Herpesviruses

1
Herpesviruses
An Overview
2
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.

3
Herpesvirus Particle
HSV-2 virus particle. Note that all herpesviruses
have identical morphology and cannot be
distinguished from each other under electron
microscopy.
(Linda Stannard, University of Cape Town, S.A.)
4
Herpes Simplex Viruses
5
Properties

• Belong to the alphaherpesvirus subfamily of
  herpesviruses
• Double stranded DNA enveloped virus with a genome
  of around 150 kb
• The genome of HSV-1 and HSV-2 share 50 - 70
  homology.
• They also share several cross-reactive epitopes
  with each other. There is also antigenic
  cross-reaction with VZV.
• Man is the only natural host for HSV.

6
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.

7
Epidemiology (2)

• Generally HSV-1 causes infection above the belt
  and HSV-2 below the belt. In fact, 40 of
  clinical isolates from genital sores are HSV-1,
  and 5 of strains isolated from the facial area
  are HSV-2. This data is complicated by oral
  sexual practices.
• Following primary infection, 45 of orally
  infected individuals and 60 of patients with
  genital herpes will experience recurrences.
• The actual frequency of recurrences varies widely
  between individuals. The mean number of episodes
  per year is about 1.6.

8
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.

9
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

10
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.

11
Gingivostomatitis
12
Ocular Herpes

• HSV causes a broad spectrum of ocular disease,
  ranging from mild superficial lesions involving
  the external eye, to severe sight-threatening
  diseases of the inner eye. Diseases caused
  include the following-
• Primary HSV keratitis dendritic ulcers
• Recurrent HSV keratitis
• HSV conjunctivitis
• Iridocyclitis, chorioretinitis and cataract

13
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.

14
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.

15
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.

16
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.

17
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.

18
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.

19
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)
20
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

21
Varicella- Zoster Virus
22
Properties

• 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.

23
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.

24
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.

25
Varicella

• Primary infection results in varicella
  (chickenpox)
• Incubation period of 14-21 days
• Presents fever, lymphadadenopathy. a widespread
  vesicular rash.
• The features are so characteristic that a
  diagnosis can usually be made on clinical grounds
  alone.
• Complications are rare but occurs more frequently
  and with greater severity in adults and
  immunocompromised patients.
• Most common complication is secondary bacterial
  infection of the vesicles.
• Severe complications which may be life
  threatening include viral pneumonia,
  encephalititis, and haemorrhagic chickenpox.

26
Rash of Chickenpox
27
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.

28
Shingles
29
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

30
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.

31
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.

32
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.)
33
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.

34
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.

35
Cytomegalovirus
36
Properties

• Belong to the betaherpesvirus subfamily of
  herpesviruses
• double stranded DNA enveloped virus
• Nucleocapsid 105nm in diameter, 162 capsomers
• The structure of the genome of CMV is similar to
  other herpesviruses, consisting of long and short
  segments which may be orientated in either
  direction, giving a total of 4 isomers.
• A large no. of proteins are encoded for, the
  precise number is unknown.

37
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.

38
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.

39
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.

40
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.

41
Cytomegalic Inclusion Disease

• CNS abnormalities - microcephaly, mental
  retardation, spasticity, epilepsy,
  periventricular calcification.
• Eye - choroidoretinitis and optic atrophy
• Ear - sensorineural deafness
• Liver - hepatosplenomegaly and jaundice which is
  due to hepatitis.
• Lung - pneumonitis
• Heart - myocarditis
• Thrombocytopenic purpura, Haemolytic anaemia
• Late sequelae in individuals asymptomatic at
  birth - hearing defects and reduced
  intelligence.

42
Incidence of Cytomegalic Disease
43
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.

44
CMV pp65 antigenaemia test
(Virology Laboratory, New-Yale Haven Hospital)
45
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.

46
Cytopathic Effect of CMV
(Courtesy of Linda Stannard, University of Cape
Town, S.A.)
47
DEAFF test for CMV
(Virology Laboratory, New-Yale Haven Hospital)
48
Specimens for Laboratory Diagnosis
49
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.

50
Prevention

• No licensed vaccine is available. There is a
  candidate live attenuated vaccine known as the
  Towne strain but there are concerns about
  administering a live vaccine which could become
  latent and reactivates.
• Prevention of CMV disease in transplant
  recipients is a very complicated subject and
  varies from center to center. It may include the
  following measures.
• Screening and matching the CMV status of the
  donor and recipient
• Use of CMV negative blood for transfusions
• Administration of CMV immunoglobulin to
  seronegative recipients prior to transplant
• Give antiviral agents such as acyclovir and
  ganciclovir prophylactically.

51
Epstein-Barr Virus
52
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.

53
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.

54
Pathogenesis

• Once infected, a lifelong carrier state develops
  whereby a low grade infection is kept in check by
  the immune defenses.
• Low grade virus replication and shedding can be
  demonstrated in the epithelial cells of the
  pharynx of all seropositive individuals.
• EBV is able to immortalize B-lymphocytes in vitro
  and in vivo
• Furthermore a few EBV-immortalized B-cells can
  be demonstrated in the circulation which are
  continually cleared by immune surveillance
  mechanisms.
• EBV is associated with several very different
  diseases where it may act directly or one of
  several co-factors.

55
Disease Association

• 1. Infectious Mononucleosis
• 2. Burkitt's lymphoma
• 3. Nasopharyngeal carcinoma
• 4. Lymphoproliferative disease and lymphoma in
  the immunosuppressed.
• 5. X-linked lymphoproliferative syndrome
• 6. Chronic infectious mononucleosis
• 7. Oral leukoplakia in AIDS patients
• 8. Chronic interstitial pneumonitis in AIDS
  patients.

56
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.

57
Burkitts 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.

58
Burkitts 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.

59
Nasopharyngeal Carcinoma

• Nasopharyngeal carcinoma (NPC) is a malignant
  tumour of the squamous epithelium of the
  nasopharynx. It is very prevalent in S. China,
  where it is the commonest tumour in men and the
  second commonest in women.
• The tumour is rare in most parts of the world,
  though pockets occur in N. and C. Africa,
  Malaysia, Alaska, and Iceland.
• Multiple copies of EBV genome and EBV EBNA-1
  antigen can be found in cells of undifferentiated
  NPC. Patients with NPC have high titres of
  antibodies against various EBV antigens.
• Besides EBV there appears to be a number of
  environmental and genetic cofactors in NPC.
• NPC usually presents late and thus the prognosis
  is poor.
• In theory NPC can be prevented by vaccination.

60
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-Hodgekins
  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.

61
Diagnosis

• Acute EBV infection is usually made by the
  heterophil antibody test and/or detection of
  anti-EBV VCA IgM.
• Cases of Burkitts 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.

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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.

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Other Human Herpes Viruses
64
Properties of HHV-6 and 7

• Belong to the betaherpesvirus subfamily of
  herpesviruses
• Double stranded DNA genome of 170 kbp
• The main target cell is the T-lymphocyte,
  although 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 and
  HSV-2.

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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.

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Clinical Manifestations (1)

• Primary HHV-6 infection is associated with
  Roseala Infantum, which is a classical disease of
  childhood.
• Most cases occur in infants between the ages of 4
  months and two years.
• A spiking fever develops over a period of 2 days
  followed by a mild rash. The fever is high enough
  to cause febrile convulsions.
• There are reports that the disease may be
  complicated by encephalitis.

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Clinical Manifestations (2)

• If primary infection is delayed until adulthood,
  there is a small chance that an infectious
  mononucleosis-like disease may develop in a
  similar manner to EBV and CMV.
• There is no firm evidence linking HHV-6 to
  lymphomas or lymphoproliferative diseases.
• There is no firm disease association with HHV-7
  at present.
• Although both viruses may be reactivated in
  immunocompromised patients, it is yet uncertain
  whether they cause significant disease since CMV
  is almost invariably present.

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Roseala Infantum
69
Diagnosis and Management

• Rosela Infantum has a very characteristic
  presentation and a diagnosis can usually be made
  on clinical grounds alone.
• Therefore very few virology laboratories offer a
  diagnostic service for HHV-6 or HHV-7 infection.
• The technique for virus isolation is complicated
  and thus not practicable as a routine diagnostic
  procedure.
• Therefore serology is the mainstay of diagnosis
  where specific IgM and IgG are detected.
• There is no specific antiviral treatment for
  HHV-6 infection.

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Human Herpes Virus 8

• Belong to the gammaherpesviruses subfamily of
  herpesviruses
• Originally isolated from cells of Kaposis
  sarcoma (KS)
• Now appears to be firmly associated with Kaposis
  sarcoma as well as some lesser known malignancies
  such as Castlemans disease and primary effusion
  lymphomas
• HHV-8 DNA is found in almost 100 of cases of
  Kaposis 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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Kaposis Sarcoma