Introduction to Zoonotic Disease: Rabies

Overview of Rabies

• Zoonotic Disease: Rabies is notably an acute, highly fatal viral disease affecting the central nervous system and is classified as a zoonosis.
• Causative Agent: The disease is caused by the Lyssavirus Type 1. The virus is typically transmitted to humans through bites or licks from rabid animals.

Problem Statement

• Rabies is both an enzootic (constantly present in certain populations) and epizootic (occurring sporadically and affecting many animals) disease of worldwide relevance.
• Epidemiological Impact: 99% of human rabies infections stem from rabid dogs, highlighting the public health significance of this disease.
• Geographical Context:
    - Endemic Regions: India is notably endemic for rabies, evidencing an incidence of animal bites at 17.4 per 1000 population and accounting for 36% of the world’s rabies fatalities, translating to approximately 20,000 deaths annually (equivalent to 2 deaths per 100,000 population at risk).
    - Natural Barriers: Water serves as a natural barrier to the spread of rabies.
• Rabies-Free Countries: Nations free from rabies include Australia, New Zealand, the UK, Ireland, Iceland, Norway, Sweden, Japan, and Taiwan.
• Rabies-Free Regions in India: Specific areas include the Lakshadweep and Andaman & Nicobar Islands. A rabies-free area is defined as one where no cases of indigenously acquired rabies in humans or any animal species have occurred for two years.

Agent Factor: Lyssavirus Type 1

• Virus Characteristics:
     - The rabies virus, a bullet-shaped neurotropic RNA virus, belongs to the Rhabdoviridae family.
     - Contains two major antigens:
       - Glycoprotein (G protein) Antigen: This antigen is derived from the virus membrane and is the only antigen capable of inducing the formation of virus-neutralizing antibodies.
       - Internal Nucleoprotein Antigen.

Types of Rabies Virus

• Street Virus:
    - Recovered from naturally occurring rabies cases and associated with a long and variable incubation period ranging from 20 to 60 days. It is pathogenic for all mammals and forms Negri bodies.
• Fixed Virus:
    - This virus is modified through serial brain-to-brain passage in rabbits, leading to a reduction in its incubation period to a constant 4-6 days. The fixed virus does not multiply in extra-neural tissues nor does it form Negri bodies when injected intracerebrally. It is used in the preparation of anti-rabies vaccines.

Source of Infection

• Infection Source: The saliva of rabid animals is infectious, containing the virus 3-4 days before symptoms begin and during the illness until death.

Epidemiological Forms of Rabies

Reservoir of Infection

• Three Forms:
    1. Wildlife Rabies (Sylvatic Rabies): Maintained in wild animals such as jackals, foxes, and hyenas. Wildlife may transmit the virus to domestic animals, and humans can contract rabies through intrusion into these natural habitats.
    2. Urban Rabies: Results from the transfer of the virus from wildlife to domestic animals, predominantly maintained by dogs (99% of human cases).
    3. Bat Rabies: Associated primarily with vampire bats, seen in regions including Brazil, Venezuela, Mexico, Germany, Denmark, the Netherlands, Trinidad and Tobago, and some areas in the U.S. Notably, bat rabies is not reported in India. Transmission can occur through bites or aerosol exposure when in caves with rabid bats.

Host Factors

• At-Risk Population: The disease commonly affects individuals between age 1 to 24 years, particularly children under 15 years, with a higher incidence noted in males. Rabies is a dead-end infection in humans, affecting mainly veterinarians, dog handlers, and laboratory staff.

Modes of Transmission

• Transmission Paths:
    - Deep bite or scratch by an infected animal.
    - Direct contact of saliva with human mucosa or fresh skin wounds.
    - Human-to-Human Transmission: Although rare, it can occur theoretically through bites.
    - Inhalation: Rare cases have been documented from inhaling aerosolized virus in bat-infested caves.
    - Transplantation: Rare instances of rabies transmission occurred through infected organ or corneal transplants.
    - Ingestion: Mostly a risk for animals that eat raw meat or tissue from infected animals.

Incubation Period

• Variability: The incubation period can range from 7 days to several years, typically spanning 3-8 weeks. The duration is influenced by several factors, including:
    - Site of Bite: Shorter incubation with bites on face, head, neck, or upper extremities.
    - Severity: More severe wounds result in shorter incubation.
    - Number of Wounds: Multiple wounds can precipitate a shorter duration.
    - Amount of Virus: The volume of virus transmitted affects incubational length, with wild animal bites resulting in a rapid onset.
    - Protection Offered: Clothing can provide an additional variable in transmission dynamics.
    - Treatment Undertaken: Post-exposure management can diminish incubation periods.

Pathogenesis

• Mechanism: The rabies virus gains entry through bites, scratches, or licks, multiplying locally in the tissues and muscles. From there, it ascends centripetally via peripheral nerves to the CNS, resulting in generalized encephalomyelitis. Once in the CNS, the virus multiplies primarily in grey matter and then spreads centrifugally through autonomic nerves to other tissues, including the salivary glands and cornea. CNS infiltration impacts brainstem functions, causing symptoms such as hydrophobia, aerophobia, and photophobia, leading ultimately to respiratory paralysis and death.
• Pathognomic Lesion: The intracytoplasmic inclusion body, known as a Negri Body, is pathognomonic of rabies but only appears following infection with the street virus, not the fixed virus.

Clinical Features

Disease Progression

1. Prodromal Symptoms: The disease typically begins with non-specific symptoms such as headache, malaise, sore throat, and fever. Patients often report pain and tingling at the bite site, a consequence of viral replication in local tissues (85% of patients).
2. Neurological Stimulation: The initial phase gives way to hyperactivity across nervous systems, manifesting in several ways:
      - Sensory System Symptoms: Patients may exhibit intolerance to noise, bright light, and cold air, with aerophobia (fear of air) being particularly characteristic, as fanning air across the face triggers violent spasms.
      - Motor System Symptoms: Increased reflexes and muscle spasms occur as the disease progresses.
      - Sympathetic Nervous System Symptoms: Features include pupil dilation and increased perspiration, salivation, and lacrimation.
      - Mental System Symptoms: Patients may experience anger, irritability, and fear, culminating in an inability to swallow, particularly triggered by the sight or sound of water, a phenomenon termed hydrophobia, which is pathognomonic in human cases (absent in animals). Death may occur unexpectedly during convulsions or advance to paralysis and coma, with recorded survivors limited to three individuals to date.
   

Diagnosis

• Clinical Diagnosis: Deduction is based on history of bite from a rabid animal coupled with characteristic signs and symptoms.
• Sample Collection:
     - Saliva
     - Cerebrospinal Fluid (CSF)
     - Skin Biopsies: Collections at the nape of the neck containing hair follicles.
     - Tears and Urine
• Detection Methods:
     - Immunofluorescence: Used for antigen detection in skin biopsies.
     - Virus Isolation: From saliva and other secretion samples.
     - Specific and neutralizing antibodies are typically not detectable in serum or CSF prior to the eighth day post-bite.
• Differential Diagnosis: Considerations include tetanus, poliomyelitis, and belladonna poisoning.

Treatment

• Lack of Specific Treatment: Management is effective but not curative.
• Case Management Goals Include:
    - Patient isolation in a quiet room.
    - Administration of sedatives for relief from anxiety and pain.
    - Morphine at a dosage of 30-45 mg for severe pain.
    - Curare-like drugs to manage spastic muscular contractions.
    - Overseeing hydration and diuresis is critical.
• Required Precautions for Nursing Staff: All nursing personnel interacting with patients should don masks, gloves, goggles, and aprons. Individuals with cuts or open wounds should not engage with patients.

Post Exposure Prophylaxis of Dog Bite

• Case Study: A hypothetical example of a dog bite incident where an individual named Arpit was attacked without provocation by a stray dog resulting in multiple deep bite wounds and scratches. Immediate transport to a nearby hospital was necessary.
• Categories of Rabies Exposure (WHO):
    1. Category I: Licks on intact skin; requires only local care.
    2. Category II: Nibbling of uncovered skin, minor scratches, or abrasions without bleeding; local treatment plus anti-rabies vaccine indicated.
    3. Category III: Transdermal bites, licking broken skin, contamination of mucosa, contact with bats; local treatment, anti-rabies vaccine, and rabies immunoglobulin required.

Rationale for Animal Observation

• Animals suspected to have rabies should be observed for 10 days. If infected, they will manifest signs of the disease within 3-5 days and typically die within 3-5 days thereafter.

Local Treatment of Wounds

1. Immediate Action: Flushing and washing the wounds and surrounding areas with soap and water (preferably running tap water) for 10-15 minutes to reduce viral load.
2. Puncture Wounds: If a puncture wound exists, catheters should be employed for irrigation.
3. Chemical Treatment: Any residual virus should be inactivated using viricidal agents such as:
      - Alcohol/Spirit (40-70%)
      - Tincture of iodine (0.01% aqueous solution)
      - Povidone iodine
4. Suturing Guidelines: Immediate suturing is not recommended as it may push the virus deeper; if necessary, delayed suturing (24-48 hours later) should be done under cover of rabies immunoglobulin.
5. Post-Cleanup Protocol: Antibiotics, like amoxicillin and clavulanic acid, along with anti-tetanus treatments should follow local wound treatment if indicated.

Immunization Protocol

Anti-Rabies Vaccine (ARV)

• Developed by Dr. Louis Pasteur in 1885. World Rabies Day is observed on September 28, commemorating his death anniversary. The first ARV was administered to Joseph Meister.
• Post-Vaccination Measures:
     - Vaccine should be utilized within 6-8 hours following reconstitution.
     - Shelf life of vaccines is greater than or equal to 3 years at 2°C to 8°C.

Types of Vaccines

1. Intradermal Vaccines:
      - Cell Culture Vaccine (CCV):
        - Purified Chick Embryo Cell Vaccine (PCECV)
          - Brands: Rabipur, Vaxirab N
        - Purified Vero Cell Rabies Vaccine (PVCRV)
          - Brands: Verorab, Abhayrab, Indira
      - Sites of Injection: Deltoid, lateral thigh, suprascapular region, lower abdomen.
2. Intramuscular Vaccines:
      - Similar offerings as intradermal vaccines with specific placement and dosage protocols.

Rabies Immunoglobulin (RIG)

• Usage: This is administered once at the initiation of post-exposure vaccination.
    - Doses include:
      - 20 IU/kg body weight of Human Immunoglobulin (maximum 1500 IU), deposited maximum in the wound and remaining intramuscularly.
      - Equine Immunoglobulin and (F(ab')2 products): 40 IU/kg body weight (maximum 3000 IU), split evenly between 50% in the wound and 50% intramuscularly.
      - Rabies Human Monoclonal Antibodies involve 3.33 IU/kg body weight.

Immunization Schedules

Various schedules should be followed based on health conditions, exposure, and vaccination history:

• Previously Vaccinated Individuals: May only require one dose of the rabies vaccine and should not require RIG.
• Pre-exposure prophylaxis for those at risk involves a regimen of multiple doses of the rabies vaccine at set intervals (Days 0, 7, and 21 or 28).
• Serological Monitoring: Antibody monitoring is crucial for those at risk; booster doses are only indicated when rabies-neutralizing antibody titers fall below 0.5 IU/ml.

Prevention of Rabies

• Control Measures for Urban Rabies:
    - Control over stray dog populations through mass immunizations (targeting at least 80% vaccination coverage).
    - Licensing and registration of all domestic dogs.
    - Educating the public regarding rabies prevention techniques.
• National Action Plan for Rabies Elimination: Objectives include achieving zero human rabies deaths due to dog-mediated rabies in India by 2030 through enhanced public health systems and access to post-exposure prophylaxis.
• Global Initiatives: WHO's 2021-2030 roadmap aims to eliminate neglected diseases, including rabies, and promote collaborative efforts across different sectors for controlling rabies.

Clinical Picture of Rabies in Dogs

• Incubation Period: In dogs, it can range from 10 days to a year. Once symptomatic, infected animals rarely survive beyond a week.
• Clinical Manifestations:
    - Furious Rabies (Mad Dog Syndrome):
      - Behavioral changes include loss of fear, aggression, and tendency to bite without provocation.
      - Animals exhibit symptoms such as excessive salivation, changes in bark quality, and a propensity to run amok.
    - Paralytic Stage: Towards the illness conclusion, paralysis prevails desensitizing affected dogs, leading to coma and death.
• Dumb Rabies: Lacking the irritative stage, characterized predominantly by paralysis.

Laboratory Diagnosis in Dogs

• Force a brain specimen sent in 50% glycerol saline for examination, assessing through fluorescence antibody tests to determine antibody tiers and microscopic evaluations for Negri Bodies (a definitive rabies indicator).

Immunization Strategies for Dogs

• Primary Immunization: All dogs should receive their primary vaccines at 3-4 months of age, utilizing BPL (Beta-propiolactone) inactivated nervous tissue vaccine, with a recommended initial dose of 5 ml for dogs and 3 ml for cats, retreated every 6 months to annually.
• Modified Live Virus Vaccine Administered: Effective as an oral vaccine, successfully used in wildlife rabies control, notably within fox populations in multiple nations.