period	20–90 days	None
Prodrome	2–10 days	Fever, malaise, paresthesias, pruritus at wound site
Acute Neurologic Disease	2–7 days	Anxiety, hyperactivity, hallucinations, hydrophobia
Paralytic Rabies	2–10 days	Flaccid paralysis progressing to quadriparesis
Coma, death	0–14 days	None

7. MANAGEMENT & TREATMENT

There is no established cure for rabies. Management includes aggressive supportive care in critical care units, with survival reported in 33 cases. PEP is the only effective intervention, involving wound debridement, rabies immune globulin (RIG), and rabies vaccine. RIG is administered at the wound site and intramuscularly, with vaccine given intramuscularly. PEP is initiated for high-risk exposures, even without laboratory confirmation.

7.1 Postexposure Prophylaxis Algorithm

1. Assess exposure risk (animal type, behavior, geographic area).
2. Confine healthy animals for 10 days; PEP not needed if healthy.
3. Administer RIG (20 IU/kg) at wound site and IM if RIG unavailable.
4. Initiate rabies vaccine (0.5 mL IM) on day 0, 3, 7, 14, and 28.
5. Monitor for 10 days; if animal develops rabies, confirm with DFA or cell culture.

8. PROGNOSIS & COMPLICATIONS

Rabies is almost uniformly fatal without PEP. Survivors typically receive vaccine before disease onset. Complications include cardiac arrhythmias, respiratory failure, water imbalance, and multi-organ failure. Early PEP significantly improves outcomes, with survival reported in 33 cases, though most deaths occur within days of symptom onset.

9. SPECIAL CONSIDERATIONS

Rabies prophylaxis is critical for travelers to endemic regions. PEP is initiated for bites from dogs, bats, or wildlife, even without a confirmed animal bite. In pregnancy, PEP is recommended for high-risk exposures. Children and immunocompromised patients require prompt PEP. Bat exposures without a recognized bite may still warrant PEP due to unrecognized bites.

10. KEY POINTS & CLINICAL PEARLS

1. Rabies is 100% fatal without PEP; early intervention is critical.
2. PEP includes RIG and rabies vaccine, with RIG administered at the wound site.
3. Clinical suspicion is key, as symptoms overlap with other encephalitides.
4. Animal observation for 10 days is a key step in determining PEP necessity.
5. Survivors typically have neutralizing antibodies in CSF or serum.
6. Non-bite exposures (e.g., aerosols, transplants) require immediate PEP.