Herpesviruses
An Overview
Properties of herpesviruses

Enveloped double stranded DNA viruses.

Genome consisits of long and short fragments which may be orientated
in either direction, giving a total of 4 isomers.

Three subfamilies:

Alphaherpesviruses - HSV-1, HSV-2, VZV

Betaherpesviruses - CMV, HHV-6, HHV-7

Gammaherpesviruses - EBV, HHV-8

Set up latent or persistent infection following primary infection

Reactivation are more likely to take place during periods of
immunosuppression

Both primary infection and reactivation are likely to be more serious in
immunocompromised patients.
Herpesvirus Particle
HSV-2 virus particle. Note that all
herpesviruses
have
identical
morphology and cannot be
distinguished from each other
under electron microscopy.
(Linda Stannard, University of Cape Town, S.A.)
Herpes Simplex
Viruses
Properties

Belong to the alphaherpesvirus subfamily of herpesviruses

Double stranded DNA enveloped virus with a genome of
around 150 kb

The genome of HSV-1 and HSV-2 share 50 - 70%
homology.

They also share several cross-reactive epitopes with each
other. There is also antigenic cross-reaction with VZV.

Man is the only natural host for HSV.
Epidemiology (1)

HSV is spread by contact, as the virus is shed in saliva, tears,
genital and other secretions.

By far the most common form of infection results from a kiss given
to a child or adult from a person shedding the virus.

Primary infection is usually trivial or subclinical in most
individuals. It is a disease mainly of very young children ie. those
below 5 years.

There are 2 peaks of incidence, the first at 0 - 5 years and the
second in the late teens, when sexual activity commences.

About 10% of the population acquires HSV infection through the
genital route and the risk is concentrated in young adulthood.
Epidemiology (2)

Generally HSV-1 causes infection above the belt and HSV-2 below
the belt. In fact, 40% of clinical isolates from genital sores are
HSV-1, and 5% of strains isolated from the facial area are HSV-2.
This data is complicated by oral sexual practices.

Following primary infection, 45% of orally infected individuals
and 60% of patients with genital herpes will experience recurrences.

The actual frequency of recurrences varies widely between
individuals. The mean number of episodes per year is about 1.6.
Pathogenesis

During the primary infection, HSV spreads locally and a short-lived
viraemia occurs, whereby the virus is disseminated in the body. Spread to
the to craniospinal ganglia occurs.

The virus then establishes latency in the craniospinal ganglia.

The exact mechanism of latency is not known, it may be true latency
where there is no viral replication or viral persistence where there is a low
level of viral replication.

Reactivation - It is well known that many triggers can provoke a
recurrence. These include physical or psychological stress, infection;
especially pneumococcal and meningococcal, fever, irradiation; including
sunlight, and menstruation.
Clinical Manifestations
HSV is involved in a variety of clinical manifestations
which includes ;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
Oral-facial Herpes

Acute Gingivostomatitis




Acute gingivostomatitis is the commonest manifestation of primary herpetic
infection.
The patient experiences pain and bleeding of the gums. 1 - 8 mm ulcers with
necrotic bases are present. Neck glands are commonly enlarged accompanied
by fever.
Usually a self limiting disease which lasts around 13 days.
Herpes labialis (cold sore)



Following primary infection, 45% of orally infected individuals will experience
reactivation. The actual frequency of recurrences varies widely between
individuals.
Herpes labialis (cold sore) is a recurrence of oral HSV.
A prodrome of tingling, warmth or itching at the site usually heralds the
recurrence. About 12 hours later, redness appears followed by papules and then
vesicles.
Gingivostomatitis
Ocular Herpes
HSV causes a broad spectrum of ocular disease, ranging
from mild superficial lesions involving the external eye, to
severe sight-threatening diseases of the inner eye. Diseases
caused include the following:
Primary HSV keratitis – dendritic ulcers

Recurrent HSV keratitis

HSV conjunctivitis

Iridocyclitis, chorioretinitis and cataract
Genital Herpes





Genital lesions may be primary, recurrent or initial.
Many sites can be involved which includes the penis, vagina, cervix,
anus, vulva, bladder, the sacral nerve routes, the spinal and the
meninges. The lesions of genital herpes are particularly prone to
secondary bacterial infection eg. S.aureus, Streptococcus, Trichomonas
and Candida Albicans.
Dysuria is a common complaint, in severe cases, there may be urinary
retention.
Local sensory nerves may be involved leading to the development of a
radiculitis. A mild meningitis may be present.
60% of patients with genital herpes will experience recurrences.
Recurrent lesions in the perianal area tend to be more numerous and
persists longer than their oral HSV-1 counterparts.
Herpes Simplex Encephalitis




Herpes Simplex encephalitis is one of the most serious complications
of herpes simplex disease. There are two forms:
Neonatal – there is global involvement and the brain is almost
liquefied. The mortality rate approaches 100%.
Focal disease – the temporal lobe is most commonly affected. This
form of the disease appears in children and adults. It is possible that
many of these cases arise from reactivation of virus. The mortality rate
is high (70%) without treatment.
It is of utmost importance to make a diagnosis of HSE early. It is
general practice that IV acyclovir is given in all cases of suspected
HSE before laboratory results are available.
Neonatal Herpes Simplex (1)






Incidence of neonatal HSV infection varies inexplicably from country
to country e.g. from 1 in 4000 live births in the U.S. to 1 in 10000 live
births in the UK
The baby is usually infected perinatally during passage through the
birth canal.
Premature rupturing of the membranes is a well recognized risk factor.
The risk of perinatal transmission is greatest when there is a florid
primary infection in the mother.
There is an appreciably smaller risk from recurrent lesions in the
mother, probably because of the lower viral load and the presence of
specific antibody
The baby may also be infected from other sources such as oral lesions
from the mother or a herpetic whitlow in a nurse.
Neonatal Herpes Simplex (2)







The spectrum of neonatal HSV infection varies from a mild disease
localized to the skin to a fatal disseminated infection.
Infection is particularly dangerous in premature infants.
Where dissemination occurs, the organs most commonly involved are
the liver, adrenals and the brain.
Where the brain is involved, the prognosis is particularly severe. The
encephalitis is global and of such severity that the brain may be
liquefied.
A large proportion of survivors of neonatal HSV infection have
residual disabilities.
Acyclovir should be promptly given in all suspected cases of neonatal
HSV infection.
The only means of prevention is to offer caesarean section to mothers
with florid genital HSV lesions.
Other Manifestations

Disseminated herpes simplex are much more likely to occur in
immunocompromised individuals. The widespread vesicular
resembles that of chickenpox. Many organs other than the skin
may be involved e.g. liver, spleen, lungs, and CNS.

Other cutaneous manifestations include



eczema herpeticum which is potentially a serious disease that
occurs in patients with eczema.
Herpetic whitlow which arise from implantation of the virus into
the skin and typically affect the fingers.
“zosteriform herpes simplex". This is a rare presentation of herpes
simplex where HSV lesions appear in a dermatomal distribution
similar to herpes zoster.
Laboratory Diagnosis

Direct Detection




Virus Isolation


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 - now used routinely for the diagnosis of herpes simple
encephalitis
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.
Serology

Not that useful in the acute phase because it takes 1-2 weeks for before
antibodies appear after infection. Used to document to recent infection.
Cytopathic Effect of HSV in cell
culture: Note the ballooning of
cells. (Linda Stannard, University
of Cape Town, S.A.)
Positive immunofluorescence test for
HSV antigen in epithelial cell.
(Virology Laboratory, New-Yale Haven
Hospital)
Management
At present, there are only a few indications of antiviral chemotherapy, with the
high cost of antiviral drugs being a main consideration. Generally, antiviral
chemotherapy is indicated where the primary infection is especially severe, where
there is dissemination, where sight is threatened, and herpes simplex encephalitis.
Acyclovir – this the drug of choice for most situations at present. It is available in
a number of formulations:



I.V. (HSV infection in normal and immunocompromised patients)
Oral (treatment and long term suppression of mucocutaneous herpes and prophylaxis
of HSV in immunocompromised patients)
Cream (HSV infection of the skin and mucous membranes)
Ophthalmic ointment
Famciclovir and valacyclovir – oral only, more expensive than acyclovir.
Other older agents – e.g. idoxuridine, trifluorothymidine, Vidarabine (ara-A).

These agents are highly toxic and is suitable for topical use for opthalmic infection
only
Varicella- Zoster Virus
Properties

Belong to the
herpesviruses
alphaherpesvirus
subfamily
of

Double stranded DNA enveloped virus

Genome size 125 kbp, long and short fragments with a
total of 4 isometric forms.

One antigenic serotype only, although there is some cross
reaction with HSV.
Epidemiology

Primary varicella is an endemic disease. Varicella is one of the
classic diseases of childhood, with the highest prevalence
occurring in the 4 - 10 years old age group.

Varicella is highly communicable, with an attack rate of 90% in
close contacts.

Most people become infected before adulthood but 10% of
young adults remain susceptible.

Herpes zoster, in contrast, occurs sporadically and evenly
throughout the year.
Pathogenesis

The virus is thought to gain entry via the respiratory tract and
spreads shortly after to the lymphoid system.

After an incubation period of 14 days, the virus arrives at its
main target organ, the skin.

Following the primary infection, the virus remains latent in the
cerebral or posterior root ganglia. In 10 - 20% of individuals, a
single recurrent infection occurs after several decades.

The virus reactivates in the ganglion and tracks down the
sensory nerve to the area of the skin innervated by the nerve,
producing a varicellaform rash in the distribution of a
dermatome.
Varicella

Primary infection results in varicella (chickenpox)

Incubation period of 14-21 days

Presents fever, lymphadadenopathy. a widespread vesicular rash.

The features are so characteristic that a diagnosis can usually be made
on clinical grounds alone.

Complications are rare but occurs more frequently and with greater
severity in adults and immunocompromised patients.

Most common complication is secondary bacterial infection of the
vesicles.

Severe complications which may be life threatening include viral
pneumonia, encephalititis, and haemorrhagic chickenpox.
Rash of Chickenpox
Herpes Zoster (Shingles)


Herpes Zoster mainly affect a single dermatome of the skin.
It may occur at any age but the vast majority of patients are more than 50
years of age.

The latent virus reactivates in a sensory ganglion and tracks down the
sensory nerve to the appropriate segment.

There is a characteristic eruption of vesicles in the dermatome which is
often accompanied by intensive pain which may last for months
(postherpetic neuralgia)

Herpes zoster affecting the eye and face may pose great problems.
As with varicella, herpes zoster in a far greater problem in
immunocompromised patients in whom the reactivation occurs earlier in
life and multiple attacks occur as well as complications.


Complications are rare and include encephalitis and disseminated herpes
zoster.
Shingles
Congenital VZV Infection


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
Neonatal Varicella

VZV can cross the placenta in the late stages of pregnancy to
infect the fetus congenitally.

Neonatal varicella may vary from a mild disease to a fatal
disseminated infection.

If rash in mother occurs more than 1 week before delivery,
then sufficient immunity would have been transferred to the
fetus.

Zoster immunoglobulin should be given to susceptible pregnant
women who had contact with suspected cases of varicella.

Zoster immunoglobulin should also be given to infants whose
mothers develop varicella during the last 7 days of pregnancy
or the first 14 days after delivery.
Laboratory Diagnosis
The clinical presentations of varicella or zoster are so characteristic
that laboratory confirmation is rarely required. Laboratory
diagnosis is required only for atypical presentations, particularly in
the immunocompromised.



Virus Isolation - rarely carried out as it requires 2-3 weeks for a
results.
Direct detection - electron microscopy may be used for vesicle fluids
but cannot distinguish between HSV and VZV. Immunofluorescense
on skin scrappings can distinguish between the two.
Serology - the presence of VZV IgG is indicative of past infection
and immunity. The presence of IgM is indicative of recent primary
infection.
Cytopathic Effect of VZV
Cytopathic Effect of VZV in cell culture: Note the ballooning of cells. (Coutesy of
Linda Stannard, University of Cape Town, S.A.)
Management

Uncomplicated varicella is a self limited disease and requires no specific
treatment. However, acyclovir had been shown to accelerate the resolution of
the disease and is prescribed by some doctors.

Acyclovir should be given promptly immunocompromised individuals with
varicella infection and normal individuals with serious complications such as
pneumonia and encephalitis.

herpes zoster in a healthy individual is not normally a cause for concern. The
main problem is the management of the postherpetic neuralgia.

The International Herpes Management Forum recommends that antiviral
therapy should be offered routinely to all patients over 50 years of age
presenting with herpes zoster.

Three drugs can be used for the treatment of herpes zoster: acyclovir,
valicyclovir, and famciclovir. There appears to be little difference in efficacy
between them.
Prevention





Preventive measures should be considered for individuals at risk of
contracting severe varicella infection e.g. leukaemic children, neonates,
and pregnant women
Where urgent protection is needed, passive immunization should be
given. Zoster immunoglobulin (ZIG) is the preparation of choice but it
is very expensive. Where ZIG is not available, HNIG should be given
instead.
A live attenuated vaccine is available. There had been great reluctance
to use it in the past, especially in immunocompromised individuals
since the vaccine virus can become latent and reactivate later on.
However, recent data suggests that the vaccine is safe, even in children
with leukaemia provided that they are in remission.
It is highly debatable whether universal vaccination should be offered
since chickenpox and shingles are normally mild diseases.
Cytomegalovirus
Properties

Belong to the betaherpesvirus subfamily of herpesviruses

double stranded DNA enveloped virus

Nucleocapsid 105nm in diameter, 162 capsomers

The structure of the genome of CMV is similar to other
herpesviruses, consisting of long and short segments
which may be orientated in either direction, giving a total
of 4 isomers.

A large no. of proteins are encoded for, the precise
number is unknown.
Epidemiology




CMV is one of the most successful human pathogens, it can be
transmitted vertically or horizontally usually with little effect on the host.
Transmission may occur in utero, perinatally or postnatally. Once infected,
the person carries the virus for life which may be activated from time to
time, during which infectious virions appear in the urine and the saliva.
Reactivation can also lead to vertical transmission. It is also possible for
people who have experienced primary infection to be reinfected with
another or the same strain of CMV, this reinfection does not differ
clinically from reactivation.
In developed countries with a high standard of hygiene, 40% of
adolescents are infected and ultimately 70% of the population is infected.
In developing countries, over 90% of people are ultimately infected.
Pathogenesis

Once infected, the virus remains in the person for life and my be
reactivated from time to time, especially in immunocompromised
individuals.

The virus may be transmitted in utero, perinatally, or postnatally.
Perinatal transmission occurs.

Perinatal infection is acquired mainly through infected genital
secretions, or breast milk. Overall, 2 - 10% of infants are infected by
the age of 6 months worldwide. Perinatal infection is thought to be 10
times more common than congenital infection.

Postnatal infection mainly occurs through saliva. Sexual transmission
may occur as well as through blood and blood products and
transplanted organ.
Clinical Manifestations

Congenital infection - may result in cytomegalic inclusion disease

Perinatal infection - usually asymptomatic

Postnatal infection - usually asymptomatic. However, in a minority of
cases, the syndrome of infectious mononucleosis may develop which
consists of fever, lymphadenopathy, and splenomegaly. The heterophil
antibody test is negative although atypical lymphocytes may be found
in the blood.

Immunocompromised patients such as transplant recipients and AIDS
patients are prone to severe CMV disease such as pneumonitis, retinitis,
colitis, and encephalopathy.

Reactivation or reinfection with CMV is usually asymptomatic except
in immunocompromised patients.
Congenital Infection

Defined as the isolation of CMV from the saliva or urine within 3
weeks of birth.

Commonest congenital viral infection, affects 0.3 - 1% of all live
births. The second most common cause of mental handicap after
Down's syndrome and is responsible for more cases of congenital
damage than rubella.

Transmission to the fetus may occur following primary or recurrent
CMV infection. 40% chance of transmission to the fetus following a
primary infection.

May be transmitted to the fetus during all stages of pregnancy.

No evidence of teratogenecity, damage to the fetus results from
destruction of target cells once they are formed.
Cytomegalic Inclusion Disease

CNS abnormalities - microcephaly, mental retardation, spasticity,
epilepsy, periventricular calcification.

Eye - choroidoretinitis and optic atrophy

Ear - sensorineural deafness

Liver - hepatosplenomegaly and jaundice which is due to
hepatitis.

Lung - pneumonitis

Heart - myocarditis

Thrombocytopenic purpura, Haemolytic anaemia

Late sequelae in individuals asymptomatic at birth - hearing
defects and reduced intelligence.
Incidence of Cytomegalic Disease
U.S.A.
U.K.
No. of live births p.a.
3,000,000
700,000
Rate of congenital CMV
1%
0.3%
No. of infected infants
30,000
2100
Symptomatic at birth (5 - 10% )
1,500-3,000
105
Fatal disease (~ 20% )
300-600
22
No. with sequelae (90% of survivors)
1080-2160
83
Asymptomatic (90 - 95% )
27000
1995
No. with late sequelae
1350-4550
315
Laboratory Diagnosis (1)

Direct detection

biopsy specimens may be examined histologically for CMV
inclusion antibodies or for the presence of CMV antigens.
However, the sensitivity may be low.

The pp65 CMV antigenaemia test is now routinely used for
the
rapid
diagnosis
of
CMV
infection
in
immunocompromised patients.

PCR for CMV-DNA is used in some centers but there may
be problems with interpretation.
CMV pp65 antigenaemia test
(Virology Laboratory, New-Yale Haven Hospital)
Laboratory Diagnosis (2)


Virus Isolation

conventional cell culture is regarded as gold standard but
requires up to 4 weeks for result.

More useful are rapid culture methods such as the DEAFF
test which can provide a result in 24-48 hours.
Serology

the presence of CMV IgG antibody indicates past infection.

The detection of IgM is indicative of primary infection
although it may also be found in immunocompromised
patients with reactivation.
Cytopathic Effect of CMV
(Courtesy of Linda Stannard, University of Cape Town, S.A.)
DEAFF test for CMV
(Virology Laboratory, New-Yale Haven Hospital)
Specimens for Laboratory Diagnosis
Site for virus culture
Urine Saliva Blood Tissue affected
Serology
IgG IgM
Neonates
+
+
-
-
-
+
Adults
+
-
+
-
+
+
Pregnant women
-
-
-
-
+
+
Immunocompromised
+
+
+
+
+
-
Treatment

Congenital infections - it is not usually possible to detect
congenital infection unless the mother has symptoms of primary
infection. If so, then the mother should be told of the chances of
her baby having cytomegalic inclusion disease and perhaps
offered the choice of an abortion.

Perinatal and postnatal infection - it is usually not necessary to
treat such patients.

Immunocompromised patients - it is necessary to make a
diagnosis of CMV infection early and give prompt antiviral
therapy. Anti-CMV agents in current use are ganciclovir,
forscarnet, and cidofovir.
Prevention


No licensed vaccine is available. There is a candidate live attenuated
vaccine known as the Towne strain but there are concerns about
administering a live vaccine which could become latent and reactivates.
Prevention of CMV disease in transplant recipients is a very
complicated subject and varies from center to center. It may include
the following measures.
 Screening and matching the CMV status of the donor and recipient
 Use of CMV negative blood for transfusions
 Administration
of CMV immunoglobulin to seronegative
recipients prior to transplant
 Give
antiviral agents such as acyclovir and ganciclovir
prophylactically.
Epstein-Barr Virus
Epstein-Barr Virus (EBV)






Belong to the gammaherpesvirus subfamily of herpesviruses
Nucleocapsid 100 nm in diameter, with 162 capsomers
Membrane is derived by budding of immature particles
through cell membrane and is required for infectivity.
Genome is a linear double stranded DNA molecule with 172
kbp
The viral genome does not normally integrate into the
cellular DNA but forms circular episomes which reside in
the nucleus.
The genome is large enough to code for 100 - 200 proteins
but only a few have been identified.
Epidemiology




Two epidemiological patterns are seen with EBV.
In developed countries, 2 peaks of infection are seen : the
first in very young preschool children aged 1 - 6 and the
second in adolescents and young adults aged 14 - 20
Eventually 80-90% of adults are infected.
In developing countries, infection occurs at a much earlier
age so that by the age of two, 90% of children are
seropositive.
The virus is transmitted by contact with saliva, in
particularly through kissing.
Pathogenesis

Once infected, a lifelong carrier state develops whereby a low
grade infection is kept in check by the immune defenses.

Low grade virus replication and shedding can be demonstrated
in the epithelial cells of the pharynx of all seropositive
individuals.

EBV is able to immortalize B-lymphocytes in vitro and in vivo

Furthermore a few EBV-immortalized B-cells can be
demonstrated in the circulation which are continually cleared by
immune surveillance mechanisms.

EBV is associated with several very different diseases where it
may act directly or one of several co-factors.
Disease Association
1. Infectious Mononucleosis
2. Burkitt's lymphoma
3. Nasopharyngeal carcinoma
4. Lymphoproliferative disease and lymphoma in the
immunosuppressed.
5. X-linked lymphoproliferative syndrome
6. Chronic infectious mononucleosis
7. Oral leukoplakia in AIDS patients
8. Chronic interstitial pneumonitis in AIDS patients.
Infectious Mononuclosis






Primary EBV infection is usually subclinical in childhood. However in
adolescents and adults, there is a 50% chance that the syndrome of
infectious mononucleosis (IM) will develop.
IM is usually a self-limited disease which consists of fever,
lymphadenopathy and splenomegaly. In some patients jaundice may be
seen which is due to hepatitis. Atypical lymphocytes are present in the
blood.
Complications occur rarely but may be serious e.g. splenic rupture,
meningoencephalitis, and pharyngeal obstruction.
In some patients, chronic IM may occur where eventually the patient
dies of lymphoproliferative disease or lymphoma.
Diagnosis of IM is usually made by the heterophil antibody test and/or
detection of EBV IgM.
There is no specific treatment.
Burkitt’s Lymphoma (1)

Burkitt's lymphoma (BL) occurs endemically in parts of Africa
(where it is the commonest childhood tumour) and Papua New
Guinea. It usually occurs in children aged 3-14 years. It respond
favorably to chemotherapy.

It is restricted to areas with holoendemic malaria. Therefore it
appears that malaria infection is a cofactor.

Multiple copies of EBV genome and some EBV antigens can be
found in BL cells and patients with BL have high titres of
antibodies against various EBV antigens.
Burkitt’s Lymphoma (2)

BL cells show a reciprocal translocation between the long arm of
chromosome 8 and chromosomes 14, 2 or 22.

This translocation result in the c-myc oncogene being transferred to
the Immunoglobulin gene regions. This results in the deregulation of
the c-myc gene. It is thought that this translocation is probably
already present by the time of EBV infection and is not caused by
EBV.

Sporadic cases of BL occur, especially in AIDS patients which may
or may not be associated with EBV.

In theory BL can be controlled by the eradication of malaria (as has
happened in Papua New Guinea) or vaccination against EBV.
Nasopharyngeal Carcinoma






Nasopharyngeal carcinoma (NPC) is a malignant tumour of the
squamous epithelium of the nasopharynx. It is very prevalent in S.
China, where it is the commonest tumour in men and the second
commonest in women.
The tumour is rare in most parts of the world, though pockets occur in
N. and C. Africa, Malaysia, Alaska, and Iceland.
Multiple copies of EBV genome and EBV EBNA-1 antigen can be
found in cells of undifferentiated NPC. Patients with NPC have high
titres of antibodies against various EBV antigens.
Besides EBV there appears to be a number of environmental and
genetic cofactors in NPC.
NPC usually presents late and thus the prognosis is poor.
In theory NPC can be prevented by vaccination.
Immunocompromised Patients

After primary infection, EBV maintains a steady low grade latent
infection in the body. Should the person become immunocompromised,
the virus will reactivate. In a few cases, lymphoproliferative lesions and
lymphoma may develop. These lesions tend to be extranodal and in
unusual sites such as the GI tract or the CNS.

Transplant recipients e.g. renal - EBV is associated with the development
of lymphoproliferative disease and lymphoma.

AIDS patients - EBV is associated with oral leukoplakia and with
various Non-Hodgekin’s lymphoma.

Ducan X-linked lymphoproliferative syndrome - this condition occurs
exclusively in males who had inherited a defective gene in the Xchromosome . This condition accounts for half of the fatal cases of IM.
Diagnosis

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Acute EBV infection is usually made by the heterophil antibody
test and/or detection of anti-EBV VCA IgM.
Cases of Burkitt’s lymphoma should be diagnosed by histology.
The tumour can be stained with antibodies to lambda light chains
which should reveal a monoclonal tumour of B-cell origin. In over
90% of cases, the cells express IgM at the cell surface.
Cases of NPC should be diagnosed by histology.
The determination of the titre of anti-EBV VCA IgA in screening
for early lesions of NPC and also for monitoring treatment.
A patient with with non-specific ENT symptoms who have elevated
titres of EBV IgA should be given a thorough examination.
Vaccination

A vaccine against EBV which prevents primary EBV infection
should be able to control both BL and NPC.

Such a vaccine must be given early in life. Such a vaccine would
also be useful in seronegative organ transplant recipients and those
developing severe IM, such as the male offspring of X-linked
proliferative syndrome carriers.

The vaccine should not preferably be a subunit vaccine since there
is a danger that a live vaccine may still have tumorigenic properties.

The antigen chosen for vaccine development is the MA antigen gp
340/220 as antibodies against this antigen are virus neutralizing.

This vaccine is being tried in Africa.
Other Human Herpes
Viruses
Properties of HHV-6 and 7

Belong to the betaherpesvirus subfamily of herpesviruses

Double stranded DNA genome of 170 kbp

The main target cell is the T-lymphocyte, although Blymphocytes may also be infected.

HHV-6 and HHV-7 share limited nucleotide homology and
antigenic cross-reactivity.

It is thought that HHV-6 and HHV-7 are related to each other
in a similar manner to HSV-1 and HSV-2.
Epidemiology and Pathogenesis

HHV-6 and HHV-7 are ubiquitous and are found worldwide.

They are transmitted mainly through contact with saliva and
through breast feeding.

HHV-6 and HHV-7 infection are acquired rapidly after the age
of 4 months when the effect of maternal antibody wears off.

By the time of adulthood, 90-99% of the population had been
infected by both viruses.

Like other herpesviruses, HHV-6 and HHV-7 remains latent in
the body after primary infection and reactivates from time to
time.
Clinical Manifestations (1)




Primary HHV-6 infection is associated with Roseala
Infantum, which is a classical disease of childhood.
Most cases occur in infants between the ages of 4 months
and two years.
A spiking fever develops over a period of 2 days followed
by a mild rash. The fever is high enough to cause febrile
convulsions.
There are reports that the disease may be complicated by
encephalitis.
Clinical Manifestations (2)

If primary infection is delayed until adulthood, there is a small
chance that an infectious mononucleosis-like disease may
develop in a similar manner to EBV and CMV.

There is no firm evidence linking HHV-6 to lymphomas or
lymphoproliferative diseases.

There is no firm disease association with HHV-7 at present.

Although
both
viruses
may
be
reactivated
in
immunocompromised patients, it is yet uncertain whether they
cause significant disease since CMV is almost invariably present.
Roseala Infantum
Diagnosis and Management





Rosela Infantum has a very characteristic presentation and
a diagnosis can usually be made on clinical grounds alone.
Therefore very few virology laboratories offer a
diagnostic service for HHV-6 or HHV-7 infection.
The technique for virus isolation is complicated and thus
not practicable as a routine diagnostic procedure.
Therefore serology is the mainstay of diagnosis where
specific IgM and IgG are detected.
There is no specific antiviral treatment for HHV-6
infection.
Human Herpes Virus 8







Belong to the gammaherpesviruses subfamily of herpesviruses
Originally isolated from cells of Kaposi’s sarcoma (KS)
Now appears to be firmly associated with Kaposi’s sarcoma as well as
some lesser known malignancies such as Castleman’s disease and
primary effusion lymphomas
HHV-8 DNA is found in almost 100% of cases of Kaposi’s sarcoma
Most patients with KS have antibodies against HHV-8
The seroprevalence of HHV-8 is low among the general population but
is high in groups of individuals susceptible to KS, such as
homosexuals.
Unlike other herpesviruses, HHV-8 does not have a ubiquitous
distribution.
Kaposi’s Sarcoma