Rabies Harrisons 20th Flashcards
Aetiology
Rhabdovirus family – Lyssavirus species Single stranded, RNA, antisense strand which codes for 5 proteins Variants are associated with specific animal vectors
Epidemiology
Zoonotic Occurs in various mammals worldwide (except Antartica and some islands) Transmitted to humans by the bite of an infected animal
Endemic canine rabies:
occurs in many resource-poor countries, especially in Africa and Asia; has been eliminated from the USA and most other resource-rich countries
Endemic in wildlife species:
a variety of animal reservoirs present in different countries N America wildlife reservoirs = bats, raccoons, skunks, foxes – “spillover” to other wildlife species and to domestic animals occurs Rabies virus variants can be identified by reverse transciptase PCR (RT-PCR) or monoclonal antibodies (helpful in human cases with no known exposure)
Transmission
Worldwide most human rabies is transmitted from dogs, in countries with endemic canine rabies and dog-to-dog transmission; human cases can be imported from these regions In North America human disease is usually associated with bat – sometimes with no history of a bite Transmission from non-bite exposure is uncommon • aerosols in lab or caves have rarely caused human rabies • transmission via corneal transplant or solid organ transplant has occurred Human to human transmission extremely rare, though barrier techniques are used in case
Pathogenesis
Incubation: 20 – 90 days (rarely a few days or >1 year); virus is present at or close to inoculation site Spreads centripetally along peripheral nerves to CNS at 250mm/d via retrograde fast axonal transport to cord or brainstem (no documented haematogenous spread) In CNS it rapidly disseminates to other parts of CNS via fast axonal transport; neurons prominently infected, astrocytes rarely infected After CNS infection established, there is centrifugal spread along sensory and autonomic nerves to other tissues, including salivary glands, heart, adrenal glands and skin. Virus is shed in saliva
Pathogenesis diagram
Pathology
Pathology
Mild inflammatory changes in CNS with mononuclear infiltrate in leptomeninges, perivascular regions, and parenchyma
Pathological changes are surprisingly mild – Occasional neuronophagia observed; lack of prominent neurodegeneration indicates that neuronal dysfunction is responsible for clinical disease; basis for behavioural changes unclear, but may be realted to infections of serotonergic neurons
Negri bodies are most characteristic (but not always present) – eosinophilic cytoplasmic inclusions in brain neurons that are composed of rabies virus proteins and viral RNA
Clinical Manifestations
Presents as an atypical encephalitis with relative preservation of consciousness; difficult to recognize late in the course where coma has occurred. Phases x3: prodromal, acute neurologic, comatose.
Minority present with acute flaccid paralysis
Clinical stages of rabies
- Prodromal phase – see above
Parasthesia, pain, pruritis near site of exposure, one or more of which occurs in 50 – 80% of patients (strongly suggestive; suggests infection with associated inflammatory changes in dorsal root or cranial sensory ganglia
- Encephalitic rabies(furious rabies; 80%)
Fever, confusion, hallucinations, combativeness, seizures (look similar to other viral encephalitides)
Autonomic dysfunction – hypersalivation, gooseflesh, arrhythmias, priapism
Episodes of hyperactivity typically followed by periods of complete lucidity, which become shorter as disease progresses
Typical for rabies: early brainstem involvement with classic features of hydrophobia and aerophobia (involuntary and painful contraction of the diaphragm and accessory respiratory, laryngeal and pharyngeal muscles in response to swallowing liquids or a draft of air).Likely due to dysfunction of infected neurons that normally inhibit inspiratory neurons neat the nucleus ambiguous, resulting in exaggerated defense reflexes that protect the respiratory tract
Brainstem dysfunction, coma and death follow rapidly; unless prolonged by supportive measures in which case late complications can occur: cardiac/resp failure; SIADH or DI; noncardiogenic pulmonary oedema; GIT bleeding
Lab investigations
Most normal/non-specific
CSF: mild mononuclear pleocytosis, mildly elevated protein
CT brain: normal
MRI: may show signal abnormalities in brainstem or other grey-matter areas (variable, non-specific)
EEG: non-specific
Diagnosis
Consider in acute atypical encephalitis or acute flaccid paralysis; may lack animal bite or hydrophobia
Once suspected, rabies specific lab tests must be performed
Diagnostically useful samples: serum, CSF, saliva, skin biopsy from base of neck (demonstrates rabies virus antigen at base of hair follicle therefore this location chosen)
negative ante-mortem tests don’t exclude rabies; may need to be repeated
Antibodies
Serum antibodies diagnostic in previously unimmunized; but may not develop until late in disease course (because rabies infects immunologically privileged sites)
CSF antibodies diagnostic regardless of previous immunization state
Diagnosis of rabies questionable if someone survives but has not antibodies
PCR
RT-PCR Amplification
Highly sensitive and specific
Saliva, CSF, skin, brain
RT-PCR Amplification
Highly sensitive and specific
Saliva, CSF, skin, brain
Highly specific and sensitive (rabies anti-bodies conjugated to fluorescent dyes)
Skin biopsies, brain tissue
DDX
Rabies specific
Notes
Other viral encephalitides
Early neurologic symptoms at bite site; early brainstem involvement
Auto-immune encephalitis (eg antiNMDA encephalitis)
Behavioural changes, autonomic instability, hypoventilation, seizures
Post infectious encephalomyelitis (Immune-mediated)
Influenza, measles, mumps, other
Sequela of immunization with rabies vaccine derived from neural tissue (resource-limited setting)
Psychiatric disorder
“Rabies hysteria” (a somatic symptom disorder)
psychological response to the fear of rabies; charcterised by shorter incubation period, aggressive behavior, inability to communicate, long course of recovery
GBS
Fever, bladder dysfunction normal sensory examination, CSF pleocytosis
GBS may occur as a complication of rabies vaccination with a neural tissue-derived product
Treatment
No established treatment
Several recent failures of antiviral drugs, ketamine, induced coma – these were measures that had been used in one previous survivor who had had neutralizing antibodies present at presentation
Post exposure prophylaxis
Decision to give PEP is made on history of exposure and local epidemiology
PEP
Healthy dogs, cats and ferrets:
Confine and observe for 10 days; if symptoms develop, euthenase and test for rabies (brain)
Any other animal
Euthenase and test (brain)
High-risk exposure or endemic rabies area
Initiate prophylaxis without lab results; if lab results then negative, discontinue vaccination course
Harrison’s approach to PEP
PEP: local wound care, active and passive immunization
PEP: local wound care, active and passive immunization
Local wound: essential; wash with soap and water; tetanus; +/- debridement and antibiotics
EDL: antibiotics only if hand bitten, or extensive wounds or human bites (Augmentin)
IMMUNOGLOBULIN ie Passive immunization: all previously unvaccinated: with rabies immune globulin (RIG) (up to 7 days post exposure); entire dose at wound site if possible; never administer at same site or with same syringe as vaccine, and never administer to previously immunised; serious adverse events uncommon
EDL: all category 3, and category 2 for HIV+ children; give vaccine first; don’t exceed maximaun dose as antibody production from vaccine is inhibited
VACCINE ie Active immunization ie inactivated rabies vaccine; highly immunogenic, safe compared to older vaccines; IMI;
First dose asap after exposure, then at 3, 7 and 14 days
Pregnancy not a contra-indication; check titres at 2-4 weeks if immunocompromised person
Give booster if previously immunized person is exposed (not with RIG)
Local and mild systemic reactions common; systemic allergic reactions uncommon
EDL: administer even if late presentation with double dose if >48 hours; Immunocompromised may need day 28 dose; NEVER IN BUTTOCK
EDL Hospital Guidelines
Pre-exposure rabies vaccination
Occupational/recreational risk of exposure
Schedule: 0, 7, 21/28
Monitor serum antibodies to determine need for boosters;
Global considerations
55,000 deaths annually
Most in Africa/Asia
Other vaccine types: vaccine grown in primary cell lines (hamster/dog) or continuous cell lines (Vero cells) are satisfactory and available; less expensive type derived from neural tissue can cause post-infectious encephalomyelitis and GBS
>10 million people receives rabies PEP annually
If human RIG unavailable, equine RIG can be used (test for hypersensitivity prior ie intradermal injection with 1:10 dilution); less anaphylaxis seen with newer equine vaccines
