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Herpesviruses

Alphaherpesviruses

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Objectives

• Knowledge of the general properties of herpesviruses

• To know how each type is transmitted or acquired

• To know the clinical presentation and the pathogenesis


of each type

• To be familiar with the effective method of laboratory


diagnosis

• To know how to treat or prevent these infections

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Herpesviruses

• Are a leading cause of human viral diseases; second


only to influenza and cold viruses

• The name herpes comes from the Greek word


herpein which means to creep: creeping or
spreading nature of the skin lesions

• Can cause active disease or remain silent lifelong to


be reactivated

• Reactivation are more likely to take place during


periods of immunosuppression
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Chronic versus latency

• Chronic and latent infections are strategies that


some viruses used to avoid host immune responses

• In chronic infections the virus continues to replicate


at low level

• In latent infections viral genomes are maintained in


specific cell types without virus replications

4
Herpesviruses: subfamilies
1. Alphaherpesviruses
– Herpes simplex virus (HSV-1)
– Herpes simplex virus (HSV-2)
– Varicella zoster virus (VZV)
2. Betaherpesviruses
– Cytomegalovirus (CMV)
– Human herpes virus-6 (HHV-6)
– Human herpes virus-7 (HHV-7)
3. Gammaherpesviruses
– Epstein bar virus (EBV)
– Human herpes virus-8 (HHV-8)
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Herpesvirus Particle

• Enveloped, icosahedral, double


stranded DNA viruses.

•Genome consisits of long and short
fragments

•All herpesviruses have identical


morphology

•Cannot be distinguished under


electron microscopy

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Properties of Herpes Simplex Viruses
(HSV)

• Are very large viruses


• Types: HSV-1 & HSV-2
• The genome of HSV-1 and HSV-2
share 50 - 70% homology.
• Man is the only natural host for
HSV
• Grow in cell culture easily
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Epidemiology
• The virus is shed in saliva, tears, genital and
other secretions:
Spreads by:
– Kissing
– Sexual contact
– Use of utensils contaminated with saliva
– Mother to child during birth and postnatal
– Mother to fetus in utero
– 60-90% of adults have HSV-1

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Sites of HSV 1 & 2 Infection

10/15/08 Almost any human cell type can be infected by HSV 9


Pathogenesis
Primary infection
• Is usually subclinical in most individuals

• Disease mainly of very young children <5


years and young adults

• Generally HSV-1 causes infection above the


waist and HSV-2 below the waist
– 40% of genital sores are due to HSV-2
– 5% of facial herpes are due to HSV-2

• HSV spreads locally and a short-lived


viraemia occurs
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Pathogenesis
• Virus replicates in the lesion

• Travels retrograde along the neurons to the ganglion


– In orofacial herpes to the trigeminal ganglia
– In genital herpes to the sacral ganglia

• The virus can also travel in the opposite direction to arrive at


the mucosa that was initially infected

• Vesicles containing infectious virus are formed on the mucosa


and the virus spreads

• The vesicle heals and there is usually no scar as a result

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Pathogenesis

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Latency in ganglia

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Pathogenesis

• Reactivation occurs due to:


– Physical or psychological stress
– Infection
– Fever
– Irradiation including sunlight
– Menstruation (stressful conditions)
• 45% of orally infected individuals and 60% of
patients with genital herpes will experience
recurrences
• Recurrence occurs at same spot each time

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The Immune Response to HSV 1 and 2

 Interferon & NK cells limit the initial infection


The cellular response

• Cytotoxic T cells and macrophages kill infected cells


The humoral response
• Antibodies lead to neutralization
• The virus can spread from one cell to another without
entering the extracellular space and do not come in
contact with antibodies. So
• Cell-mediated response is vital in controlling
infection
• The cell mediated and inflammatory response lead to
some of the disease symptoms

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Clinical Manifestations

HSV clinical manifestations include;


1. Acute gingivostomatitis
2. Herpes Labialis (cold sore)
3. Ocular Herpes
4. Herpes Genitalis
5. Other forms of cutaneous herpes
7. Meningitis
8. Encephalitis
9. Neonatal herpes
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Oral-facial Herpes
Acute Gingivostomatitis
• The commonest manifestation
of primary herpetic infection
• Pain and bleeding of the gums
• Ulcers with necrotic bases
• Neck glands are commonly
enlarged
• Fever
• Usually a self limiting disease
which lasts around 13 days.

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Oral-facial Herpes

Herpes labialis (cold sore)


• Is a recurrence of oral HS in about
45% of individuals
• A prodrome of tingling, warmth or
itching at the site
• About 12 hours later, redness appears
followed by papules and then vesicles

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Ocular Herpes

A broad spectrum disease: from mild


superficial lesions of the external eye, to
severe sight-threatening diseases of the
inner eye.
– Primary HSV keratitis – dendritic ulcers
– Recurrent HSV keratitis
– HSV conjunctivitis
– Iridocyclitis, chorioretinitis and cataract

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Genital Herpes
• May be primary or recurrent
• Primary mostly asymptomatic
• Infection sites can be the penis, vagina, cervix, anus,
vulva, bladder, the sacral nerve routes, and the
meninges
• Redness on the external genitalia followed by itching
papules and then vesicles
• Dysuria is a common complaint, in severe cases, there
may be urinary retention.
• The lesions are prone to secondary infection eg.
S.aureus, Streptococcus, Trichomonas and Candida
Albicans
• 60% of patients with genital herpes experience
recurrences

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Herpes Simplex Encephalitis (HSE)
Is one of the most serious complications of herpes
simplex disease.
There are two forms:
Neonatal: there is global involvement of the brain
• The brain is almost liquefied
• The mortality rate approaches 100%
Focal disease – the temporal lobe is commonly
affected
• Appears in children and adults
• The mortality rate is high (70%) without
treatment
• IV acyclovir is given in all cases of suspected
HSE before laboratory results
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Neonatal Herpes Simplex
• Infection acquired:
– During birth or
– Oral lesions from mother
– A herpetic whitlow in a nurse
• May be a mild skin infection to a fatal disseminated
infection involving liver, adrenals and the brain
– A large proportion have residual
disabilities
Treatment:
• Acyclovir given promptly in all suspected cases
Prevention:
• Caesarean section to mothers with florid genital HSV
lesions
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Other Cutaneous Manifestations
Eczema Herpeticum
• A potentially serious disease
that occurs in patients with
eczema
Herpetic Whitlow
Herpetic Whitlow
• Arise from implantation of the
virus into the skin and typically
affect the fingers Herpetic Whitlow

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HSV in immunocompromised

• Mostly disseminated infection


• The widespread chickenpox-like lesions
• Many organs may be involved e.g. liver,
spleen, lungs, and CNS.

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Laboratory Diagnosis
• Direct Detection
– Electron microscopy of vesicle fluid - rapid
result but cannot distinguish between HSV
and VZV
– Immunofluorescence of skin scrappings -
can distinguish between HSV and VZV
– PCR of CSF in HSV encephalitis
• Virus Isolation
– HSV-1 and HSV-2 are among the easiest
viruses to cultivate. It usually takes only 1
- 5 days for a result to be available. (CPE)
• Serology
– Not that useful in the acute phase because
it takes 1-2 weeks for before antibodies
appear after infection.
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CPE eosinophilic intra nuclear inclusion bodies
(HSV)

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Treatment
Only a few indications of antiviral chemo­therapy:
– Severe primary infection
– Sight-threatening ocular herpes
– Herpes simplex encephalitis
Acyclovir
• I.V. (immunocompromised patients)
• Oral (mucocutaneous herpes and prophylaxis of
HSV in immunocompromised patients)
• Cream (infection of the skin and mucous
membranes)
• Ophthalmic ointment
Famciclovir and valacyclovir
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Properties of Varicella-Zoster
Virus (VZV or HHV 3)

•Chickenpox (Varicella), usually in childhood. Is a


primary infection

•Shingles (Zoster), later in life. Is a reactivation of


an earlier varicella infection

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Pathogenesis

Entry of virus via Reactivation


respiratory tract

Becomes latent in
Lymphoid system the cerebral or
posterior root ganglia

After 14 days
Viremia reaches the main
Target: the skin

Epithelium at
different sites
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Varicella
• Is a primary infection with incubation period of: 14-21 days
• Highest prevalence in the 4 - 10 years old age group
• The patient is considered infectious from approximately 48 h
before the onset of the rash until all the vesicles have crusted
over and there is no new visicle formation
• Presents fever, lymphadadenopathy. a widespread vesicular rash.
• Characteristic features: diagnosis can be made on clinical
grounds alone.
• Is highly communicable, with an attack rate of 90% in close
contacts.
Complications are rare:
• In immunocompromised patients secondary bacterial infection
of the vesicles may occur
• Severe complications include viral pneumonia, encephalititis, and
haemorrhagic chickenpox.

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Rashes of Chickenpox
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Varicella-Zoster In Pregnancy
• 90% of pregnant women already immune, therefore
primary infection is rare during pregnancy.

• Primary infection during pregnancy carries a greater


risk of severe disease, in particular pneumonia.

First 20 weeks of Pregnancy

• Up to 3% chance of transmission to the fetus,


recognised congenital varicella syndrome;
– Scarring of skin
– Hypoplasia of limbs
– CNS and eye defects
– Death in infancy normal
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Herpes Zoster (Shingles)

• Is a reactivation of an earlier varicella infection

• Mainly affects a single dermatome of the skin

• Any age but majority >50 years of age

• The latent virus reactivates in a sensory ganglion


and tracks down the sensory nerve to the
appropriate segment

• Characteristic vesicles often accompanied by


intensive pain which may last for months
(postherpetic neuralgia)

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Herpes Zoster (Shingles)

• Herpes zoster affecting the eye and face may


pose great problems

• A far greater problem in immunocompromised

• Complications are rare and include encephalitis


and disseminated herpes zoster.

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Laboratory Diagnosis
• Characteristic clinical presentations
• Laboratory confirmation is rarely required
• Only required in immunocompromise

– Direct detection - electron microscopy on vesicle


fluids but cannot distinguish between HSV and VZV.
– Immunofluorescense on skin scrapings can
distinguish between the two
– Virus Isolation - requires 2-3 weeks for a results
– Serology
• VZV IgG is indicative of past infection and
immunity
• VZV IgM indicates recent primary infection
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Management

Varicella
• Uncomplicated varicella is a self limiting disease
• Acyclovir given in:
– Immunocompromised individuals
– Serious complications
Herpes Zoster
• Acyclovir, valicyclovir, and famciclovir to all
patients over 50 years of age with herpes
zoster
• The main problem is postherpetic neuralgia
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Prevention

• Isolating an infected person from others until the disease is no


longer contagious is perhaps the most well-known preventative
measure
• For urgent protection passive immunization with Zoster
immunoglobulin (ZIG)
• A live attenuated vaccine is available (between 1-12 years)
• The vaccine is often given during the same visit as the measles
-mumps-rubella (MMR) vaccine.
– However, recent data suggests that the vaccine is safe,
even in children with leukaemia provided that they are in
remission.

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Case presentation

A 25-year-old woman presented with genital


ulceration. This was accompanied by malaise
and low grade fever. The patient complained
of considerable local discomfort with a
burning sensation of the external genitalia
which preceded the development of genital
ulceration. On questioning she gave no history
of previous episodes of genital ulceration. An
association inguinal lymphadenopathy was
noted on clinical examination
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Questions

• What is your clinical diagnosis?


• How is this disease transmitted?
• What complication may be associated with
this clinical condition?
• How would you confirm your clinical diagnosis
in the laboratory?
• What is your differential diagnosis?

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Case presentation
A 7-year-old child was taken to her general
practitioner with a rash that was mainly
centripetal in distribution, with lesions
being most prominent on the abdomen.
On examination the child had a
temperature of 37.50C. The skin rash
consisted of papules, vesicles and scabs

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Questions
• What is your clinical diagnosis?
• How would you confirm the clinical diagnosis in
the laboratory?
• What complication may occur?
• What group of children is likely to develop
severe diseases?
• For how long would the expect the child to be
infectious?
• What therapeutic options are available?

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