Rabies: Deadly Zoonotic disease; One should know the facts
Dr. Annu Yadav
PhD Scholar, Department of Veterinary Medicine, LUVAS, Hisar)
Introduction:
Rabies is a devastating and societally important zoonotic disease, which is transmitted principally to humans through the bite of infected dogs. This acute zoonotic, highly fatal and progressive viral encephalitis has the highest case fatality of any infectious disease and kills tens of thousands of people annually, with children and impoverished communities being affected disproportionately.
Etiology: Lyssavirus, family- Rhabdoviridae (enveloped, bullet-shaped ssRNA virus measuring 75 × 180 nm with seven distinct genotypes. It is extremely labile when exposed to ultraviolet light and heat and readily inactivated by formalin, phenol, alcohol, halogens, mercurials, mineral acids and other disinfectants.
Epidemiology: All warm-blooded animals vulnerable to infection, but mammals are the only known vectors and reservoirs in nature with foxes, coyotes, jackals, wolves, and certain rodents to be highly susceptible and birds or primitive mammals (opossum) to be least. Major route of transmission is animal bite while airborne infection, lick on broken skin or mucous membrane, scratches, ingestion and corneal transplantation (human to human) also important source.
Pathogenesis: Incubation period influenced by age of bitten individual, degree of innervation of bite site, distance from point of inoculation to spinal cord or brain, variant and amount of virus introduced. Prolonged incubation period due to route of virus entry into and spread within central nervous system (CNS). Virus spreads passively by intra-axonal flow in peripheral nerves at rate of up to 100 (range, 10 to 400) mm per day. Both motor and sensory fibers may transport virus. Greater the degree of innervation at site of bite, shorter the incubation period. Following inoculation through virus-laden saliva by bite, licking on abraded skin or mucus membrane, scratching by claws of rabid dog or animal, virus travels in nerves and carried centripetally by flow of axoplasm to dorsal root ganglion. From there it travels to brain, where massive viral replication occurs. Then virus migrates along efferent nerves to almost every organ such as adrenal medulla, cornea, pancreas, nerve twiglet of hair follicle, and salivary gland, and leads to virus shedding in saliva. Range of incubation periods before CNS signs reported: 3 to 24 weeks (average, 3 to 8 weeks) in dogs, 2 to 24 weeks (average, 4 to 6 weeks) in cats, and 3 weeks to 1 year or more (average, 3 to 6 weeks) in humans.
Spread in the Central Nervous System:
Virus enters spinal cord or brainstem ipsilateral to site of initial virus inoculation by retrograde axoplasmic flow. Once in CNS, virus spreads by intra-axonal means to involve contralateral neurons and ascends rapidly and bilaterally in spinal cord or brainstem to forebrain. Localisation occur in limbic areas, thalamic nuclei, reticular formation, trigeminal and vagal nuclei. Damage to motor neurons causes progressive lower motor neuron (LMN) disease, producing typical ascending flaccid (hyporeflexic) paralysis of rabies. Host immune responses to rabies virus may accentuate inflammation and degeneration of nervous tissue. Interference with cardiorespiratory control results in death.
Spread from the Central Nervous System:
Virus moves outward to other body tissues via peripheral, sensory and motor nerves at rate of 100 to 400 mm per day. Both visceral and somatic portions of cranial and spinal cord nerves involved, including autonomic nervous system. Virus spreads via cranial nerves to acinar cells of salivary glands. Rate (20% to 88% positive) of salivary gland infection varies depending on species infected and virus variant. Death may occur before salivary gland involvement
Clinical findings: Two major forms: furious and paralytic
Prodromal phase: lasts 2 to 3 days, apprehension, nervousness, anxiety, solitude and variable fever may be noted. Friendly animals may become shy or irritable and may snap, whereas fractious ones may become more docile and affectionate. Pupillary dilation with or without sluggish palpebral or corneal reflexes may become apparent. Most animals constantly lick site of viral inoculation. Some may develop pruritus at site of exposure and claw and chew at area until it is ulcerated. Behavior of cats during prodromal period is similar to that of dogs; however, cats more typically show fever spikes and unusual or erratic behavior for only 1 or 2 days.
Furious or psychotic: usually lasts 1 to 7 days, associated with forebrain involvement. Animals become restless and irritable, have increased responses to auditory and visual stimuli. They frequently become excitable, photophobic, and hyperesthetic and bark or snap at imaginary objects. As they become more restless, they begin to roam, usually becoming more irritable and vicious. Avoid contact with people and prefer to hide in dark or quiet places. When caged or confined, dogs often try to bite or attack their enclosure. Develop muscular incoordination, disorientation or generalized grand mal seizures during this phase. If do not die during a seizure, may experience short paralytic stage and then
Paralytic or dumb form: develops within 2 to 4 days after first clinical signs observed. LMN paralysis usually progresses from site of injury until entire CNS involved. Cranial nerve paralysis first recognizable clinical syndrome if bite occurs on face. When brainstem affected, change in tone of bark, due to laryngeal paralysis may be observed. Dogs with such signs may begin to salivate or froth excessively as a result of the inability to swallow and deep labored respiration that occurs. Dropped jaw develops due to paralysis of masticatory muscles. Dogs may make choking sound, which convinces an owner that something is caught in the animal’s throat. Owners or veterinarians may then become exposed to virus in saliva while attempting to remove suspected foreign object. Course of paralytic phase lasts 2 to 4 days. Animal often goes into coma and dies of respiratory failure.
Diagnosis:
- Direct fluorescent antibody (FA) test: Definitive diagnostic test for demonstration of rabies virus antigen in suitable brain tissue.
- Direct immunochemical methods using light microscopy.
- No premortem diagnostic reliable for rabies diagnosis in animals.
- No hematologic or serum biochemical changes characteristic or specific for rabies.
- Mouse inoculation test: Virus isolation in mice (3-4 weeks old or 2 day-old new-born mice) or in cell lines like mouse neurobrastoma cell line (Neuro2a/CCL 131), baby hamster kidney (BHK) 21/C13, Vero cells and McCoy cells.
- Detection of Virus in Dermal Tissues: predominantly used to diagnose rabies antemortem in people. Due to heavy sensory innervation, skin at nape of neck (humans) and sensory vibrissae on maxillary areas (animals) may be selected for direct FA testing.
- Polymerase chain reaction (PCR) testing of skin has higher degrees of sensitivity and specificity compared to direct FA methods. Living human patients, RT-PCR (saliva, CSF, and urine) and in dogs, quantitative PCR (saliva and CSF).
- Testing of Saliva for Virus: Detection in dog saliva by slide agglutination using latex particles coated with polyclonal immunoglobulin. Increased sensitivity and specificity of saliva testing can be achieved by using virus isolation or genetic detection methods.
- Direct Fluorescent Antibody and Immunohistochemical Testing of Nervous Tissue: Both rapid and sensitive and currently most widely used and preferred and reliable method of diagnosing potential rabies infection in animals. False-negative results rare in comparison with mouse inoculation. Thin touch impressions of medulla, cerebellum, or hippocampus used for this test. In decomposing canine brains at room temperature of 25°C to 29°C, direct FA test result remains positive in most cases for up to 96 hours; while corresponding mouse inoculation test (MIT) usually becomes negative by 48 hours.
- Immunoperoxidase technique
- Genetic Detection of Virus and Genetic Sequencing: Amplified sequences include phosphoprotein, nucleoprotein, and glycoprotein genes.
- Intracellular Inclusions: presence of intracytoplasmic inclusions known as Negri bodies. Most commonly found in thalamus, hypothalamus, pons, cerebral cortex, and dorsal horns of spinal cord. Negri bodies are most common in neurons of hippocampus in carnivores and in Purkinje’s cells of herbivores. Negri bodies in tissue sections or impressions of brain tissue best demonstrated with Seller’s or Van Gieson’s stains, in which they stain magenta. Unfortunately, Negri bodies take time to develop and cannot be found during all stages of infection. They usually cannot be detected until neurologic signs are apparent. Detection of Negri bodies no longer used in most developed nations for routine diagnostic confirmation.
Prevention: Vaccination different regimen:
- Site Regimen (updated TRC): 1 ml / ID site, Upper arm over each deltoid Schedule: 2- 2- 2- 0- 2
- Thai Red Cross (TRC) regimen: 1 ml/ID site over upper arm over each deltoid
Schedule: 2- 2- 2- 0- 1-1.
ID regimen- Intradermal Rabies Vaccination: Following vaccines currently approved by DCGI for use by ID route:
PVRV – Verorab, Aventis Pasteur (Sanofi Pasteur India Pvt. Ltd.)
PCECV – Rabipur, Chiron Behring Vaccines Pvt. Ltd.
PVRV – Pasteur Institute of India, Coonoor, India
PVRV – Abhayrab, Human Biologicals Institute
IM regimen– currently 4 types of vaccines available (Tissue culture vaccines)
Human diploid cell vaccine (HDCV): One dose – 1 ml (IM)
Purified chick embryo cell vaccine (PCECV): One dose – 1 ml (IM)
Purified Vero cell rabies vaccine (PVRV): One dose – 0.5 ml (IM)
Purified duck embryo vaccine (Vaxirab): One dose – 1 ml (IM)
Pre-exposure: 0, 7, 21/28; Post exposure: 0, 3, 7, 14, 28 (given in deltoid region or for young children into antero-lateral area of thigh muscle).
Key challenges in rabies control:
- Current challenges are lack of intersectoral coordination between multiple disciplines involved in rabies control like public health department, animal husbandry department, government and non-government agencies.
- Limited information on dog population
- Poor surveillance data on human and animal rabies
- Lack of adequate dog bite epidemiology for predicting vaccine requirement
- Delay in scaling up of successful pilot interventions from local setting to national level
- Poor diagnostic capacity
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