*Definition and Overview -
Rabies is an acute, progressive viral encephalomyelitis caused by neurotropic
viruses of the genus Lyssavirus (family Rhabdoviridae). It is nearly
always fatal once clinical signs appear. Transmission typically occurs through
the bite or scratch of an infected mammal—most commonly domestic dogs in many
endemic regions, including India. After entry into peripheral tissues, the
virus travels centripetally via peripheral nerves to the central nervous system
(CNS), where it replicates and causes widespread neuronal dysfunction.
1. Etiology and Epidemiology
1. Causative
Agent
o
The classical rabies virus (Rabies lyssavirus)
is a bullet-shaped, enveloped RNA virus (~12 kb negative-sense genome).
o
Other Lyssavirus species (e.g., Lagos
bat virus, Australian bat lyssavirus) can also cause rabies-like disease, but
classical rabies virus accounts for by far the majority of human cases
worldwide.
2. Reservoirs
and Transmission
o
Domestic Dogs:
Responsible for >99% of human rabies transmissions globally, particularly in
Asia and Africa.
o
Wild Mammals:
In some regions, skunks, raccoons, foxes, bats, and mongooses can serve as
reservoirs or vectors. In India, the most significant reservoirs remain stray
dogs and, to a lesser extent, wild canids (jackals) or mongooses in certain
locales.
o
Routes of Transmission:
§ Bite
or Scratch: Virus is present in saliva; entry through broken
skin or mucous membranes.
§ Mucosal
Exposure: Licking of intact mucosa (rare but possible).
§ Organ
Transplantation: Exceptionally rare (e.g., corneal transplant
from an undiagnosed infected donor).
o
Incubation Period:
Typically 1–3 months (range: a few days to over a year), influenced by factors
such as viral load, location of the bite (closer to the head/neck tends to have
shorter incubation), and host immune status.
3. Global
and Regional Burden
o
Worldwide:
Approximately 59,000 human deaths occur annually (WHO estimate), with India
accounting for an estimated 35–40% of global rabies mortality.
o
Age Distribution:
Children (5–15 years) are disproportionately affected due to greater exposure
risk and inability to recognize danger in stray animals.
o
Seasonality:
In some regions, cases peak during cooler months but transmission can occur
year-round.
2. Pathogenesis
1. Viral
Entry and Local Replication
o
Following inoculation into muscle or
subcutaneous tissue, rabies virus initially replicates at the wound site in
myocytes and nearby non-neuronal cells for a variable period (often 1–2 weeks),
generally without producing detectable viremia.
2. Neuroinvasion
o
The virus gains access to peripheral nerves,
binding to nicotinic acetylcholine receptors at neuromuscular junctions or
other neuronal receptors (e.g., NCAM, p75NTR).
o
It travels retrograde via axons to the dorsal
root ganglia and spinal cord, ultimately reaching the brain. Axonal transport
occurs at ~12–100 mm/day.
3. CNS
Spread and Neuronal Dysfunction
o
Once within the CNS, virus replicates in
neurons—especially in hippocampus, brainstem, and thalamic nuclei—causing
neuronal dysfunction rather than prominent neuronal cell death or inflammation.
o
The virus then disseminates centrifugally
through peripheral nerves to various tissues, including salivary glands,
cornea, skin (hair follicles), and other organs.
o
Viral antigen in salivary glands leads to
high-titre viral shedding in saliva, making the animal highly infectious
shortly before, during, and after clinical disease onset.
4. Immune
Response
o
There is minimal neutralizing antibody
production in the early stages because peripheral replication remains
localized.
o
By the time robust neutralizing antibodies
appear (once CNS involvement is advanced), neuronal damage is typically
irreversible.
o
Pathology shows Negri bodies (eosinophilic
cytoplasmic inclusions of viral nucleocapsid) in neurons, perivascular cuffing,
and mild meningoencephalitis; neuronal necrosis can be patchy.
3. Clinical Presentation
A. Incubation (Asymptomatic Phase)
·
Duration:
Generally 1–3 months, though shorter (days) if bite is on the face/head.
·
Symptoms:
Absent. Patients remain asymptomatic even though virus is replicating locally.
B. Prodromal Phase (2–10 days; sometimes up to 14 days)
·
Early, Non‐Specific
Symptoms:
o
Fever, malaise, anorexia, headache, fatigue.
o
Paresthesia, itching, or pain at bite site
(“paresthetic prodrome”).
·
Behavioral Changes:
Anxiety, agitation, insomnia—reflecting early neuronal involvement.
C. Furious (Encephalitic) Rabies (~80% of cases)
1. Hyperactivity
and Excitability
o
Restlessness, irritability, confusion, delirium,
and episodic aggression.
o
Aerophobia (fear or panic when encountering
drafts of air).
o
Hydrophobia: Recurrent, violent spasms of
pharynx and diaphragm upon attempts to swallow liquids; even the sight or sound
of water can trigger intense laryngeal spasms.
o
Photophobia and hypersalivation.
o
Periods of lucidity may alternate with agitated
phases.
2. Neurological
Signs
o
Signs of meningoencephalitis: Neck stiffness,
photophobia, and hyperacusis.
o
Myoclonus, involuntary jerking, seizures.
o
Autonomic dysfunction: Hypersalivation,
arrhythmias, sweating.
D. Paralytic (Dumb) Rabies (~20% of cases)
1. Flaccid
Paralysis
o
Gradual ascending paralysis resembling
Guillain–Barré syndrome.
o
Bulbar palsy: Dysphagia, dysarthria, and facial
weakness.
o
Progression to quadriparesis and respiratory
muscle paralysis.
o
Myocarditis or renal failure can occur.
2. Lack
of Furious Features
o
Hydrophobia and hyperactivity are often absent
or minimal.
o
May be misdiagnosed unless high clinical
suspicion based on history.
E. Terminal Stage
·
Coma and Death
o
Once encephalopathy advances, there is
progression to coma (1–2 days after encephalitic phase begins).
o
Death usually results from respiratory
failure—paralysis of diaphragm and intercostal muscles—or autonomic
instability.
o
Case fatality approaches 100% once symptoms
appear. Only a handful of survivors have been documented globally (e.g.,
Milwaukee protocol cases), and most survivors have severe neurological
sequelae.
4. Diagnosis
Early diagnosis is crucial for initiating post-exposure prophylaxis (PEP)
before symptom onset. Once clinical signs appear, confirming rabies does not
alter the near-universally fatal prognosis, but can guide public health and
animal control measures.
A. Ante-Mortem Testing (Human)
1. Sample
Types
o
Saliva
(for viral RNA detection).
o
Skin Biopsy
(nuchal skin with hair follicles)—demonstrates viral antigen in cutaneous
nerves.
o
Cerebrospinal Fluid
(CSF)—usually lymphocytic pleocytosis; may contain
rabies-specific antibody or viral RNA.
o
Serum
(paired acute and convalescent) for rabies neutralizing antibodies, though
often negative until late.
o
Corneal Impressions
(fluorescent antibody test)—less commonly used.
2. Diagnostic
Modalities
o
Direct Fluorescent
Antibody (DFA) Test on nuchal skin biopsy (gold standard for
ante-mortem).
o
Reverse Transcriptase
Polymerase Chain Reaction (RT-PCR) for viral RNA in saliva,
CSF, or tissue.
o
Immunohistochemistry
on biopsy.
o
Serology:
Detection of rabies virus-neutralizing antibodies in CSF or serum (not useful
early).
3. Interpretation
Considerations
o
Multiple specimens (e.g., three consecutive
saliva samples) may improve sensitivity.
o
Negative tests early in disease do not rule out
rabies; serial testing may be needed if suspicion is high.
B. Post-Mortem Confirmation
·
Brain Tissue
Examination:
o
Direct Fluorescent
Antibody (DFA) on brain impressions (hippocampus, cerebellum).
o
Viral Isolation
in cell culture or mouse inoculation (slow, rarely done clinically).
o
Negri Body Detection
on histopathology (eosinophilic intracytoplasmic inclusions in pyramidal
neurons of hippocampus, Purkinje cells of cerebellum) is supportive but less
sensitive than immunofluorescence.
5. Differential Diagnosis
·
Viral Encephalitides:
Herpes simplex, Japanese encephalitis, West Nile virus.
·
Tetanus:
Especially for referable muscle spasms.
·
Guillain–Barré Syndrome:
In paralytic form.
·
Other Causes of
Hydrophobia/Spastic Paralysis:
o
Organophosphate poisoning (excessive salivation,
spasms).
o
Severe diphtheria with bull neck,
pseudomembranes.
·
Psychiatric Disorders:
Rarely misinterpreted phobic behaviors as psychiatric in origin.
6. Management
A. Pre-Exposure Prophylaxis (PrEP)
Recommended for individuals at high risk (veterinarians, animal handlers,
laboratory personnel handling rabies virus, travelers to highly endemic areas
without reliable access to PEP).
1. Vaccine
Schedule (WHO 2018 Revised)
o
Intramuscular (IM)
Regimen:
§ Days
0, 7, and either day 21 or day 28 (Essen regimen, 3 doses).
o
Intradermal (ID)
Regimen:
§ Two-site
ID on days 0, 7, and 28 (4 injections of 0.1 mL each visit).
o
Serologic Testing:
Not routinely required for immunocompetent individuals post-vaccination; check
if immunocompromised.
2. Indications
o
All lab personnel working with live virus,
spelunkers visiting bat caves, veterinarians, dog catchers, forest rangers, and
international travelers spending >1 month in high-risk areas.
B. Post-Exposure Prophylaxis (PEP)
Bite from suspected or confirmed rabid animal, scratch, or mucosal exposure
mandates PEP unless thorough risk assessment deems otherwise. PEP combines
immediate wound care, passive immunization (immunoglobulin), and active
immunization (vaccine).
1. Immediate
Wound Management
o
Thorough Cleansing:
Wash wound with soap/detergent and running water for ≥15 minutes.
o
Virucidal Agents:
Irrigate with povidone–iodine or other suitable antiseptic.
o
No Suturing:
If possible, leave wound open or loosely approximate—closing can trap virus.
2. Passive
Immunization
o
Human Rabies
Immunoglobulin (HRIG) or, if unavailable, equine RIG (ERIG),
infiltrated around wound(s) and any remaining volume given intramuscularly at a
distant site.
o
Dose:
§ HRIG:
20 IU/kg body weight.
§ Equine
(ERIG): 40 IU/kg (after appropriate skin testing and dilution due to higher
rate of hypersensitivity).
o
Timing:
As soon as possible—ideally at presentation—up to 7 days after first vaccine
dose. After day 7, RIG is not given since active immunity from vaccine should
have begun.
3. Active
Immunization (Vaccine)
o
Vaccine Types:
Modern cell-culture or embryonated egg–based vaccines (e.g., purified chick
embryo cell vaccine—PCECV, or human diploid cell vaccine—HDCV).
o
Schedules
(Category II or III exposures—see WHO categorization below):
§ Essen
Regimen (IM): 5 doses on days 0, 3, 7, 14, and 28.
§ Zagreb
Regimen (IM): 2 doses on day 0 (one in each arm), then single
doses on days 7 and 21 (total 4 doses).
§ Intradermal
Regimens (TRC, Thai Red Cross): Two-site ID injections on days
0, 3, 7, and 28 (4 visits total).
o
Category of Exposure
(WHO):
§ Category
I: Touching or feeding animals, licks on intact skin → No PEP;
just observe animal.
§ Category
II: Nibbling of uncovered skin, superficial scratches without
bleeding → Vaccine only (no RIG).
§ Category
III: Single or multiple transdermal bites or scratches, licks
on broken skin, contamination of mucous membranes with saliva (i.e., licks),
exposures due to direct contact with bats → Vaccine + RIG.
o
Special Considerations:
§ Immunocompromised:
May require additional doses and serologic testing to confirm adequate
response.
§ Delay
should be minimized; first vaccine dose ideally within 24 hours of exposure.
4. Monitoring
and Follow-Up
o
Serology:
Not routinely done for immunocompetent; consider for immunosuppressed to ensure
protective titers (≥0.5 IU/mL).
o
Animal Observation:
If the biting animal can be kept alive and observed (e.g., dog or cat), monitor
for 10 days. If remains healthy, no further PEP beyond what was given. If dies
or exhibits signs, consider it rabid.
o
Reporting:
Notify public health authorities promptly for surveillance and possible mass
vaccination initiatives.
C. Management of Clinical Rabies
Once a patient develops clinical signs of rabies, the illness is almost universally
fatal. Management is purely supportive and palliative, focusing on comfort,
airway control, and prevention of secondary complications. A few rare survivors
have been documented under experimental protocols (e.g., Milwaukee protocol),
but such successes are exceptional and often associated with severe neurologic
deficits.
1. Supportive
Care Principles
o
Isolation:
Strict droplet/contact precautions to prevent nosocomial spread via saliva.
o
Airway Management:
Many patients require intubation or tracheostomy due to hypersecretions and
respiratory muscle involvement.
o
Sedation:
Deep sedation or barbiturate coma has been tried to reduce cerebral metabolic
demand.
o
Control of Seizures and
Autonomic Storms: Benzodiazepines, anticonvulsants (e.g.,
phenytoin), beta-blockers for tachyarrhythmias.
o
Nutritional and Fluid
Support: Via feeding tubes or parenteral routes if necessary.
o
Management of Secondary
Infections: Ventilator‐associated pneumonia, urinary tract
infections, and sepsis require prompt antibiotic therapy.
o
Psychological Support:
Counseling for family, as the prognosis is dire.
2. Experimental
Therapies
o
Milwaukee Protocol:
Induced coma (ketamine, midazolam) plus antiviral agents (amantadine,
ribavirin). Despite initial media attention in 2004, reproducible success has
been minimal; most subsequent attempts have failed.
o
Novel
Antivirals/Immunotherapies: Research ongoing but none approved
or widely effective in established disease.
7. Pathology
·
Gross Findings:
Brain may appear normal or show mild congestion; evidence of meningeal
congestion may be present.
·
Microscopic Findings:
o
Negri Bodies:
Eosinophilic intracytoplasmic inclusions (aggregates of viral nucleocapsid)
best seen in hippocampal neurons (Ammon’s horn) and Purkinje cells of the
cerebellum.
o
Perivascular Cuffing:
Lymphocytic infiltrates around small blood vessels.
o
Neuronophagia:
Minimal compared to other viral encephalitides.
o
Immunohistochemistry/DFA:
Detects viral antigen in neurons or salivary gland epithelium.
8. Prevention Strategies
1. Mass
Dog Vaccination Campaigns
o
Rationale:
Interrupt transmission at the primary source.
o
Target Coverage:
≥70% of the canine population to achieve herd immunity.
o
India:
National programs (e.g., National Rabies Control Programme under NCDC) promote
community dog vaccination and sterilization drives.
2. Public
Awareness and Education
o
Avoidance of Stray
Animals: Teach children and adults to stay away from unfamiliar
or roaming dogs.
o
Immediate Wound Care:
Emphasize washing and seeking medical attention promptly after any bite or
scratch.
o
Timely Access to PEP:
Ensure PEP centers are accessible, especially in rural and peri-urban areas.
3. Legislation
and Animal Control
o
Stray Dog Population
Management: Combination of “catch-neuter-vaccinate-release”
(CNVR) and adoption initiatives.
o
Responsible Pet
Ownership: Mandate vaccination of pet dogs; leash laws,
licensing.
4. Pre-Exposure
Vaccination for High-Risk Groups
o
As detailed in the PrEP section above
(laboratory workers, veterinarians, field animal handlers, travelers to remote
areas).
9. Prognosis and Outcomes
1. Prognosis
o
Without PEP:
Case fatality >99% once clinical symptoms develop.
o
With Complete PEP:
Nearly 100% effective at preventing disease if administered appropriately
(wound care + RIG + vaccine).
o
Delayed or Incomplete
PEP: Significantly higher risk of treatment failure; bites to
head/neck carry particularly high risk.
2. Survivors
o
Extremely rare; most documented survivors have
severe and permanent neurological impairments (e.g., cognitive deficits, brainstem
dysfunction).
o
Even with aggressive critical care, mortality
remains exceedingly high.
3. Economic
and Social Impact
o
Costs include PEP expenses (vaccine, RIG),
hospitalization, loss of productivity, and emotional trauma.
o
In resource-limited settings, PEP may not be
affordable or readily available, leading to underreporting and continued high
mortality.
10. Special Considerations in India
1. Burden
o
India reports ~20,000–30,000 human rabies deaths
annually—one of the highest national burdens globally.
o
Underreporting remains an issue; many deaths
occur outside formal healthcare settings.
2. Challenges
o
Limited Accessibility:
Rural and remote areas often lack immediate access to RIG or even modern
cell-culture vaccines.
o
Cost Constraints:
Although vaccines are subsidized in many government facilities, HRIG remains
expensive; some practitioners still use equine RIG despite risk of
serum-sickness reactions.
o
Stray Dog
Overpopulation: Urbanization and inadequate animal‐control
infrastructure lead to high numbers of unvaccinated, free-roaming dogs.
3. Ongoing
Initiatives
o
National Rabies Control
Programme (NRCP): Focuses on decentralized PEP clinics, free or
subsidized vaccines, and community engagement.
o
Animal Birth Control
(ABC) Programs: “Catch-Neuter-Vaccinate-Release” for street
dogs, combined with community awareness campaigns.
o
One Health Approach:
Collaboration between human health, veterinary, and wildlife sectors to address
rabies holistically.
11. Key Takeaways
·
Rabies is Preventable:
Through prompt PEP (wound care + RIG + vaccine) after suspected exposure.
·
Early Action Is
Critical: Once clinical symptoms develop, rabies is almost
invariably fatal; there is no reliably effective treatment.
·
Health Education Saves
Lives: Public awareness of how to manage animal bites and the
importance of vaccination (both human and canine) is essential, particularly in
endemic regions.
·
Mass Dog Vaccination:
The single most impactful measure to reduce human rabies incidence in areas
where canine rabies is endemic.
·
Global and National
Commitment: The WHO has set a goal of “Zero Human Rabies Deaths
by 2030” (Zero by 30), relying on coordinated animal and human health
strategies.
By understanding the virus’s neurotropic nature, the clear delineation
between pre-exposure, post-exposure, and clinical management, and by
emphasizing prevention—especially in rabies-endemic regions like India—public
health authorities and clinicians can work collaboratively to drastically
reduce, and ultimately eliminate, this ancient but still deadly disease.
