MICROBIOLOGY PPT LECTURE NOTES | Karya Tulis Ilmiah
HERPESVIRUSES
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
Size: 180-200nm
Replication: Nuclear.
Assembly: Nuclear.
Envelope: Present; associated glycoproteins.
Tegument: Protein-filled region between capsid
and envelope.
Capsid: Icosahedral, 95-105nm diameter; 162
hexagonal capsomers.
Core: DNA around protein , ~75nm
Genome: Linear, d/s DNA, 105-235kbp
Common Antigens:None
Herpes viruses can replicate in human diploid
cells except of BBV
Produce cytopathic effect(CPE)
Intranuclear acidophilic inclusion bodies
Categories of herpes virus
正式命名
人类疱疹病毒 1
型（ HHV1）
人类疱疹病毒 2
型（ HHV2）
人类疱疹病毒 3
型（ HHV3）
人类疱疹病毒 4
型（ HHV4）
人类疱疹病毒 5
型（ HHV5）
人类疱疹病毒 6
型（ HHV6）
人类疱疹病毒 7
型（ HHV7）
人类疱疹病毒 8
型（ HHV8）
弥猴疱疹病毒 1
常用名
单纯疱疹病毒 1 型
（ HSV-1 ）
单纯疱疹病毒 2 型
（ HSV-2 ）
水痘 - 带状疱疹病
毒（ VZV ）
Epstein-Barr 病毒
（ EBV ）
病毒亚科
重要生物学性状
所致疾病
繁殖快、杀细胞性感染
感觉神经节中潜伏
同上
唇疱疹、龈口炎、角膜结膜炎
、脑炎等
同上
水痘、带状疱疹、脑炎
淋巴细胞中繁殖与潜伏
传染性单核细胞增多症、 Burki
tt 淋巴瘤、鼻咽癌（ ? ）等
常在淋巴细胞、肾脏及
分泌腺体中潜伏
生殖器疱疹、新生儿疱疹
人类巨细胞病毒
先天性巨细胞包涵体病、单核
细胞增多症、间质性肺炎、
先天性畸形、肝炎
婴儿急疹、间质性肺炎、骨髓
抑制
人类疱疹病毒 6 型
同人巨细胞病毒
人类疱疹病毒 7 型
同人巨细胞病毒
人类疱疹病毒 8 型
同 EB 病毒
Kaposi 肉瘤
猿猴 B 病毒
同 HSV
脊髓炎、出血性脑炎
未明确
1 Herpes Simplex
Viruses
Properties
Belong
to the
herpesviruses
ds
kb
alphaherpesvirus
subfamily
of
DNA enveloped virus with a genome of around 150
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.
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.
Pathogenesis
Clinical Manifestations
HSV is involved in a variety of clinical manifestations
which includes ;1. Acute gingivostomatitis 龈口炎
2. Herpes Labialis (cold sore) 唇疱疹
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.
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 虹膜睫状体炎 , chorioretinitis 脉络膜视网
膜炎 and cataract 白内障
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
– 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
– 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
2 Varicella- Zoster Virus
Properties
Belong to the alphaherpesvirus subfamily of
herpesviruses
ds 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.
Pathogenesis
shingles
Varicella
Primary infection results in varicella (chicken-pox)
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.
3 Cytomegalovirus
Properties
Belong to the betaherpesvirus subfamily of
herpesviruses
ds 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
Late
purpura, Haemolytic anaemia
sequelae in individuals asymptomatic at birth hearing defects and reduced intelligence.
Incidence of Cytomegalic
Disease
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
DEAFF test for CMV
Specimens for Laboratory Diagnosis
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
recipients prior to transplant
– Give
to
seronegative
antiviral agents such as acyclovir and ganciclovir
prophylactically.
4 Epstein-Barr Virus
Pathogenesis
Transformation of B cells
Burkitt's lymphoma
Nasopharyngeal cancer
Oral hairy leukoplakia
Infectious mononucleosis
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
vivo
able to immortalize B-lymphocytes in vitro and in
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(IM)
2. Burkitt's lymphoma( BL)
3. Nasopharyngeal carcinoma( NPC)
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.
Burkitt's Lymphoma
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.
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 X-chromosome . This condition accounts for half of the fatal
cases of IM.
Diagnosis
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.
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.
Roseala Infantum
Kaposi’s Sarcoma
Human herpes virus 6
Worldwide
In the saliva of the majority of adults (>90%).
It infects almost all children by the age of two and the infection
is life-long. Again, it replicates in B and T lymphocytes, megaka
ryocytes, etc
Latent infection in T cells . Infected cells are larger than norma
l with inclusions in both cytoplasm and nucleus.
Cell-mediated immunity is essential in control, although infecti
on is life-long, and the virus can reactivate in immune-suppres
sion.
Pathogenesis
Two forms: HHV-6A and HHV-6B.
The latter causes ex
anthem subitum, otherwise known as roseola infantum.
This a common disease of young children (in the US >4
5% of children are seropositive for HHV-6 by two years
of age) and symptoms include fever and sometimes upp
er respiratory tract infection and lymphadenopathy.
Incubation period : 14 days.
Pathogenesis
The fever subsides leaving a macropapular rash on the trunk
and neck that last a few days longer. In adults, primary infecti
on is associated with a mononucleosis.
Patients with HIV have a higher infection rate than the normal
population.
HHV-6 has been associated with a number of neurological di
sorders, including encephalitis and seizures.
It has been postulated to play a role in multiple sclerosis and
chronic fatigue immunodeficiency syndrome.
Human herpes virus 7
This virus binds to the CD4 antigen and replicate
s in T4 (CD4+) cells and is found in the saliva of
the majority of the adult population (>75%).
Most people acquire the infection as children an
d it remains with them for the rest of their lives. It
is similar to HHV-6 and may be responsible for s
ome cases of exanthem subitum
Human herpes virus 8
This was formerly known as Kaposi`s sarcoma a
ssociated herpes virus and is found in the saliva
of many AIDS patients.
It infects peripheral blood lymphocytes.
The distribution of the virus may explain why so
me populations of HIV-infected people go down
with Kaposi`s sarcoma
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
Size: 180-200nm
Replication: Nuclear.
Assembly: Nuclear.
Envelope: Present; associated glycoproteins.
Tegument: Protein-filled region between capsid
and envelope.
Capsid: Icosahedral, 95-105nm diameter; 162
hexagonal capsomers.
Core: DNA around protein , ~75nm
Genome: Linear, d/s DNA, 105-235kbp
Common Antigens:None
Herpes viruses can replicate in human diploid
cells except of BBV
Produce cytopathic effect(CPE)
Intranuclear acidophilic inclusion bodies
Categories of herpes virus
正式命名
人类疱疹病毒 1
型（ HHV1）
人类疱疹病毒 2
型（ HHV2）
人类疱疹病毒 3
型（ HHV3）
人类疱疹病毒 4
型（ HHV4）
人类疱疹病毒 5
型（ HHV5）
人类疱疹病毒 6
型（ HHV6）
人类疱疹病毒 7
型（ HHV7）
人类疱疹病毒 8
型（ HHV8）
弥猴疱疹病毒 1
常用名
单纯疱疹病毒 1 型
（ HSV-1 ）
单纯疱疹病毒 2 型
（ HSV-2 ）
水痘 - 带状疱疹病
毒（ VZV ）
Epstein-Barr 病毒
（ EBV ）
病毒亚科
重要生物学性状
所致疾病
繁殖快、杀细胞性感染
感觉神经节中潜伏
同上
唇疱疹、龈口炎、角膜结膜炎
、脑炎等
同上
水痘、带状疱疹、脑炎
淋巴细胞中繁殖与潜伏
传染性单核细胞增多症、 Burki
tt 淋巴瘤、鼻咽癌（ ? ）等
常在淋巴细胞、肾脏及
分泌腺体中潜伏
生殖器疱疹、新生儿疱疹
人类巨细胞病毒
先天性巨细胞包涵体病、单核
细胞增多症、间质性肺炎、
先天性畸形、肝炎
婴儿急疹、间质性肺炎、骨髓
抑制
人类疱疹病毒 6 型
同人巨细胞病毒
人类疱疹病毒 7 型
同人巨细胞病毒
人类疱疹病毒 8 型
同 EB 病毒
Kaposi 肉瘤
猿猴 B 病毒
同 HSV
脊髓炎、出血性脑炎
未明确
1 Herpes Simplex
Viruses
Properties
Belong
to the
herpesviruses
ds
kb
alphaherpesvirus
subfamily
of
DNA enveloped virus with a genome of around 150
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.
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.
Pathogenesis
Clinical Manifestations
HSV is involved in a variety of clinical manifestations
which includes ;1. Acute gingivostomatitis 龈口炎
2. Herpes Labialis (cold sore) 唇疱疹
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.
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 虹膜睫状体炎 , chorioretinitis 脉络膜视网
膜炎 and cataract 白内障
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
– 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
– 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
2 Varicella- Zoster Virus
Properties
Belong to the alphaherpesvirus subfamily of
herpesviruses
ds 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.
Pathogenesis
shingles
Varicella
Primary infection results in varicella (chicken-pox)
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.
3 Cytomegalovirus
Properties
Belong to the betaherpesvirus subfamily of
herpesviruses
ds 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
Late
purpura, Haemolytic anaemia
sequelae in individuals asymptomatic at birth hearing defects and reduced intelligence.
Incidence of Cytomegalic
Disease
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
DEAFF test for CMV
Specimens for Laboratory Diagnosis
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
recipients prior to transplant
– Give
to
seronegative
antiviral agents such as acyclovir and ganciclovir
prophylactically.
4 Epstein-Barr Virus
Pathogenesis
Transformation of B cells
Burkitt's lymphoma
Nasopharyngeal cancer
Oral hairy leukoplakia
Infectious mononucleosis
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
vivo
able to immortalize B-lymphocytes in vitro and in
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(IM)
2. Burkitt's lymphoma( BL)
3. Nasopharyngeal carcinoma( NPC)
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.
Burkitt's Lymphoma
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.
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 X-chromosome . This condition accounts for half of the fatal
cases of IM.
Diagnosis
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.
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.
Roseala Infantum
Kaposi’s Sarcoma
Human herpes virus 6
Worldwide
In the saliva of the majority of adults (>90%).
It infects almost all children by the age of two and the infection
is life-long. Again, it replicates in B and T lymphocytes, megaka
ryocytes, etc
Latent infection in T cells . Infected cells are larger than norma
l with inclusions in both cytoplasm and nucleus.
Cell-mediated immunity is essential in control, although infecti
on is life-long, and the virus can reactivate in immune-suppres
sion.
Pathogenesis
Two forms: HHV-6A and HHV-6B.
The latter causes ex
anthem subitum, otherwise known as roseola infantum.
This a common disease of young children (in the US >4
5% of children are seropositive for HHV-6 by two years
of age) and symptoms include fever and sometimes upp
er respiratory tract infection and lymphadenopathy.
Incubation period : 14 days.
Pathogenesis
The fever subsides leaving a macropapular rash on the trunk
and neck that last a few days longer. In adults, primary infecti
on is associated with a mononucleosis.
Patients with HIV have a higher infection rate than the normal
population.
HHV-6 has been associated with a number of neurological di
sorders, including encephalitis and seizures.
It has been postulated to play a role in multiple sclerosis and
chronic fatigue immunodeficiency syndrome.
Human herpes virus 7
This virus binds to the CD4 antigen and replicate
s in T4 (CD4+) cells and is found in the saliva of
the majority of the adult population (>75%).
Most people acquire the infection as children an
d it remains with them for the rest of their lives. It
is similar to HHV-6 and may be responsible for s
ome cases of exanthem subitum
Human herpes virus 8
This was formerly known as Kaposi`s sarcoma a
ssociated herpes virus and is found in the saliva
of many AIDS patients.
It infects peripheral blood lymphocytes.
The distribution of the virus may explain why so
me populations of HIV-infected people go down
with Kaposi`s sarcoma