RabiesPresented by Abhinay Bhugoo

Ml-610

18.11.2011

1. Some facts about rabies2. Morphology and genome3. Important viral proteins4. History of the rabies virus5. Transmission6. Prevalence7. Pathophysiology8. clinics9. Diagnostic Techniques10. Prevention, including pre- and post-exposure

treatments

Presentation Outline

Belongs to the family Rhabdoviridae

Genus Lyssavirus (Greek root “lyssa”)

Rabies  is a viral disease that causes acute encephalitis in warm-blooded animals, including humans

It is zoonotic(i.e., transmitted by animals), most commonly by a bite from an infected animal.

The rabies virus infects the central nervous system, ultimately causing disease in the brain and death

Some Facts about Rabies

Morphology of rabies virus

Virology :

oBelongs to Genus – Lyssavirus in the family Rhabdoviridae

oThe rabies virus is a bullet-shaped virion with a single-stranded negative sense RNA genome and lipoprotein envelope.

oThe RNA genome encodes for 5 genes : nucleoprotein(N) , phosphoprotein(P) , matrix protein (M) , glycoprotein (G) and viral RNA polymerase.

oIts nucleocapsid material comprises the Negri bodies observed in the cytoplasm of infected neurons.

oRabies is a highly neurotropic virus that evades immune surveillance by its sequestration in the nervous system

Morphology of rabies virus

N-protein

• makes up most of the nucleocapsid

• catalyzes replication process

G-protein

• glycoprotein, come together to form the spikes of the viral envelope

• mediates fusion

• its presence triggers immune response of host

• determines pathogenic ability of the virus

L-protein

• Small part of nucleocapsid

• Codes for RNA polymerase

• Functions in polymerizing activity

P-protein

• Also makes up a small portion of the nucleocapsid

• Contributes to the ability of the L-protein to both bind and move down template strand during the attachment of nucleotides

Man described the disease in 2300 B.C. in the Eshnunna Code of Mesopotomia.

The origin “rabhas”, meaning “to do violence” comes from the language Sanskrit dating 3000 B.C.

Many cultures have incorporated myths and legends that can be connected to the rabies virus.

History of Rabies Virus

•Outbreak of rabies in Europe in 20th century spawned the Vampire myth- linked to bats.•Rabies epidemic in 13th

century France may have spurred Werewolf myth as well- linked to wolves. •Rabies is commonly spread by bats and wolves and other wildlife like foxes and coyotes.

History of the Rabies Virus

Since Roman times, man established the link between the infectivity of a rabid dogs saliva and the spread of the disease.

Because there is no cure for rabies, those that had been bitten by a rabid dog would commonly commit suicide to avoid the painful death that would inevitably follow.

History of the Rabies Virus

Louis Pasteur was the first person to diagnose that rabies targeted the CNS.

Also determined that nervous tissue of an infected human or animal also contained the virus.

In 1890 created the rabies vaccine and saved 9 year old Joseph Meister after he had been bitten by a rabid dog.

History of the Rabies Virus

Transmission

Vectors : Infected bats, monkeys , raccoons , foxes , skunks , cattle , wolves , coyotes , dogs or cats.

Other possible vectors : Domestic farm animals , groundhogs , weasels , bear.

The virus is usually present in the nerves and saliva of a symptomatic rabid animal.

Route of Infection : Bite of the rabid animal.

N.B. In Human transmission can through transplant surgery.

Can also enter via any mucous membrane, such as the eye, nose or mouth.

Handling and skinning of infected animal carcasses.

Few cases of human to human transmission.

Can be transmitted via aerosol, but that’s also uncommon.

Transmission of Rabies

Red Fox Silvertailed Bat

Striped SkunkRacoon

Racoons, Skunks, Foxes and Bats Are Major Rabies Reserviors

Significant Exposure

Inside the U.S., important reservoirs for the transmission of the disease are wild animals such as raccoons, skunks, foxes, bats, and coyotes.

The time it takes for rabies to affect the animal averages 1-3 months. Sometimes may only be a few days, and rarely longer than a year after exposure.

Transmission of Rabies

Prevalence :

oRabies is more prevalent in the developing world than in the developed world.

oThe WHO estimates that rabies is responsible for 35,000-50,000 deaths annually worldwide and that gross underreporting is likely.

oIf rabies treatment is not initiated before the onset of symptoms, death is imminent.

World wide: Dogs most commonly infected and cause more transmission to humans

Bats: An important source in North & South America and Mexico.

Epidemiology

Classic Picture of rabid, mangy dog foaming at the mouth…not often seen, signs frequently more subtle.

Animals can display aggressive behavior, ataxia, irritability, anorexia, lethargy or excessive salivation.

Animal behaviour

RUN!!!!!

The rabies infection and the symptoms that accompany it is classified by five stages:

1. Incubation (1-3 months)

2. Prodromal, where first symptoms occur

3. Acute neurological phase

4. Coma

5. Death or recovery

Pathophysiology :

Upon inoculation, it enters the peripheral nerves.

A prolonged incubation follows, the length of which depends on the size of the inoculum and its proximity to the CNS.

Amplification occurs until bare nucleocapsids spill into the myoneural junction and enter motor and sensory axons travelling along them at a rate of 12-24 mm/d to enter the spinal ganglion.

Its multiplication in the ganglion is heralded by the onset of pain or paresthesia at the site of the inoculum, which is the first clinical symptom and a hallmark finding.

From here, the rabies virus spreads quickly, at a rate of 200-400 mm/d, into the CNS, and spread is marked by rapidly progressive encephalitis.

Thereafter, the virus spreads to the periphery and salivary glands.

Clinical Findings :

Incubation Period :

The average duration of incubation is 20-90 days. Rarely, incubation lasts as long as 19 years.

The incubation period is less than 50 days if the patient is bitten on the head or neck or if a heavy inoculum is transferred through multiple bites, deep wounds, or large wounds.

The rabies virus is segregated from the immune system during this period, and no antibody response is observed.

Prodromal period

The virus enters the CNS. The duration of this period is 2-10 days.

Nonspecific symptoms and signs develop.

Paresthesia or pain at the inoculation site is pathognomonic for rabies and occurs in 50% of cases during this phase; this may be the individual’s only presenting sign.

Syndromes :Constitutional syndrome : Fever , headache , malaise , chills.GI syndrome : Diarrhea , nausea , emesisRespiratory syndrome : PharyngitisEncephalopathy syndrome : Insomnia , agitation , depression

, anxiety.

Physical Findings :Fever , agitation , emesis , diarrhea

Acute neurologic period

• This period is associated with objective signs of developing CNS disease. The duration is 2-7 days.

• Furious rabies may develop in this period.

Signs and Symptoms : Agitation, hyperactivity, restlessness, thrashing, biting,

confusion, or hallucinations.

After several hours to days, this becomes episodic and interspersed with calm, cooperative, lucid periods.

 Episodes may be triggered by visual, auditory, or tactile stimuli or may be spontaneous. Seizures may occur.

This phase may end in cardiorespiratory arrest or may progress to paralysis.

Furious rabies symptoms are as follows:

Patients present with episodic delirium, psychosis, restlessness, thrashing, muscular fasciculations, seizures, and aphasia

Hydrophobia and aerophobia are pathognomonic for rabies.Attempting to drink or having air blown in the face produces severe laryngeal or diaphragmatic spasms and a sensation of choking.

Autonomic instability is observed, including fever, tachycardia, hypertension, hyperventilation, drooling, anisocoria, mydriasis, lacrimation, salivation, perspiration, and postural hypotension.

Other neurologic signs include cranial nerve involvement with diplopia, facial palsy, and optic neuritis.

Paralytic rabies symptoms are as follows:

Fever and nuchal rigidity may occur.

Paralysis is symmetric and may be either generalized or ascending and may be mistaken for Guillain-Barré syndrome.

The sensory system is usually spared.

Calm clarity gradually progresses to delirium, stupor, and then coma.

Management

Post-exposure prophylaxis(PEP) is highly successful in preventing the disease if administered promptly, generally within ten days of infection.

Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is very effective at reducing the number of viral particles.

If available, a virucidal antiseptic such as povidone-iodine, aqueous iodine solution, or alcohol should be applied after washing.

Exposed mucous membranes such as eyes, nose or mouth should be flushed well with water.

Patients must receive one dose of human rabies immunoglobulin (HRIG). HRIG provides protection for 1-2 weeks until the vaccine elicits protective antibody. 

Coma

This begins within 10 days of onset; the duration varies.

Without intensive supportive care, respiratory depression, arrest, and death occur shortly after coma.

Physical findings :

Hypoventilation and metabolic acidosis

Wide variation in BP and cardiac arrhythmias .

Death or Recovery

Death results from encephalitis of the brain.

Heart failure along with major organ failure are the main causes of death.

Only four known cases of human recovery, and they were permanently brain damaged.

Labs :

•Detection of viral RNA from saliva using polymerase chain reaction (PCR) and viral antigen from brain biopsy specimens yield 100% specificity

•Saliva culture for rabies virus

•Serum rapid fluorescent focus inhibition test (RFFIT) titer results are positive in 50% of rabies cases.

•CSF examination will show monocystosis after 1st week of infection.

•Blood test : Increased Leucocytes level and atypical monocytes

• MRI and CT scanning findings of the brain often indicate that no abnormalities are present.

•Eosinophilic cytoplasmic inclusions (Negri bodies) are observed in 70% of rabies cases and are pathognomonic 

Hematoxylin and eosin stain of Negri body in a rabies-infected neuron.

Four doses of rabies vaccine over a fourteen day period.

  DO NOT administer immunoglobulin and vaccine

with the same syringe or in the same site.

If no prior rabies vaccination, unknown status, or over 5 years since last vaccination:

• Rabies vaccine IM (deltoid) 1 mL on days on days 0, 3, 7, and 14 (If immunocompromised, add an additional dose: 1 mL IM deltoid on days 0, 3, 7, 14, and 28)

• Rabies IG, 20 IU/kg infiltrated as much as feasible around and under the bite wound; if any left over, give IM (gluteus)

If prior rabies vaccination:Rabies vaccine IM (deltoid) 1 mL on days on days

0 and 3

•  Prophylaxis may be discontinued if the animal does not develop rabies within 10 days or is found to be free of rabies upon sacrifice.

• Pregnancy is not a contraindication to post exposure prophylaxis against rabies

• After the onset of rabies symptoms intensive cardiopulmonary supportive care is the only treatment available for patients.

• Regardless of treatment, symptomatic rabies is invariably fatal, resulting from autonomic dysfunction that leads to cardiac arrhythmia and hypotension

Vaccines types :

2 types

Cell cultured vaccine Nerve tissue vaccine

Suckling mouse brain vaccine(SMBV) Semple type (STV)

STV is obtained from inactivated virus prepared on adult animal nerve tissue. It is inexpensive and relatively easy to produce.

STV may produce neurological reactions, including postvaccination encephalomyelitis, in up to 1 in 220 courses.

• SMBV is cultured on immature mouse brain tissue, which contains little myelin.

• It is the most widely used rabies post exposure vaccine in Vietnam.

• Rare neurologic reactions occur, with complications in 1 in 27,000 treated people.

• Cell-cultured rabies vaccines benefit from efficacy demonstrated in trials and a high level of immunogenicity; this permits a rational dosing schedule.