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Rabies and Other Rhabdovirus Infections

Chapter 214 | Harrison's 22e · Part 5 – Infectious Diseases: Viral (incl. HIV) · Chapter 214

Key Clinical Points

  1. Rabies is a rapidly progressive CNS infection caused by lyssaviruses (Rhabdoviridae) with nearly 100% fatality once clinical symptoms develop.
  2. Transmission occurs primarily via animal bites; dogs are responsible for approximately 99% of human cases globally.
  3. Postexposure prophylaxis (PEP) involving Rabies Immune Globulin (RIG) and a vaccine is 100% effective if initiated before symptom onset.
  4. Rabies virus variants are linked to specific reservoirs: bats (North America), raccoons (Eastern U.S.), skunks (Midwest), and foxes (Europe/Canada).
  5. Negri bodies (eosinophilic cytoplasmic inclusions) in CNS neurons, specifically cerebellar Purkinje cells, are pathognomonic for rabies.
  6. Pathogenesis involves binding to nicotinic acetylcholine receptors at the neuromuscular junction followed by retrograde axonal transport (250 mm/d) to the CNS.
  7. Clinical presentation is divided into Furious rabies (80%) and Paralytic rabies (20%).
  8. Preexposure prophylaxis consists of a 3-dose vaccine series for high-risk individuals.
  9. No effective treatment exists once clinical disease has manifested.
  10. Diagnostic confirmation includes RT-PCR, immunohistochemistry, and virus isolation from CSF, saliva, or skin biopsy.

DEFINITION & CLASSIFICATION

• Rabies: An acute, progressive CNS infection caused by lyssaviruses (family Rhabdoviridae). • Mortality: Nearly 100% fatal once clinical symptoms develop. • Other Rhabdoviruses: Includes vesicular stomatitis virus (causing self-limited illness in humans). • Other Lyssaviruses: Six other lyssavirus species (Aravan, Khujand, West African, Mokola, Duvenhage, and Lysavirus) can cause rabies-like clinical syndromes.

EPIDEMIOLOGY

• Global Impact: ◦ Approximately 59,000 human deaths annually. ◦ Predominantly in Asia and Africa. ◦ 90% of cases occur in rural populations with limited access to PEP. ◦ Endemic canine rabies persists in 15 countries. • U.S. Context: ◦ Bat rabies variants cause most indigenous cases (present in all states except Hawaii). ◦ No human rabies deaths reported in the U.S. since 2022. • Transmission Dynamics: ◦ Dogs are responsible for ~99% of human cases globally. ◦ Domestic animal rabies eliminated from most developed nations via vaccination.

Geographic Distribution of Reservoirs

• North America: Bats (all states except Hawaii), Raccoons (Eastern U.S.), Skunks (Midwest). ◦ Europe/Canada: Foxes. ◦ Asia/Africa: Endemic canine rabies persists in 15 countries.

ETIOLOGY & PATHOPHYSIOLOGY

• Incubation Period: Ranges from days to >1 year, depending on inoculation site. • Mechanism of Entry: Virus binds nicotinic acetylcholine receptors at neuromuscular junctions. • Transport: Retrograde axonal transport (250 mm/d) moves virus through peripheral nerves to the spinal cord and brainstem. • CNS Establishment: Occurs within 7–14 days post-exposure. • Centrifugal Spread: From CNS via sensory/autonomic nerves to salivary glands, heart, and skin. • Transmission Mechanism: Viral replication in acinar cells of salivary glands enables transmission through saliva.

CLINICAL FEATURES

• Prodromal Phase (2–10 days): ◦ Fever, malaise, headache. ◦ Pain at the site of inoculation. • Acute Neurological Phase: ◦ Encephalitic (Furious) Rabies (80%): Duration 2–7 days; features include anxiety, agitation, hyperactivity, bizarre behavior, hallucinations, and autonomic dysfunction. ◦ Paralytic Rabies (20%): Duration 2–10 days; characterized by flaccid paralysis in limb(s) progressing to quadriparesis with facial paralysis. • Specific Manifestations: ◦ Hydrophobia (due to pharyngeal spasms). ◦ Aerophobia. ◦ Laryngophrenic spasm of inspiratory muscles associated with terror.

DIAGNOSTIC APPROACH

  1. Clinical Assessment: • History of animal exposure (bite, scratch, or contact with contaminated objects). • Clinical signs of encephalitis/autonomic dysfunction.
  2. Laboratory Confirmation: • RT-PCR. • Immunohistochemistry (IHC). • Virus isolation from CSF, saliva, or skin biopsy.
  3. Imaging: • CT/MRI: Typically normal in early stages; later stages show diffuse cerebral edema and meningeal enhancement.

MANAGEMENT & TREATMENT

  1. Immediate Action: • Wash wound thoroughly with soap and water.
  2. Postexposure Prophylaxis (PEP): • Rabies Immune Globulin (RIG): Administer at the wound site. • Vaccine Regimen: 4-dose series administered on days 0, 3, 7, and 14.
  3. Preexposure Prophylaxis: • 3-dose vaccine series for high-risk individuals.
  4. Prognosis: • No effective treatment exists once clinical disease develops.

Rabies Postexposure Prophylaxis (PEP) Decision Logic

  1. Exposure Event: Did the animal bite the patient or did saliva contaminate a scratch, abrasion, open wound, or mucous membrane? → No → None → Yes → Proceed to Risk Assessment
  2. Risk Assessment: Is rabies known or suspected to be present in the species and the geographic area? → No → None → Yes → Proceed to Containment Status
  3. Containment Status: Was the animal captured? → No → RIG and vaccine → Yes → Proceed to Species/Behavioral Profile
  4. Species/Behavioral Profile: Was the animal a normally behaving dog, cat, or ferret? → Yes → Observation Period (10 days) → No rabies after 10 days → None → Rabies confirmed via fluorescent antibody staining → RIG and vaccine → No (e.g., bat or wild animal) → Fluorescent antibody staining of brain → Positive result → RIG and vaccine

COMPLICATIONS & PROGNOSIS

• Mortality: Nearly 100% fatal once clinical symptoms develop. • Clinical Progression: ◦ Prodrome → Acute Neurological Phase (Furious or Paralytic). ◦ Late stage: Laryngophrenic spasm and autonomic instability.

KEY PEARLS & HIGH-YIELD POINTS

• Pathognomonic Finding: Negri bodies (eosinophilic cytoplasmic inclusions) in CNS neurons, specifically cerebellar Purkinje cells. • Critical Window: PEP is 100% effective only if initiated before symptom development. • Key Timing: Retrograde axonal transport occurs at 250 mm/d; CNS infection established in 7–14 days. • Clinical Distinction: Furious rabies (80%) vs. Paralytic rabies (20%). • Table 214-1 Summary: ◦ Incubation: 20–90 days (or 2–10 days). ◦ Encephalitic (80%): 2–7 days; features include anxiety, agitation, and hydrophobia. ◦ Paralytic (20%): 2–10 days; features flaccid paralysis progressing to quadriparesis.

Reference Tables

TABLE 214-1 Clinical Stages of Rabies STAGE Incubation period Prodrome

Harrison's 22e, p.1653

STAGE TYPICAL DURATION SYMPTOMS AND SIGNS
Incubation period 20–90 days None
2–10 days
Acute Neurologic Disease
Encephalitic (80%) 2–7 days Anxiety, agitation, hyperactivity,
bizarre behavior, hallucinations,
autonomic dysfunction, hydrophobia
Paralytic (20%) 2–10 days Flaccid paralysis in limb(s)
progressing to quadriparesis with
facial paralysis
0–14 days