Rabies Harrisons 20th

Question 1

Aetiology

Answer 1

Rhabdovirus family – Lyssavirus species Single stranded, RNA, antisense strand which codes for 5 proteins Variants are associated with specific animal vectors

Question 2

Epidemiology

Answer 2

Zoonotic Occurs in various mammals worldwide (except Antartica and some islands) Transmitted to humans by the bite of an infected animal

Question 3

Endemic canine rabies:

Answer 3

occurs in many resource-poor countries, especially in Africa and Asia; has been eliminated from the USA and most other resource-rich countries

Question 4

Endemic in wildlife species:

Answer 4

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)

Question 5

Transmission

Answer 5

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

Question 6

Pathogenesis

Answer 6

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

Question 7

Pathogenesis diagram

Question 8

Pathology

Answer 8

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

Question 9

Clinical Manifestations

Answer 9

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

Question 10

Clinical stages of rabies

Question 11

1. Prodromal phase – see above

Answer 11

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

Question 12

2. Encephalitic rabies(furious rabies; 80%)

Answer 12

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

Question 13

Lab investigations

Answer 13

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

Question 14

Diagnosis

Answer 14

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

Question 15

Antibodies

Answer 15

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

Question 16

PCR

Answer 16

RT-PCR Amplification

Highly sensitive and specific

Saliva, CSF, skin, brain

Question 17

RT-PCR Amplification

Highly sensitive and specific

Saliva, CSF, skin, brain

Answer 17

Highly specific and sensitive (rabies anti-bodies conjugated to fluorescent dyes)

Skin biopsies, brain tissue

Question 18

DDX

Answer 18

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

Question 19

Treatment

Answer 19

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

Question 20

Post exposure prophylaxis

Answer 20

Decision to give PEP is made on history of exposure and local epidemiology

Question 21

PEP

Answer 21

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

Question 22

Harrison’s approach to PEP

Question 23

PEP: local wound care, active and passive immunization

Answer 23

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

Question 24

EDL Hospital Guidelines

Question 25

Pre-exposure rabies vaccination

Answer 25

Occupational/recreational risk of exposure

Schedule: 0, 7, 21/28

Monitor serum antibodies to determine need for boosters;

Question 26

Global considerations

Answer 26

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