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Flashcards in viruses: polio, rabies, HSV Deck (101):


Poliomyelitis (myelitis = inflammation of spinal chord) is an acute systemic infectious disease.

In its rare, severe form, it affects CNS, destroying motor neurons in spinal cord, which results in a flaccid, ascending, asymmetrical paralysis.
Old name is infantile paralysis.


poliovirus etiology

An enterovirus -
Human Enterovirus C - Polio viruses
a non-enveloped, +sense RNA virus


poliovirus serotypes

3 serotypes designated as PV1, PV2, and PV3:

infection with one serotype results in lifelong immunity but they do not cross neutralize

An adequate vaccine must contain all three types (i.e., is trivalent).

serotype 1 causes nearly all cases (85%) of paralytic polio.

types 2 and 3 are more often isolated in vaccine-associated poliomyelitis.


poliovirus incidence/prevalence

Rare today in US due to vaccination

Polio was thought to be primarily a disease of developed/industrialized countries. Most cases occurred in slightly older, susceptible children and yong adults who manifested with more serious disease

paralytic polio is a significant concern in underdeveloped countries.


poliovirus transmission

Infection is acquired from an infected or diseased person:

primarily by the fecal-oral route via contaminated food and water.
The virus is present in stool 3-6 weeks.

less so by respiratory secretions/aerosol droplets and saliva (oral-oral transmission).

Highly communicable: Poliovirus is highly infectious, with seroconversion (attack rates?) rates in susceptible household contacts of children nearly 100% and of adults over 90%.


polio reservoir

Humans are the sole host (the virus only infects humans).

Transmission occurs most frequently by persons with inapparent infections. Communicable 7→10 days both before symptoms onset and after onset.

Humans and water are the reservoirs.


Populations affected by PV:



PV Seasonality/Temporal pattern

- Summer-fall/autumn (in temperate zone, i.e., Northern hemisphere), little seasonality occurs in the tropics


PV pathogenesis
incubation period??

After virus enters the ??, the virus infects cells and then spreads to draining lymph nodes along the ??, first in pharynx and later in the intestinal tract where infection can persist for weeks to months and the patient may manifest with signs and symptoms.

Incubation period is prolonged (5 → 35 days [average 7 → 14 days]).

This is a lytic virus.

mouth or nose
gastrointestinal tract


The poliovirus is shed in ?? for several weeks and in the ?? for several months.

A ?? will also occur.

oral secretions

Rarely, the viremia is high.

With the viremia, virus can infect and replicate in brown fat cells, enotheial cells and muscle cells for up to 4 months.


Rarely, the poliovirus enters the CNS by:

crossing the blood-brain barrier.

travels by neural routes (infects skeletal muscle, then travels up innervated nerves of skeletal muscles) and along the PNS via retrograde axoplasmic flow as per herpes, and/or rabies viruses to CNS.


“Once in the CNS, poliovirus spreads along certain nerve fiber pathways, preferentially replicating in and destroying ?? within the ??.

This leads to the development of ??, the various forms of which (spinal, bulbar, and bulbospinal) vary only with the amount of neuronal damage and inflammation that occurs, and the region of the CNS that is affected” -->Results in ??

motor neurons
spinal cord, brain stem, or motor cortex

paralytic poliomyelitis

lower motor neuronal damage (FLACCID PARALYSIS) with no sensory loss (Unlike GBS).


PV Clinical syndromes following infection

Inapparent/Asymptomatic infection is the most common (90→95%) result.

Disease accounts for remainder of infected persons


Inapparent/Asymptomatic PV infection

Person is either asymptomatic or no more than minor malaise lasting 1→2 days.

virus shed in feces can be detected, are able to transmit the virus to others.

seroconversion occurs.


PV Disease:
Most (4→8%) common disease form – Minor illness/gastroenteritis/abortive poliomyelitis:

malaise, fatigue, drowsiness,
muscle aches
sore throat/pharyngitis,
nausea and vomiting,
abdominal pain,
constipation, rarely diarrhea.

*Lasts 72 hours or less,
no paralysis


PV disease:
Aseptic meningitis without paralysis/non-paralytic (Abortive illness/Abortive polio (next most common): s/s of minor form and...

Pain in front part of neck
Back pain or backache
Muscle stiffness
Leg pain (calf muscles)
Muscle tenderness and spasm in any area of the body.
Pain or stiffness of the back, arms, legs, abdomen.

*Symptoms usually last 1 - 2 weeks, symptoms resolve, no permanent paralysis


PV disease:
Least (0.1 →2%) common form is paralytic poliomyelitis:

Initially s/s of aseptic meningitis without paralysis but now an acute onset, febrile, ascending, acute asymmetric flaccid paralysis occurs:

paralysis begins 1→ 10days after the early symptoms began.
progresses for two to three days
is usually complete by the time the fever breaks.

Severe muscle aches or spasms, muscle pain

Loss of superficial and deep reflexes (Diminished deep-tendon reflexes/areflexic leg weakness).
for some patients, paralysis is temporary, lasting weeks.

*Sensory involvement - Abnormal sensations (but not loss of sensation-Guillain-Barre) in an area; sensitivity to touch, paresthesia.


paralytic poliomyelitis electromyography/nerve conduction velocity studies demonstrate ??

axonal-type polyneuropathy affecting anterior horn cells or their axons vs. demyelination


3 forms of paralytic poliomyelitis – 3 Different types of paralysis may occur, depending on the nerves involved:

Spinal Bulbar polio Bulbospinal polio


Residual complications of paralytic polio often occur following ??

the initial recovery process.


Post-polio Syndrome:
Some (25% of) paralytic polio survivors from 1940s→1950s are experiencing:

unaccustomed fatigue,
new or recurrent muscle weakness and pain,
progressive muscle atrophy.

Peak incidence is 30 → 40 years following acute polio

Disease develops when patient's remaining motor units/motor neurons start to respond poorly due to their overuse throughout many years. Not due to activation of latent poliovirus


ddx of acute flaccid paralysis

ECHO, Coxsackie and Enterovirus 68→71,
polio/post polio vaccination.
tick paralysis.
dumb rabies.
myasthenia gravis.
intoxication due to poisons.


PV dx

The diagnosis is made by identifying poliovirus in clinical specimens (usually stool) obtained from an acutely ill patient.

Cx on appropriate cell lines followed by identification by neutralization tests or by *PCR*. (way it's usually done)

Poliovirus may also be identified by *direct amplification from stool specimens* followed by partial genomic sequencing to establish identity and possible source of the virus.

Shedding in fecal specimens can be intermittent, but usually poliovirus can be detected for up to 4 weeks after onset of illness.

During the first 3–10 days of the illness, poliovirus can also be detected from oropharyngeal specimens.

Poliovirus is rarely detected in the blood or cerebrospinal fluid.


PV tx



PV ppx

Inactivated (killed) polio vaccine (IPV) AKA Salk vaccine, AKA IPO
-->Enhanced potency vaccine (*e-IPV*)

Oral polio vaccine (OPV)




prepared by formalin inactivation of wt virus grown in primate tissue culture.

Primary series is at least 4 inoculations over a 1→ 2 years

Highly (> 90%) efficacy (seroconversion/immunity).



is more potent than original IPV

results in increased seroconversion rates

is the only IPV vaccine approved in US, i.e., IPV = e-IPV

4 doses e-IPV (IPOL) ONLY to eliminate any chance of vaccine-associated paralytic polio (no OPV or IPV used)


IPV Advantages:

Safe/no risk for unvaccinated persons, e.g., the immunocompromised


IPV limitations

Given parentally (i.e., injected) – more expensive than Oral polio vaccine (OPV) administration.

Does not generate high sIgA responses but rather a serum IgG response. This response is still efficacious since if a vaccinated person is exposed to WT virus, the WT virus must first disseminate in blood and lymphatics to reach the CNS and serum anti-polio-IgG helps clear virus from these sites.

Boosters are needed. In developing countries, a 4th booster may be required

Only protects those actually vaccinated. So religious/philosophical groups not participating in vaccine program can/do occasionally become infected in local outbreaks → the spread of wild-type (wt) virus



acute, fulminant, fatal, focal encephalitis and myelitis due to infection of brain and spinal column

This virus can infect nearly all mammals and is transmitted between them by infected secretions, usually saliva and is fatal to virtually all humans and nearly all mammals.

Human survivors are very rare.


Characteristics of rabies virus, a neurotrophic virus:

Rhabdoviridae group, a Lyssavirus: a (-) ssRNA, bullet–shaped virus (enveloped with helical symmetry)


RV: serotypes

Single serotype (one major surface antigen).

Each virus possess many copies of a single glycoprotein peplomer which is specific for the brain, alter one amino acid in the glycoprotein results in an attenuated strain.


Virus replicates in the ??, forming eosinophilic cytoplasmic inclusions consisting of viral nucleoprotein (??).


Negri bodies


Rabies: common or rare today?

very rare today because we control infections in cats and dogs.


RV transmission

Animal bites or scratches, contact with animal saliva or excretions.

Inhalation of aerosols, e.g., bat droppings.
Transplants (Corneal, others) is rare.


Rabies reservoir

The host range is very wide - All mammals are susceptible.

The natural reservoirs are:
domestic with *dogs* (WW) and cats

feral/sylvatic animals with:
*bats* (US)


Geographic distribution of rabies is ??:

In the US, rabies is ??


epizootic in feral/sylvatic animals


Rabies Age and Gender and Season:



Rabies Risk factors

Control of human rabies is contingent on control of dog and cat rabies:
Worldwide, infected dogs are the most important source of infection for humans (80→90% of all cases):
In areas of the world where rabies in poorly controlled, dog bites resulting in death due to rabies is common (@50,000 deaths/year world wide).

In the US: vaccination and control programs have eliminated the domestic dog and cat as a reservoir for rabies, thus human rabies in the US is rare ((


From 1980 → 1997 there have been ?? cases of rabies in the US and most (~ ½) of the cases involved ?? which are most common cause of rabies in US.

few (


Rabies strains are ??


human viral isolates can be indentified by monoclonal antibodies or genetic analysis, allowing health officials to indentify the animal (reservior) source.


Rabies pathogenesis:
Virus is injected/passes through the ?? and initially replicates in the adjacent ??

epidermis (at the bite or lick site) -saliva gets in wound and replicates locally (2-3 wks)

striated skeletal muscle.

need to stop it at the bite site! or will succumb


When the rabies virus titer is high enough, it enters the ??

peripheral nervous system (PNS) at unmyelinated sensory terminals and neuromuscular junctions (where it is sequestered from the immune system).


Rabies Virus travels slowly (mm per day) by ?? (like polio and herpes viruses) up the nerves to the CNS where it disseminates via transynaptic spread first to the ?? and then rapidly to ??

retrograde axoplasmic flow

spinal cord
the brain

The slow axoplasmic flow account, in part, for the long incubation period for person with a bite which occurred at a site far from the bite site


The rabies virus predominates in ??, but localizes in the ??, and also infects neurons in almost all brain areas

the Gray matter

limbic region (focal symptoms)
responsible for aggressive behavior, or docile switch


Rabies Virus then travels back down the autonomic nerves to the:

salivary glands (unlikely to infect, but will give post-exp ppx to contacts/HCW)
adrenal medulla,
bite site.


The patient is considered to be potentially infectious during the period from ?? until ??

2 weeks before onset of symptoms (when humans can begin to shed rabies virus in saliva and tears)-hard to dx!

his/her death!


The moment the virus enters sensory terminals and neuromuscular junctions, the pt. will eventually die, because the virus is sequestered from ??.

Explains importance of ?? - it can prevent an infected person from developing rabies!

rabies-specific Ab

post-exposure prophylaxis

The virus can spread throughout the body, but is never isolated from the blood.


Rabies Incubation period:

highly variable (2 → 16 weeks – can be years and varies with:

-number of bites
-total infectious dose of virus
-location of the wound with respect to the head.


Rabies Prodrome is nonspecific flu-like illness lasting 2→4 d and includes:

nausea and vomiting
loss of appetite- anorexia,
pain, itching, paresthesias at bite site, if one exists.


Rabies disease

usually 5 → 6 days and is always fatal.

Highly variable presentation: One person may present with paralytic symptoms, another may present with all stages from prodrome to paralytic, while another may lack one or more stages.


Paralytic/Dumb rabies form:

Less common (20%).
s/s are indistinguishable from viral encephalitis

The patient manifests with paralysis starting at extremities and then spreads to the trunk.

Paralysis leads to:

hypoventilation (inhibition of the pharyngeal and respiratory center of brain causes respiratory paralysis).

hypotension (cardiac failure).

eventually coma and death.


Neurological phase/Excitation-Furious Rabies form:

More common (80%):

Increased sensory sensitivity to external stimuli:

Encephalitic symptoms - CNS dysfunction:
loss of natural timidity/aggressive sexual behavior (focal signs)
confusion, delirium
hydrophobia and foaming at the mouth arise from excruciatingly painful, laryngeal spasms which occur when the patent tries to swallow so that excessive salivation is really failure to swallow persons own saliva.

Signs and symptoms → coma → death.


ddx rabies (focal encephalitis)

Dumb vs Furious rabies,
non-polio enteroviruse,


rabies dx:

CSF specimen – protein and glucose levels as per viral infection and mononuclear pleocytosis.

intracytoplasmic viral inclusion via direct fluorescent antibody (DFA)

Isolation of virus via mouse inoculation


Rabies dx: intracytoplasmic viral inclusion via direct fluorescent antibody (DFA)

corneal impression smears

skin biopsy from nape of neck

brain biopsy - the definitive test.
-A negative DFA test on animal brain specimen means virus is not in saliva, thus no post-exposure prophylaxis is needed.


Rabies dx: Isolation of virus via mouse inoculation

very sensitive and required by law in some states in cases of human exposure to a potentially rabid animal. Cerebral inoculation of mice with brain tissue from sacrificed, captured animal should result in encephalitis and death in 3→10d.


other rabies dx tests

Negri bodies – Rabies virus inclusion bodies.

Immunohistochemcial staining for viral antigens.


Rabies antibodies in the blood and CSF (Ab appear only very late in disease).


rabies tx

so called Milwaukee Protocol is not reproducible.


rabies: Pre-exposure management and prophylaxis

?? is mainstay of controlling human rabies.


pre-exposure prophylaxis for vets, spelunkers, lab workers, animal handlers, etc.


Purpose of Rabies pre-exp. ppx is to prime immune system for an anamnestic response when booster is administered; this anamnestic response:

eliminates the need for passive immunization.

reduces number of doses of rabies vaccine needed for postexposure treatment (3 doses i.m., 3 days apart).


Rabies Vaccination:

Pre AND Post-exposure prophylaxis protocol is:
3 doses i.m. in deltoid muscle in adult or anterolateral zone of thigh in children

People provided pre-exposure vaccination, were bitten by a rapid dog and then failed to receive appropriate post-exposure prophylaxis died.


Rabies vaccination is NEVER done ??

as a gluteal injections → neuropathy, lower antirabies antibody titers,
true for both Pre- and Post-exposure vaccination.


Post-exposure management: It is efficacious (it works), if done how so ??

in time!! but you have time “But treatment is an urgency, NOT an emergency”

knowledge of the animals in which rabies is endemic and the geographic distribution/range of the viral infection in each animal is important for ppx


wound tx in Rabies

Immediate and through cleansing with soap and water

Tetanus prophylaxis must be done unless patient is protected by appropriate immunization.


More Post-exposure management:

Vaccination + antirabies serum. Must do both unless ??

pre-exposure prophylaxis is done

Human antirabies immune globulin (HRIG). Two HRIG (IgG) formulations prepared from hyperimmunized human donors are licensed and available for use in the United States:
HyperRab™ S/D (Talecris Biotherapeutics) and
Imogam® Rabies-HT (sanofi pasteur).


HRIG is given at the same time as the vaccine but at a different site:

Half of the dose i.m., in gluteal region.

Half of the dose should be injected in and around the wound site ("squirt" into wound) then suture


Rabies vaccine

Human diploid cell strain rabies vaccine (HDCV)

PCECV, RabAvert®, (Novartis Vaccines and Diagnostics)

2 other approved rabies vaccines but only HDCV and purified chick embryo cell vaccine (PCECV) available in the US today.


Rabies vaccines: HDCV, PCECV

All are killed (by chemical treatment) vaccines.

Administer vaccine:
i.m. in deltoid muscle in adult, anterolateral zone of thigh in young children.

on 5 days: 0, 3, 7, 14, 28→30.


Factors in decision to do post-exposure prophylaxis:

Observe biting animal for 10 d for symptoms, rabid animals (dogs) die in 4→5d.

IL Dept of Public Health - 217/785-1557.
CDC - 404/963-9211.



Causes @ 20% of all cases of viral encephalitis in US and *most common cause (@ 2,000 cases/y or ½) of all non-epidemic/sporadic, focal encephalitis*


HSV-1,2 peak incidence in who ??

Neonates - infection occurs during natural child birth with an infected mother.

Young adults and the elderly via a reactivation of latent infection.


HSV transmission

is via direct contact with secretions (containing virus):
vaginal secretions,

in utero infection occurs (rarely). (part of TORCH test)

More commonly, intrapartum contact of fetus with infected maternal genital secretions.
-There is much greater risk of neonatal infection if the pregnant mother has a *primary HSV infection* versus a recrudescent/recurrent infection.


HSV Spreads to CNS by:

hematogenous route

neural routes along the PNS via retrograde axoplasmic flow as per polio and rabies viruses.

lytic virus: causes syncytia and can lyse human cells


HSV disease progression age groups

In the neonate, the primary infection may progress to disease

In adult, CNS disease is due to reactivation of latent infection, recrudescence!


In the adult, herpes infection (usually HSV-1) in the brain is usually a ??

focal encephalopathy with distinctive clinical features due to its remarkable localization.


HSV cerebral localization

Usually one lobe - primarily the cerebral cortex with characteristic localization of lesions (inflammation, focal hemorrhage, necrosis) in inferior-orbito-frontal and medial temporal regions of brain (altered smell)

With temporal lobe involvement (areas of brain affected/infected) clinical manifestations are memory defects, psychosis, slurred speech, personality changes.

Fatality rate is high (70%). Many (>90% of) survivors show considerable disability.

Relapse is common (@25%) mostly due to HSV reactivation.


In the adult, primary genital herpes infections can result in a benign, aseptic meningitis during which:

transverse myelitis may also occur and result in:
urinary retention,
weakness of the lower extremities

ascending myelitis may also occur.


In the neonate, 3 possible presentations of HSV-2 or 1 infection, which occurs in a few (1:5,000 births) of all live births in the US: manifests with ??

Child manifests with S/Ss 9 →14 d post-birth:
(late onset, unlike GBS)

Localized herpes infection (SEM)

Disseminated disease

CNS disease


HSV: Localized herpes infection -

SEM; classic triad:

Skin (vesicular rash).
Eye (keratitis).
Mouth (papular→vesicular→ pustular → crusted rash).


HSV: Disseminated disease:

Systemic infection of many organs (liver, lungs, skin, eye, CNS).

The fatality rate is high (70%).


HSV: CNS disease:

A diffuse or focal encephalitis + systemic infection involving many organs.

Fatality rate is high (50%).

Most survivors have significant neurological sequelae.


other manifestations HSV:
Aseptic (Mollaret’s) meningitis (most often caused by ??)


in young adults and elderly via a reactivation of latent infection – A recurrent/recurring meningitis.


other manifestations HSV: Acute peripheral facial palsy (APFP) and idiopathic peripheral facial palsy (Bell’s palsy)

Major etiologic agents are HSV or varicella-zoster virus (VZV).

also B. burgdorfi?


HSV dx is important to differentiate

About 4,000 cases of focal encephalitis in the US/year. Physician must differentiate between herpes (@ 1/2 of all cases) and non-herpes viral agents of focal encephalitis (remainder of cases).

HSV encephalitis is treatable with antiviral agents, other causes focal encephalitis are NOT


HSV ddx

Other viral agents of focal encephalitis include any viral agent of diffuse encephalitis:


Some bacterial agents of CNS abscess or encephalitis can also cause a focal encephalitis.

Intracerebral hemorrhage.
Temporal lobe epilepsy.


HSV dx

Patient’s clinical presentation (focal symptoms).

CSF specimen


HSV CSF specimen:

Protein and glucose levels as per viral infection and mononuclear pleocytosis.

large numbers of RBCs are present – *HSV causes a vasculitis → RBC in CSF!*

*PCR* on CSF specimen (is done) because there is a successful treatment regimen.

Detection of elevated CSF antibody index (serum-to-CSF antibodies to HSV)


other lab dx tests for HSV


CT scan or MRI will show lesions localized to inferior-orbito-frontal and medial temporal regions of brain.

Viral culture is the gold standard but is usually not done

Histochemical staining or immunohistochemical staining/ immunofluorescence to detect viral antigen on specimen(s)


Histochemical staining or immunohistochemical staining/ immunofluorescence to detect HSV viral antigen on specimen(s) from:


Brain biopsy specimen (is no longer done).

Vesicular skin lesions

Tzanck or Papanicolaou smear of scrapping at base of skin lesion reveals:

ballooning cytoplasm.
syncytia formation (multinucleated giant cells).
intranuclear inclusions.


HSV tx

Antiviral agents(s), nucleoside analogs, not a cure! Inhibits HSV DNA Polymerase and acts as a chain terminator.

Acyclovir has selective toxicity because it is activated by HSV’ s thymidine kinase, so only HSV infected cells will be killed. (start early)

Others: vidarabine/adenosine arabinoside (AraA); idoxuridine (iododeoxyuridine), trifluridine, famciclovir, valacyclovir.

CNS or disseminated disease in neonates: High-dose Acyclovir (60mg/kg/d; IV in 3 divided doses).


Must initiate HSV treatment immediately after ??

obtaining sample, if test results are negative, stop treatment.
Only treatment can decrease both fatality rate and neurological sequelae (Mortality decreases to 19→ 38% with efficacious antiviral therapy).


Pregnant women with HSV, usually HSV-2 infection:

Clinical presentation in the pregnant woman is either:

asymptomatic infection(lesions are absent)

symptomatic (lesions are present), either.
primary infection
recurrent infection

Pregnant women will shed virus in vaginal tract if lesions are present but MAY also if the lesions are absent (women is asymptomatic).



A trivalent vaccine.

A live attenuated virus which replicates in oropharynx and intestinal tract but cannot infect neuronal cells, less transimisable than wt virus.

OPV has significant advantages over e-IPV.


OPV limitations

Puts other unvaccinated family members and contacts at risk, may spread to immunocompromised persons.

During viral replication in vaccinated children, the attenuated virus mutates back to the virulent/wt virus , but only causes extremely rare cases of vaccine-associated paralytic polio/poliomyelitis (VAPP) in the US (8→10 cases/year).
-Vaccine-derived poliovirus can actually circulate in the population, (cVDPV).


HSV Infection of child occurs:

intrapartum (most common).


HSV dx

1. Clinical exam.

2. Swab specimen tested by:
viral culture.

3. Serology for type-specific antibody tests not Full antigen assays

1 + 2 OR 3


HSV: ACOG recommendations for prophylaxis and cesarean section:

Treat with suppressive therapy only during the last 4 weeks of pregnancy.

Women experiencing recurrent outbreaks during pregnancy should only be treated if symptoms are extreme.

Treat with acyclovir, everyday; the dosages used during pregnancy are the same as for standard dosages.

Delivery strategies also vary according to when the infection was acquired:

Women who were seropositive prior to pregnancy are unlikely to pass on HSV because they transfer antibodies to the fetus in utero, and can give birth vaginally if there are no lesions present.

If there are lesions present at the onset of labor, or if primary infection was acquired during the last trimester, cesarean section is recommended.


Neonates with HSV manifests with ??

SEM, disseminated, or CNS disease.


OTHER AGENTS OF ENCEPHALITIS: diffuse besides arbovirus





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