The L gene encodes a polymerase for RNA synthesis 11, The commonest way of rabies transmission is by the bite of an infected mammal Figure 1 2. Bites by rabid animals generally inoculate virus-laden saliva through the skin into muscle and subcutaneous tissues Other inoculation routes are rare. Rabies virus entry occurs through wounds or direct contact with mucosal surfaces. The virus cannot cross intact skin. Bat virus might be more infectious when inoculated superficially into the epidermis since it replicates more rapidly in non-neuronal cells and at lower temperatures than do dog rabies viruses.
Percutaneous infection probably occurs during unnoticed skin contact, which may result in a minute bite. The route of viral entry into epithelial nerves and eventually into the central nervous system CNS is unknown 23, Inhalation of aerosolized RV occurred accidentally in laboratories of vaccine production or in caves inhabited by numerous infected bats Infection through the digestive tract has also been reported 16, Contact with animal vaccines may be significant when attenuated vaccine is used.
In these situations, rabies prophylaxis is necessary. The handling and skinning of infected carcasses can be of risk for workers in refrigeration plants and butchers' shops, and veterinarians. The contact with infected people could be a potential risk for their relatives and health workers when unprotected direct contact with secretions from a patient containing viable virus occurs 30, There are many reports of organ transplantation involved in the transmission of rabies.
The most frequent cases have been observed in corneal transplantation The most recent case reported was of a German patient and occurred in 43, In , the Centers for Disease Control CDC in the United States confirmed the first case of rabies transmission through solid organ transplantation by testing autopsy samples after the death of 4 patients who received organ transplants two kidney receptors, one liver receptor, and one receptor of an arterial segment from the same donor.
Subsequently, it was learned that a bat had bitten the donor Three other cases of rabies-related organ transplantation were reported in Germany in Before transplantation, the donor if possible and his relatives and friends should be questioned as to any history of physical contact with bats or bites by them or other mammals anywhere in the world. Patients with such a history should not be accepted as donors, even if post-exposure prophylaxis was carried out.
There are no suitable screening tests to distinguish whether potential donors are infected. It has been recommended that donors, particularly those with neurological symptoms, should be screened for rabies So far, cases of rabies infection via blood transfusion have not been reported and rabies viraemia has not been demonstrated in animals or men. The virus seems to be strictly intra-neuronal during the incubation phase of the disease. There are no evidences that apparently healthy blood donors can transmit rabies, even if they incubate the infection.
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The one-year deferral of donation following post-exposure rabies prophylaxis remains a reasonable precaution In Brazil, the Sanitary Surveillance Center ANVISA has decided that the interval between rabies post-exposure treatment and blood donation should be one year and that for rabies pre-exposure vaccination, 4 weeks The RV migrates along peripheral nerves via the fast axonal transport system towards the CNS at about mm per day. This movement is strictly retrograde, which indicates infection is via sensory and motor nerves.
The incubation period or eclipse phase varies from 2 weeks to 6 years average: 2 to 3 months according to the amount of viral inoculum and the inoculation site. Bites on the head, face, neck and hands, particularly together with bleeding, offer the highest risk and are generally associated with a shorter incubation period.
The RV can stay in the muscle tissue for long periods and in certain circumstances, its long persistence may provide an opportunity for host immune clearance and post-exposure treatment 45, One of the most surprising aspects of rabies immunopathology is the almost complete lack of an inflammatory response within the CNS characterized by perivascular cuffing with mononuclear cells, local gliosis and neuronophagia.
Lesions occur in most areas of the CNS but are frequently more severe in the brainstem. This contrasts with other viral diseases of the CNS, in which inflammation is the major pathological characteristic.
Rabies review: immunopathology, clinical aspects and treatment
These observations suggest that neuronal dysfunction, rather than neuronal death, is probably responsible for the fatal outcome of rabies under normal conditions. Contrasting with the protective role of immunity, immune mechanisms even those generally thought to be protective often have pathological attributes depending on the extent of the infection when immune effectors come into play.
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This is the case of reactions occurring in the nervous tissue. The anti-RV immune response elicited after exposure to the virus can prevent rabies, indicating that the pathogenicity of a particular RV strain may depend on its capability to spread without inducing a protective immune response. The virus neurotropism is probably a key element in this process, as CNS tissues are naturally sequestered from the immune system. Other aspects of the RV nature clearly have a major impact on the virus capacity to induce a protective antiviral immune response, which has been extensively studied 48, 55, Viral glycoprotein is the target for most RV-neutralizing antibodies and has been a strong inducer of apoptosis in infected cells, which is evidently an immunogenic process in rabies 28, If an immune response to rabies develops either inappropriately or after the infection has spread sufficiently, an extensive immune-mediated damage of CNS tissues could be expected Researches using mice showed that when the infection route were the extremities such as the mouse footpad, peripheral nerve damage was more likely to occur leading to paralytic rabies with some prospects of survival; differently from lethal encephalitic rabies following intracerebral infection by the same strain The possibility that immunity contributes to the pathogenesis of rabies is also supported by what has been termed the "early death" phenomenon, in which inadequately immunized mice may die more rapidly of rabies than unvaccinated controls.
Insights into the contribution of the immune response to the accelerated death of RV-infected animals result from classic experiments in which immunocompromised mice survived RV infection for longer periods than normal animals. However, immunosuppression can increase the overall mortality. Clinical signs of rabies and death were accelerated in immunosupressed mice when immune serum was administered or the immune response to rabies re-appeared, suggesting that an antiviral antibody can contribute to rabies immunopathogenesis 78, Pathological aspects of the immune reactivity in the CNS are sufficient to explain the contribution of immune responses to rabies pathogenesis.
However, there is another potential contribution that has not been examined in great detail: elements of either the adaptive or the innate immune response may directly or indirectly stimulate the virus replication and dissemination. Evidences that cells of the immune system are infected 90 suggest that such cells might transport the virus from poorly to highly innervated areas such as the lymph nodes, facilitating the RV spread to the CNS.
This could explain how the RV can enter the nervous system when introduced via organ transplants, as has recently occurred Cells of the immune and central nervous systems may share similar functions: secretion of immunoregulatory cytokines, response to cytokines, and antigen presentation. These properties allow physical contact between the two systems, i. The induction and ultimate downregulation of the immune response and cytokine production within the CNS is dependent on: a dynamic interaction between a variety of peripheral immune and CNS cells; the activation status of these cells; the presence of cytokines with pleiotropic effects IFN- g , IL-1, IL-6, IFN- a , and others ; the concentration and location of these cytokines in the CNS; and the temporal sequence in which a particular cell responds to the cytokines 6.
The cause of functional alterations in RV-infected neurons is not clear yet.
Experimental studies have investigated possible abnormalities in the neurotransmission involving acetylcholine 25, 50, Defective neurotransmission involving neurotransmitters other than acetylcholine could be important in the pathogenesis of rabies, and both serotonin and gamma-aminobutyric acid GABA have been studied Neurotransmission essentially involves four steps, namely: synthesis, storage, release and interaction with postsynaptic receptors, and intracellular events Measurement of one, some, or all of the aspects of neurotransmission has been used as an indicator of neuronal activity Koprowski et al.
Neurotropic viruses may cause cell death through either apoptosis or necrosis. Apoptosis depends on the synthesis of macromolecules and requires energy whereas necrosis is associated with energy failure 29, Apoptosis is induced via both virus-dependent and cell-dependent mechanisms. In RV infection, complex mechanisms may be involved in the death or survival of neurons both in vitro and in vivo using different viral strains and inoculation routes. Both in vitro and in vivo observations demonstrated that apoptosis might be a protective rather than a pathogenic mechanism in RV infections because few pathogenic viruses induced more apoptosis than a higher number of pathogenic viruses both in vitro and in vivo using peripheral inoculation routes.
Thus, preservation of the neurons and limitation of such network by inhibiting apoptosis and limiting inflammation and destruction of T cells that invade the CNS in response to the infection is crucial for the RV neuroinvasion and transmission to another animal 3, Human rabies may manifest in encephalitic furious or paralytic dumb forms.
The brainstem is involved in both clinical forms, although there are no clinical signs of dysfunction in this portion of the brain. Differences in the tropism at the inoculation site or in the CNS, in the dissemination route, or in the triggering of the immune cascade in the brainstem may account for clinical variations Classical signs of brain involvement include spasms in response to tactile, auditory, visual or olfactory stimuli aerophobia and hydrophobia alternating with periods of lucidity, agitation, confusion and signs of autonomic dysfunction.
Spasms occur in almost all rabid patients in whom excitation is prominent. However, spontaneous inspiratory spasms usually occur continuously until death. Clinical features may be divided into 5 stages: incubation period, prodrome, acute neurological phase, coma, and death Table 1. Non-classical symptoms can be observed in patients with bat-related rabies and consist of neuropathic pain, radicular pain, objective sensory or motor deficits, and choreiform movements of the bitten limb during the prodromal phase.
Both focal brainstem signs and myoclonus are common. Localized signs like hemiparesis or hemisensory loss, ataxia, Hener's vertigo syndrome, convulsive and non-convulsive seizures, and hallucinations are frequent. Myoclonus and hemichorea, agitation at night and calm during the day, repeated spontaneous ejaculation, paraphasia, facial and bulbar weakness with preserved arm strength, or bilateral weakness may occur. Patients do not present phobic spasms or autonomic hyperactivity. During coma, inspiratory spasms increase; in the paralytic form, weakness is intense. Viral involvement at the sinus or atrioventricular node, myocarditis as well as changes in the cardiac rhythm and function may happen.
Coma precedes circulatory insufficiency, a prime cause of death. Renal dysfunction is secondary to dehydration Laboratory diagnosis of rabies in humans and animals is essential for timely post-exposure prophylaxis 45, Rabies diagnosis may be carried out either in vivo or postmortem Table 2 Antibodies appear in the cerebrospinal fluid later 47, Skin biopsy samples are usually taken from the nuchal area containing hair follicles with peripheral nerves.
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Examination of at least 20 sections is recommended to detect rabies nucleocapside inclusions around the hair follicles. Corneal imprint using fluorescent antibody technique can be carried out for detection of RV antigen.
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Results depend on the quality of the material sent to the laboratory. Brain biopsy is not practicable, nor is it recommended for the diagnosis of rabies, but it could be of high sensitivity False negative results may occur when biopsy of the frontal and temporal regions is carried out on the first day of the disease. 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 Such specimens can be used to detect the RV using intracranial inoculation into mice or neuroblast cell cultures, and to detect the virus RNA using reverse transcription polymerase chain reaction.
Serial samples should be tested since not all of them are positive due to the intermittent shedding of the virus 21, Molecular detection using polymerase chain reaction PCR and nucleic acid sequence-based amplification techniques shows the highest level of sensitivity but can produce false positive or false negative results and should only be used in combination with other conventional techniques. Virus identification using molecular techniques is of epidemiological importance.
Studies on molecular virology have permitted the classification of lyssavirus in genotypes and demonstrated the virus isolation from a particular geographic area 9, 91, Brain tissue specimens are the preferred sampling for postmortem diagnosis in both humans and animals. In cases where brain tissue is not viable, other tissues may be of diagnostic value; also, other routes such as transorbital or trans-foramen magnum should be used to obtain brain tissue.
To preserve tissues refrigeration, glycerin can be used. Dried smear of brain tissue can be kept on filter papers when safe transportation of the infected material is possible The amount of antigens has varied among different regions of the brain 7. The thalamus, pons and medulla can be considered the most reliable parts of the brain, as they were positive in all the specimens tested.
The cerebellum, hippocampus and other parts of brain were negative in 4. The thalamus was positive in all specimens and had the most frequent prevalence Antigen detection may be performed using the fluorescent antibody test FAT , a rapid and sensitive method to diagnose rabies infection in animals and humans.
This is the gold standard for rabies diagnosis. However, FAT can lead to a false negative result when bat or horse specimens are involved Virus isolation may be necessary to confirm the results of antigen detection tests and for further characterization of the isolate using intracranial inoculation into mice or neuroblast cells. Molecular detection using PCR and other amplification techniques are not currently recommended for routine postmortem diagnosis of rabies Efforts to prevent fatal outcome have failed, and no spontaneous recovery has been observed Rabies in humans progresses to death five to seven days after the onset of symptoms.
Medical management may prolong survival by days Treatment seems to be incapable of changing the evolution to death. Rabies experts have recommended that the approach to rabies encephalitis management be only palliative. The following characteristics and resources could be considered favorable for an aggressive therapy: administration of any rabies vaccine before the clinical onset of rabies; manifestation of the disease at a very early stage, with minimal neurological symptoms or signs; previously good health and absence of chronic diseases; relatives who accept both the high probability of an unsuccessful outcome and the possibility of neurological disability in a rabies survivor; and access to appropriate resources and facilities Therapy should combine antiexcitatory and antiviral drugs as well as intense care while natural native immune response combats the viral infection 52 ; rabies vaccine at multiple sites by intradermal route the intramuscular route takes at least one week to produce immunity and the intradermal route accelerates the immune response ; rabies immunoglobulin human or equine rabies immunoglobulin can lead to viral clearance ; monoclonal antibodies RV-neutralizing antibodies by intravenous and intrathecal route ; ribavirin and amantadine in vitro antiviral activity 87 ; interferon-alpha administered by intravenous and intrathecal route through the Ommaya reservoir ; ketamine an anesthetic agent that has anti-rabies activity by interacting with N-methyl-D-aspartate receptor antagonist 62, 77 ; benzodiazepines and barbiturates GABA-receptor agonists and induced therapeutic coma reduce the brain excitatory metabolism and autonomic reactivity.
Corticosteroids should not be used in mouse models, the use of corticosteroids increased the mortality rate and shortened the incubation period Severe edema associated with risk of brain herniation is rare in rabies patients, although this is a possible complication in intrathecal therapy using human rabies immunoglobulin.