• 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
• Herpes Simplex encephalitis is one of the most serious complications of herpes simplex
• Neonatal – there is global involvement and the brain is almost liquefied. The mortality rate
• 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.
Section II - Virology By Dr. Kareem Lilo
• 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
- Herpetic whitlow which arise from implantation of the virus into the skin and typically affect
- “zosteriform herpes simplex". This is a rare presentation of herpes simplex where HSV
lesions appear in a dermatomal distribution similar to herpes zoster.
- Electron microscopy of vesicle fluid - rapid result but cannot distinguish between HSV and
- Immunofluorescence of skin scrappings - can distinguish between HSV and VZV
- PCR - now used routinely for the diagnosis of herpes simplex encephalitis
- HSV-1 and HSV-2 are among the easiest viruses to cultivate. It usually takes only 1 - 5 days
- 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.
A-Cytopathic Effect of HSV in cell culture: Note the
ballooning of cells. (Linda Stannard, University of Cape
B-Positive immunofluorescence test for HSV antigen in epithelial
cell. (Virology Laboratory, New-Yale Haven Hospital(
Section II - Virology By Dr. Kareem Lilo
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
Acyclovir – this the drug of choice for most situations at present. It is available in a number of
- 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)
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
• Belong to the alphaherpesvirus subfamily of herpesviruses
• 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.
• 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.
• The virus is thought to gain entry via the respiratory tract and spreads shortly after to the
• After an incubation period of 14 days, the virus arrives at its main target organ, the skin.
Section II - Virology By Dr. Kareem Lilo
• 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
• Primary infection results in varicella (chickenpox)
• Incubation period of 14-21 days
• Presents fever, lymphadadenopathy. a widespread vesicular rash.(Figure2-29)
• The features are so characteristic that a diagnosis can usually be made on clinical grounds
• Complications are rare but occurs more frequently and with greater severity in adults and
• Most common complication is secondary bacterial infection of the vesicles.
• Severe complications which may be life threatening include viral pneumonia, encephalititis,
• Herpes Zoster mainly affect a single dermatome of the skin (Figure2-30).
• 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
• 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.
Figure(2-29) Rash of Chickenpox
Section II - Virology By Dr. Kareem Lilo
• 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 are rare and include encephalitis and disseminated herpes zoster.
• 90% of pregnant women already immune, therefore primary infection is rare during
• Primary infection during pregnancy carries a greater risk of severe disease, in particular
- Up to 3% chance of transmission to the fetus, recognised congenital varicella syndrome;
Virus Isolation - rarely carried out as it requires 2-3 weeks for a results.
Section II - Virology By Dr. Kareem Lilo
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.
• 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
• Acyclovir should be given promptly immunocompromised individuals with varicella
infection and normal individuals with serious complications such as pneumonia and
• 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.
• 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
• 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.
1. Belong to the betaherpesvirus subfamily of herpesviruses
2. double stranded DNA enveloped virus
Section II - Virology By Dr. Kareem Lilo
3. Nucleocapsid 105nm in diameter, 162 capsomers
4. 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.
5. A large no. of proteins are encoded for, the precise number is unknown.
• 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.
• 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
• 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.
• 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
Section II - Virology By Dr. Kareem Lilo
• 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
- 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.
- 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
- 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.
Figure (2-31)CMV pp65 detected in nuclei peripheral blood neutrophils
Section II - Virology By Dr. Kareem Lilo
• 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
• 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
• 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%
• The virus is transmitted by contact with saliva, in particularly through kissing.
• Once infected, a lifelong carrier state develops whereby a low grade infection is kept in check
• 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
4. Lymphoproliferative disease and lymphoma in the immunosuppressed.
5. X-linked lymphoproliferative syndrome
Section II - Virology By Dr. Kareem Lilo
6. Chronic infectious mononucleosis
7. Oral leukoplakia in AIDS patients
8. Chronic interstitial pneumonitis in AIDS patients.
• 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
• 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,
• 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
• There is no specific treatment.
• 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
• 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.
• BL cells show a reciprocal translocation between the long arm of chromosome 8 and
• 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
Section II - Virology By Dr. Kareem Lilo
• Sporadic cases of BL occur, especially in AIDS patients which may or may not be associated
• In theory BL can be controlled by the eradication of malaria (as has happened in Papua New
Guinea) or vaccination against EBV.
• 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
• 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
• 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.
• A vaccine against EBV which prevents primary EBV infection should be able to control both
Section II - Virology By Dr. Kareem Lilo
• 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.
• Belong to the betaherpesvirus subfamily of herpesviruses
• Double stranded DNA genome of 170 kbp
• The main target cell is the T-lymphocyte, although B-lymphocytes 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
• 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.
• Primary HHV-6 infection is associated with Roseala Infantum, which is a classical disease of
• 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.
Section II - Virology By Dr. Kareem Lilo
• 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.
• Rosela Infantum has a very characteristic presentation and a diagnosis can usually be made
• Therefore very few virology laboratories offer a diagnostic service for HHV-6 or HHV-7
• The technique for virus isolation is complicated and thus not practicable as a routine
• Therefore serology is the mainstay of diagnosis where specific IgM and IgG are detected.
• There is no specific antiviral treatment for HHV-6 infection.
• 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(Figure 2-32)
• 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.
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