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Basic Information ⬇

AUTHOR: Glenn G. Fort, MD, MPH

Definition

Rabies is a fatal zoonotic illness caused by a number of species of neurotropic viruses in the Rhabdoviridae family and transmitted to human beings by the bite of an infected animal.

Synonym

Hydrophobia

ICD-10CM CODE
A82.9Rabies, unspecified
Epidemiology & Demographics
Incidence (In U.S.)

Approximately 1 to 3 U.S. cases annually; 25 human cases of rabies in the U.S. from 2009 to 2018. Of these, 7 cases were imported rabies in people who were exposed to rabid animals in endemic nations and 1 to 2 cases were in tissue or organ transplantation recipients. Of the 25 cases, 23 died and 2 survived. Tens of thousands of cases of rabies occur worldwide annually.

In the U.S., most cases are transmitted by bats; in the world, most cases are transmitted by dogs.

Predominant Sex

Men are more commonly affected (70% of cases).

Physical Findings & Clinical Presentation

  • Incubation period is usually 1 to 3 mo in humans but can range from several days to 8 yr
  • Shorter incubation period with bites on the face. Longer if extremities involved
  • In domestic animals, a quarantine of 10 days is usually mandated
  • Prodrome:
    1. Fever
    2. Headache
    3. Malaise
    4. Pain or anesthesia at exposure site
    5. Sore throat
    6. GI symptoms
    7. Psychiatric symptoms
  • Acute neurologic period, with objective evidence of central nervous system involvement
  • Two types of presentation
  • “Furious” (encephalopathic) rabies (80% of cases):
    1. Extreme hyperactivity and bizarre behavior alternating with periods of relative calm
    2. Hallucinations, disorientation
    3. Seizures
    4. Paralysis
    5. Fear, pain, and spasm of the pharynx and larynx caused by drinking
    6. Coma, death
  • “Dumb” (paralytic) rabies (20% of cases):
    1. Ascending flaccid paralysis
    2. Often prominent in the bitten limb
    3. Deep tendon and plantar reflexes lost
    4. Fasciculations
Etiology

  • Rabies virus: Bullet-shaped viruses that belong to Rhabdoviridae family, genus Lyssavirus
  • Cases in the U.S. are associated with:
    1. Bats
    2. Raccoons
    3. Foxes
    4. Skunks
  • Small rodents (squirrels, mice, rats, chipmunks) and lagomorphs such as rabbits almost never have rabies and have never been a source of transmission of rabies to humans in the U.S.
  • In 13/25 cases of rabies occurring in the U.S. from 2009 to 2018, exposure to bats was thought to be the source, although many did not have a clinically evident bite or scratch
  • Imported cases are usually associated with dogs
  • Unusual acquisition:
    1. By organ transplantation: Kidney, liver, arterial segment
    2. By aerosol transmission in laboratory workers and spelunkers

Diagnosis ⬆ ⬇

Differential Diagnosis

  • Delirium tremens
  • Tetanus
  • Hysteria
  • Psychiatric disorders
  • Other viral encephalitides (Box E1)
  • Guillain-Barré syndrome
  • Poliomyelitis

BOX E1 Differential Diagnosis of Rabies

Viral-borne encephalitis

Herpes simplex virus (HSV-1)

Arboviruses (e.g., Eastern equine encephalitis, Western equine encephalitis, West Nile, Japanese encephalitis, California encephalitis, Rift Valley fever)

Enterovirus: Enterovirus 71

Cerebral malaria

Acute disseminated encephalomyelitis (ADEM)

Limbic encephalitis

Guillain-Barré syndrome

Poliomyelitis

Post-rabies vaccine encephalomyelitis

Tetanus

Botulism

Drugs

Direct toxicity: Drug-induced psychosis (e.g., phencyclidine [PCP])

Drug syndromes: Serotonin syndrome, neuroleptic malignant syndrome

Drug withdrawal: Severe alcohol withdrawal

Florid mental illness

Rabies hysteria

From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

Workup

  • Antemortem diagnosis requires multiple specimens (saliva, skin that requires a full-thickness biopsy from posterior neck at the hairline, cerebrospinal fluid, serum) and multiple testing modalities: Polymerase chain reaction (PCR), antibodies, immunofluorescence of viral antigens, viral culture.
  • Animals submitted for rabies testing should be euthanized in a way that maintains the integrity of the brain.
  • Negri bodies are eosinophilic cytoplasmic inclusions found in neurons. They are the best-known histologic feature of rabies usually found at postmortem examination.
  • The national case definition for animal rabies requires laboratory confirmation by either:
    1. A positive DFA test (preferably performed on central nervous system (CNS) tissue) or
    2. Isolation of rabies virus (in cell culture or in a laboratory animal)
  • Fig. E1 describes an approach to assessing rabies exposure and initiating postexposure prophylaxis (PEP) in the U.S.

Figure E1 Approach to Assessing Rabies Exposure and Initiating Postexposure Prophylaxis (PEP) in the U

S.

!!flowchart!!

CDC, Centers for Disease Control and Prevention.

From Adams JG et al: Emergency medicine: clinical essentials, 2nd ed, Philadelphia, 2013, Elsevier.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

  • Isolation of the patient to prevent transmission to others
  • Supportive therapy
Acute General Rx

  • No known beneficial therapy. A case report from 2005 describes a 15-yr-old girl who survived rabies and had been treated with a combination of ketamine, midazolam, ribavirin, and amantadine. It is known as the Milwaukee protocol. The protocol has been unsuccessful in over 40 subsequent reports and is considered ineffective.
  • Other nonproven agents include interferon, corticosteroids, therapeutic coma, minocycline, and prevention of cerebral vasospasm. Research is ongoing in vitro and mice with favipiravir, a viral RNA polymerase inhibitor.
  • Emphasis is placed on prophylaxis of potentially exposed individuals after an exposure (Table E1):
    1. Thorough wound cleansing and irrigation of the wound with soap and water as soon as possible. If available, a viricidal agent (e.g., povidone-iodine solution) should be used to irrigate the wounds.
    2. Active and passive immunization is most effective when used within 72 hr of exposure.
  • Vaccinations: The CDC has recently recommended reducing the number of vaccine doses for postexposure prophylaxis. Current recommendations for rabies postexposure prophylaxis are as follows:
    1. Human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) 1 ml intramuscularly (IM) (deltoid area) 1 each on days 0, 3, 7, and 14 in patients not previously vaccinated. In patients previously vaccinated, administer HDCV or PCECV 1 ml IM (deltoid area) 1 each on days 0 and 3. Human rabies hyperimmune globulin (RIG) 20 IU/kg body weight should be administered to persons not previously vaccinated. If anatomically feasible, the full dose should be infiltrated into the wound; any remaining volume should be given IM at a site separate from vaccine administration.
  • Preexposure prophylaxis with HDCV or RVA (1 ml IM on days 0, 7, and 21 or 28) in individuals at high risk for acquisition:
    1. Veterinarians
    2. Laboratory workers working with rabies virus
    3. Spelunkers
    4. Visitors to endemic areas

TABLE E1 Regimen Examples for Preexposure and Postexposure Vaccination With Rabies Vaccines

VaccinationRouteDays on Which Doses Are GivenRemarks
PreexposureIM∗0, 7, 21, or 28Standard U.S. and WHO three-dose regimen
ID†0, 7, 21, or 28Economical, but not to be used in those taking antimalarial medications; unlicensed route in U.S.; WHO recommended
Postexposure‡IM∗0, 3, 7, 14Standard U.S. four-dose recommendation
IM∗0 (2 doses), 7, 21Used in some countries when RIG is not indicated; so-called 2-1-1 schedule
ID†0, 3, 7 (2 doses each), 28Used in Thailand with PVRV, PCECV; so-called 2-2-2-0-1 schedule
ID†,§0 (8 doses), 7 (4 doses), 28, 90Used in developing countries with HDCV, PCECV, or PVRV cell culture vaccines; so-called 8-0-4-0-1-1
Booster (for reexposure)IM∗0, 3Only after documented vaccination with cell culture vaccine
ID†0, 3Only after documented vaccination with cell culture vaccine

HDCV, Human diploid cell vaccine; ID, intradermal; IM, intramuscular; PCECV, purified chick embryo cell vaccine; PVRV, purified Vero cell rabies vaccine; RIG, rabies immune globulin; WHO, World Health Organization.

∗Together with rabies immunoglobulin.

† Give 0.1 ml, over the deltoids.

‡ Give 0.5 ml (PVRV) or 1 ml, depending on the vaccine, into the deltoid.

§ Give 0.1 ml at multiple sites (see text).

Or demonstrated presence of virus-neutralizing antibodies after other vaccines.

From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

Disposition

Virtually always fatal once clinical syndrome develops. Rabies has one of the highest case/fatality ratios of any infectious disease.

Referral

  • To infectious disease consultant
  • To local health authorities

Pearls & Considerations ⬆ ⬇

Comments

  • Most cases in the U.S. are caused by:
    1. Bat bites, often after minimal contact and inapparent exposure to infected bat saliva
    2. Dog bites occurring outside the U.S.
  • Rare cases can be transmitted by mucous membrane contact with aerosolized virus (caves, laboratory-acquired cases).
  • Rabies is preventable if exposed persons receive postexposure prophylaxis. Public understanding of rabies exposure risk from bat contact needs to be improved.
  • The World Health Organization (WHO) has a goal of eliminating cases of rabies transmitted by dogs by 2030.
Related Content

Rabies (Patient Information)

Suggested Readings ⬆

  1. Boland T.A. : Phylogenetic and epidemiologic evidence of multiyear incubation in human rabiesAnn Neurol. ;75, 2014.
  2. Dyer J.L. : Rabies surveillance in the United States during 2013J Am Vet Med Assoc. ;245, 2014.
  3. Fooks A.R. : Current status of rabies and prospects for eliminationLancet. ;384:1389-1399, 2014.
  4. Fooks A.R. : RabiesNat Rev Dis Primers. ;3, 2017.
  5. Harrist A. : Human rabies-Wyoming and UtahMMWR Morb Mortal Wkly Rep. ;65(21), 2016.
  6. Jackson A.C. : Human rabies: a 2016 updateCurr Infect Dis Rep. ;18, 2016.