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Transcript
Herpesviruses
Properties of herpesviruses
 Enveloped double stranded DNA viruses.
 Roughly spherical particles with icosahedral capsid symmetry.
 They are surrounded by a loose envelop which is composed of
material which in part originates from the host cells.
 Three subfamilies:
 Alphaherpesviruses - HSV-1, HSV-2, VZV
 Betaherpesviruses - CMV, HHV-6, HHV-7
 Gammaherpesviruses - EBV, HHV-8
 They have the ability to remain inactive (latent) in host cells often for
long periods. Reactivation of viruses can occur.
 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
 Note that all herpesviruses have identical morphology and cannot be
distinguished from each other under electron microscopy.
1- Herpes Simplex Viruses
Properties
 Belong to the alphaherpesvirus subfamily of herpesviruses
 Double stranded DNA enveloped virus
 Man is the only natural host for HSV.
Epidemiology
 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.
 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,
34
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 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
Laboratory Diagnosis
 Direct Detection
 Specimens: vesicles fluid, skin swab, saliva, conjunctival fluid,
congenital scrapings, brain biopsy.
 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
 Virus Isolation
35
 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
 ALISA + complement fixation: useful for diagnosing primary
infections, difficult to interpret in recurrent infections because
of high levels of existing Abs and because recurrences do not
usual cause a rise in titre.
2- Herpes virus simiae ( B virus of monkeys).
Infection occur by contact with infected monkeys, or by accidental
infection in laboratory when handling materials containing the virus.
Human Infection with H. simiae can cause sever and fetal encephalitis
3- Varicella- Zoster Virus
Properties
 Belong to the alphaherpesvirus subfamily of herpesviruses
 Double stranded DNA enveloped virus
 One antigenic serotype only, although there is some cross reaction
with HSV.
 VZV causes two separate diseases, chickenpox ( varicella) and
Shingles (herpes zoster).
 The virus infects human only.
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.
36
 Herpes zoster, in contrast, occurs sporadically and evenly throughout
the year.
Pathogenesis
 The virus is thought to enter 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 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 occur 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.
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
 Herpes zoster affecting the eye and face may pose great problems.
37
 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.
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
 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.
38
 If required, collect sample from pustule fluid, and examine by
electron microscopy or immunofluorescence.
 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.
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
 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.
4- Cytomegalovirus
Properties
 Belong to the betaherpesvirus subfamily of herpesviruses
 double stranded DNA enveloped virus
 the virus is so called because it causes enlargement of the
cell it infects.
 A large no. of proteins are encoded for, the precise
number is unknown.
Epidemiology
39
 CMV is one of the most successful human pathogens, it can be
transmitted vertically or horizontally usually with little effect on the
host.
 Disease caused by CMV can occur as congenital, neonatal or
childhood infection.
 Only very occasionally this virus can cause primary infection in adult.
Most adult infections are caused by reactivation of the virus which
was acquired early in life.
 An association exists between CMV and HIV.
 Transmission may occur in uterus, perinatally or postnatal. 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.
Prenatal 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
40
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. 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.
 Damage to the fetus results from destruction of target cells once they
are formed.
Cytomegalic Inclusion Disease
 CNS abnormalities - microcephaly, mental retardation, spasticity,
epilepsy.
 Eye - optic atrophy
 Ear - deafness
 Liver - hepatosplenomegaly and jaundice which is due to hepatitis.
 Lung - pneumonitis
 Heart - myocarditis
 Thrombocytopenic purpura, Haemolytic anaemia
Laboratory Diagnosis
 Direct detection
 biopsy specimens may be examined histologically for CMV
inclusion bodies 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.
41
 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.
Specimens for Laboratory Diagnosis
Site for virus culture
Urine Saliva Blood Tissue affected
Serology
IgG IgM
Neonates
+
+
-
-
-
+
Adults
+
-
+
-
+
+
Pregnant women
-
-
-
-
+
+
Immunocompromised
+
+
+
+
+
-
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.
Epstein-Barr Virus
 Belong to the gammaherpesvirus subfamily of herpesviruses
 Membrane is derived by budding of immature particles through cell
membrane and is required for infectivity.
Epidemiology
 Two epidemiological patterns are seen with EBV.
 This EBV is mainly a disease of older children and young adult
42
 The virus is transmitted by contact with saliva, in particularly through
kissing.
Pathogenesis
 EBV causes infectious mononucleosis (glandular fever).
 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 associated with several very different diseases where it may
act directly or one of several co-factors.
Disease Association
1. Burkitt's lymphoma
2. Nasopharyngeal carcinoma
3. Lymphoproliferative disease.
Infectious Mononucleosis
 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.
Diagnosis
 The laboratory diagnosis can be made by examining Rowanowsky
stain blood film for atypical mononuclear lymphocytes.
 Cases of Burkitt’s lymphoma should be diagnosed by histology.
43
 Testing serum for heterophil Abs using the Paul-Bunnell
haemoagglutination test, which is positive in about 90% of patients.
and/or detection of anti-EBV IgM.
 Cold agglutinin (anti-i) and occasionally rheumatoid factor may also
be found in serum of patients with infectious mononucleosis.
 Isolation: EBV can be isolated by usual tissue culture technique. The
irus can only be grown in culture of human lymphoblasts.
44