All mammals can get rabies, but only a few species are important as reservoirs for the disease. In the United States, distinct strains of rabies virus have been identified in bats, raccoons, skunks, foxes, and mongooses.
In many other parts of the world, rabies in dogs is still common. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Section Navigation. Facebook Twitter LinkedIn Syndicate. How is rabies transmitted? Minus Related Pages. Which animals carry rabies? Phylogenetic tree constructed using Bayesian methods based on nucleotides of the complete glycoprotein gene. Serological evidence of RABV circulation, biological and ecological factors influencing seroprevalence Nine hundred and ninety-five bats including those captured during vampire monitoring belonging to 30 species were sampled and analysed to investigate the environmental and bioecological factors that could be related to variation in seroprevalence Table 1.
Temporal variations of serology in the Desmodus rotundus vampires In both caves, repeated visual estimations by two independent observers suggest that the size of the population ranges from 60 to individuals in cave 1 and from to individuals in cave 2.
Fig 4. Changes in the percentage of RABV seropositive vampire bats from November to May in the two caves and the number of animals captured and recaptured during the same period. Discussion In South America, numerous studies have investigated the circulation of RABV through molecular and serological surveys but only a few have focused on wild bat populations in the Amazonian forest region. High diversity of hosts The survey reported herein increases the diversity of bat species explored for RABV infection in Amazonia and it demonstrates that a large set of species exhibit antibodies, some of which have not been evidenced before [ 2 , 29 ] such as, Phylloderma stenops , Pteronotus rubiginosus and Sturnira tildae.
Factors influencing infection: Importance of habitat and community richness We observed considerable variations of the seroprevalence rates according to species. Temporal variation of seroprevalence in vampires: Enzootic vs.
The emergence risk: Importance of the conservation status of habitats and bat communities Emergence of viral diseases, including rabies, is classically linked to pressures and threats on natural habitats. Supporting Information. S1 Table. Study sites for bat sampling, French Guiana. S2 Table. References 1. Rabies update for Latin America and the Caribbean.
Emerg Infect Dis. Bat-Borne rabies in Latin America. Bat-transmitted human rabies outbreaks, Brazilian Amazon. Molecular epidemiology of rabies virus isolated from different sources during a bat-transmitted human outbreak occurring in Augusto Correa municipality, Brazilian Amazon.
Rabies transmitted by vampire bats to humans: an emerging zoonotic disease in Latin America? Rev Panam Salud Publica. Rabies re-examined. Lancet Infect Dis. Vampire bat rabies ecology, epidemiology and control. Host phylogeny constrains cross-species emergence and establishment of rabies virus in bats.
Human rabies and rabies in vampire and non vampire bat species, Southeastern Peru, Updated list of bat species positive for rabies in Brazil. Rev Soc Bras Med Trop. Serological investigation of rabies virus neutralizing antibodies in bats captured in the eastern Brazilian Amazon. View Article Google Scholar Phylodynamics of vampire bat-transmitted rabies in Argentina.
Mol Ecol. Virus Genes. Rabies virus in insectivorous bats: implications of the diversity of the nucleoprotein and glycoprotein genes for molecular epidemiology.
Molecular characterization of rabies virus isolated from nonhaematophagous bats in Brazil. Antigenic and genetic characterization of rabies virus isolates from Uruguay. Virus Res. Determination of the rate of rabies attack in bats. Bol Oficina Sanit Panam.
Mungrue K, Mahabir R. The rabies epidemic in Trinidad of to an evaluation with geographic information system. Wilderness Envir Med. Resolving the roles of immunity, pathogenesis, and immigration for rabies persistence in vampire bats.
Ecological and anthropogenic drivers of rabies exposure in vampire bats: implications for transmission and control. Proc R Soc B. Host and viral ecology determine bat rabies seasonality and maintenance. Rates of viral evolution are linked to host geography in bat rabies. PLOS Patho. Moreno J, Baer GM. Experimental rabies in the vampire bat.
Am J Trop Med Hyg. Salivary excretion of rabies virus in healthy vampire bats. Epidemiol Infect. Molecular epidemiological analysis of bat rabies viruses in Brazil. J Med Vet Sci. Molecular diversity of rabies viruses associated with bats in Mexico and other countries of the Americas. J Clin Microbiol. Constantine DG. Bat rabies and other lyssavirus infections.
Reston, VA: U. Geological Survey Circular ; Does alteration in biodiversity really affect disease outcome? Saudi J Biol Sci. Modelling multi-scale spatial variation in species richness from abundance data in a complex neotropical bat assemblage. Ecol Model. Evidence of rabies virus exposure among humans in the Peruvian Amazon.
Direccion General de Epidemiologia. Bol Epidemiol Lima. Desmodus rotundus and Artibeus spp. Braz J Infect Dis. Rabies risk: difficulties encountered during management of grouped cases of bat bites in 2 isolated villages in French Guiana. First human rabies case in French Guiana, epidemiological investigation and control. Guidelines of the American Society of Mammalogists for the use of wild mammals in research.
J Mammal. Rapid evaluation of threats to biodiversity: human footprint score and large vertebrate species responses in French Guiana. Biodiv Conserv. Broad-scale spatial pattern of forest landscapes types in the Guiana shield. Paget D. DNA barcoding in surveys of small mammal communities: a field study in Suriname. Mol Ecol Res. Les Chauves-souris de Guyane.
A reliable diagnosis of human rabies based on analysis of skin biopsy specimens. Clin Infect Dis. Multidisciplinary approach to epizootiology and pathogenesis of bat rabies viruses in the United States.
Zoonoses Public Health. The origin and phylogeography of dog rabies virus. J Gen Virol. Genomic Diversity and Evolution of the Lyssaviruses. Evolutionary history and dynamics of dog rabies virus in western and central Africa.
Tamura K. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol. Nylander JAA. MrModeltest v2. Program distributed by the author. Evolutionary Biology Centre, Uppsala University, MrBayes 3.
Syst Biol. Bourhy H, Sureau P. Serologic evidence of lyssavirus infection in bats, Cambodia. Bat Rabies in Guatemala. Seroprevalence dynamics of European bat lyssavirus type 1 in a multispecies bat colony. J Wildl Dis. Regular exposure to rabies virus and lack of symptomatic disease in Serengeti spotted hyenas. R Core Team. R: A language and environment for statistical computing.
Bat communities and deforestation in French Guiana. Can J Zool. Acta Chiropterologica. Genetic polymorphism in the rabies virus nucleoprotein gene. Estrutura e analise zoogeografica de uma taxocenose de morcegos no norte do Estado do Amazonas, Brasil.
Chiroptera Neotropical. Rabies virus and antibody in bats in Grenada and Trinidad. Determination and Molecular analysis of the complete genome sequence of two wild-type rabies viruses isolated from a haematophagous bat and a frugivorous bat in Brazil.
J Vet Med Sci. Prevalence of rabies and LPM paramyxovirus antibody in non-hematophagous bats captured in the Central Pacific coast of Mexico. Delaval M, Charles-Dominique P. Edge effects on frugivorous and nectarivorous bat communities in a neotropical primary forest in French Guiana. Rev Ecol. Distinguishing paralytic rabies from GBS is a frequent clinical dilemma. In a study carried out at our center, fever at onset, paresthesias, muscular fasciculations, flaccid weakness confined to the bitten extremity, rapid deterioration with encephalon and autonomic involvement, cerebrospinal fluid CSF pleocytosis with demyelination, and axonal degeneration on electrophysiological studies were the cardinal features in cases of paralytic rabies, in contrast to conduction blocks in nerve conduction studies of GBS [ 84 ].
Variable lymphocytic infiltration, microglial nodules, and neuronophagia can be observed in the spinal cord in both GBS and paralytic rabies. The striking similarity in clinical, as well as pathological, changes between the paralytic form of rabies and GBS raised the possibility that the same immunopathogenetic mechanism implicated in GBS associated with Campylobacter jejuni , Mycoplasma pneumonia , cytomegalovirus, and Epstein—Barr virus could also be operative in paralytic rabies, with the development of autoantibodies to peripheral myelin due to molecular mimicry [ 86 ].
In fact, one of the initial historical cases of the acute motor sensory variant of GBS was found, on review, to be a case of paralytic rabies [ 87 ]. Participation of autoantibodies against peripheral nerve antigens in the evolution of paralysis is also suggested by vivid enhancement of ventral and dorsal nerve roots on magnetic resonance imaging, similar to GBS [ 77 , 88 ].
However, neither neutralizing antibodies nor antiganglioside nor myelin basic protein antibodies have been consistently demonstrated in CSF in paralytic rabies [ 78 , 81 , 89 ]. The biological basis for the characteristic aggressive behavior in the encephalitic form of rabies remains unclear. In an analysis of 42 autopsied cases of rabies at our center, 5 subjects had behavioral abnormalities, including aggression, and were admitted to psychiatric services with diagnoses of manic psychosis [ 90 ].
The aggressive behavior observed in natural hosts like human and canines has not been observed in experimental animals inoculated with a laboratory-attenuated fixed strain of the virus [ 91 ]. Madhusudana [ 92 ] reported a case of rabies presenting with hypersexuality, reflecting the probable involvement of amygdala, hypothalamus, and cingulate gyrus. The basic physiology of aggressive behavior in mammals correlates with finding of rabies viral antigen in raphe nuclei, red nucleus, and substantia nigra, implicating aberrant serotonin neural transmission [ 93 ].
The aggressive behavior in canines with furious rabies is a natural strategy for horizontal transmission of the virus and maintains survival of the virus in the canine population. Although the clinical symptomatology is dramatic, at autopsy, the findings that typify most viral encephalitis inflammation and neuronophagia are surprisingly minimal and the infected neurons do not show morphologic signs of degeneration Fig.
Several hypotheses have been proposed to explain this strange dichotomy. Fu et al. Others have demonstrated dysfunction of ion channels in infected cell culture [ 97 ], and defective cholinergic neurotransmission [ 98 ]. Induction of inducible nitric oxide synthase mRNA and increased levels of nitric oxide have been demonstrated in rodents inoculated with the virus [ 96 , 97 , 99 , ]. The role of these in natural rabies infection in humans is uncertain.
Neuropathological changes in rabies viral encephalitis. A Pyramidal neurons of cerebral cortex show multiple characteristic eosinophilic intracytoplasmic Negri bodies arrows. Note the well-preserved neuronal morphology of infected neurons without evidence of neuronal degeneration and prominent nucleoli.
B Microglial nodules surrounding a degenerating neuron arrow. Similar to other viral diseases, early reports suggested that apoptosis played an important role in causing cell death in animals inoculated with a laboratory-adapted CVS strain of rabies virus [ — ] Apoptosis was found only in suckling mice when intracerebrally inoculated with rabies virus CVS strain , and correlated with viral load and severity of clinical symptoms progressing to death, but apoptosis was absent in adult mice and in peripherally inoculated animals [ — ].
More neurovirulent strains produced less apoptosis and vice versa [ , ]. Ubol and Kassisith [ ] reported massive apoptosis in the brains of Swiss albino mice inoculated with the bat strain of rabies virus [ ]. However Yan et al. In human rabies, however, studies have conclusively shown that neuronal apoptosis is absent and has no role in natural infection with the wild-type viral strain of rabies [ , ].
On the contrary, using dUTP nick end labeling, we found that many of the inflammatory cells showed apoptotic cell death, which suggests that apoptosis in human rabies is protective rather than pathogenic, and serves as an efficient evasive mechanism of depleting host inflammatory cells, to ensure the survival and propagation of the virus in the infected neurons [ ].
In a recent study, transgenic mice expressing yellow fluorescent protein inoculated with fixed strain of rabies virus revealed prominent neuronal vacuolation of the cell soma, dendrites, and presynaptic endings in cerebral cortical and hippocampal neurons, suggesting mitochondrial damage and organelle failure [ ]. Kammouni et al. Early diagnosis of rabies is essential for initiation of specific therapy if an aggressive approach is considered and for the prevention of the exposure of healthcare workers to the virus.
The lack of sensitive tests for antemortem diagnosis has been a limiting factor but reflects the peculiar pathogenesis of the virus lacking a viremic phase and evading exposure to the systemic immune responses. This makes routine serological tests used for diagnosis of other viral infections of little use in rabies diagnosis. The test results are highly influenced by intermittent virus shedding, the timing of sample collection in relation to disease onset, the type of specimens collected, and, importantly, the type of rabies negative test results are especially seen in paralytic form of rabies, compounding the diagnostic dilemma.
Ensuring cold chain and refrigeration of fluids and tissue samples during storage and transport and rapid processing should be carried out to preserve RNA for tests employing RT-PCR assays. The study demonstrated higher sensitivity of detection from skin biopsies Table 1 summarizes the information available from studies of diagnostic tests and their sensitivity and specificity in diagnosis [ — ]. The Centers for Disease Control recommends that if no vaccine or rabies immune serum has been given, the presence of high-titre antibody to rabies virus in the serum is diagnostic and tests on CSF may not be necessary.
However, antibody to rabies virus in the CSF, regardless of the immunization history, suggests a rabies virus infection [ ]. Laboratory tests for antibody include indirect immunofluorescence and virus neutralization. Rabies viral antibodies usually appear after 7 days of the illness and may be a good diagnostic marker in patients with paralytic rabies, who usually survive longer.
Antibodies appear in the CSF later in the disease course [ , ]. Skin biopsy samples should be taken from the nuchal area containing hair follicles with peripheral nerves. The recommended sampling area is the upper portion of the nape of the neck, an easily accessible area with a high density of hair. Viral nucleocapsids are located in the nerve endings around the hair follicles. Testing methods available include fluorescent antibody testing FAT on frozen sections but is the least sensitive.
Laboratory tests of secretions and biological fluids such as saliva, spinal fluid, tears, and tissues may be used to diagnose rabies. A positive result is indicative of rabies, but a negative result does not rule out the possibility of infection [ ].
The highest virus yield was noted with specimens collected within 3 days of onset and tested by RT-PCR for the N gene. Saliva samples had the highest rate of positivity, followed by CSF and urine samples. While the sensitivity of all specimens dropped after day 3, saliva remained the most reliable source for virus detection from days 4 to 9 and sensitivity of urine and CSF during days 4 to 6 was almost the same. Test results of saliva specimens, CSF, and urine obtained during days 10 to 12 were all negative [ ].
The timing of saliva sample collection greatly influences the yield of molecular diagnosis. Virus detection is highest during the first 2 to 3 days after the onset of symptoms and remains stable from day 2 to day 7, or even later [ , ].
Intermittent shedding of the virus in saliva influences the diagnostic yield. The difference in sensitivities between saliva swab samples Brain biopsy is the gold standard for diagnosis, but is not recommended for antemortem diagnosis, as its impractical [ ].
The site and timing of biopsy is important, as false-negative results may occur when biopsy of the frontal and temporal regions is carried out on the first day of the disease when antigen localization will be mostly in brain stem and cerebellum. The use of molecular diagnostic tests, RT-PCR and nucleic acid sequence-based amplification techniques in antemortem human rabies diagnosis, has helped overcome the low sensitivity of viral antigen detection methods.
They have the highest level of sensitivity but can produce false-positive or false-negative results and therefore must be interpreted with caution.
Molecular genetic studies have assisted in epidemiological studies by genotyping the lyssavirus and is of importance in vaccine development. The development of several improved diagnostic assays for rabies viral antigen [and antibody detection sandwich enzyme-linked immunosorbent assay and highly sensitive assays for viral nucleic acid detection RT-PCR and real-time PCR] on clinical samples has revolutionized rabies diagnosis.
The available techniques for human rabies diagnosis have been reviewed in a recent publication [ ]. In a study from our center, Mani et al. As an inverse correlation has been reported between the presence of viral RNA and detection of rabies virus neutralizing antibodies in CSF, whenever feasible, a combination of these methods should be used.
Detection of viral RNA by PCR-based techniques on multiple clinical samples such as saliva, nuchal skin biopsy, and CSF, and serial sampling for both antibody and viral RNA detection is recommended to enhance the sensitivity of antemortem diagnosis [ , ].
Antibody testing is also an effective way to monitor the immune response within the CNS and predict a possible clearance of the rabies virus in patients initiated on any experimental therapy [ ]. Despite significant advances in antemortem diagnostic techniques, a negative result using multiple tests on several clinical samples obtained antemortem cannot categorically exclude a diagnosis of rabies.
Detection of rabies antigen in brain tissue obtained postmortem by the FAT technique remains the gold standard with which to establish unequivocally a diagnosis of rabies. Rabies tissue culture infection test and mouse inoculation test are confirmatory tests for direct fluorescence assay, but are time consuming and labor intensive. Brain biopsies is the preferred sampling for postmortem diagnosis in humans and animals.
A brain biopsy specimen can be obtained via the orbital, or transnasal route using Tru-Cut biopsy needles [ — ], or via the occipital route through foramen magnum with use of lumbar puncture needles [ ]. The transforamen magnum route will obtain samples from cerebellum and brain stem. Antigen detection by FAT is both a rapid and sensitive method with which to diagnose rabies infection in animals and humans and is currently the gold standard for rabies diagnosis.
However, FAT can provide false-negative results, owing to variability in antigen localization, as well as when bat specimens are tested. Virus isolation can be used for confirmation of FAT. Antigen detection can also be performed by immunohistochemistry or the newly developed direct and indirect rapid immunohistochemical test Centers for Disease Control, Atlanta, GA, USA [ ], but both tests require optimum preservation of morphology.
The sensitivity of detection is determined by distribution of antigen within brain regions, which is highly variable. Binghem et al. The cerebellum, hippocampus, and other parts of brain were negative in 4. The highest prevalence of antigen was seen in thalamus Quantitative proteomic analysis of human brain tissues obtained at autopsy from confirmed cases of encephalitic and paralytic rabies identified signature proteins differentially regulated using high-resolution mass spectrometry.
Certain proteins like Karyopherin alpha 4 and calcium calmodulin-dependent kinase 2 alpha were overexpressed only in paralytic rabies, and glutamate ammonia ligase was overexpressed in both paralytic and encephalitic rabies. Metabolomic study of CSF from humans treated for rabies with proton nuclear magnetic resonance 1 HNMR spectroscopy identified metabolites that differentiated rabies survivors from those who subsequently died [ ].
Further studies may provide new insights into the diagnostic and prognostic significance of these tests and mechanisms of rabies pathogenesis that may open up newer therapeutic avenues. The aim of treatment is to prevent the development of rabies.
The most critical steps include thorough wound cleaning and the use of postexposure prophylaxis with hyperimmune serum and active immunization, based on the category of bite [ ]. The main aim of postexposure prophylaxis is to neutralize the inoculated virus before it gains entry into the nervous system. The window of opportunity available is only up to 2 h following the bite. Postexposure prophylaxis includes wound care, passive immunization with immunoglobulin, and active vaccination.
Wound care is the most critical step in the prevention of infection. In experimental animals, it has been demonstrated that wound cleaning within the first 3 h of exposure to rabies almost completely prevented transmission of the virus [ ]. The rabies virus is susceptible to killing by soap and drying.
Suturing of the wound must be avoided. The rationale of passive immunization is to provide rabies-specific antibodies that neutralize the virus locally and systemically within the first week, as response to active immunization takes 2 weeks to take effect.
This is especially important in those at severe risk of infection e. Technically, immunoglobulin should be given in all previously unvaccinated cases. HRIG is very expensive and not freely available in the developing countries that have the highest prevalence of rabies.
ERIG is available but caries risk of allergic reactions. Once the symptoms of rabies set in, however, death is inevitable.
The mainstay of treatment is intensive care support via induction of paralysis, sedation, and ventilation, and administration of narcotic analgesics, antiepileptic medications, and neuromuscular blockers to abrogate the neurological manifestations. Adequate care to prevent exposure of healthcare workers or family members to the virus using barrier nursing is essential; transmission of rabies virus from patients to healthcare workers has, to date, not been documented [ ].
In , Willoughby et al. She was treated with an intense antiexcitotoxic strategy while the native immune response matured. However, despite the initial optimism and a few more success stories, several attempts to replicate this have been unsuccessful, leading to skepticism and reservations regarding its scientific rationale for routine use [ — ].
Wherever excellent critical care resources are available, an aggressive management approach can be considered on a case-by-case basis. Young, healthy, and immunocompetent individuals; patients who have received rabies vaccination prior to onset of illness; those who develop rabies due to a bat variant; early appearance of rabies-neutralizing antibodies in CSF and serum; and mild neurological illness at the initiation of therapy are regarded as favorable circumstances in which to attempt aggressive therapy [ ].
In the early stage of the illness, when results of diagnostic tests for rabies may not yet be positive or unavailable, treatment initiation should not be delayed if there is strong clinical evidence in support of a diagnosis of rabies [ ]. Currently aggressive therapy combines the use of antiexcitatory ketamine and antiviral drugs ribavirin, amantadine, and intensive care, while immune response is enhanced by immunization active and passive immunization, monoclonal antibodies.
Intradermal active immunization with rabies vaccine at multiple sites is used to accelerate antibody response the intramuscular route takes at least 1 week to produce immunity. Monoclonal rabies viral antibodies intravenous and intrathecal route can cross the BBB and, in rat models, immunoglobulins have shown ability to inhibit cell-to-cell spread of virus within the CNS and restrict rabies virus RNA transcription.
Postexposure treatment of rats with a monoclonal antibodies successfully resulted in viral clearance from the CNS and protected animals against a lethal rabies virus infection [ ]. Ketamine is an anesthetic agent that is considered a potential therapeutic agent in the management of human rabies on account of its inhibitory effect on RNA transcription and N -methyl D-aspartate receptor antagonistic function that might limit viral spreading in tissue [ , ].
Amantadine and ribavirin have demonstrated antiviral activity [ ]. In vitro studies have demonstrated its efficacy [ ], but this has not been seen in in vivo studies, owing to its limited capacity to cross the BBB [ ]. Corticosteroids are not recommended for use as in mouse models as the use of corticosteroids increased the mortality rate and shortened the incubation period [ ]. Lack of inflammatory response, despite widespread antigen distribution in the brain, makes cerebral edema a rare complication in rabies.
Hence, corticosteroids are used only for treatment of adrenocortical insufficiency and are not recommended for rabies therapy. It is also believed that corticosteroids may close the BBB and thereby reduce the passage of therapeutic agents through it [ ].
Currently, there is no specific, effective treatment for human rabies. A combination of therapies, as mentioned above, has been used, but none has demonstrated significantly promising results in various clinical trials.
The first 12 reported cases have been reviewed in detail by De Souza and Madhusudana [ ], including 2 cases from India [ ]. Recently, 3 more cases of survival from human rabies have been reported from India [ — ]. All 12, except three, had received complete or partial postexposure prophylaxis prior to the onset of clinical symptoms. A hyperactive immune response with very high levels of antibodies in serum and CSF was documented in all the survivors including those who did not receive postexposure prophylaxis.
Two of the cases received rabies immunoglobulins, and the rabies virus was not isolated nor antigen demonstrated. One of the cases demonstrated classical signs of rabies. Only one case with complete neurologic recovery was documented [ ], while all others had partial recovery with disabling neurological complications. The robust immune response causing clearance of rabies virus from the periphery or infection by less virulent isotype has been debated.
Medical management has been shown to prolong survival for up to days [ , ]. Autopsy study of cases with prolonged survival of up to 14 days after intensive care with ventilation, IFN therapy, and ribavirin demonstrated widespread Negri bodies with minimal inflammation [ ].
Factors influencing prolonged survival is unclear. In vitro studies in experimental animals found survival correlated with low IL-6 levels [ ]. Inhibition of inducible nitric oxide synthase prolonged survival via its effect on viral replication and apoptotic cell death [ ].
To date, no human live attenuated or recombinant rabies vaccine has been licensed for use in humans. All human rabies vaccines in use are inactivated and do not elicit a cytotoxic T-cell response important for virus clearance [ ]. Several types of vaccines are in use, and are compared with human diploid cell rabies vaccine considered the gold standard for cell culture vaccines , and include Vero cell vaccine produced in monkey kidney cells and Rabipur vaccine chick cell line.
These have greater effectiveness and lower adverse reactions than the neural tissue-derived Semple vaccine. There is no contraindication for the vaccine and can be administered to pregnant women, children, and those on any medication. Neurological reactions associated with cell culture vaccine are extremely rare; documented in approximately 1 in , patients.
Only 6 cases prior to of neurological reactions such as weakness or paresthesias and permanent deficit of the deltoid muscle have been recorded. One patient developed a disease similar to multiple sclerosis. Pre-exposure vaccination is recommended to those who are at the risk of exposure to rabies such as dog-handlers, veterinarians, laboratory workers, children living in high-endemic countries playing with street dogs, and travelers to such countries for periods exceeding 1 month [ , ].
Three doses of tissue culture vaccine is administered in the deltoid on days 0, 3, and The estimated seroconversion rate is It is not deemed essential to check antibody levels except in those at high risk of infection e.
Booster doses at between 6 and 24 months is recommended for those at high risk, to prolong protection [ ]. Various scientifically approved regimens for postexposure prophylaxis are used worldwide. Protocol varies depending on previous vaccination status. In unvaccinated individuals, 5 doses are to be given on days 0, 3, 7, 14, and Previously vaccinated individuals, if re-exposed, should receive 2 booster doses on days 0 and 3, in the deltoid region.
Intramuscular administration of rabies vaccine is the gold standard recommended by the WHO. The subcutaneous route and intradermal routes have been explored. Subcutaneous routes have low seroconversion rates and a faster fall in antibody response [ ]. The intradermal use of rabies vaccines is considered by the WHO as an acceptable alternative regimen as it requires less vaccine to produce a comparable degree of rabies protection [ 82 , 86 ].
Intradermal administration has become standard practice in a number of countries worldwide. Vaccination by the intradermal route has become more popular as it requires a smaller volume of vaccine per dose, and is therefore cost-effective, and is as efficacious as the intramuscular route. This route is now accepted by WHO and has become standard practice in several countries [ , ]. The WHO recommends 8 or 4 sites for intradermal immunization [ ]. The intradermal route is contraindicated in the immunocompromised and those taking steroids or chloroquine.
As per the WHO recommendation, 2 doses of any modern vaccine is required on days 0 and 3 for people who are re-exposed to rabies and have taken a course of complete postexposure treatment with any of the modern cell culture vaccines any time in the past. There is no need for administration of rabies immunoglobulin [ ]. Despite the optimism generated by the few human rabies survivors, survival continues to be an exceptionally rare occurrence. Moreover, most survivors continue to suffer from disabling neurological sequelae.
The mechanisms operative for its exclusive neurotropism, successful immune evasion, and almost fatal outcome without causing evident morphological alterations remain to be elucidated. The greatest stumbling block has been that despite animal models being available, the findings seen in vitro with laboratory strains of the virus do not reflect in vivo findings with wild-type strain. Until the modus operandi of the elusive rabies virus is decoded, treatment of this fatal encephalomyelitis will remain a distant dream.
We acknowledge the technical help with the figures provided by Mr. Kanakalakshmi and Mrs. Manjula Madan for their secretarial assistance. We also acknowledge the fruitful discussions with and encouragement received from Professor Dr. Alan C.
Jackson [Department of Internal Medicine Neurology , University of Manitoba] during his recent visit to our institute. This study is dedicated to the memory of Professor S. Madhusudana, Professor of Neurovirology, and long-term collaborator who spent his entire professional life researching rabies and who sadly passed away on 3 December This review is dedicated to his memory and his enormous research contributions to rabies viral pathogenesis, development of diagnostic kits, clinical trials on intradermal vaccines with cell culture vaccines, development of plant-based vaccines for rabies, and monoclonal antibodies for rabies.
Disclosure forms provided by the authors are available with the online version of this article. Electronic supplementary material. National Center for Biotechnology Information , U. Journal List Neurotherapeutics v.
Published online Jun Anita Mahadevan , 1 M. Suja , 1 Reeta S. Mani , 2 and Susarala K. Shankar 1. Reeta S. Susarala K. Author information Copyright and License information Disclaimer. Anita Mahadevan, Email: moc. Corresponding author. This article has been cited by other articles in PMC. Abstract Rabies viral encephalitis, though one of the oldest recognized infectious disease of humans, remains an incurable, fatal encephalomyelitis, despite advances in understanding of its pathobiology.
Electronic supplementary material The online version of this article doi Introduction Rabies is one of the oldest and most dreaded of human diseases. Viral Transmission Rabies is an infection of domestic and wild animals that spreads to humans by 3 main modes: bites, mucous membranes exposure, and, less commonly, aerosol inhalation.
Rabies Viral Entry and Incubation The incubation period IP is highly variable, ranging from 6 days to as long as 6 years akin to a slow virus disease [ 25 , 26 ].
Open in a separate window. Clinical Features Clinically, the disease presents in 2 distinct forms—furious encephalitic or paralytic dumb rabies; two-thirds of patients develop the furious form [ 25 , 76 ]. Furious Rabies Furious rabies is characterized by periods of agitation and confusion alternating with period of lucidity, and signs of autonomic dysfunction like lacrimation, pupillary dilatation, hypersalivation, and excessive sweating. Paralytic Rabies Paresthesia and weakness mark the onset of the paralytic form in the bitten extremity, progressively involving all the limbs, and pharyngeal and respiratory muscles.
Bat Rabies Patients with bat-related rabies have nonclassical signs—neuropathic pain, radicular pain, sensory motor deficits, and, in the prodromal phase, choreiform movements of the bitten limb. Diagnosis Early diagnosis of rabies is essential for initiation of specific therapy if an aggressive approach is considered and for the prevention of the exposure of healthcare workers to the virus. Skin Biopsy Skin biopsy samples should be taken from the nuchal area containing hair follicles with peripheral nerves.
Body Fluids Laboratory tests of secretions and biological fluids such as saliva, spinal fluid, tears, and tissues may be used to diagnose rabies. Brain Biopsy Brain biopsy is the gold standard for diagnosis, but is not recommended for antemortem diagnosis, as its impractical [ ].
Treatment The aim of treatment is to prevent the development of rabies. Postexposure Prophylaxis The main aim of postexposure prophylaxis is to neutralize the inoculated virus before it gains entry into the nervous system. Local Wound Treatment Wound care is the most critical step in the prevention of infection. Passive Immunization The rationale of passive immunization is to provide rabies-specific antibodies that neutralize the virus locally and systemically within the first week, as response to active immunization takes 2 weeks to take effect.
Indications for Institution of Aggressive Therapy Wherever excellent critical care resources are available, an aggressive management approach can be considered on a case-by-case basis.
Pharmacological Bases for Aggressive Therapy Currently aggressive therapy combines the use of antiexcitatory ketamine and antiviral drugs ribavirin, amantadine, and intensive care, while immune response is enhanced by immunization active and passive immunization, monoclonal antibodies. Immunization Intradermal active immunization with rabies vaccine at multiple sites is used to accelerate antibody response the intramuscular route takes at least 1 week to produce immunity.
Prophylaxis Pre-exposure Prophylaxis To date, no human live attenuated or recombinant rabies vaccine has been licensed for use in humans. Post-Exposure Prophylaxis Various scientifically approved regimens for postexposure prophylaxis are used worldwide. Vaccination after Re-exposure As per the WHO recommendation, 2 doses of any modern vaccine is required on days 0 and 3 for people who are re-exposed to rabies and have taken a course of complete postexposure treatment with any of the modern cell culture vaccines any time in the past.
Conclusion Despite the optimism generated by the few human rabies survivors, survival continues to be an exceptionally rare occurrence. Electronic supplementary material Below is the link to the electronic supplementary material. ESM 1 1. Acknowledgments We acknowledge the technical help with the figures provided by Mr.
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